Treatment for Non-Hodgkin Lymphoma

Hematopoietic Cell Transplantation

HCT is a procedure in which hematopoietic stem cells are intravenously infused to restore bone marrow and immune function in cancer patients who receive bone marrow-toxic doses of cytotoxic drugs with or without whole-body radiotherapy. Hematopoietic stem cells may be obtained from the transplant recipient (autologous HCT) or a donor (allogeneic HCT [allo-HCT]). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood shortly after delivery of neonates. Cord blood transplantation is discussed in a separate policy on 'Placental and Umbilical Cord Blood as a Source of Stem Cells' (Policy #012 in the Surgery Section).

Immunologic compatibility between infused hematopoietic stem cells and the recipient is not an issue in autologous HCT. In allogeneic stem cell transplantation, immunologic compatibility between donor and patient is a critical factor for achieving a successful outcome. Compatibility is established by typing of human leukocyte antigens (HLA) using cellular, serologic, or molecular techniques. HLA refers to the gene complex expressed at the HLA-A, -B, and -DR (antigen-D related) loci on each arm of chromosome 6. An acceptable donor will match the patient at all or most of the HLA loci.

Conditioning for Hematopoietic Cell Transplantation

Conventional Conditioning

The conventional (“classical”) practice of allo-HCT involves administration of cytotoxic agents (e.g., cyclophosphamide, busulfan) with or without total body irradiation at doses sufficient to cause bone marrow ablation in the recipient. The beneficial treatment effect of this procedure is due to a combination of the initial eradication of malignant cells and subsequent graft-versus-malignancy effect mediated by non-self-immunologic effector cells.While the slower graft-versus-malignancy effect is considered the potentially curative component, it may be overwhelmed by existing disease in the absence of pretransplant conditioning. Intense conditioning regimens are limited to patients who are sufficiently medically fit to tolerate substantial adverse effects. These include opportunistic infections secondary to loss of endogenous bone marrow function and organ damage or failure caused by cytotoxic drugs. Subsequent to graft infusion in allo-HCT, immunosuppressant drugs are required to minimize graft rejection and graft-versus-host disease, which increases susceptibility to opportunistic infections.

The success of autologous HCT is predicated on the potential of cytotoxic chemotherapy, with or without radiotherapy, to eradicate cancerous cells from the blood and bone marrow. This permits subsequent engraftment and repopulation of the bone marrow with presumably normal hematopoietic stem cells obtained from the patient before undergoing bone marrow ablation. Therefore, autologous HCT is typically performed as consolidation therapy when the patient’s disease is in complete remission. Patients who undergo autologous HCT are also susceptible to chemotherapy-related toxicities and opportunistic infections before engraftment, but not graft-versus-host disease.

Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation

RIC refers to the pretransplant use of lower doses of cytotoxic drugs or less intense regimens of radiotherapy than are used in traditional full-dose myeloablative conditioning treatments. Although the definition of RIC is variable, with numerous versions employed, all regimens seek to balance the competing effects of relapse due to residual disease and non-relapse mortality. The goal of RIC is to reduce disease burden and to minimize associated treatment-related morbidity and non-relapse mortality in the period during which the beneficial graft-versus-malignancy effect of allogeneic transplantation develops. RIC regimens range from nearly total myeloablative to minimally myeloablative with lymphoablation, with intensity tailored to specific diseases and patient condition. Patients who undergo RIC with allo-HCT initially demonstrate donor cell engraftment and bone marrow mixed chimerism. Most will subsequently convert to full-donor chimerism. In this review, the term reduced-intensity conditioning will refer to all conditioning regimens intended to be nonmyeloablative.

Regulatory Status

The FDA regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, under Code of Federal Regulation, Title 21, parts 1270 and 1271. Hematopoietic stem cells are included in these regulations.

Related Policies

• Placental and Umbilical Cord Blood as a Source of Stem Cells (Policy #012 in the Surgery Section)
• Hematopoietic Cell Transplantation for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (Policy #036 in the Treatment Section)
• Hematopoietic Cell Transplantation for Hodgkin Lymphoma (Policy #039 in the Treatment Section)
• Hematopoietic Cell Transplantation for Primary Amyloidosis (Policy #065 in the Treatment Section
• Hematopoietic Cell Transplantation for Waldenstrom Macroglobulinemia (Policy #083 in the Treatment Section)

A. The law only applies to autologous bone marrow or peripheral stem cell transplant for the treatment of cancer. Medical necessity criteria must NOT be applied to these cases. They are automatically eligible for coverage under the law.

[INFORMATIONAL NOTE: Please note that self-insured accounts are exempt from the law. However, they have the option to adopt the law upon renewal of the contract.

Policy Statement II of this policy deals with eligibility and medical necessity criteria which must be applied specifically to those self-insured accounts which opted NOT to adopt the law.]

B. In cases of multiple, repeat, or tandem autologous bone marrow or peripheral stem cell transplant procedures for the same member, the first or initial transplant is automatically covered under the law. However, subsequent transplant procedures are NOT automatically covered under the law but are subject to medical necessity criteria.

C. The law applies to contracts delivered, issued, executed or renewed in New Jersey. Services rendered outside New Jersey are covered by the law as long as the member has a contract that is written or issued in New Jersey.

D. Exclusions to the law:
Policy Statement II of this policy addresses medical necessity criteria as it applies to the following requests for:
• an allogeneic bone marrow or peripheral stem cell transplant.
• treatment of non-cancerous conditions even if it involves autologous bone marrow or peripheral stem cell transplant.
• mini-transplants or non-myeloablative transplants since they are allogeneic transplants.

A. This procedure is subject to the specific terms of the member's contract.
[Also refer to a separate policy on Transplant Donor and Recipient Policy (Policy #003) under the Surgery Section.]

B. Medical necessity is established based on review of the following information:
1. Stage to which the malignancy has progressed;
2. Clinical history of the member including results of diagnostic procedures performed (i.e., laboratory, pathology, radiology), and previous modes of therapy with results;
3. Treatment protocol of the facility where the procedure is being performed.

C. For members with non-Hodgkin lymphoma (NHL) B-cell subtypes considered aggressive (except mantle cell lymphoma), either autologous hematopoietic cell transplantation (HCT) or allogeneic hematopoietic cell transplantation (HCT) using a myeloablative conditioning regimen is considered medically necessary:
• as salvage therapy for members who do not achieve a complete remission (CR) after first-line treatment (induction) with a full course of standard-dose chemotherapy;
• to achieve or consolidate a CR for those in a chemo-sensitive first or subsequent relapse; or
• to consolidate a first CR in members with diffuse large B-cell lymphoma, with an age-adjusted International Prognostic Index (IPI) score that predicts a high- or high-intermediate risk of relapse.

D. For members with mantle cell lymphoma:
• Autologous HCT is considered medically necessary to consolidate a first remission.
• Allogeneic HCT, with myeloablative or reduced-intensity conditioning is considered medically necessary as salvage therapy.
• Autologous HCT is considered investigational as salvage therapy.
• Allogeneic HCT is considered investigational to consolidate a first remission.

E. For members with NHL B-cell subtypes considered indolent, either allogeneic HCT using a myeloablative conditioning regimen or autologous HCT is considered medically necessary:
• as salvage therapy for members who do not achieve a complete remission (CR) after first-line treatment (induction) with a full course of standard-dose chemotherapy; or
• to achieve or consolidate CR for those in a first or subsequent chemosensitive relapse, whether or not their lymphoma has transformed to a higher grade.

F. Either autologous HCT or allogeneic HCT is considered investigational:
• as initial therapy (i.e., without a full course of standard-dose induction chemotherapy) for any NHL;
• to consolidate a first complete remission (CR) for members with diffuse large B-cell lymphoma and an International Prognostic Score that predicts a low- or low-intermediate risk of relapse;
• to consolidate a first CR for those with indolent NHL B-cell subtypes.

Before making a determination that this procedure is investigational, please refer to Policy Statement I of this policy for the applicability of the New Jersey State Law on High Dose Chemotherapy (HDC) and Autologous Bone Marrow Transplant (BMT) or Peripheral Stem Cell Transplant (PSCT).

G. For members with mature T-cell or natural killer cell (peripheral T-cell) neoplasms:
• Autologous HCT is considered medically necessary to consolidate a first complete remission in high-risk subtypes (see Policy Guidelines section).
• Autologous or allogeneic HCT (with myeloablative or reduced-intensity conditioning) is considered medically necessary as salvage therapy.
• Allogeneic HCT is considered investigational to consolidate a first remission.
H. Reduced-intensity conditioning allogeneic HCT is considered medically necessary as a treatment of NHL in members who meet the criteria for an allogeneic HCT but who do not qualify for a myeloablative allogeneic SCT (see Policy Guidelines section).
I. Tandem transplants are considered investigational to treat members with any stage, grade, or sub-type of NHL.
Before making a determination that this procedure is investigational, please refer to Policy Statement I of this policy for the applicability of the New Jersey State Law on High Dose Chemotherapy (HDC) and Autologous Bone Marrow Transplant (BMT) or Peripheral Stem Cell Transplant (PSCT).

J. Harvesting and storage of autologous hematopoietic stem cells is considered medically necessary for:
• a member who is in remission but at high risk for relapse, and the condition being treated is one of the eligible conditions for autologous peripheral blood stem cell transplantation (PBSCT) or autologous bone marrow transplantation; OR
• a member whose current clinical condition qualifies him/her for imminent transplantation (within 30 days), and the condition being treated is one of the eligible conditions for PBSCT or autologous bone marrow transplantation.
Harvesting and storage of allogeneic hematopoietic stem cells or umbilical cord blood is considered medically necessary for:
• a member whose current clinical condition qualifies him/her for imminent transplantation (within 30 days), and the condition being treated is one of the eligible conditions for allogeneic bone marrow transplantation.

[Also refer to a separate policy on Transplant Donor and Recipient Policy (Policy#003) under the Surgery Section of this database.]

For members enrolled in Medicaid and NJ FamilyCare plans, Horizon BCBSNJ applies the above medical policy.

FIDE SNP:

For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

Policy Guidelines: (Information to guide medical necessity determination based on the criteria contained within the policy statements above.)

Reduced-intensity conditioning (RIC) would be considered an option in patients who meet criteria for an allogeneic hematopoietic cell transplantation (HCT), but whose age (typically >55 years) or comorbidities (eg, liver or kidney dysfunction, generalized debilitation, prior intensive chemotherapy) preclude the use of a standard conditioning regimen.

In patients who qualify for a myeloablative allogeneic HCT on the basis of overall health and disease status, allogeneic HCT using either myeloablative or RIC may be considered. However, a myeloablative conditioning regimen with allogeneic HCT may benefit younger patients with good performance status and minimal comorbidities more than allogeneic HCT with RIC.

A chemosensitive relapse is defined as relapsed non-Hodgkin lymphoma that does not progress during or immediately after standard-dose induction chemotherapy (ie, achieves stable disease or a partial response).

Transformation describes a lymphoma whose histologic pattern has evolved to a higher grade lymphoma. Transformed lymphomas typically evolve from a nodular pattern to a diffuse pattern.

Tandem transplants usually are defined as the planned administration of two successive cycles of high-dose myeloablative chemotherapy, each followed by infusion of autologous hematopoietic stem cells, whether or not there is evidence of persistent disease following the first treatment cycle. Sometimes, the second cycle may use nonmyeloablative immunosuppressive conditioning followed by infusion of allogeneic stem cells.

The term salvage therapy describes therapy given to patients with refractory or relapsed disease. For patients with peripheral T-cell lymphoma, salvage therapy includes patients who do not achieve a complete response (eg, achieve only a partial response, have no response, or have progressive disease) with first-line induction chemotherapy (refractory disease) or who relapse after achieving a complete response with first-line induction chemotherapy. For mantle cell lymphoma, salvage therapy includes patients with progressive disease with first-line induction chemotherapy (refractory disease) or in patients who relapse after a complete or partial response after initial induction chemotherapy, or patients who fail a previous autologous HCT.

High-risk (aggressive) T-cell and natural killer (NK) cell neoplasms are a clinically heterogeneous group of rare disorders, most of which have an aggressive clinical course and poor prognosis. The exception includes the following subtypes, which typically have a relatively indolent and protracted course: T-cell large granulocyte leukemia, chronic lymphoproliferative disorder of NK cells, early-stage mycosis fungoides, primary cutaneous anaplastic large-cell lymphoma, and anaplastic lymphoma kinaseanaplastic large-cell lymphomas.


[RATIONALE: This policy was created in 2001 and has been updated regularly with searches of the MEDLINE database. The most recent literature update was performed through November 11, 2019.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function¾including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. TheRCT is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

This review has been informed by several TEC Assessments.^1,2,3,4, Since the publication of the 2000 Assessment, the classification of non-Hodgkin lymphoma (NHL) has undergone significant changes, and several new and unique subtypes have emerged (eg, mantle cell lymphoma [MCL], peripheral T-cell lymphoma [PTCL]). The following is a summary of key literature to date.

Non-Hodgkin Lymphoma

A heterogeneous group of lymphoproliferative malignancies, NHL usually originates in lymphoid tissue. Historically, uniform treatment of patients with NHL was hampered by the lack of a uniform classification system. In 1982, the Working Formulation was developed to unify different classification systems into one.^5,The Working Formulation divided NHL into low-, intermediate-, and high-grade, with subgroups based on histologic cell type. Because our understanding of NHL has improved, the diagnosis has become more sophisticated and includes the incorporation of new immunophenotyping and genetic techniques. As a result, the Working Formulation has become outdated.

European and American pathologists proposed a new classification, the Revised European-American Lymphoma (REAL) Classification^6, and an updated version of the REAL system, the new World Health Organization classification.^7, The WHO/REAL classification recognized 3 major categories of lymphoid malignancies based on morphology and cell lineage: B-cell neoplasms, T-cell/natural killer cell neoplasms, and Hodgkin lymphoma.

The most recent lymphoma classification is the 2016 WHO classification (see Table 1).^8,

Table 1. Updated WHO Classification (2016)

Classification of Neoplasms

Mature B-cell neoplasms

Chronic lymphocytic leukemia/small lymphocytic lymphoma

Monoclonal B-cell lymphocytosisa

B-cell prolymphocytic leukemia

Splenic marginal zone lymphoma

Hairy cell leukemia

Splenic lymphoma/leukemia, unclassifiable

Splenic diffuse red pulp small B-cell lymphoma

Hairy cell leukemia-variant

Lymphoplasmacytic lymphoma

Waldenström macroglobulinemia

Monoclonal gammopathy of undetermined significance, IgMa

Heavy chain diseases

Alpha heavy chain disease

Gamma heavy chain disease

Mu heavy chain disease

Monoclonal gammopathy of undetermined significance, IgG/IgAa

Plasma cell myeloma

Solitary plasmacytoma of bone

Extraosseous plasmacytoma

Monoclonal immunoglobulin deposition diseasesa

Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)

Nodal marginal zone lymphoma (MZL)

Pediatric nodal MZL

Follicular lymphoma

In situ follicular neoplasiaa

Duodenal-type follicular lymphomaa

Pediatric type follicular lymphomaa

Large B-cell lymphoma with IRF4 rearrangementa

Primary cutaneous follicle center lymphoma

Mantle cell lymphoma

In situ mantel cell neoplasiaa

Diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS)

Germinal center B-cell typea

Activated B-cell typea

T-cell/histiocyte-rich large B-cell lymphoma

DLBCL associated with chronic inflammation

Lymphomatoid granulomatosis

Primary mediastinal (thymic) large B-cell lymphoma

Intravascular large B-cell lymphoma

Primary cutaneous DLBCL, leg type

ALK [anaplastic lymphoma kinase]-positive large B-cell lymphoma

Plasmablastic lymphoma

Primary effusion lymphoma

HHV8 DLBCL NOSa

Burkitt lymphoma

Burkitt-like lymphoma with 11q aberrationa

High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6rearrangementsa

High-grade B-cell lymphoma, NOSa

B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma

Mature T-cell and NK-cell neoplasms

T-cell prolymphocytic leukemia

T-cell large granular lymphocytic leukemia

Chronic lymphoproliferative disorder of NK cells

Aggressive NK-cell leukemia

Systemic Epstein-Barr virus-positive T-cell lymphoproliferative of childhooda

Hydroa vacciniforme-like lymphoproliferative disordera

Adult T-cell leukemia/ lymphoma

Extranodal NK/T-cell lymphoma, nasal type

Enteropathy-associated T-cell lymphoma

Monomorphic epitheliotropic intestinal T-cell lymphomaa

Indolent T-cell lymphoproliferative disorder of the GI tracta

Hepatosplenic T-cell lymphoma

Subcutaneous panniculitis-like T-cell lymphoma

Mycosis fungoides

Sézary syndrome

Primary cutaneous CD30-positive T-cell lymphoproliferative disorder

Lymphomatoid papulosis

Primary cutaneous anaplastic large-cell lymphoma

Primary cutaneous gamma-delta T-cell lymphoma

Primary cutaneous aggressive epidermotropic CD8-positive cytotoxic T-cell lymphomaa

Primary cutaneous acral CD8+ T-cell lymphomaa

Primary cutaneous small/medium CD4-positive T-cell lymphoproliferative disordera

Peripheral T-cell lymphoma, NOS

Angioimmunoblastic T-cell lymphoma

Follicular T-cell lymphomaa

Nodal peripheral T-cell lymphoma with TFH phenotypea

Anaplastic large-cell lymphoma (ALCL), ALK-positive

Anaplastic large-cell lymphoma (ALCL), ALK-negativea

Breast implant-associated anaplastic large-cell lymphomaa

ALK: anaplastic lymphoma kinase; GI: gastrointestinal; Ig: immunoglobulin; NK: natural killer.
^a Changes from 2008 WHO classification. Provisional entities are listed in italics.

In the United States, B-cell lymphomas represent 80% to 85% of cases of NHL, and T-cell lymphomas represent 15% to 20%. Natural killer lymphomas are relatively rare.^9,

The International Lymphoma Classification Project identified the most common NHL subtypes as follows: DLBCL 31%, follicular lymphoma 22%, small lymphocytic lymphoma and chronic lymphocytic leukemia 6%,MCL 6%,PTCL 6%, and marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue lymphoma 5%. All other subtypes each represent fewer than 2% of cases of NHL.^9,

Types of NHL

In general, NHL can be divided into 2 prognostic groups, indolent and aggressive. Indolent NHL has a relatively good prognosis, with a median survival of 10 years; however, it is not curable in advanced clinical stages.^5, Early-stage indolent NHL (stage I or II) may be effectively treated with radiotherapy alone.^5, Although indolent NHL is responsive to radiotherapy and chemotherapy, a continuous rate of relapse is seen in advanced stages.^5, These patients can often be treated again if their disease remains of the indolent type. Indolent NHL may transform into a more aggressive form, which is generally treated with regimens that are used for aggressive, recurrent NHL. Histologic transformation to higher grade lymphoma occurs in up to 70% of patients with low-grade lymphoma,^10, and median survival with conventional chemotherapy is 1 year or less.

Follicular lymphoma is the most common indolent NHL (70%-80% of cases), and often the terms indolent lymphoma and follicular lymphoma are used synonymously. Also included in the indolent NHL are small lymphocytic lymphoma/chronic lymphocytic lymphoma, lymphoplasmacytic lymphoma, marginal zone lymphomas, and cutaneous T-cell lymphoma.

Aggressive NHL has a shorter natural history; however, 30% to 60% of these patients can be cured with intensive combination chemotherapy regimens.^5, Aggressive lymphomas include DLBCL, MCL, PTCL, anaplastic large-cell lymphoma, and Burkitt lymphoma.

Risk Assessment

Oncologists developed a clinical tool to aid in predicting the prognosis of patients with aggressive NHL (specifically DLBCL), referred to as the International Prognostic Index (IPI).^11, Before its development in 1993, the prognosis was predominantly based on disease stage.

Based on the following 5 risk factors prognostic of overall survival (OS) and adjusted for patient age, the IPI defines 4 risk groups: low, low-intermediate, high-intermediate, and high-risk:

1. Age older than 60 years
2. Elevated serum lactate dehydrogenase (LDH) level
3. Ann Arbor stage III or IV disease
4. Eastern Cooperative Oncology Group (ECOG) Performance Status of 2, 3, or 4
5. Involvement of more than 1 extranodal site.

Patients with 2 or more risk factors have a less than 50% chance of relapse-free survival and OS at 5 years. Age-adjusted IPI and stage-adjusted modifications of this IPI are used for younger patients with localized disease.

Adverse risk factors for age-adjusted IPI include stage III or IV disease, elevated LDH and ECOG Performance Status of 2 or greater and can be calculated as follows: 0 is low-risk, 1 is low-intermediate, 2 is high-intermediate, and 3 is high-risk.

With the success of the IPI, a separate prognostic index was developed for follicular lymphoma, which has multiple independent risk factors for relapse after first complete remission (CR). The proposed and validated Follicular Lymphoma International Prognostic Index contains 5 adverse prognostic factors:

1. Age older than 60 years
2. Ann Arbor stage III or IV disease
3. Hemoglobin level less than 12.0 g/dL
4. More than 4 lymph node areas involved
5. Elevated serum LDH level.

Indolent B-Cell Lymphomas

Clinical Context and Test Purpose

The purpose of autologous hematopoietic cell transplantation (HCT) as first-line therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with indolent B-cell NHLs.

The question addressed in this policy is: Does the use of autologous HCT improve the net health outcome in patients with indolent B-cell NHLs?

The following PICO was used to select literature to inform this review.

Patients

The relevant population of interest is individuals with indolent B-cell NHLs.

Interventions

The therapy being considered is autologous HCT as first-line therapy. Patients with NHL are actively managed by hematologists/oncologists in an inpatient and outpatient clinical setting.

Comparators

Comparators of interest include standard of care. Patients with NHL are actively managed by hematologists/oncologists in an inpatient and outpatient clinical setting.

Outcomes

The general outcomes of interest areOS, disease-specific survival (DSS), change in disease status, morbid events, treatment-related mortality, and treatment-related morbidity.Follow-up over years is of interest for relevant outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Systematic Reviews

Al Khabori et al (2012) performed a systematic review and meta-analysis of the use of autologous HCT in untreated, advanced follicular lymphoma (FL).^13, Four RCTs comparing autologous HCT with conventional chemotherapy (total n=941 patients) were included. Three trials reported OS; moderate-quality evidence from these trials did not show improvement in OS with the use of HCT as part of the initial treatment of FL. Adverse events, including treatment-related mortality and the development of myelodysplastic syndrome, acute myeloid leukemia, and solid tumors, did not differ between treatment arms.

Schaaf et al (2012) performed a systematic review of RCTs comparing autologous HCT with chemotherapy or immunochemotherapy in patients with previously untreated or relapsed FL concerning OS, progression-free survival (PFS), treatment-related mortality, adverse events, and secondary malignancies.^14, Five RCTs involving 1093 patients were included, with 4 trials in previously untreated patients and 1 in relapsed patients. The quality of the 5 trials was judged to be moderate. There was a statistically significant increase in PFS in previously untreated FL patients in the HCT arm (hazard ratio [HR], 0.42; 95% confidence interval [CI], 0.33 to 0.54; p<0.001). However, there was no statistically significant OS advantage (HR=0.97; 95% CI, 0.76 to 1.24; p=0.81). In the 4 trials in previously untreated patients, there were no statistically significant differences between HCT and the control arm in terms of treatment-related mortality (relative risk [RR], 1.28; 95% CI, 0.25 to 6.61; p=0.77), secondary acute myeloid leukemia/myelodysplastic syndromes (RR=2.87; 95% CI, 0.7 to 11.75; p=0.14), or solid cancers (RR=1.20; 95% CI, 0.25 to 5.77; p=0.82). Adverse events were rarely reported but were more frequent in patients who underwent HCT. For patients with relapsed FL, there was some evidence from 1 trial with 70 patients that HCT was advantageous regarding PFS (HR=0.30; 95% CI, 0.15 to 0.61) and OS (HR=0.40; 95% CI, 0.18 to 0.89). No results were reported from this trial for treatment-related mortality, adverse events, or secondary cancers.

Randomized Controlled Trials

Ladetto et al (2008) reported on the results of a phase 3, randomized, multicenter trial of patients with high-risk FL, treated at diagnosis.^15, A total of 134 patients were randomized to rituximab-supplemented high-dose chemotherapy plus autologous HCT or up to 6 courses of cyclophosphamide, doxorubicin (Adriamycin), vincristine (Oncovin), and prednisolone (CHOP) followed by rituximab (CHOP-R). Of these patients, 79% completed HCT and 71% completed CHOP-R.CR was 85% with HCT and 62% with CHOP-R. At a median follow-up of 51 months, the 4-year event-free survival (EFS) rate was 61% for HCT and 28% for CHOP-R, with no difference in OS. Molecular remission (defined as negative results by polymerase chain reaction on ≥2 consecutive bone marrow samples spaced 6 months apart in patients who reached CR) was achieved in 80% of HCT and 44% of CHOP-R patients and was the strongest independent outcome predictor. In 71% of the CHOP-R patients who had relapsed, salvage HCT was performed and achieved an 85% CR rate and a 68% 3-year EFS rate.

Sebban et al (2006) reported on the results of a randomized, multicenter study.^16, A total of 209 patients received cyclophosphamide, doxorubicin, etoposide, prednisolone, interferon plus cyclophosphamide, doxorubicin, etoposide, prednisolone, and 131 patients received CHOP followed by high-dose chemotherapy with total body irradiation and autologous HCT. Response rates were similar in both groups (79% and 78% after induction therapy, respectively). After a median follow-up of 7.5 years, intention-to-treat analysis showed no difference between the arms for OS (p=0.53) or EFS (p=0.11).

Deconinck et al (2005) investigated the role of autologous HCT as initial therapy in 172 patients with FL considered at high-risk due to the presence of either B symptoms (ie, weight loss, fever, or night sweats), a single lymph node larger than 7 cm, more than 3 involved nodal sites, massive splenomegaly, or a variety of other indicators of high tumor burden.^17, The patients were randomized to an immunochemotherapy regimen or a high-dose therapy followed by purged autologous HCT. While the autologous HCT group had a higher response rate and longer median EFS, there was no significant improvement in OS rate due to an excess of secondary malignancies.

Lenz et al (2004) reported on the results of a trial of 307 patients with advanced-stage lymphoma in first remission, including FL, MCL, or lymphoplasmacytoid lymphoma.^18, Patients were randomized to consolidative therapy plus autologous HCT or interferon therapy. The 5-year PFS rate was considerably higher in the autologous HCT arm (64.7%) than in the interferon arm (33.3%). However, the median follow-up of patients in this trial was too short to permit any comparison of OS.

HCT for Relapsed or Refractory, Indolent NHL

In most patients with FL relapse, and with relapsed disease, a cure is unlikely, with a median survival of 4.5 years after recurrence.^19,In the European CUP trial (2004), 89 patients with relapsed, nontransformed FL with partial response (PR) or CR after standard induction chemotherapy were randomized to 1 of 3 arms: 3 additional cycles of conventional chemotherapy (n=24), high-dose chemotherapy and unpurged autologous HCT (n=33), or high-dose chemotherapy with purged autologous HCT (n=32).^18, OS rates at 4 years for chemotherapy versus unpurged versus purged arms were 46%, 71%, and 77%, respectively. Two-year PFS rates were 26%, 58%, and 55%, respectively. No difference was found between the autologous HCT arms. Although several studies have consistently shown improved disease-free survival with autologous HCT for relapsed FL, this study was the first to show a difference in OS benefit.^9,

A single-center retrospective study by Bozkaya et al (2017) analyzed data from 38 patients who were treated between 2004 and 2014 with high-dose chemotherapy followed by autologous HCT.^20, All cases presented refractory or relapsed Hodgkin lymphoma (n=22) or a number of subtypes of NHL (n=18). Among the regimens given to patients were ifosfamide, carboplatin, and etoposide, and carmustine, etoposide, cytosine arabinoside, and melphalan; additionally, doxorubicin, bleomycin, vinblastine, and dacarbazine were administered to Hodgkin lymphoma patients, and R-CHOP was given to those with NHL. Given the small sample size, multivariate analysis was precluded; however, univariate analysis found no statistically significant differences between groups, except regarding chemosensitive versus chemoresistant cases and between patients undergoing ifosfamide, carboplatin, and etoposide and carmustine, etoposide, cytosine arabinoside, and melphalan regimens. After salvage therapy, 22 patients showed a PR; 6 patients showed a CR, and 8 had stable disease. The study found the 5-year OS rate was significantly higher for chemosensitive patients (50%) than for chemoresistant patients (22%; p=0.02); however, given the small size of the population, other analyses were primarily descriptive or showed no statistical significance.

Jiménez-Ubieto et al (2018) analyzed the GELTAMO (Grupo Español de Linfomas y Trasplantes de Médula Ósea) registry to evaluate the effectiveness of autologous stem cell transplant (ASCT) for patients withFL who experience early therapy failure (ETF) within 2 years of frontline immunochemotherapy.^21, The analysis included patients with non-transformed FL treated with rituximab. ETF was defined as relapse or progression within 2 years of first-line therapy. Two groups were studied: the ETF group (n=52; 38 receiving ASCT in second complete response [CR2] and 14 in second partial response [PR2]) and the non-ETF group (n=16; 14 patients receiving ASCT in CR2 and 2 in PR2, but who did not experience ETF). No significant difference was found between the ETF and non-ETF groups in 5-year PFS (49% vs. 60%, respectively; p=.49) or 5-year OS (81% vs. 83%, p=.8). The authors also found that patients in the ETF cohort who underwent ASCT in CR showed a plateau in the PFS curves beyond 7 years of follow-up at 50%. The authors concluded that because patients with FL who experience ETF after frontline therapy have few treatment options, ASCT may be an early consolidation option for those patients who respond to rescue treatments.

Section Summary: Indolent B-Cell Lymphomas

Randomized trials have shown no survival advantage to HCT as first-line therapy for indolent B-cell lymphomas; however, randomized studies have shown a survival benefit for relapsed disease. Observational studies have shown similar results.

Aggressive B-Cell Lymphomas

Clinical Context and Test Purpose

The purpose of autologous HCT as consolidation therapy after first CR is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with aggressive B-cell NHLs, excluding MCL.

The question addressed in this policy is: Does the use of autologous HCT improve the net health outcome in patients with aggressive B-cell NHLs, excluding MCL?

The following PICO was used to select literature to inform this review.

Patients

The relevant population of interest is individuals with aggressive B-cell NHLs, excluding MCL.

Interventions

The therapy being considered is autologous HCT as consolidation therapy after first CR. Patients with NHL are actively managed by hematologists/oncologists in an inpatient and outpatient clinical setting.

Comparators

Comparators of interest include standard of care. Patients with NHL are actively managed by hematologists/oncologists in an inpatient and outpatient clinical setting.

Outcomes

The general outcomes of interest are OS, DSS, change in disease status, morbid events, treatment-related mortality, and treatment-related morbidity. Follow-up over years is of interest for relevant outcomes.

Study Selection Criteria

Methodologically credible studies were selected using principles described in the first indication.

HCT for First-Line Therapy for Aggressive NHL

Systematic Reviews

Greb et al (2008) conducted a systematic review and meta-analysis to determine whether high-dose chemotherapy with autologous HCT as first-line treatment in patients with aggressive NHL would improve survival compared with conventional chemotherapy.^22, Fifteen RCTs (total n=3079 patients) were eligible for the meta-analysis. Thirteen studies (n=2018 patients) showed significantly higher CR rates in the autologous HCT group (p=0.004). However, autologous HCT did not affect OS when compared with conventional chemotherapy. According to the IPI, subgroup analysis of prognostic groups showed no survival differences between autologous HCT and conventional chemotherapy in 12 trials, and EFS also did not differ between the 2 groups. Despite higher CR rates, the evidence suggested no benefit with autologous HCT as first-line treatment in aggressive NHL.

Randomized Controlled Trials

Several randomized trials reported between 1997 and 2002 have compared outcomes of autologous HCT used to consolidate a first CR in patients with intermediate or aggressive NHL, with outcomes of an alternative strategy that delayed transplants until relapse.^23,24,25,26, As summarized in a 2002 editorial, the preponderance of evidence showed that consolidating first CRs with HCT did not improve OS for the full population of enrolled patients.^27, However, a 2000 subgroup analysis at 8-year median follow-up focused on 236 patients at high- or high-intermediate risk of relapse (based on age-adjustedIPI scores) who were enrolled in the largest of these trials, Survival Benefit of High-Dose Therapy in Poor-Risk Aggressive Non-Hodgkin's Lymphoma: Final Analysis ofthe Prospective LNH87-2 Protocol (LNH87-2 protocol).^28, The subgroup analysis reported superior OS (64% vs. 49%, respectively; RR=1.51, p=0.04) and disease-free survival (DFS; 55% vs. 39%, respectively; RR=1.56, p=0.02) for patients at elevated risk of relapse who received autologous HCT as consolidation therapy.

A large, multigroup, prospective, randomized phase 3 comparison of these strategies, Autologous Transplantation as Consolidation in Aggressive Lymphoma (S9704 trial) was designed to confirm results of the subgroup analysis in a larger population with DLBCL at high- and high-intermediate risk of relapse. Nevertheless, many clinicians have viewed the LNH87-2 subgroup analysis^29, as sufficient evidence to support the use of autologous HCT to consolidate a first CR when the risk of relapse is high. In contrast, editorials ^27,29, and reviews^30,31,32, concluded that available evidence showed no survival benefit from autologous HCT to consolidate the first CR in patients with intermediate or aggressive NHL at low- or low-intermediate risk of relapse (using age-adjusted IPI score).

Betticher et al (2006) reported on the results of a phase 3 multicenter, randomized trial comparing sequential high-dose chemotherapy plus autologous HCT with standard CHOP as first-line therapy in 129 patients with aggressive NHL.^33, Remission rates were similar in the 2 groups, and, after a median observation time of 48 months, there was no difference in OS (46% in the sequential autologous HCT group vs. 53% in the group that received CHOP; p=0.48). Sequential autologous HCT did not confer any survival benefit as initial therapy in patients with aggressive NHL.

Baldissera et al (2006) reported on the results of a prospective RCT comparing high-dose chemotherapy plus autologous HCT with conventional chemotherapy as first-line therapy in 56 patients with high-risk aggressive NHL.^34, The 5-year actutimes OS and PFS rates did not differ statistically between the 2 study groups; only DFS differed statistically (97% for the autologous HCT group vs. 47% for the conventional group; p=0.02.)

Olivieri et al (2005) reported on a randomized study of 223 patients with aggressive NHL using upfront high-dose chemotherapy plus autologous HCT versus conventional chemotherapy plus autologous HCT in cases of failure.^35, In the conventional group, 29 patients achieved a PR or no response and went on to receive high-dose chemotherapy plus autologous HCT. With a median follow-up of 62 months, there was no difference in the 7-year probability of survival (60% and 57.8%, p=0.5), DFS (62% and 71%, p=0.2), or PFS (44.9% and 40.9%, p=0.7, all respectively) between the 2 groups. Patients with aggressive NHL did not benefit from upfront autologous HCT.

Results of a phase 3 multicenter randomized trial, Chemoradiotherapy and Peripheral Stem Cell Transplantation Compared With Combination Chemotherapy in Treating Patients With Non-Hodgkin's Lymphoma (SWOG-9704) of autologous HCT as consolidation for aggressive (high-intermediate or high-risk) diffuse B-cell NHL were published in 2013.^36, In this trial, 253 patients received 5 cycles of induction chemotherapy (CHOP with [n=156 (47%)] or without rituximab). Those who had at least a PR to 5 cycles of induction therapy were randomized to 3 additional cycles of CHOP (n=128) or 1 additional cycle of CHOP followed by autologous HCT (n=125). The primary efficacy endpoints of the trial were 2-year PFS and OS. Two-year PFS rates were 69% and 55% in the HCT and control group, respectively (HR control vs. HCT=1.72; 95% CI, 1.18 to 2.51; p=0.005). The 2-year OS rates in the HCT and control group were 74% and 71%, respectively (HR=1.26; 95% CI, 0.82 to 1.94; p=0.30). Unplanned exploratory analyses showed a differential treatment effect by disease risk level. Among high-risk patients, the 2-year OS rate was 82% in the HCT group and 64% in the control group (p=0.01). The main results of this trial comport with earlier study results in not discerning a significant effect of early autologous HCT on OS among a group of patients with high-, intermediate-, and high-risk diffuse B-cell NHL. However, the survival curve appeared to plateau among the high-risk HCT patients out to 10 years after study registration. Although this evidence was from exploratory subset analysis, it further supports the efficacy of this approach in such cases compared with nontransplant strategies.

A single-center cohort study by Strüßmann et al (2017) compared high-dose chemotherapy plus subsequent autologous HCT with an early-intensified regimen (6-cycle CHOP-14) that included rituximab and methotrexate in 63 patients with DLBCL and poor prognosis.^37, All patients had an age-adjusted IPI score of 2 or 3, and demographic information was comparable for both cohorts (eg, median ages were 48 and 53 for cohorts 1 and 2, respectively). Four cycles of R-CHOP-21 were administered to cohort 1, followed by high-dose carmustine, etoposide, cytosine arabinoside, and melphalan, and autologous HCT; cohort 2 was initially given 6-cycle CHOP-14, then rituximab and high-dose methotrexate. At 2-year follow-up, PFS and OS rates were compared between cohorts, and patients in cohort 2 had significantly better outcomes, even when adjusted for multiple variables (including that of age-adjusted IPI score). The 2-year PFS rate was 60.6% for those in cohort 1, compared with 93.37% in cohort 2 (HR=7.2; 95% CI, 1.64 to 31.75; p=0.009), a finding was also statistically significant in multivariate analysis (HR=8.12; 95% CI, 1.73 to 36; p=0.006). The OS rate at 2 years was 69.7% for cohort 1 and 93.3% (HR=5.86; 95% CI. 1.28 to 26.8) after multivariate analysis. Also, patients in cohort 2 showed significantly higher overall response and CR rates (93.3% and 90%) than did patients in cohort 1 (66.7% and 63.6%), respectively; furthermore, no treatment-related mortality was reported for cohort 2 during follow-up, despite the initial intensive treatment protocol.

A phase 2 clinical trial, A Study of Two Associations of Rituximab and Chemotherapy, With a PET-driven Strategy, in Lymphoma (LNH2007-3B) by Casasnovas et al (2017) randomized 211 patients to receive a 4-cycle regimen of doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone plus rituximab or R-CHOP14, to be followed by standard immunochemotherapy or autologous HCT.^38, Of the 200 patients who completed the trial, 109 were assigned to doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone plus rituximab and 97 were assigned to R-CHOP14; all patients had confirmed DLBCL and had 2 or 3 risk factors according to age-adjusted IPI. Neither group achieved the primary endpoint, which was CR greater than 50%, as defined by 2007 International Harmonization Project criteria, with 47% (95% CI, 38% to 67%) of doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone plus rituximab patients and 39% (95% CI, 28% to 54%) showing CR. Investigators noted the disparity between the low response according to International Harmonization Project criteria and the improvement of outcomes predicted by positron emission tomography (PET) results and assessed by change in maximum standard uptake value (∆SUVmax), suggesting that the latter might be a superior indicator of disease progression than International Harmonization Project criteria. PET scans were performed on all patients at baseline, after 2 cycles of the induction regimen (PET2), and again after 4 cycles of treatment (PET4); patients who showed negative results for both PET2 and PET4 were assigned to standard immunochemotherapy (n=51), while those who showed positive results for PET2 but negative results for PET4 were recommended for autologous HCT (n=40). No statistically significant differences in outcome were observed between these groups; however, investigators observed significant differences in outcomes when they assessed ∆SUVmax in patients. At measurement of PET2, rates of 4-year PFS and OS were higher for patients with âˆ†SUVmax greater than 66% than for those showing a smaller change in SUVmax (PFS for the respective groups was 80% vs. 56%, p<0.001; OS was 87% vs 69% in patients with an ∆SUVmax <66%, p=0.003). When ∆SUVmax was assessed following PET4, similar improvements were observed: the 4-year PFS rate was 84% in those showing an âˆ†SUVmax greater than 70%, compared with 35% in those with an∆SUVmax of 70% or less (p<0.001); likewise, OS rates were 91% and 57% for the respective groups (p<0.001). Differences between the potential treatments (standard chemotherapy, autologous HCT, or salvage therapy) were not statistically significant.

Qualls et al (2017) published a small retrospective study of 20 individuals (13 men, 7 women) treated with autologous HCT for systemic NHL with some form of central nervous system (CNS) involvement.^39, Most patients presented with DLBCL histology (n=17 [85%]), and CNS involvement varied: the 2 most common types of CNS involvement were parenchymal involvement (n=12 [60%]) and leptomeningeal disease (n=9 [45%]). As an induction regimen, the majority of patients (n=13 [65%]) were given R-CHOP, or, as a treatment for CNS involvement, high-dose methotrexate (n=16 [80%]). The high-dose chemotherapy regimen for all patients included thiotepa, busulfan, and cyclophosphamide, and 6 patients received rituximab plus thiotepa, busulfan, and cyclophosphamide; all patients received autologous HCT during first CR. PFS rates were high at 1-year (84%; 95% CI, 59% to 95%) and 4-year (77%; 95% CI, 48% to 91%) follow-ups. OS rates were similarly high at 1 year (95%; 95% CI, 68% to 99%) and 4 years (82%; 95% CI, 54% to 94%). The most commonly experienced treatment-related adverse events were febrile neutropenia, which was observed in 80% (n=16) of patients. Despite the small size of the study, the authors noted the rare occurrence of relevant cases, suggesting that the high survival rates observed in the study supported the use of autologous HCT in the first CR.

HCT for Relapsed, Aggressive NHL

Autologous HCT is the treatment of choice for relapsed or refractory aggressive NHL for patients who achieve a CR or PR with second-line therapy.^5,40, The pivotal trial that established the superiority of autologous HCT for relapsed DLBCL is the Autologous Bone Marrow Transplantation as Compared with SalvageChemotherapy in Relapses of Chemotherapy-Sensitive Non-Hodgin's Lymphoma ([1995] PARMA trial), a prospective randomized study in which 215 patients with chemosensitive disease in first or second relapse of aggressive lymphoma were given 2 courses of conventional chemotherapy.^41, One hundred nine patients responded and were randomized to 4 courses of chemotherapy plus radiotherapy (n=54) or radiotherapy plus intensive chemotherapy and autologous HCT (n=55). The groups did not differ in baseline characteristics. Median follow-up was 63 months. The response rate was 84% in the HCT group and 44% in the nontransplant group. The EFS rate for the transplant group was 46% and 12% in the nontransplant group (p=0.001), and the OS rate was 53% in the transplant group and 32% in the nontransplant group (p=0.038).

Using the national registry of hematopoietic stem cell transplantation in Japan, Fujita et al (2019) conducted a retrospective study on the effect of allogeneic or autologous HCT in children and adolescents (<18 years old) with relapsed or refractory B-cell non-Hodgkin lymphoma.^42, They analyzed 5-year survival rates for 31 autologous HCTs and 48 allo- HCTs and found that with any HCT, the rate was 41% (95% CI: 30 to 52%). When data on the 2 types of HCT were separated, auto-HCT had a significantly higher survival rate than allo-HCT (55% [95% CI: 36% to 70] vs. 32% [95% CI: 18% to 46%]; p=.036). Factors for poor prognosis included allogeneic graft, Burkitt histology, and lack of response to chemotherapy. Better survival was associated with positive response to chemotherapy before HCT, autologous graft, and diffuse large B-cell histology. In addition, treatment-related mortality was significantly higher with allo-HCT than with auto-HCT (23% [95% CI: 12% to 35%] vs. 3.2% [95% CI: 2.4% to 14%]; p=.017). For relapse, no statistically significant difference was found between allo-HCT and auto-HCT.

Section Summary: Aggressive B-Cell Lymphomas

Data from randomized trials have shown conflicting results, but some studies have shown an OS benefit with HCT to consolidate a first CR in patients with aggressive B-cell lymphomas at high or high-intermediate risk of relapse. Randomized studies of HCT for relapsed aggressive B-cell lymphomas have shown an OS benefit with this approach. Results of 1 retrospective study comparing autologous and allo-HCT for relapsed or refractory showed more positive outcomes for autologous HCTs.

Tandem Autologous and Allogeneic Transplants

Clinical Context and Test Purpose

The purpose of tandem autologous and allo- HCT is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with NHLs, excluding MCL.

The question addressed in this policy is: Does the use of tandem autologous and allo- HCT improve the net health outcome in individuals with NHLs, excluding MCL?

The following PICO was used to select literature to inform this review.

Patients

The relevant population of interest is individuals with NHLs, excluding MCL.

Interventions

The therapy being considered is tandem autologous and allo- HCT. Patients with NHL are actively managed by hematologists/oncologists in an inpatient and outpatient clinical setting.

Comparators

Comparators of interest include standard of care. Patients with NHL are actively managed by hematologists/oncologists in an inpatient and outpatient clinical setting.

Outcomes

The general outcomes of interest are OS, DSS, change in disease status, morbid events, treatment-related mortality, and treatment-related morbidity. Follow-up over years is of interest for relevant outcomes.

Study Selection Criteria

Methodologically credible studies were selected using principles described in the first indication.

No prospective controlled studies comparing tandem HCT with single HCT have been identified in the published literature.

A pilot phase 2 trial (2011) evaluated tandem high-dose therapy with stem cell support between 1994 and 1999 in 45 patients with untreated aggressive NHL and an age-adjusted IPI of 3.^43, After induction, responders underwent tandem autologous transplantation; 31 of 41 evaluable patients completed the program. There were 4 toxicity-related deaths. The primary endpoint of the trial was the CR rate, which was 49%. With a median follow-up of 114 months for surviving patients, the OS rate was 51%, and 19 (86%) of the 22 patients who reached a CR were alive and relapse-free. Prospective evaluation of the quality of life and comorbidities of surviving patients did not reveal long-term toxicities.

A pilot study in 2005 evaluated 41 patients with poor-risk NHL and Hodgkin disease who were given tandem high-dose chemotherapy and autologous HCT.^44, Thirty-one (76%) patients completed both transplants. The overall toxicity-related death rate was 12%. The study evaluated the maximally tolerated dose of the chemotherapeutic regimen and did not compare tandem with single transplants for NHL.

Tarella et al (2007) reported on a multicenter, nonrandomized, prospective trial consisting of 112 patients with previously untreated DLBCL and age-adjusted IPI score of 2 or 3.^45, All patients received rituximab-supplemented, early-intensified high-dose chemotherapy with multiple autologous HCT. Although the treatment regimen appeared to improve patients’ life expectancy, the comparisons were made with historical controls who had received conventional chemotherapy.

A 2013 retrospective analysis of 34 high-risk NHL patients who underwent autologous HCT followed closely by reduced-intensity conditioning (RIC)allo-HCT evaluated patients treated from 2002 to 2010.^36, In this study, researchers identified appropriate allogeneic donors at the initiation of the salvage regimen. Patients' median age was 47 years. Histologic subtypes were: diffuse large B-cell (n=5), follicular (n=14), transformed follicular (n=4), mantle cell (n=5), plasmacytoid lymphoma (n=1), anaplastic large T-cell (n=2), and peripheral T-cell (n=3). Human leukocyte antigen-identical sibling donors were located for 29 patients, and 10 of 10 matched unrelated individuals were identified for 5 cases. The median interval between autologous HCT and allo-HCT was 77 days (range, 36-197 days). At a median follow-up of 46 months since allo-HCT, the 5-year OS rate was 77%, and the PFS rate was 68%. Six patients experienced disease relapse or progression, the 100-day treatment-related mortality was 0%, and 2-year treatment-related mortality incidence was 6%. These results suggested tandem autologous-allogeneic transplantation is feasible in high-risk NHL patients having a human leukocyte antigen-identical donor, but further study is necessary to establish its role in this setting.

Results of a non-randomized study on the sequential combination of myeloablative therapy and autologous stem cell transplantation (STC) followed by reduced-intensity allo-SCT and post-SCT adoptive cellular immunotherapy for refractory or recurrent NHL and Hodgkin's Disease have been posted on ClinicalTrials.gov, Sequential Myeloablative Stem Cell Transplantation and Reduced Intensity Allogeneic Stem Cell Transplantation in Patients With Refractory or Recurrent Non-Hodgkin's Lymphomaand Hodgkin's Disease (NCT00802113).[76] The participants were divided into 2 arms: Arm A received allogeneic stem cells from a family member (n=6), and Arm B received stem cells from an unrelated donor (n=17). All participants were followed for 1 year after treatment. A complete response was seen in 66.7% of Arm A and 70.6% in Arm B. Disease relapse or progression was experienced by 16.7% of Arm A and 17.6% of Arm B. Partial response or stable disease was seen in 66.7% of Arm A and 52.9% of Arm B. Two participants (33.3%) in Arm A and 6 (35.3%) in Arm B died of transplant-related causes by the 1-year follow-up.

Section Summary: Tandem Autologous and Allogeneic Transplants

No randomized studies have been conducted on the use of tandem HCT for the treatment of NHL, and the published evidence comprises small numbers of patients. Therefore, the data on tandem transplants are insufficient to determine outcomes with this type of treatment.

NHL Subtypes

Several subtypes have emerged with unique clinical and biologic features that are addressed separately herein (specifically MCL and PTCL).

Autologous, Allogeneic, or Tandem Transplant for Mantle Cell Lymphoma

MCL comprises 65% to 68% of NHL and has been recognized for some time now as a unique lymphoma subtype with a particularly aggressive course. MCL is characterized by a chromosomal translocation t(11;14), and the term mantle cell lymphoma was proposed by Banks et al (1992).^46, The number of therapeutic trials is not as numerous for MCL as for other NHL, because it was not widely recognized until the REAL classification. MCL shows a strong predilection for senior men, and most cases (70%) present with disseminated (stage IV) disease; extranodal involvement is common. Localized MCL is quite rare. MCL has a median survival of approximately 2 to 4 years, and although most patients achieve remission with first-line therapy, relapse inevitably occurs-often within 12 to 18 months. MCL is rarely, if ever, cured with conventional therapy, and no standardized therapeutic approach to MCL is used.

Risk Assessment

A prognostic index has recently been established for patients with MCL. Application of the IPI or Follicular Lymphoma International Prognostic Index system to patients with MCL has shown limitations, which included no separation of some important risk groups. In addition, some of the individual IPI and Follicular Lymphoma International Prognostic Index risk factors, including the number of extranodal sites and number of involved nodal areas, showed no prognostic relevance, and hemoglobin showed no independent prognostic relevance in patients with MCL.^47,Therefore, a new prognostic index for patients with MCL was developed and should prove useful in comparing clinical trial results for MCL.

The MCL IPI is based on the following risk factors prognostic for OS.

1. Age
2. ECOG Performance Status
3. Serum LDH (calculated as a ratio of LDH to a laboratory’s upper limit of normal)
4. White blood cell (WBC) count
• 0 points each are assigned to age younger than 50 years, ECOG Performance Status score of 0-1, LDH ratio of less than 0.67 U/L, WBC of less than 6700/mL
• 1 point each for age 50 to 59 years, LDH ratio of 0.67-0.99 U/L, WBC of 6700-9999/mL
• 2 points each for age 60 to 69 years, ECOG Performance Status score of 2-4, LDH ratio of 1.00-1.49 U/L, WBC of 10000-14999/mL
• 3 points each for age 70 years or older, LDH ratio of 1.5 U/L or greater, WBC of 15000/mL or more.

• 0-3 points denote low-risk, which affects 44% of patients, who have a 5-year OS rate of 60% (median OS, not reached)
• 4-5 points denote intermediate risk, which affects 35% of patients, who have a median OS of 51 months
• 6-11 points denote high-risk, which affects 21% of patients, who have a median OS of 29 months

The purpose of autologous, allogeneic, or tandem HCT is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with MCL.

The question addressed in this policy is: Does the use of autologous, allogeneic, or tandem HCT improve the net health outcome in patients with MCL?

The following PICO was used to select literature to inform this review.

Patients

The relevant population of interest is individuals with MCL.

Interventions

The therapy being considered is autologous, allogeneic, or tandem HCT.Patients with NHL are actively managed by hematologists/oncologists in an inpatient and outpatient clinical setting.

Comparators

Comparators of interest include standard of care. Patients with NHL are actively managed by hematologists/oncologists in an inpatient and outpatient clinical setting.

Outcomes

The general outcomes of interest are OS, DSS, change in disease status, morbid events, treatment-related mortality, and treatment-related morbidity. Follow-up over years is of interest for relevant outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the principles described in the first indication e.

Autologous HCT

To improve outcomes of MCL, several phase 2 trials have investigated the efficacy of autologous HCT, with published results differing substantially.^47,48, Some studies found no benefit to HCT, and others suggested an EFS advantage, at least in a subset of patients.^47, The differing results were likely due to different time points of transplant (first vs. second remission) and patient selection criteria.^48,

The results of the first randomized trial were reported by Dreyling et al (2005) of the European MCL Network.^48, A total of 122 patients with MCL received autologous HCT or interferon as consolidation therapy in first CR or PR. Among these patients, 43% had a low-risk, 11% had a high-intermediate risk, and 6% had a high-risk profile. Autologous HCT resulted in a PR rate of 17% and a CR rate of 81% (vs. PR of 62% and CR of 37% with interferon). Survival curves for time to treatment failure after randomization showed that autologous HCT was superior to interferon (p=0.003). There was also a significant improvement in the 3-year PFS rate in the autologous HCT arm (54%) versus the interferon arm (25%; p=0.01). At the time of the reporting, no advantage was seen in OS, with 3-year OS rates of 83% and 77%, respectively. The results also suggested that the impact of autologous HCT could depend on the patient’s remission status before the transplant, with a median PFS of 46 months in patients in CR and 33 months in patients in PR.

Till et al (2008) reported on the outcomes for 56 patients with MCL treated with induction chemotherapy plus cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) with or without rituximab followed by autologous HCT in first CR or PR (n=21), CHOP with or without rituximab followed by autologous HCT in first CR or PR (n=15), or autologous HCT following disease progression (n=20).^49, OS and PFS rates at 3 years among patients transplanted in CR or PR were 93% and 63% compared with 46% and 36%, all respectively, for patients transplanted with relapsed or refractory disease. The hazard of mortality among patients transplanted with the relapsed or refractory disease was 6.1 times that of patients transplanted in first CR or PR (p<0.001).

Geisler et al (2008) reported on 160 previously untreated patients with MCL with dose-intensified induction immunochemotherapy.^50, Responders received high-dose chemotherapy with in vivo purged autologous HCT. OS and CR rates were achieved in 96% and 54%, respectively. The 6-year OS, EFS, and PFS rates were 70%, 56%, and 66%, respectively, with no relapses occurring after 5 years.

Evens et al (2008) reported on 25 untreated patients with MCL who received induction chemotherapy, with an overall response rate of 74%.^51, Seventeen patients received a consolidative autologous (n=13) or allogeneic (n=4) HCT. Five-year EFS and OS rates for all patients were 35% and 50%, respectively. After a median follow-up of 66 months, the 5-year EFS and OS rates for patients who received autologous HCT were 54% and 75%, respectively.

In a retrospective case series of 268 patients drawn from the GELTAMO registry and 35 hospitals in Spain, García-Noblejas et al (2017) evaluated the response of individuals with MCL to autologous HCT as first-line treatment.^52, Investigators noted a significant improvement in PFS for patients who underwent transplantation during first CR, compared with patients with other disease statuses (ie, PR, chemosensitive, chemorefractory): in univariate analysis, PFS for first CR patients was 48 months (95% CI, 37 to 62 months) compared with 26 months (95% CI, 66 to 128 months) for other statuses (p=0.01). There was a similar association between first CR status and OS, compared with other statuses: 97 months versus 57 months (p=0.03). When adjusted for multiple variables, both associations were also statistically significant (RR for PFS=1.6 [95% CI, 1.1 to 2.2], p=0.015 vs. RR for OS=0.8 [95% CI, 1.2 to 2.7], p=0.003). During univariate analysis, prior exposure to rituximab was associated with a greater PFS and OS (respectively, p=0.02; p<0.001); however, this association was confirmed by multivariate analysis because of the limited data on rituximab in all patients. The investigators noted that improvements in survival rates were restricted to patients who received transplantation during first CR; for more uncertain statuses (eg, PR or chemosensitivity), the positive association disappeared. However, in 70% of the patients who received transplants and were chemosensitive or achieved a PR, CR was achieved posttransplantation, supporting the use of autologous HCT in patients with CR or near CR.

Allo-HCT

Several studies have assessed allo-HCT withRIC.^53, Khouri et al (2003) reported on results of allo-HCT with RIC in 18 patients with relapsed MCL; after a median follow-up of 26 months, the actutimes probability of EFS was 82% at3 years.^54, Maris et al (2004) evaluated allo-HCT in 33 patients with relapsed and recurrent MCL. At 2 years, the relapse and nonrelapse mortality rates were 9% and 24%, respectively, and the OS and DFS rates were 65% and 60%, respectively.^55,

Tandem Autologous HCT and Allo-HCT

Two recent major therapeutic advances have substantially altered the outlook of patients with MCL: (1) the introduction of rituximab, which in combination with chemotherapy, has improved the results of both first-line and salvage treatments for MCL; and (2) the combination of rituximab and hyper-CVAD, which is capable of achieving CR rates of up to 90% in the first-line setting, with a prolonged 5-year failure-free survival rate of 60% in younger patients.

Tam et al (2009) reported on a retrospective study that included all patients with MCL who had undergone HCT in sequential phase 2 protocols (autologous or nonmyeloablative allogeneic) at a university cancer center between 1990 and 2007.^56,The approach to transplantation was risk-adapted and based primarily on the patient’s treatment status. Autologous HCT was performed as consolidation therapy for patients in the first remission after chemotherapy (1990-2001). From 2001 onward, because of the favorable clinical outcomes found with rituximab (R)-hyper-CVAD chemotherapy, autologous HCT was performed only in patients not in CR after R-hyper-CVAD and in patients who had received less intensive induction chemotherapy (eg, CHOP-R). For patients with relapsed or primary refractory MCL, autologous HCT was performed before the use of nonmyeloablative allogeneic in 1997. After 1997, nonmyeloablative allogeneic was performed whenever a histocompatible donor was available. Patients generally underwent autologous HCT up to the age of 70 and allo-HCT with RIC up to the age of 65 years. Since 2004, patients up to the age of 75 years could receive an autologous transplant. The study included 121 patients with MCL: 50 who underwent autologous HCT in first CR (46%) or PR (54%) (AUTO1), 36 who underwent autologous HCT for relapsed or refractory disease (AUTO2), and 35 who underwent nonmyeloablative allo-HCT for relapsed or refractory disease. The ages at transplantation were similar in all 3 groups (median, 57 years [range, 38-73 years] for AUTO1; median, 59 years [range, 42-76 years] for AUTO2; median, 58 years [range, 43-68 years] for nonmyeloablative allo-HCT).

For the AUTO1 group, at a median follow-up of 6 years, the actutimes PFS and OS rates were 39% and 61%, respectively, with median PFS and OS durations of 42 months and 93 months. Of the AUTO2 patients, 31% did not respond to initial chemotherapy but did experience a PR or better to salvage therapy with hyper-CVAD (n=6), R-hyper-CVAD (n=4), or methotrexate and ara-C (n=1). Seventeen (47%) patients were in their second remission, 3 (8%) were in their third or subsequent remission, and 5 (14%) had a chemorefractory relapse and were transplanted in less than partial remission. The actutimes 6-year PFS and OS rates were 10% and 35%, respectively (p=0.01 and 0.02 vs. AUTO1), and the median PFS and OS durations were 27 and 52 months, respectively. These inferior results for both PFS and OS compared with AUTO1 patients were confirmed in a multivariate analysis that accounted for differences in baseline factors.

Of the patients who underwent nonmyeloablative allo-HCT for relapsed or refractory MCL, 20% did not respond to initial chemotherapy but experienced a PR or better to salvage therapy with R-hyper-CVAD. Thirty-one percent were in the second remission, 31% were in third or subsequent remission, and 17% had a refractory relapse and received a transplant in less than PR. With a median follow-up of 56 months (range, 19-110 months), the median PFS duration was 60 months, and the median OS had not yet been reached. The 6-year actutimes PFS rate was 46%, and the 6-year actutimes OS rate was 53%. Plateaus in the survival curves were observed for both PFS and OS, with no relapses or deaths occurring in 9 patients followed between 63 and 110 months. These outcomes were significantly superior to that of AUTO2 patients, whereby relapses and deaths occurred continuously (p=0.01 for PFS; p=0.005 for OS [4-year landmark for OS]). Compared with AUTO1 patients, the patients who received allo-HCT with RIC had an initially lower OS; however, this reversed at 8 years among nonmyeloablative allogeneic patients.

This study provided evidence that MCL may be curable in both the first-line and salvage settings. In chemotherapy-naive patients, the results showed that rituximab plus autologous HCT in the first remission might result in long-term disease control, with only 1 relapse occurring among 11 patients followed between 2 years and 8 years, in contrast to that of autologous transplantation without rituximab, in which relapses occurred continuously. In contrast to first-line transplantation, the outcomes of autologous transplantation in patients with relapsed or refractory MCL remain unsatisfactory, with no evidence of a cured fraction on survival curves. The results of autologous and nonmyeloablative allo-HCT in patients with relapsed or refractory MCL also differed markedly. Patients receiving a nonmyeloablative allogeneic transplant showed significantly superior disease control and a disease-free plateau, extending between 5 years and 9 years; whereas patients who received an autologous transplant had a median remission of 2 years and experienced a continuous pattern of relapse. Therefore, nonmyeloablative allo-HCT might be a salvaging treatment option for patients no longer curable with maximum cytotoxic strategies.

As noted in the Tam et al (2009) study,^56, review articles on high-dose therapy for MCL have affirmed the finding in several studies of a superior result of transplantation in first CR (autologous or allogeneic) rather than in the relapsed setting, and that intensive immunochemotherapy as induction therapy preceding high-dose therapy plus autologous HCT is indicated.^47,57, Also noted were the results of the use of allo-HCT with RIC in the relapsed setting, showing survival plateaus and suggesting curative potential, and suggesting benefit in the use of this approach in younger, fit patients with relapsed MCL.^57,

Section Summary: Autologous, Allogeneic, or Tandem Transplant forMCL

Due in part to the relative rarity of the disease, randomized studies on the use of HCT in MCL have not been conducted. Case series have shown long-term disease control of this aggressive lymphoma with the use of autologous HCT (with rituximab) to consolidate a first remission; however, the use of autologous HCT in the relapsed setting has not shown improved outcomes. Allo-HCT has shown prolonged disease control in the relapsed or refractory setting.

Autologous or Allogeneic Transplant for Peripheral T-Cell Lymphoma (Mature T-Cell or Natural Killer Cell Neoplasms)

MostPTCL are aggressive and fall into the category of PTCL, unspecified PTCL, or PTCL not otherwise survival, angioimmunoblastic or anaplastic large-cell, which combined make up 60% to 70% of all T-cell lymphomas. PTCLs are less responsive to standard chemotherapy than DLBCLs and carry a worse prognosis than aggressive B-cell counterparts. Survival rates at 5 years with standard chemotherapy regimens range from 20% to 35%. The poor results with conventional chemotherapy have prompted exploration of the role ofHCT as therapy.

Staging

The Ann Arbor staging classification is commonly used to stage lymphomas. Originally developed for Hodgkin disease, the classification was later expanded to include NHL (see Table 2).

Table 2. Ann Arbor Classification

Stage	Involvement
I	Involvement of a single lymph node region (I) or of a single extralymphatic organ or site (IE)
II	Involvement of 2 or more lymph node regions on the same side of the diaphragm (II) or localized involvement of extralymphatic organ or site and one or more lymph node regions on the same side of the diaphragm (IIE)
III	Involvement of lymph node regions on both sides of the diaphragm (III), which may also be accompanied by localized involvement of extralymphatic organ or site (IIIE) or by involvement of the spleen (IIIS) or both (IIISE)
IV	Diffuse or disseminated involvement of one or more extralymphatic organs or tissues with or without associated lymph node enlargement

Clinical Context and Test Purpose

The purpose of autologous or allo- HCT is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with PTCL.

The question addressed in this policy is: Does the use of autologous or allo- HCT improve the net health outcome in individuals with PTCL?

The following PICO was used to select literature to inform this review.

Patients

The relevant population of interest is individuals with PTCL.

Interventions

The therapy being considered is autologous or allo-HCT. Patients with NHL are actively managed by hematologists/oncologists in an inpatient and outpatient clinical setting.

Comparators

Comparators of interest include standard of care. Patients with NHL are actively managed by hematologists/oncologists in an inpatient and outpatient clinical setting.

Outcomes

The general outcomes of interest are OS, DSS, change in disease status, morbid events, treatment-related mortality, and treatment-related morbidity. Follow-up over years is of interest for relevant outcomes.

Study Selection Criteria

Methodologically credible studies were selected using principles described in the first indication.

First-Line Autologous HCT (Newly Diagnosed PTCL)

Only a few prospective studies with small numbers of patients have investigated autologous HCT in patients with aggressive PTCL. The results are described next.

Reimer et al (2009) conducted a large prospective study of 83 patients with PTCL from multiple centers to undergo autologous HCT as first-line therapy.^58, Patients had various histologies, including PTCL-NOS (not otherwise specified) (n=32), angioimmunoblastic (n=27), anaplastic lymphoma kinase-anaplastic large-cell lymphomas (ALCL) (n=13), and the remainder with extranodal subtypes. Sixty-six percent of the patients received the transplant (for those who chose not to receive the transplant, they cited their progression of the disease as the main reason for not doing so.) Of the patients who proceeded to transplant, 32 were in CR and 33 in PR. The treatment-related mortality rate was 3.6%. Median follow-up was 33 months and estimated 3-year OS and PFS rates were 48% and 36%, respectively.

Corradini et al (2006) reported on the results of 2 phase 2 studies involving 62 patients with advanced-stage PTCL at diagnosis.^59, In an intention-to-treat analysis, 46 (74%) of the 62 completed the whole program. Sixteen patients failed to undergo transplants due to early disease progression and/or toxicity. Pretransplant, 56% of patients were in CR and 16% in PR. Median follow-up was 76 months, with the estimated 12-year OS, DFS, and EFS rates of 34%, 55%, and 30%, respectively. Five-year EFS and OS rates were 40% and 50%, respectively. Multivariate analysis revealed that patients who achieved CR before HCT had a statistically significant benefit in OS and EFS (p<0.001).

Mercadal et al (2008) reported on the results of a phase 2 trial involving 41 patients diagnosed consecutively with PTCL (median age, 47 years).^60, Patients who responded to induction chemotherapy (CR or PR) went on to autologous HCT. Twenty-four patients responded (CR, n=20, PR, n=4). Seventeen of these 24 underwent HCT (the remaining patients did not, for various reasons including lack of stem cell mobilization, toxicity, and early relapse). For patients who completed the entire procedure, CR was 51% and PR, 7%. Median follow-up was 3.2 years (range, 0.6-8.1 years), and 5 of 21 CR patients relapsed, and 2 died in CR due to a secondary malignancy. The 4-year PFS rate was 30% (95% CI, 15% to 45%), and the OS rate was 39% (95% CI, 22% to 56%). No difference in OS was noted among the 24 patients eligible for transplant, 17 of whom did, and7 of whom did not undergo a transplant.

A prospective phase 2 trial by Rodriguez et al (2007) showed that autologous HCT as first-line consolidation therapy improved treatment outcome in patients responding to induction therapy.^61, Nineteen of 26 patients who showed CR or PR to induction therapy received an autologous HCT. At 2 years posttransplant, OS, PFS, and DFS rates were 84%, 56%, and 63%, respectively.

Wang et al (2018) conducted a retrospective study to investigate the efficacy of HCT in treating extranodal natural killer/T-cell lymphoma. Researchers compared 20 patients from a single-center who received the treatment followed by radiotherapy and chemotherapy with 60 additional patients who received chemotherapy and radiotherapy without HCT. The analysis found that 5-year OS was 79.3% for the HCT group compared with 52.3% for the control group (p=0.026). Limitations included the retrospective design, lack of multiple centers, and small sample size. ^62,

Salvage Autologous HCT (Relapsed or Refractory) PTCL

Kewalramani et al (2006) retrospectively compared results for 24 consecutive patients who had PTCL and underwent autologous HCT for the relapsed or refractory disease after responding to second-line therapy with the results of 86 consecutive patients who had chemosensitive relapsed or primary refractory DLBCL.^63, Patients with less aggressive histologies (eg, ALCL expressing the ALK protein) were excluded. Median follow-up was 6 years, and the 5-year PFS rates for PTCL and DLBCL were 24% and 34%, respectively (p=0.14). OS rates were 33% and 39%, respectively. Disease progression occurred in 83% of patients with PTCL and 65% of patients with DLBCL (p=0.13). In a univariate analysis of survival for patients with PTCL, response to second-line therapy and the second-line age-adjusted IPI score were prognostic for both PFS and OS. The outcomes for PTCL and DLBCL patients were similar when stratified by the second-line age-adjusted IPI score, in contrast to patients undergoing first-line chemotherapy, where T-cell histology consistently confers a poorer prognosis across IPI subgroups.

Song et al (2003) compared the outcomes of 36 patients who had PTCL who underwent autologous HCT with 97 patients who had relapsed DLBCL.^64, Of patients with PTCL, 27 were at first relapse, 2 at greater than 1 relapse and 7 had the primary refractory disease. Twenty patients had unspecified PTCL, 9 had ALCL, and the remainder a mixture of rarer subtypes. Baseline patient characteristics were similar between the PTCL and DLBCL groups. Three-year OS and EFS rates were 48% and 37%, respectively, for PTCL and 53% and 42% for DLBCL (p=0.41 and 0.29, respectively). The patients with unspecified PTCL had an inferior EFS rate when compared with the DLBCL patients (23%, p=0.028), and those with ALCL had a nonsignificant trend for improved EFS (67%, p=0.41).

Rodriguez et al (2007) reported on the largest series of patients with refractory or relapsed PTCL who received an autologous HCT.^65, One hundred twenty-three patients were derived from registry data between 1990 and 2004. Response to transplantation was as follows: in patients in whom response could be assessed (119/123), 73% achieved a CR, 11% a PR, and transplant failed to produce benefit 16% of patients with stable or progressive disease. Median follow-up was 61 months (range, 0-182 months). The 5-year PFS rate was 34% (95% CI, 25% to 44%) and the 5-year OS rate was 45% (95% CI, 36% to 55%). The DFS rate at 5 years for complete responders was 47% (95% CI, 35% to 58%).

First-Line Allo-HCT for PTCL

A 2006 review of the impact of HCT in PTCLs found that no relevant data on the use of allo-HCT in the front-line setting.^63, To further investigate the role of HCT in previously untreated PTCL, the Die Deutsche Studiengruppe für Hochmaligne Non-Hodgkin-Lymphome (German High-grade NHL Study Group) initiated a prospective randomized multicenter trial in 2010 comparing upfront autologous HCT with allo-HCT following induction chemotherapy.^58,

Salvage Allo-HCT (Relapsed or Refractory) PTCL

For relapsing and refractory PTCL, data on the use of allo-HCT consist of case reports and a number of retrospective series with at least 10 patients.^58,

Jacobsen et al (2011) reported on a single-center experience over 12 years using allo-HCT in 52 patients with PTCL or advanced mycosis fungoides/Sézary syndrome.^66, Patients had a variety of disease subtypes, including nodal and extranodal histologies. Eleven patients had undergone a prior autologous HCT. At the time of the allo-HCT, 23 (44%) patients were in first, or subsequent CR and 16 (31%) had a PR. Thirty-one (60%) patients underwent myeloablative conditioning, and 21 (40%) underwent RIC. The median follow-up was 49 months. Three-year PFS rate was 30% (45% in patients with nodal histologies, 6% in patients with extranodal histologies). The OS rate at 3 years was 41% for all patients. The evidence suggested allo-HCT can produce long-term remissions in relapsed/refractory T-cell lymphoma; plateaus in both OS and PFS curves suggested that allo-HCT might be curative in a select group of patients.

Kyriakou et al (2009) reported on the outcomes of 45 patients with angioimmunoblastic lymphoma who were in the European Group for Blood and Marrow Transplantation database and had undergone an allo-HCT between 1998 and 2005.^67, Angioimmunoblastic lymphoma is characterized by an aggressive clinical course and carries a poor prognosis; with chemotherapy, the OS rate is less than 30% at 5 years. Eleven patients had failed a prior autologous transplant. Twenty-five patients underwent myeloablative and 20 RIC. Nonrelapse mortality rates were 18%, 22%, and 25% at 3, 6, and 12 months, respectively. The median follow-up time for the surviving patients was 29 months (range, 6-76 months). The estimated OS rates at 1 and 3 years were 66% and 64%, respectively. OS for chemotherapy-sensitive patients was significantly better at 81% at 3 years.

Corradini et al (2004) reported on outcomes for 17 patients with relapsed or refractory PTCL who underwent a reduced-intensity allo-HCT.^68, Median age was 41 years (range, 23-60 years). Two of the patients had the primary chemorefractory disease, 15 had relapsed disease, and 8 had disease relapse after a prior autologous HCT. After a median follow-up of 28 months (range, 3-57 months), 14 patients were alive. PFS and OS rates at 3 years were 64% (95% CI, 39% to 89%) and 81% (95% CI, 62% to 100%), respectively. In this initial series, 15 of the 17 patients had the chemotherapy-sensitive disease before transplant. In an update of their experience in 35 patients with a median follow-up of 44 months, PFS and OS rates were 49% and 54%, respectively.

Le Gouill et al (2008) reported on a large retrospective series of patients with different aggressive histologic subtypes of PTCL who underwent allo-HCT.^69, Seventy-seven patients from 20 French centers who underwent transplants between 1988 and 2006 were included. Median age at diagnosis was 36 years (range, 12-61 years). Median follow-up was 43 months (range, 3.5-195 months). Fifty-seven patients received a myeloablative conditioning regimen. All patients had received at least 1 line of therapy before the allo-HCT, including an autologous HCT in 25% of cases. Five-year toxicity-related mortality incidence was 33% (95% CI, 24% to 46%). Overall 5-year OS and EFS rates were 57% (95% CI, 45% to 68%) and 53% (95% CI, 4% to 64%), respectively. There was a large variation in OS and EFS rates by the histopathologic subtypes: 5-year OS and EFS rates were 80% (95% CI, 39% to 94%) and 80% (95% CI, 39% to 94%) for patients with angioimmunoblastic T-cell lymphoma, 63% (95% CI, 41% to 79%) and 58% (95% CI, 35% to 75%) for PTCL-NOS, and 55% (95% CI, 35% to 72%), and 48% (95% CI, 28% to 65%) for ALCL patients, respectively. The 5-year OS rate for other histopathologic subtypes (n=12) was 33% (95% CI, 8% to 58%), and 4 of these patients were still alive in CR. All patients who could not achieve CR after allo-HCT died within 10 months of disease progression. In a multivariate analysis, the strongest predictors of OS were a chemotherapy-resistant disease at the time of the allogeneic transplant and the occurrence of severe (grade 3 or 4) acute graft-versus-host disease.

Section Summary: Autologous or Allogeneic Transplant for PTCL (Mature T-Cell or Natural Killer Cell Neoplasms)

The role of HCT in PTCL is not well-defined. Few studies have been conducted, many of these retrospectively, with small numbers of patients and heterogeneous patient populations including good- and poor-risk patients in the same study. This is partly due to the rarity and heterogeneity of this group of lymphomas. In particular, studies often mix patients with PTCL-NOS, which has a poorer prognosis, with patients with ALK-positive ALCL, which has a better prognosis (even with conventional chemotherapy regimens), and ALK-negative ALCL patients who have a worse prognosis than ALK-positive ALCL but better than PTCL-NOS patients.

There have been no randomized studies comparing chemotherapy regimens solely in patients with PTCL (ie, some randomized studies have included PTCL with aggressive B-cell lymphomas).

Reviews have summarized larger studies (2009, 2011) on the use of HCT as first-line (newly diagnosed) and salvage therapy for PTCL.^70,71, For first-line therapy, results from phase 2 studies using autologous HCT as consolidation therapy offer the best survival outcomes for patients with high-risk features; confirmatory randomized trials have not been performed. No relevant data on the use of allo-HCT in the first-line setting is available.

Approximately 30% to 60% of these patients do not reach transplantation due to early disease progression or toxicity, and 20% to 30% relapse after transplantation. Patients with relapsed or refractory disease are generally considered incurable with chemotherapy alone. In the salvage setting, the data show that the use of HCT may improve survival outcomes similar to the results seen in corresponding aggressive B-cell lymphomas in the same treatment setting.

Summary of Evidence

For individuals who have indolent B-cell non-Hodgkin lymphomas (NHL) who receive autologous HCT as first-line therapy, the evidence includes randomized trials and systematic reviews. The relevant outcomes are overall survival (OS), disease-specific survival (DSS), change in disease status, morbid events, and treatment-related mortality and morbidity. Randomized trials have not shown a survival advantage with HCT as first-line therapy for indolent B-cell lymphomas; however, randomized studies have shown a survival benefit for relapsed disease. Observational studies have shown similar results. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have aggressive B-cell NHL, excluding mantle cell lymphoma (MCL), who receive autologous HCT as consolidation therapy after first complete remission, the evidence includes randomized trials and systematic reviews. The relevant outcomes are OS, DSS, change in disease status, morbid events, and treatment-related mortality and morbidity. While the data from the randomized trials offer conflicting results, some data have revealed an OS benefit in patients with aggressive B-cell lymphomas (at high- or high-intermediate risk of relapse) who receive HCT to consolidate a first complete remission. Randomized studies of HCT for relapsed aggressive B-cell lymphomas have also shown an OS benefit with the previously described approach. Results of a retrospective study comparing autologous and allo-HCT for relapsed or refractory showed more positive outcomes for autologous HCTs. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have NHL, excluding MCL, who receive tandem autologous and allo-HCT, the evidence includes several nonrandomized trials. The relevant outcomes are OS, DSS, change in disease status, morbid events, and treatment-related mortality and morbidity. No randomized studies have been conducted on the use of tandem HCT for the treatment of NHL, and the published evidence comprises a limited number of patients. Presently, conclusions on the use of tandem transplants cannot be made about autologous and allo-HCT. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have MCL who receive autologous, allogeneic, or tandem HCT, the evidence includes case series. The relevant outcomes are OS, DSS, change in disease status, morbid events, and treatment-related mortality and morbidity. Due in part to the rarity of this disease, randomized trials on the use of HCT for MCL have not been conducted. Case series have shown long-term disease control of this aggressive lymphoma with autologous HCT (with rituximab) to consolidate a first remission; however, the use of autologous HCT in the relapsed setting has not shown improved outcomes. Allo-HCT has shown prolonged disease control in the relapsed or refractory setting. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have peripheral T-cell lymphoma (PTCL) who receive autologous or allo-HCT, the evidence includes prospective trials and case reports. The relevant outcomes are OS, DSS, change in disease status, morbid events, and treatment-related mortality and morbidity. The role of HCT in PTCL is not well-defined. Few studies have been conducted, and most were performed retrospectively, with a limited number of patients; moreover, the patient populations were heterogeneous and included good- and poor-risk patients in the same study. Patient population and characteristics of the studies can be explained partially by the rarity and heterogeneity of the particular group of lymphomas addressed. Additionally, studies of this nature often mix 3 types of patients: one type of patient has PTCL not otherwise specified, which has a poorer prognosis; another type has anaplastic lymphoma kinase-positive anaplastic large-cell lymphomas, which has a better prognosis-even with conventional chemotherapy regimens; and a third type has anaplastic lymphoma kinase-negative anaplastic large-cell lymphomas, which has a worse prognosis than anaplastic lymphoma kinase-positive anaplastic large-cell lymphomas (but better than patients with PTCL not otherwise specified). There have been no randomized studies comparing chemotherapy regimens solely in patients with PTCL (ie, some randomized studies have included PTCL with aggressive B-cell lymphomas). For first-line therapy, results from recent phase 2 studies with autologous HCT as consolidation offers the best survival outcomes for patients with high-risk features; randomized trials to confirm this have not been performed. No relevant data for the use of allo-HCT in the first-line setting is available. Patients with relapsed or refractory PTCL are generally considered incurable with chemotherapy alone. In the salvage setting, data have shown that the use of HCT may improve survival outcomes similar to the results seen in corresponding aggressive B-cell lymphomas in the same treatment setting. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

SUPPLEMENTAL INFORMATION

Clinical Input From Physician Specialty Societies and Academic Medical Centers

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

2011 Input

In response to requests, input was received from 3 physician specialty societies and 3 academic medical centers while this policy was under review in 2011. Input was solicited particularly for the use of hematopoietic cell transplantation (HCT) in mantle cell lymphoma (MCL) and peripheral T-cell lymphoma. There was a uniform agreement for the use of autologous HCT to consolidate the first remission in MCL. There was a general agreement for the use of allogeneic HCT as salvage therapy for MCL, with less agreement on the use of autologous HCT in the salvage setting. For peripheral T-cell lymphoma, there was general agreement on the use of autologous HCT to consolidate a complete remission in high-risk patients and the salvage setting. Input was split on the use of allogeneic HCT to consolidate a first complete remission or as salvage therapy, but there was more support to consider it medically necessary in both settings.

2009 Input

In response to requests, input was received from 1 physician specialty society and 1 academic medical center while this policy was under review in 2009. There was general agreement with the policy statements. Both reviewers agreed that allogeneic HCT with reduced-intensity conditioning should be considered medically necessary in patients with non-Hodgkin lymphoma who do not qualify for a myeloablative allogeneic HCT. One reviewer responded on the medical necessity of HCT in patients with MCL in the first remission and recently published literature supported this. There was conflicting input on whether HCT should be considered investigational for peripheral T-cell lymphoma. Also, the 1 reviewer commented that with the increasing use of rituximab and its success in improving patient outcomes, the role of HCT in consolidating first complete response in high-risk patients is coming into question.

Practice Guidelines and Position Statements

National Comprehensive Cancer Network

Current National Comprehensive Cancer Network guidelines on B-cell lymphomas (v.6.2019) include the following recommendations^72,:

• For follicular lymphoma, marginal zone lymphomas, and mantle cell lymphoma, recommend allogeneic HCT as second-line consolidation therapy.
• For DLBCL, “[a]llogenic HCT should be considered in selected patients with mobilization failures and persistent bone marrow involvement or lack of adequate response to second-line therapy, though patients should be in CR or near CR at the time of transplant.”
• For Burkitt lymphoma, allogeneic HCT is an option for selected patients to achieve a complete or partial response to second-line therapy.

“Second-line systematic therapy followed by consolidation with HDT [high-dose therapy]/ASCR [autologous stem cell rescue] or allogeneic HCT for those with a CR [complete response] or PR [partial response] is recommended for patients who are candidates for transplant.”

“Allogeneic HCT should be considered for patients with acute or lymphoma [ATLL] subtype, if donor is available.”

“In patients with acute or lymphoma subtypes who achieve a response to second-therapy, allogeneic HSCT should be considered if a donor is available.”

“In patients [with T-PLL] who achieve a CR or PR following initial therapy, consolidation with allogeneic HCT should be considered. Autologous HCT may be considered, if a donor is not available and if the patient is not physically fit enough to undergo allogeneic HCT.”

U.S. Preventive Services Task Force Recommendations

Not applicable.

Ongoing and Unpublished Clinical Trials

Some currently unpublished phase 3 trials that might influence this review are listed in National Cancer Institute’s Physician Data Query database.

Other currently unpublished trials that might influence this review are listed in Table 3.

Table 3. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT01811368	Use of Zevalin to Enhance the Efficacy of Non-Myeloablative Allogeneic Transplantation in Patients With Relapsed or Refractory CD20+ Non-Hodgkin’s Lymphoma	20	Jun 2020
NCT01908777	A Phase 2 Multicenter Study of High Dose Chemotherapy With Autologous Stem Cell Transplant Followed by Maintenance Therapy With Romidepsin for the Treatment of TCell Non-Hodgkin Lymphoma	34	Jul 2020
NCT02859402	Allogenic Stem Cell Transplantation With 3-days Busulfan Plus Fludarabine as Conditioning in Patients With Relapsed or Refractory T-, NK/T-cell Lymphomas	34	Dec 2021
NCT03583424	A Phase I/II Trial of Venetoclax and BEAM Conditioning Followed by Autologous Stem Cell Transplantation for Patients With Primary Refractory Non-Hodgkin Lymphoma	18	Dec 2021
Unpublished
NCT00802113	Sequential Myeloablative Stem Cell Transplantation and Reduced Intensity Allogeneic Stem Cell Transplantation in Patients With Refractory or Recurrent Non-Hodgkin’s Lymphoma and Hodgkin's Disease	30	Oct 2014 (results posted on clinicaltrials.gov; summarized in Indication 3)
NCT01296256	Bendamustine, Cytarabine, Etoposide and Melphalan as Conditioning for Autologous Stem Cell Transplant in Patients With Aggressive Non-Hodgkin’s Lymphoma	60	Nov 2015 (updated Feb 2016)

NCT: national clinical trial.]
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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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Index:
Hematopoietic Cell Transplantation for Non-Hodgkin Lymphomas
Hematopoietic Stem Cell Transplantation for Non Hodgkin Lymphomas
High Dose Chemotherapy with Hematopoietic Stem Cell Support for Non Hodgkin's Lymphomas
Allogeneic Bone Marrow Transplant, Non Hodgkin's Lymphomas
Autologous Bone Marrow Transplant, Non Hodgkin's Lymphomas
Bone Marrow Transplant, Non Hodgkin's Lymphomas
Non Hodgkin's Lymphomas, High Dose Chemotherapy
Stem Cell Transplant, Non Hodgkin's Lymphomas
Transplantation, Bone Marrow/Stem Cell for Non Hodgkin's Lymphomas

References:
1. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Autologous bone marrow transplantation for the treatment of non-Hodgkin's lymphoma. TEC Evaluations 1987;2:61.

2. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Allogeneic bone marrow transplantation (BMT) in the treatment of Hodgkin's disease (lymphoma) and non-Hodgkin's lymphoma. TEC Evaluations 1990;5:178.

3. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). High-dose chemotherapy with autologous stem-cell support or allogeneic stem-cell support for follicular non-Hodgkin's lymphoma. TEC Assessments 1995;Volume 10:Tab 28

4. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Salvage high-dose chemotherapy with allogeneic stem-cell support for relapse or incomplete remission following high-dose chemotherapy with autologous stem-cell transplantation for hematologic malignancies. TEC Assessments 2000;Volume 15:Tab 9.

5. National Cancer Institute. Adult Non-Hodgkin Lymphoma Treatment (PDQ)Health Professional Version. 2019; http://www.cancer.gov/cancertopics/pdq/treatment/adult-non-hodgkins/healthprofessional. Accessed November 1, 2019.

6. Harris NL, Jaffe ES, Stein H, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood. Sep 1 1994;84(5):1361-1392. PMID 8068936

7. Harris NL, Jaffe ES, Diebold J, et al. The World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues. Report of the Clinical Advisory Committee meeting, Airlie House, Virginia, November, 1997. Ann Oncol. Dec 1999;10(12):1419-1432. PMID 10643532

8. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. May 19 2016;127(20):2375-2390. PMID 26980727

9. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Non- Hodgkin's Lymphomas. Version 2.2015. https://www2.tri-kobe.org/nccn/guideline/hematologic/nhl/english/nhl.pdf. Accessed December 1, 2019.

10. Laport GG. The role of hematopoietic cell transplantation for follicular non-Hodgkin's lymphoma. Biol Blood Marrow Transplant. Jan 2006;12(1 Suppl 1):59-65. PMID 16399587

11. A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med. Sep 30 1993;329(14):987-994. PMID 8141877

12. Solal-Celigny P, Roy P, Colombat P, et al. Follicular lymphoma international prognostic index. Blood. Sep 1 2004;104(5):1258-1265. PMID 15126323

13. Al Khabori M, de Almeida JR, Guyatt GH, et al. Autologous stem cell transplantation in follicular lymphoma: a systematic review and meta-analysis. J Natl Cancer Inst. Jan 4 2012;104(1):18-28. PMID 22190633

14. Schaaf M, Reiser M, Borchmann P, et al. High-dose therapy with autologous stem cell transplantation versus chemotherapy or immuno-chemotherapy for follicular lymphoma in adults. Cochrane Database Syst Rev. Jan 18 2012;1:CD007678. PMID 22258971

15. Ladetto M, De Marco F, Benedetti F, et al. Prospective, multicenter randomized GITMO/IIL trial comparing intensive (R-HDS) versus conventional (CHOP-R) chemoimmunotherapy in high-risk follicular lymphoma at diagnosis: the superior disease control of R-HDS does not translate into an overall survival advantage. Blood. Apr 15 2008;111(8):4004-4013. PMID 18239086

16. Sebban C, Mounier N, Brousse N, et al. Standard chemotherapy with interferon compared with CHOP followed by high-dose therapy with autologous stem cell transplantation in untreated patients with advanced follicular lymphoma: the GELF-94 randomized study from the Groupe d'Etude des Lymphomes de l'Adulte (GELA). Blood. Oct 15 2006;108(8):2540-2544. PMID 16835383

17. Deconinck E, Foussard C, Milpied N, et al. High-dose therapy followed by autologous purged stem-cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: a randomized multicenter study by GOELAMS. Blood. May 15 2005;105(10):3817-3823. PMID 15687232

18. Lenz G, Dreyling M, Schiegnitz E, et al. Myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission prolongs progression-free survival in follicular lymphoma: results of a prospective, randomized trial of the German Low-Grade Lymphoma Study Group. Blood. Nov 1 2004;104(9):2667-2674. PMID 15238420

19. Schouten HC, Qian W, Kvaloy S, et al. High-dose therapy improves progression-free survival and survival in relapsed follicular non-Hodgkin's lymphoma: results from the randomized European CUP trial. J Clin Oncol. Nov 1 2003;21(21):3918-3927. PMID 14517188

20. Bozkaya Y, Uncu D, Dagdas S, et al. Evaluation of lymphoma patients receiving high-dose therapy and autologous stem cell transplantation: experience of a single center. Indian J Hematol Blood Transfus. Sep 2017;33(3):361-369. PMID 28824238

21. Jimenez-Ubieto A, Grande C, Caballero D, et al. Autologous stem cell transplantation may be curative for patients with follicular lymphoma with early therapy failure who reach complete response after rescue treatment. Hematol Oncol. 2018 Dec;36(5). PMID 30129233

22. Greb A, Bohlius J, Schiefer D, et al. High-dose chemotherapy with autologous stem cell transplantation in the first-line treatment of aggressive non-Hodgkin lymphoma (NHL) in adults. Cochrane Database Syst Rev. Jan 23 2008(1): CD004024. PMID 18254036

23. Haioun C, Lepage E, Gisselbrecht C, et al. Benefit of autologous bone marrow transplantation over sequential chemotherapy in poor-risk aggressive non-Hodgkin's lymphoma: updated results of the prospective study LNH87-2. Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol. Mar 1997;15(3):1131-1137. PMID 9060555

24. Kaiser U, Uebelacker I, Abel U, et al. Randomized study to evaluate the use of high-dose therapy as part of primary treatment for aggressive lymphoma. J Clin Oncol. Nov 15 2002;20(22):4413-4419. PMID 12431962

25. Kluin-Nelemans HC, Zagonel V, Anastasopoulou A, et al. Standard chemotherapy with or without high-dose chemotherapy for aggressive non-Hodgkin's lymphoma: randomized phase III EORTC study. J Natl Cancer Inst. Jan 3 2001;93(1):22-30. PMID 11136838

26. Sweetenham JW, Santini G, Qian W, et al. High-dose therapy and autologous stem-cell transplantation versus conventional-dose consolidation/maintenance therapy as postremission therapy for adult patients with lymphoblastic lymphoma: results of a randomized trial of the European Group for Blood and Marrow Transplantation and the United Kingdom Lymphoma Group. J Clin Oncol. Jun 1 2001;19(11):2927-2936. PMID 11387366

27. Fisher RI. Autologous stem-cell transplantation as a component of initial treatment for poor-risk patients with aggressive non-Hodgkin's lymphoma: resolved issues versus remaining opportunity [comment]. J Clin Oncol. Nov 15 2002;20(22):4411-4412. PMID 12431961

28. Haioun C, Lepage E, Gisselbrecht C, et al. Survival benefit of high-dose therapy in poor-risk aggressive non- Hodgkin's lymphoma: final analysis of the prospective LNH87-2 protocol--a groupe d'Etude des lymphomes de l'Adulte study. J Clin Oncol. Aug 2000;18(16):3025-3030. PMID 10944137

29. Fisher RI. Autologous bone marrow transplantation for aggressive non-Hodgkin's lymphoma: lessons learned and challenges remaining. J Natl Cancer Inst. Jan 3 2001;93(1):4-5. PMID 11136829

30. Hahn T, Wolff SN, Czuczman M, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of diffuse large cell B-cell non-Hodgkin's lymphoma: an evidence-based review. Biol Blood Marrow Transplant. Jul 2001;7(6):308-331. PMID 11464975

31. Kimby E, Brandt L, Nygren P, et al. A systematic overview of chemotherapy effects in aggressive non-Hodgkin's lymphoma. Acta Oncol. Jul 2001;40(2-3):198-212. PMID 11441932

32. Philip T, Biron P. High-dose chemotherapy and autologous bone marrow transplantation in diffuse intermediate- and high-grade non-Hodgkin lymphoma. Crit Rev Oncol Hematol. Feb 2002;41(2):213-223. PMID 11856597

33. Betticher DC, Martinelli G, Radford JA, et al. Sequential high dose chemotherapy as initial treatment for aggressive subtypes of non-Hodgkin lymphoma: results of the international randomized phase III trial (MISTRAL). Ann Oncol. Oct 2006;17(10):1546-1552. PMID 16888080

34. Baldissera RC, Nucci M, Vigorito AC, et al. Frontline therapy with early intensification and autologous stem cell transplantation versus conventional chemotherapy in unselected high-risk, aggressive non-Hodgkin's lymphoma patients: a prospective randomized GEMOH report. Acta Haematol. Jan 2006;115(1-2):15-21. PMID 16424644

35. Olivieri A, Santini G, Patti C, et al. Upfront high-dose sequential therapy (HDS) versus VACOP-B with or without HDS in aggressive non-Hodgkin's lymphoma: long-term results by the NHLCSG. Ann Oncol. Dec 2005;16(12):1941-1948. PMID 16157621

36. Stiff PJ, Unger JM, Cook JR, et al. Autologous transplantation as consolidation for aggressive non-Hodgkin's lymphoma. N Engl J Med. Oct 31 2013;369(18):1681-1690. PMID 24171516

37. Strubmann T, Fritsch K, Baumgarten A, et al. Favourable outcomes of poor prognosis diffuse large B-cell lymphoma patients treated with dose-dense rituximab, high-dose methotrexate and six cycles of CHOP-14 compared to first-line autologous transplantation. Br J Haematol. Sep 2017;178(6):927-935. PMID 28643323

38. Casasnovas RO, Ysebaert L, Thieblemont C, et al. FDG-PET-driven consolidation strategy in diffuse large B-cell lymphoma: final results of a randomized phase 2 study. Blood. Sep 14 2017;130(11):1315-1326. PMID 28701367

39. Qualls D, Sullivan A, Li S, et al. High-dose thiotepa, busulfan, cyclophosphamide, and autologous stem cell transplantation as upfront consolidation for systemic non-Hodgkin lymphoma with synchronous central nervous system involvement. Clin Lymphoma Myeloma Leuk. Dec 2017;17(12):884-888. PMID 28870642

40. Jaffe ES. The 2008 WHO classification of lymphomas: implications for clinical practice and translational research. Hematology Am Soc Hematol Educ Program. Dec 2009:523-531. PMID 20008237

41. Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med. Dec 7 1995;333(23):1540-1545. PMID 7477169

42. Fujita N, Kobayashi R, Atsuta Y et al. Hematopoietic stem cell transplantation in children and adolescents with relapsed or refractory B-cell non-Hodgkin lymphoma. Int. J. Hematol. 2019 Apr;109(4). PMID 30701466

43. Monjanel H, Deconinck E, Perrodeau E, et al. Long-term follow-up of tandem high-dose therapy with autologous stem cell support for adults with high-risk age-adjusted international prognostic index aggressive non-Hodgkin Lymphomas: a GOELAMS pilot study. Biol Blood Marrow Transplant. Jun 2011;17(6):935-940. PMID 21109011

44. Papadopoulos KP, Noguera-Irizarry W, Wiebe L, et al. Pilot study of tandem high-dose chemotherapy and autologous stem cell transplantation with a novel combination of regimens in patients with poor risk lymphoma. Bone Marrow Transplant. Sep 2005;36(6):491-497. PMID 16044139

45. Tarella C, Zanni M, Di Nicola M, et al. Prolonged survival in poor-risk diffuse large B-cell lymphoma following front-line treatment with rituximab-supplemented, early-intensified chemotherapy with multiple autologous hematopoietic stem cell support: a multicenter study by GITIL (Gruppo Italiano Terapie Innovative nei Linfomi). Leukemia. Aug 2007;21(8):1802-1811. PMID 17554382

46. Banks PM, Chan J, Cleary ML, et al. Mantle cell lymphoma. A proposal for unification of morphologic, immunologic, and molecular data. Am J Surg Pathol. Jul 1992;16(7):637-640. PMID 1530105

47. Hoster E, Dreyling M, Klapper W, et al. A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood. Jan 15 2008;111(2):558-565. PMID 17962512

48. Dreyling M, Lenz G, Hoster E, et al. Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression-free survival in mantle- cell lymphoma: results of a prospective randomized trial of the European MCL Network. Blood. Apr 1 2005;105(7):2677-2684. PMID 15591112

49. Till BG, Gooley TA, Crawford N, et al. Effect of remission status and induction chemotherapy regimen on outcome of autologous stem cell transplantation for mantle cell lymphoma. Leuk Lymphoma. Jun 2008;49(6):1062-1073. PMID 18452065

50. Geisler CH, Kolstad A, Laurell A, et al. Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group. Blood. Oct 1 2008;112(7):2687-2693. PMID 18625886

51. Evens AM, Winter JN, Hou N, et al. A phase II clinical trial of intensive chemotherapy followed by consolidative stem cell transplant: long-term follow-up in newly diagnosed mantle cell lymphoma. Br J Haematol. Feb 2008;140(4):385-393. PMID 18162124

52. Garcia-Noblejas A, Cannata-Ortiz J, Conde E, et al. Autologous stem cell transplantation (ASCT) in patients with mantle cell lymphoma: a retrospective study of the Spanish lymphoma group (GELTAMO). Ann Hematol. Aug 2017;96(8):1323-1330. PMID 28536895

53. Villanueva ML, Vose JM. The role of hematopoietic stem cell transplantation in non-Hodgkin lymphoma. Clin Adv Hematol Oncol. Jul 2006;4(7):521-530. PMID 17147239

54. Khouri IF, Lee MS, Saliba RM, et al. Nonablative allogeneic stem-cell transplantation for advanced/recurrent mantle-cell lymphoma. J Clin Oncol. Dec 1 2003;21(23):4407-4412. PMID 14645431

55. Maris MB, Sandmaier BM, Storer BE, et al. Allogeneic hematopoietic cell transplantation after fludarabine and 2 Gy total body irradiation for relapsed and refractory mantle cell lymphoma. Blood. Dec 1 2004;104(12):3535- 3542. PMID 15304387

56. Tam CS, Bassett R, Ledesma C, et al. Mature results of the M. D. Anderson Cancer Center risk-adapted transplantation strategy in mantle cell lymphoma. Blood. Apr 30 2009;113(18):4144-4152. PMID 19168784

57. Geisler C. Mantle cell lymphoma: are current therapies changing the course of disease? Curr Oncol Rep. Sep 2009;11(5):371-377. PMID 19679012

58. Reimer P. Impact of autologous and allogeneic stem cell transplantation in peripheral T-cell lymphomas. Adv Hematol. 2010;2010:320624. PMID 21253465

59. Corradini P, Tarella C, Zallio F, et al. Long-term follow-up of patients with peripheral T-cell lymphomas treated up-front with high-dose chemotherapy followed by autologous stem cell transplantation. Leukemia. Sep 2006;20(9):1533-1538. PMID 16871285

60. Mercadal S, Briones J, Xicoy B, et al. Intensive chemotherapy (high-dose CHOP/ESHAP regimen) followed by autologous stem-cell transplantation in previously untreated patients with peripheral T-cell lymphoma. Ann Oncol. May 2008;19(5):958-963. PMID 18303032

61. Rodriguez J, Conde E, Gutierrez A, et al. Frontline autologous stem cell transplantation in high-risk peripheral T- cell lymphoma: a prospective study from The Gel-Tamo Study Group. Eur J Haematol. Jul 2007;79(1):32-38. PMID 17598836

62. Wang J, Wei L, Ye J, et al. Autologous hematopoietic stem cell transplantation may improve long-term outcomes in patients with newly diagnosed extranodal natural killer/T-cell lymphoma, nasal type: a retrospective controlled study in a single center. Int J Hematol. Jan 2018;107(1):98-104. PMID 28856590

63. Kewalramani T, Zelenetz AD, Teruya-Feldstein J, et al. Autologous transplantation for relapsed or primary refractory peripheral T-cell lymphoma. Br J Haematol. Jul 2006;134(2):202-207. PMID 16759221

64. Song KW, Mollee P, Keating A, et al. Autologous stem cell transplant for relapsed and refractory peripheral T-cell lymphoma: variable outcome according to pathological subtype. Br J Haematol. Mar 2003;120(6):978-985. PMID 12648067

65. Rodriguez J, Conde E, Gutierrez A, et al. The adjusted International Prognostic Index and beta-2-microglobulin predict the outcome after autologous stem cell transplantation in relapsing/refractory peripheral T-cell lymphoma. Haematologica. Aug 2007;92(8):1067-1074. PMID 17640855

66. Jacobsen ED, Kim HT, Ho VT, et al. A large single-center experience with allogeneic stem-cell transplantation for peripheral T-cell non-Hodgkin lymphoma and advanced mycosis fungoides/Sezary syndrome. Ann Oncol. Jul 2011;22(7):1608-1613. PMID 21252059

67. Kyriakou C, Canals C, Finke J, et al. Allogeneic stem cell transplantation is able to induce long-term remissions in angioimmunoblastic T-cell lymphoma: a retrospective study from the lymphoma working party of the European group for blood and marrow transplantation. J Clin Oncol. Aug 20 2009;27(24):3951-3958. PMID 19620487

68. Corradini P, Dodero A, Zallio F, et al. Graft-versus-lymphoma effect in relapsed peripheral T-cell non-Hodgkin's lymphomas after reduced-intensity conditioning followed by allogeneic transplantation of hematopoietic cells. J Clin Oncol. Jun 1 2004;22(11):2172-2176. PMID 15169805

69. Le Gouill S, Milpied N, Buzyn A, et al. Graft-versus-lymphoma effect for aggressive T-cell lymphomas in adults: a study by the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire. J Clin Oncol. May 10 2008;26(14):2264-2271. PMID 18390969

70. Hosing C, Champlin RE. Stem-cell transplantation in T-cell non-Hodgkin's lymphomas. Ann Oncol. Jul 2011;22(7):1471-1477. PMID 21551006

71. Rodriguez J, Gutierrez A, Martinez-Delgado B, et al. Current and future aggressive peripheral T-cell lymphoma treatment paradigms, biological features and therapeutic molecular targets. Crit Rev Oncol Hematol. Sep 2009;71(3):181-198. PMID 19056295

72. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: B-Cell Lymphomas. Version 6.2019. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf. Accessed November 1, 2019.

73. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: T-Cell Lymphomas. Version 2.2019. https://www.nccn.org/professionals/physician_gls/pdf/t-cell.pdf. Accessed December 30, 2019.

74. Centers for Medicare & Medicaid Services. National Coverage Determination (NCD) for Stem Cell Transplantation (Formerly 110.8.1) (110.23). 2016; https://www.cms.gov/medicare-coverage- database/details/ncd- details.aspx?NCDId=366&ncdver=1&DocID=110.23&list_type=ncd&bc=gAAAAAgAAAAAAA%3d%3d&. Accessed January 2, 2020.

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

38204
38205
38206
38207
38208
38209
38210
38211
38212
38213
38214
38215
38220
38221
38230
38240
38242

Q0083
Q0084
Q0085
G0265
G0266
G0627
S2140
S2142
S2150