Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are neoplasms of hematopoietic origin characterized by the accumulation of lymphocytes with a mature, generally well-differentiated morphology. In CLL, these cells accumulate in the blood, bone marrow, lymph nodes, and spleen; in SLL they are generally confined to lymph nodes. The Revised European-American/World Health Organization Classification of Lymphoid Neoplasms considers B-cell CLL and SLL a single disease entity.

CLL and SLL share many common features and are often referredto as blood and tissue counterparts of each other, respectively. Both tend to present as asymptomatic enlargement of the lymph nodes, tend to be indolent, but can undergo transformation to a more aggressive form of the disease (eg, Richter transformation). The median age at diagnosis of CLL is approximately 72 years, but it may present in younger individuals, often as a poor-risk disease with significantly reduced life expectancy.

Treatment regimens used for CLL are generally the same as those used for SLL, and treatment outcomes are comparable for both diseases. Both low- and intermediate-risk CLL and SLL demonstrate relatively good prognoses, with median survivals of 6 to 10 years; however, the median survival of high-risk CLL or SLL may only be 2 years. Although typically responsive to initial therapy, CLL and SLL are rarely cured by conventional therapy, and nearly all patients ultimately die of their disease. This natural disease history prompted an investigation of HCT as a possible curative regimen.

Hematopoietic Cell Transplantation

Hematopoietic cell transplantation (HCT) is a procedure in which hematopoietic stem cells are infused to restore bone marrow function in cancer patients who receive bone-marrow-toxic doses of 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. Although cord blood is an allogeneic source, the stem cells in it are antigenically "naive" and thus are associated with a lower incidence of rejection or graft-versus-host disease. Cord blood is addressed 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. However, immunologic compatibility between donor and patient is critical for achieving a good outcome of allo-HCT. Compatibility is established by typing of human leukocyte antigens (HLA) using cellular, serologic, or molecular techniques. HLA refers to the tissue type expressed at the HLA-A, -B, and -DR loci on each arm of chromosome 6. Depending on the disease being treated, an acceptable donor will match the patient at all or most of the HLA loci.

Conditioning for HCT

Conventional Conditioning for HCT

The conventional practice of allo-HCT involves administration of cytotoxic agents (eg, cyclophosphamide, busulfan) with or without total body irradiation at doses sufficient to destroy endogenous hematopoietic capability in the recipient. The beneficial treatment effect in this procedure is due to a combination of initial eradication of malignant cells and subsequent graft-versus-malignancy effect that develops after engraftment of allogeneic stem cells within the patient's bone marrow space. The slower graft-versus-malignancy effect is considered the potentially curative component, but it may be overwhelmed by extant disease without the use of pretransplant conditioning. However, intense conditioning regimens are limited to patients who are sufficiently fit medically to tolerate substantial adverse events that include pre-engraftment opportunistic infections secondary to loss of endogenous bone marrow function and organ damage and failure caused by the cytotoxic drugs. Furthermore, in any allo-HCT, immunosuppressant drugs are required to minimize graft rejection and graft-versus-host disease, which also increases the susceptibility of the patient to opportunistic infections.

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

Reduced-Intensity Conditioning for Allo-HCT

Reduced-intensity conditioning (RIC) refers to the pretransplant use of lower doses or less intense regimens of cytotoxic drugs or radiation than are used in conventional full-dose myeloablative conditioning treatments. The goal of RIC is to reduce disease burden but also to minimize as much as possible associated treatment-related morbidity and nonrelapse mortality in the period during which the beneficial graft-versus-malignancy effect of allogeneic transplantation develops. Although the definition of RIC remains arbitrary, with numerous versions employed, all seek to balance the competing effects of nonrelapse mortality and relapse due to residual disease. RIC regimens can be viewed as a continuum in effects, from near totally 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, which may be supplemented with donor lymphocyte infusions to eradicate residual malignant cells. For this policy, the term reduced-intensity conditioning will refer to all conditioning regimens intended to be nonmyeloablative, as opposed to fully myeloablative (conventional) regimens.

Regulatory Status

The U.S. Food and Drug Administration regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, under the Code of Federal Regulation title 21, parts 1270 and 1271. Hematopoietic cells are included in these regulations.

Related Policies

• Hematopoietic Cell Transplantation for Non-Hodgkin Lymphomas (Policy #040 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.

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 and permits coverage for non-emergency services out-of-network.

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.
[INFORMATIONAL NOTE: Also refer to a separate policy on Transplant Donor and Recipient Policy (Policy #003) in 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. Allogeneic hematopoietic cell transplantation is considered medically necessary to treat chronic lymphocytic leukemia or small lymphocytic lymphoma in members with markers of poor-risk disease (see Policy Guidelines section).

Use of a myeloablative or reduced-intensity pretransplant conditioning regimen should be individualized based on factors that include member age, the presence of comorbidities, and disease burden.

D. Autologous hematopoietic cell transplantation is considered investigational to treat chronic lymphocytic leukemia or small lymphocytic lymphoma.

[NOTE: 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).]

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.)

Staging and Prognosis of Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
Two scoring systems are used to determine stage and prognosis of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). As outlined in Table PG1, the Rai and Binet staging systems classify patients into 3 risk groups with different prognoses and are used to make therapeutic decisions.

Table PG1. Rai and Binet Classification for CLL or SLL

Rai Stage	Risk	Description	Median Survival, y	Binet Stage	Description	Median Survival, y
0	Low	Lymphocytosis	>10	A	≤3 lymphoid areas, normal hemoglobin and platelets	>10
I	Int	Lymphocytosis + lymphadenopathy	7-9	B	≥3 lymphoid areas, normal hemoglobin and platelets	7
II	Int	Lymphocytosis + splenomegaly ± lymphadenopathy	7-9
III	High	Lymphocytosis + anemia ± lymphadenopathy or splenomegaly	1.5-5	C	Any number of lymphoid areas, anemia, thrombocytopenia	5
IV	High	Lymphocytosis + thrombocytopenia ± anemia, splenomegaly, or lymphadenopathy	1.5-5

CLL: chronic lymphocytic leukemia; Int: Intermediate; SLL: small lymphocytic lymphoma.

Because prognoses of patients vary within the different Rai and Binet classifications, other prognostic markers are used in conjunction with staging to determine clinical management. These are summarized in Table PG2, according to availability in clinical centers.

Table PG2. Markers of Poor Prognosis in CLL or SLL

Community Center	Specialized Center
· Advanced Rai or Binet stage · Male sex · Atypical morphology or CLL or SLL · Peripheral lymphocyte doubling time <12 mo · CD38+ · Elevated 2-microglobulin level · Diffuse marrow histology · Elevated serum lactate dehydrogenase level · Fludarabine resistance	· IgVh wild type · Expression of ZAP-70 protein · Del(11q22-q23) (loss of ATM gene) · del(17p13)/variant TP53 · Trisomy 12 · Elevated serum CD23 · Elevated serum tumor necrosis factor-á · Elevated serum thymidine kinase

CLL: chronic lymphocytic leukemia; IgVH: immunoglobulin heavy-chain variable-region; SLL: small lymphocytic lymphoma.

An expert panel convened by the American Society for Blood and Marrow Transplantation was queried about criteria used to define high-risk CLL, as part of the process for developing 2016 guidelines. Panelists responded that criteria are presence of del17P and/or TP53 mutations (100%) and presence of complex karyotype (67%).

Reduced-Intensity Conditioning for Allogeneic Hematopoietic Cell Transplantation
Some patients for whom a conventional myeloablative allotransplant could be curative may be considered as candidates for reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (allo-HCT). They include those patients whose age (typically >60 years) or comorbidities (eg, liver or kidney dysfunction, generalized debilitation, prior intensive chemotherapy, low Karnofsky Performance Status) preclude use of a standard myeloablative conditioning regimen. A patient who relapses following a conventional myeloablative allo-HCT could undergo a second myeloablative procedure if a suitable donor is available and his or her medical status would permit it. However, this type of patient would likely undergo RIC before a second allo-HCT if a complete remission could be reinduced with chemotherapy.

The ideal allogeneic donors are human leukocyte antigen (HLA)‒identical siblings, matched at the HLA-A, -B, and -DR loci on each arm of chromosome 6. Related donors mismatched at 1 locus are also considered suitable donors. A matched, unrelated donor identified through the National Marrow Donor Registry is typically the next option considered. Recently, haploidentical donors—typically a parent or a child of the patient—with whom usually there is sharing of only 3 of the 6 major histocompatibility antigens, have been under investigation as a stem cell source. Most patients will have such a donor; however, the risk of graft-versus-host disease and overall morbidity of the procedure may be severe, and experience with these donors is not as extensive as that with matched donors.


[RATIONALE: This policy was created in 2001 and has been updated regularly with searches of the MEDLINE and EMBASE databases. The most recent literature update was performed through November 1, 2019.

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function-including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to 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 a technology, 2 domains are examined: the relevance and the 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. The randomized controlled trial (RCT) 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.

The original review was based on 2 TEC Assessments, 1 from 1999 that examined autologous hematopoietic cell transplantation (HCT) for chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL)^1,; the other from 2002 on allogeneic HCT (allo-HCT) to treat CLL and SLL.^2, Both assessments indicated that existing data were insufficient to permit scientific conclusions on the use of either procedure, and were limited by interstudy heterogeneity in patients' baseline characteristics, procedural differences, sample size, and short follow-up. A direct comparative analysis from the International Bone Marrow Transplant Registry commissioned by TEC in 2002 to analyze allo-HCT results was insufficient to permit scientific conclusions on the net health outcome of this procedure for relapsed or refractory CLL or SLL.

Subsequent reviews through 2008 have discussed uncertainties concerning the type of transplant (autologous vs allogeneic), the intensity of pretransplant conditioning, the optimal timing of transplantation in the disease course, the baseline patient characteristics that best predict likelihood of clinical benefit from transplant, and the long-term risks of adverse outcomes.^3,4,5,6,7,8, The conclusions reached at that time suggested that, although autologous HCT may prolong survival in select patients with CLL or SLL (eg, those with chemotherapy-sensitive malignancy who had a good response to front-line therapy and were transplanted early in the course of disease), it had not yet been shown to be curative.

ALLOGENEIC HCT

Clinical Context and Therapy Purpose

The purpose of allogeneic HCT in patients who have CLL or SLL and markers of poor-risk disease is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this policy is: does allogeneic HCT improve the net health outcome in patients with CLL or SLL and markers of poor-risk disease?

The following PICOs were used to select literature to inform this review.

Patients

The relevant populations of interest are patients with CLL or SLL and markers of poor-risk disease.

Interventions

The therapy being considered is allogeneic HCT.

Comparators

The following therapies are currently being used to treat CLL and SLLxxx: chemotherapy and/or immunotherapy.

Outcomes

The general outcomes of interest are disease status, morbidity and mortality.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

a.To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

b.In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

c.To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

d.Studies with duplicative or overlapping populations were excluded.

Data compiled in review articles through 2012 suggested that myeloablative allo-HCT has curative potential for CLL or SLL.^6,7,8,9, Long-term disease control (33%-65% overall survival [OS] at 3-6 years) due to a low rate of late recurrences has been observed in all published series, regardless of donor source or conditioning regimen.^10, However, high rates (24%-47%) of treatment-related mortality discourage this approach in early- or lower risk disease, particularly among older patients whose health status typically precludes the use of myeloablative conditioning.

The development of reduced-intensity conditioning regimens has extended the use of allo-HCT to older or less fit patients who account for the larger proportion of this disease than younger patients, as outlined in two 2009 review articles.^10,11, Six published nonrandomized studies involved a total of 328 patients with advanced CLL who underwent reduced-intensity conditioningallo-HCT using regimens that included fludarabine in various combinations including cyclophosphamide, busulfan, rituximab, alemtuzumab, and total body irradiation.^{12,13,14,15,16,17,} Most patients in these series were heavily pretreated, with a median of 3 to 5 courses of prior regimens. Among individual studies, 27% to 57% of patients had the chemotherapy-refractory disease, genetic abnormalities including a 17p13 deletion, 11q22 deletion, and VH unmutated, or a combination of those characteristics. A substantial proportion in each study (18%-67%) received stem cells from a donor other than a human leukocyte antigen‒identical sibling. Reported nonrelapse mortality associated primarily with graft-versus-host disease and its complications ranged from 2% at 100 days to 26% overall at median follow-up ranging from 1.7 to 5 years. OS rates ranged from 48% to 70% at follow-up that ranged from 2 to 5 years. Similar results were reported for progression-free survival (PFS), which was 34% to 58% at 2- to 5-year follow-up. Very similar results were reported from a phase 2 study published in 2010 evaluating use of reduced-intensity conditioning allo-HCT in patients (n=90; median age, 53 years; range, 27-65) with poor-risk CLL, defined as having one of the following: refractoriness or early relapse (ie, <12 months) after purine-analogue therapy; relapse after autologous HCT; or progressive disease in the presence of an unfavorable genetic marker (11q or 17p deletion, and/or unmutated immunoglobulin heavy-chain variable-region status and/or usage of the VH3-21 gene).^18, With a median follow-up of 46 months, 4-year NRM, event-free survival (EFS), and OS rates were 23%, 42%, and 65%, respectively. EFS estimates were similar for all genetic subsets, including those with a 17p deletion.

Section Summary: Allogeneic HCT

No RCTs evaluating allo-HCT in patients with CLL were identified. Data from nonrandomized studies found OS rates between 48% and 70% at 2 to 5 years and PFS rates of 34% to 58% at 2 to 5 years after allo-HCT for poor-risk CLL. Despite not being randomized, these studies suggest that allo-HCT can provide long-term disease control and OS in patients with poor-risk CLL and SLL.

Autologous HCT

Clinical Context and Therapy Purpose

The purpose of autologous HCT in patients who have CLL or SLL is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this policy is: does autologousHCT improve the net health outcome in patients with CLL or SLL?

The following PICOs were used to select literature to inform this review.

Patients

The relevant populations of interest are patients with CLL or SLL.

Interventions

The therapy being considered is autologous HCT.

Comparators

The following therapies are currently being used to treat CLL and SLL: chemotherapy and/or immunotherapy.

Outcomes

The general outcomes of interest are disease status, morbidity and mortality.

Study Selection Criteria Methodologically credible studies were selected using principles described above.

Review of Evidence

A 2015 systematic review of autologous HCT as the first-line consolidation in CLL included a literature search through November 2014.^19, Four RCTs in adults were selected. Outcomes included OS, PFS, EFS, and harms (adverse events, treatment-related mortality, secondary malignancies). In these 4 trials, 301 patients were randomized to the autologous HCT arm and 299 to the control arm using first-line therapy without HCT as consolidation. Autologous HCT did not result in a statistically significant improvement in OS (hazard ratio, 0.91; 95% confidence interval [CI], 0.62 to 1.33) or in PFS (hazard ratio, 0.70; 95% CI, 0.32 to 1.52). There was a statistically significant improvement in EFS favoring autologous HCT (hazard ratio, 0.46; 95% CI, 0.26 to 0.83). A higher rate of secondary malignancy or treatment-related mortality was not associated with autologous HCT.

A phase 3 European Intergroup RCT (2011) evaluated autologous HCT as second- or third-line treatment of CLL.^20, The trial compared autologous HCT (n=112) with postinduction observation (n=111) for consolidation in patients with CLL who achieved a complete response (59% of total) or very good partial response (27% of total) following fludarabine-containing induction therapy. Overall, patients' age ranged from 31 to 65 years, and they presented with Binet stage A progressive (14%), B (66%), and C (20%) disease. The population either did not have a 17p deletion or 17p deletion status was unknown. Median EFS (the primary outcome) was 51 months (range, 40-62 months) in the autograft group and 24 months (range, 17-32 months) in the observation group; 5-year EFS rates were 42% and 24%, respectively (p<0.001). The relapse rate at 5-year follow-up was 54% in the autograft group and 76% in the observational group (p<0.001); median time to relapse requiring therapy or to death (whichever came first) was 65 months (range, 59-71 months) and 40 months (range, 25-56 months), respectively (p=0.002). OS probability at 5-year follow-up was 86% (95% CI, 77% to 94%) in the autograft arm and 84% (95% CI, 75% to 93%) in the observation arm (p=0.77), with no evidence of a plateau in the areas under the curve. There was no significant difference in nonrelapse morality between groups (4% for autologous HCT vs 0% for observation; p=0.33). The myelodysplastic syndrome was observed at follow-up in 3 patients receiving an autograft and in 1 patient in the observational group.

In a subsequent 2014 report, authors of the European Intergroup RCT presented quality of life (QOL) findings from this trial.^21, Two secondary analyses were performed to investigate the impact of HCT and relapse on QOL. In the primary analysis, the authors demonstrated an adverse impact of HCT on QOL, which was largest at 4 months and continued throughout the first year after randomization. Further, a sustained adverse impact of relapse on QOL was observed, which worsened over time. Thus, despite better disease control by autologous HCT, the side effects turned the net effect toward inferior QOL in the first year and comparable QOL in the following 2 years after randomization.

Section Summary: Autologous HCT

A systematic review of RCTs did not find that autologous HCT as first-line consolidation therapy for CLL significantly improved OS or PFS compared with alternative treatments. An RCT evaluating autologous HCT as second- or third-line treatment of CLL did not find that HCT improved the net health outcome.

Summary of Evidence

For individuals who have CLL/SLL and markers of poor-risk disease who receive allo-HCT, the evidence includes single-arm prospective and registry-based studies as well as a TEC Assessment. Relevant outcomes are overall survival, disease-specific survival, change in disease status, and treatment-related mortality and morbidity. Data have suggested that allo-HCT can provide long-term disease control and overall survival in patients with poor-risk CLL/SLL. High rates of treatment-related morbidity discourage this approach in lower risk disease, particularly among older patients whose health status typically precludes the use of myeloablative conditioning. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have CLL/SLL who receive autologous HCT, the evidence includes randomized controlled trials, systematic reviews, and a TEC Assessment. Relevant outcomes are overall survival, disease-specific survival, change in disease status, and treatment-related mortality and morbidity. Autologous HCT is feasible in younger patients but is not curative, particularly in those with poor-risk CLL. Studies of autologous HCT published to date have not shown improvement in overall survival in patients with CLL/SLL, and results must be considered in the context of improved outcomes with the use of newer chemoimmunotherapy agents. Furthermore, evidence from the European Intergroup randomized controlled trial has suggested the quality of life issues are important in selecting patients for autologous HCT and may dictate the management course for patients who are otherwise candidates for this approach. The evidence is insufficient to determine the effects of the technology on health outcomes.

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.

In response to requests, input was received from 1 specialty medical center reviewer, 1 academic medical center reviewer, and 2 Blue Distinction Center reviewers while this policy was under review in 2010. Three of 4 reviewers agreed that allogeneic hematopoietic cell transplantation was of value to patients with poor-risk chronic lymphocytic leukemia (see Policy Guidelines section) and that this procedure should be medically necessary for this setting. However, reviewers indicated that the specific approach (eg, reduced-intensity conditioning vs myeloablative conditioning) should be individualized based on criteria such as age and health status. All reviewers concurred with the policy statement that autologous HCT is investigational.

Practice Guidelines and Position Statements

American Society for Blood and Marrow Transplantation

In 2015, the American Society for Blood and Marrow Transplantation published guidelines on indications for allogeneic (allo-) and autologous hematopoietic cell transplantation (HCT) for chronic lymphocytic leukemia (CLL).^22, Recommendations described the current consensus on the use of HCT in and out of the clinical trial setting. Treatment recommendations are shown in Table 1.

Table 1. 2015 Recommendations for Allogeneic and Autologous HCT for CLL

Adult Indications	Allogeneic HCT	Autologous HCT
High-risk, first or greater remission	C	N
T cell, prolymphocytic leukemia	R	R
B cell, prolymphocytic leukemia	R	R
Transformation to high-grade lymphoma	C	C

C: standard of care, clinical evidence available; CLL: chronic lymphocytic leukemia; HCT: hematopoietic cell transplantation; N: not generally recommended; R: standard of care, rare indication.

In 2016, the Society published clinical practice recommendations with additional detail on allo-HCT for CLL.^23, Recommendations are shown in Table 2.

Table 2. 2016 Recommendations for Allogeneic HCT for CLL

Indications	Allogeneic HCT
High-risk CLL	Not recommended in the first-line consolidation setting
	Not recommended for patients who relapse after first-line therapy and demonstrate sensitive disease after second-line therapy (not BCR inhibitors)
	Recommended for patients who relapse after first-line therapy, have refractory disease after second-line therapy (not BCR inhibitors), and show an objective response to BCR inhibitors or to a clinical trial
	Recommended for patients who relapse after first-line therapy, have refractory disease after second-line therapy (including BCR inhibitors but not BCL-2 inhibitors), and show an objective response to BCL-2 inhibitors or to a clinical trial
	Recommended when there is a lack of response or there is progression after BCL-2 inhibitors
Richter transformation	Recommended after achieving an objective response to anthracycline-based chemotherapy
Purine analogue relapsed and/or refractory disease	Not recommended

BCR: B-cell receptor; BCL-2: B-cell lymphoma 2; CLL: chronic lymphocytic leukemia; HCT: hematopoietic cell transplantation.

National Comprehensive Cancer Network Guidelines

Current National Comprehensive Cancer Network guidelines (v.2.2019) for CLL and small lymphocytic lymphoma (SLL) state that allogeneic HCT may be considered for patients^24,:

•Without significant comorbidities and CLL refractory to small molecule inhibitor therapy

•With relapsed CLL or SLL and without a 17p deletion or TP53 variant

•With CLL or SLL, a response to treatment, and with a complex karyotype

•With CLL (Rai stages 0-IV) or SLL (Lugano stages II-IV), after histologic transformation to diffuse large B-cell/Hodgkin lymphoma.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Ongoing and Unpublished Clinical Trials

A search of ClinicalTrials.gov in November 2017 did not identify any ongoing or unpublished trials that would likely influence this review.]
________________________________________________________________________________________

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.

___________________________________________________________________________________________________________________________

Index:
Hematopoietic Cell Transplantation for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Hematopoietic Stem Cell Transplantation for Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma
High Dose Chemotherapy with Hematopoietic Stem Cell Support for Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma
Allogeneic Bone Marrow Transplant, Chronic Lymphocytic Leukemia
Allogeneic Bone Marrow Transplant, Small Lymphocytic Lymphoma
Autologous Bone Marrow Transplant, Chronic Lymphocytic Leukemia
Autologous Bone Marrow Transplant, Small Lymphocytic Lymphoma
Bone Marrow Transplant, Chronic Lymphocytic Leukemia
Bone Marrow Transplant, Small Lymphocytic Lymphoma
Chronic Lymphocytic Leukemia, High Dose Chemotherapy
CLL, High Dose Chemotherapy
SLL, High Dose Chemotherapy
Small Lymphocytic Lymphoma, High Dose Chemotherapy
Stem Cell Transplant, Chronic Lymphocytic Leukemia
Stem Cell Transplant, Small Lymphocytic Lymphoma
Transplantation, Bone Marrow/Stem Cell for Chronic Lymphocytic Leukemia
Transplantation, Bone Marrow/Stem Cell for Small Lymphocytic Lymphoma

References:
1. Blue Cross and Blue Shield Association (TEC). High-dose chemotherapy with autologous stem cell support for chronic lymphocytic leukemia/small lymphocytic lymphoma. TEC Assessments. 1999;Volume 14:Tab 20.

2. Blue Cross and Blue Shield Association (TEC). High-dose chemotherapy plus allogeneic stem cells to treat chronic lymphocytic leukemia or small lymphocytic lymphoma. TEC Assessments. 2002;Volume 17:Tab 4.

3. Abbott BL. Chronic lymphocytic leukemia: recent advances in diagnosis and treatment. Oncologist. Jan 2006;11(1):21-30. PMID 16401710

4. Brugiatelli M, Bandini G, Barosi G, et al. Management of chronic lymphocytic leukemia: practice guidelines from the Italian Society of Hematology, the Italian Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation. Haematologica. Dec 2006;91(12):1662-1673. PMID 17145603

5. Dreger P, Brand R, Michallet M. Autologous stem cell transplantation for chronic lymphocytic leukemia. Semin Hematol. Oct 2007;44(4):246-251. PMID 17961723

6. Gine E, Moreno C, Esteve J, et al. The role of stem-cell transplantation in chronic lymphocytic leukemia risk- adapted therapy. Best Pract Res Clin Haematol. Sep 2007;20(3):529-543. PMID 17707838

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13. Delgado J, Thomson K, Russell N, et al. Results of alemtuzumab-based reduced-intensity allogeneic transplantation for chronic lymphocytic leukemia: a British Society of Blood and Marrow Transplantation Study. Blood. Feb 15 2006;107(4):1724-1730. PMID 16239425

14. Dreger P, Brand R, Hansz J, et al. Treatment-related mortality and graft-versus-leukemia activity after allogeneic stem cell transplantation for chronic lymphocytic leukemia using intensity-reduced conditioning. Leukemia. May 2003;17(5):841-848. PMID 12750695

15. Khouri IF, Saliba RM, Admirand J, et al. Graft-versus-leukaemia effect after non-myeloablative haematopoietic transplantation can overcome the unfavourable expression of ZAP-70 in refractory chronic lymphocytic leukaemia. Br J Haematol. May 2007;137(4):355-363. PMID 17456058

16. Schetelig J, Thiede C, Bornhauser M, et al. Evidence of a graft-versus-leukemia effect in chronic lymphocytic leukemia after reduced-intensity conditioning and allogeneic stem-cell transplantation: the Cooperative German Transplant Study Group. J Clin Oncol. Jul 15 2003;21(14):2747-2753. PMID 12860954

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22. Majhail NS, Farnia SH, Carpenter PA, et al. Indications for autologous and allogeneic hematopoietic cell transplantation: guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. Nov 2015;21(11):1863-1869. PMID 26256941

23. Kharfan-Dabaja MA, Kumar A, Hamadani M, et al. Clinical practice recommendations for use of allogeneic hematopoietic cell transplantation in chronic lymphocytic leukemia on behalf of the Guidelines Committee of the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. Dec 2016;22(12):2117- 2125. PMID 27660167

24. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: chronic lymphocytic leukemia/small lymphocytic lymphoma. Version 2.2019. https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf. Accessed November 1, 2019.

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
38241
38242

G0265
G0266
G0267