Waldenström Macroglobulinemia

Waldenström macroglobulinemia (WM) is a clonal disorder of B lymphocytes that accounts for 1% to 2% of hematologic malignancies, with an estimated 1500 new cases annually in the United States. Symptoms include weakness, headaches, stroke-like symptoms (confusion, loss of coordination), vision problems, excessive bleeding, unexplained weight loss, and frequent infections. The median age of WM patients is 63 to 68 years, with men comprising 55% to 70% of cases. Median survival of WM ranges from 5 to 10 years, with age, hemoglobin concentration, serum albumin level, and b₂-microglobulin level as predictors of outcome.

The Revised European American Lymphoma and World Health Organization classification and a consensus group formed at the Second International Workshop on Waldenström’s Macroglobulinemia recognize WM primarily as a lymphoplasmacytic lymphoma with an associated immunoglobulin M (IgM) monoclonal gammopathy. The definition also requires the presence of a characteristic pattern of bone marrow infiltration with small lymphocytes demonstrating plasmacytic differentiation with variable cell surface antigen expression. The Second International Workshop indicated no minimum serum concentration of IgM is necessary for a diagnosis of WM.

Treatment

The goal of therapy for patients with WM is to achieve symptomatic relief and reduce organ damage without compromising quality of life. Treatment of WM is indicated only in symptomatic patients and should not be initiated solely on the basis of serum IgM concentration. Clinical and laboratory findings that indicate the need for therapy of diagnosed WM include a hemoglobin concentration less than 10 g/dL; platelet count less than 100,000/mL; significant adenopathy or organomegaly; symptomatic Ig-related hyperviscosity (>50 g/L); severe neuropathy; amyloidosis; cryoglobulinemia; cold-agglutinin disease; or evidence of disease transformation.

Primary chemotherapeutic options in patients that may undergo autologous hematopoietic cell transplantation (HCT) often combine rituximab with other agents (eg, dexamethasone, cyclophosphamide, bortezomib, bendamustine), but other agents may also be used including purine analogues (cladribine, fludarabine). Plasma exchange is indicated for acute treatment of symptomatic hyperviscosity.

Conventional Preparative Conditioning for HCT

The conventional (“classical”) practice of allogeneic 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 patients’ bone marrow space. While the slower graft-versus-malignancy effect is considered the potentially curative component, 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 preengraftment opportunistic infections secondary to loss of endogenous bone marrow function and organ damage and failure caused by the cytotoxic drugs. Furthermore, in any allogeneic HCT, immune suppressant drugs are required to minimize graft rejection and graft-versus-host disease, which also increases susceptibility of the patient to opportunistic infections.

The success of autologous HCT is predicated on the ability of cytotoxic chemotherapy with or without radiotherapy 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 prior to engraftment, but not graft-versus-host disease.

Reduced-Intensity Conditioning for Allogeneic HCT

Reduced-intensity conditioning (RIC) refers to the pretransplant use of lower doses or less intense regimens of cytotoxic drugs or radiotherapy 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 nearly totally myeloablative to minimally myeloablative with lymphoablation, with intensity tailored to specific diseases and patient condition. Patients who undergo RIC with allogeneic 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 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 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. Autologous hematopoietic cell transplantation is considered medically necessary as salvage therapy of chemosensitive Waldenstrom macroglobulinemia.

B. Allogeneic hematopoietic cell transplantation is considered investigational to treat Waldenstrom macroglobulinemia.

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.

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 function¾including 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 is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials 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.

Hematopoietic Cell Transplantation for Waldenström Macroglobulinemia

Clinical Context and Test Purpose

The purpose of hematopoietic cell transplantation is to provide a treatment option that is an alternative to or an improvement on existing therapies in individuals with Waldenström macroglobulinemia.

The question addressed in this policy is: does the use of hematopoietic cell transplantation improve the net health outcomes ofindividuals with Waldenström macroglobulinemia?

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

Patients

The relevant population of interest are patients with Waldenström macroglobulinemia.

Interventions

The therapy being considered is hematopoietic cell transplantation.

Comparators

Comparators of interest include chemotherapy, targeted therapy drugs, ad biologic therapy drugs.

Outcomes

The general outcomes of interest include overall survival, quality of life, treatment-related mortality, and treatment-related morbidity.

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 longer 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.

Few published data are available and there is a lack of studies comparing hematopoietic cell transplantation (HCT) with other treatments (eg, chemotherapy) in patients who have Waldenström macroglobulinemia (WM). Several retrospective series have been published.

Autologous HCT

Kyriakou et al (2010) evaluated 158 adults with WM reported to the European Group for Blood and Marrow Transplantation between 1991 and 2005.^1, Median time from diagnosis to autologous HCT was 1.7 years (range, 0.3-20.3 years); 32% of the patients experienced treatment failure with at least 3 lines of therapy; and 93% had sensitive disease at the time of HCT. Median follow-up for surviving patients was 4.2 years (range, 0.5-14.8 years). Nonrelapse mortality was 3.8% at 1 year. Relapse rate was 52.1% at 5 years. Progression-free survival and overall survival (OS) were 39.7% and 68.5%, respectively, at 5 years and were significantly influenced by number of lines of therapy and chemo-refractoriness at HCT. Authors concluded that autologous HCT is a feasible procedure in young patients with advanced WM but that it should not be offered to patients with chemoresistant disease or to those who have received more than 3 lines of therapy.

Allogeneic HCT

Data from the Center for International Blood and Marrow Transplant Research registry have been published periodically, most recently in 2017. Cornell et al (2017) reported retrospectively on 144 adults with WM entered in the registry between 2001 and 2013 who underwent allogeneic HCT.^2, Patients had relapsed after receiving at least 1 line of prior therapy. Hematopoietic cells were obtained from human leukocyte antigen-matched or -mismatched donors; cord blood stem cells were excluded. Sixty-seven patients received myeloablative conditioning (MAC) and 67 received reduced-intensity conditioning (RIC). Over half of patients (n=82 [57%]) had chemosensitive disease. Median follow-up after transplant was 70 months. OS rates were 74% at 1 year and 52% at 5 years. Patients with chemosensitive disease had significantly better 1- and 5-year OS rates compared with patients who had chemoresistant disease. Conditioning intensity (MAC vs RIC) did not impact treatment-related mortality, relapse, or progression-free survival rates. Sixty-five deaths were reported, with the most common causes being graft-versus-host disease (28%) and primary disease (23%).

Kyriakou et al (2010) retrospectively analyzed data on 86 patients who had allogeneic HCT for WM.^3, Patients underwent MAC (n=37) or RIC (n=49) regimens. Median age was 49 years (range, 23-64 years); 47 patients had received 3 or more previous lines of therapy; and 8 patients had experienced failure on a prior autologous HCT. Fifty-nine (68.6%) patients had chemosensitive disease at the time of allogeneic HCT. Median follow-up of the surviving patients was 50 months. The overall response rate was 75.6%. Relapse rates at 3 years were 11% for MAC and 25% for RIC. The OS rate at 5 years was 62% for MAC and 64% for RIC. Thirty deaths were reported; causes of death included graft-versus-host disease (23%) and primary disease (23%). The occurrence of chronic graft-versus-host disease was associated with a lower relapse rate.

Section Summary: Hematopoietic Cell Transplantation for Waldenström Macroglobulinemia

Several retrospective series have evaluated HCT for WM. Analyses of registry data have reported 5-year OS rates of 52% after allogeneic HCT and 68.5% after autologous HCT. The total number of patients studied was small and there is a lack of published controlled studies.

Summary of Evidence

For individuals who have WM who receive HCT,the evidence includes case series. Relevant outcomes are overall survival, change in disease status, quality of life, and treatment-related mortality and morbidity. Several retrospective series have evaluated HCT for WM. Analyses of registry data have found 5-year overall survival rates of 52% after allogeneic HCT and 68.5% after autologous HCT. The total number of patients studied is small and there is a lack of published controlled studies. The evidence is insufficient to determine the effects of the technology on health outcomes.

Clinical input obtained in 2011 and national and international clinical guidelines support the use of autologous HCT as salvage therapy for patients with chemosensitive Waldenström macroglobulinemia. Allogeneic HCT is recommended in the context of clinical trials. Thus, autologous HCT may be considered medically necessary as salvage therapy for patients with chemosensitive Waldenström macroglobulinemia. Allogeneic HCT for patients with Waldenström macroglobulinemia is considered investigational.

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 5 academic medical centers, including 3 transplant centers, while this policy was under review in 2011. Input indicated that autologous hematopoietic cell transplantation may be considered medically necessary as salvage therapy for Waldenström macroglobulinemia that is chemosensitive. Input was mixed on use of allogeneic hematopoietic cell transplantation, with comments suggesting the procedure be performed as part of a clinical trial.

Practice Guidelines and Position Statements

National Comprehensive Cancer Network

National Comprehensive Cancer Network guidelines on Waldenström macroglobulinemia (WM) and lymphoplasmacytic lymphoma (v.2.2019) indicate that, for patients with previously treated WM, stem cell transplantation may be appropriate in selected cases with either: high-dose therapy with autologous stem cell rescue or allogeneic cell transplant (myeloablative or nonmyeloablative).^4, The Network noted that allogeneic cell transplantation “should ideally be undertaken in the context of a clinical trial.” For potential autologous cell transplantation candidates, the guidelines also provide suggested treatment regimens considered non-stem-cell toxic.

Mayo Clinic Cancer Center

In 2017, the Mayo Clinic Cancer Center updated its guidelines on the diagnosis and management of WM.^5, The guidelines noted that patients who are potentially eligible for autologous hematopoietic cell transplantation (HCT; <70 years of age and with chemosensitive disease), should consider harvesting stem cells during first remission after a low tumor burden has been achieved. The guidelines recommended: “Autologous HCT should be considered for first or second relapse in transplant-eligible patients with chemosensitive disease, especially if the first remission duration is short (<2 years). Patients with refractory WM should not be offered [autologous HCT] (level 3, grade B).”

Eighth International Workshop on Waldenström’s Macroglobulinemia

In 2016, consensus recommendations from the Eighth International Workshop on Waldenström’s Macroglobulinemia were published.^6, The panel concluded that autologous HCT is a treatment option for high-risk WM patients who are eligible for transplant. It further stated that autologous HCT should be offered at early relapses and is not as beneficial once patients have been exposed to more than 3 lines of therapy or in those with chemotherapy-refractory disease. Regarding allogeneic HCT, it stated that this treatment, “when appropriate, should preferably be considered in the context of clinical trials.”

Myeloma Foundation of Australian

In 2017, the Myeloma Foundation of Australia published practice guidelines on the treatment of patients with WM.^7, The guidelines provided the following treatment recommendation for HCT: “Younger patients with good physical fitness should be considered for autologous and allogeneic stem cell transplantation at first or second relapse and should avoid stem cell-toxic therapies such as fludarabine (Level III, grade C).”

U.S. Preventive Services Task Force Recommendations

Not applicable.

Ongoing and Unpublished Clinical Trials

Currently unpublished trials that might influence this review are listed in Table 1.

Table 1. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT01251575	Sirolimus, Cyclosporine, and Mycophenolate Mofetil in Preventing Graft-versus-Host Disease in Treating Patients with Blood Cancer Undergoing Peripheral Blood Stem Cell Transplant	80	Dec 2019
NCT02844361	Comparison of ASCT and Conventional Chemotherapy in High Risk Waldenström Macroglobulinemia (BDH-WM03)	70	May 2020

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 Waldenstrom Macroglobulinemia
Hematopoietic Stem Cell Transplantation for Waldenstrom Macroglobulinemia
Autologous Bone Marrow Transplant, Waldenstrom’s Macroglobulinemia
Bone Marrow Transplant, Waldenstrom’s Macroglobulinemia
High Dose Chemotherapy with Hematopoietic Stem Cell Support for Waldenstrom’s Macroglobulinemia
Macroglobulinemia, High Dose Chemotherapy
Stem Cell Transplant, Waldenstrom’s Macroglobulinemia
Transplantation, Bone Marrow/Stem Cell for Waldenstrom’s Macroglobulinemia
Waldenstrom’s Macroglobulinemia, High Dose Chemotherapy

References:
1. Kyriakou C, Canals C, Sibon D, et al. High-dose therapy and autologous stem-cell transplantation in Waldenstrom macroglobulinemia: the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. May 1 2010;28(13):2227-2232. PMID 20368570

2. Cornell RF, Bachanova V, D'Souza A, et al. Allogeneic transplantation for relapsed Waldenstrom macroglobulinemia and lymphoplasmacytic lymphoma. Biol Blood Marrow Transplant. Jan 2017;23(1):60-66. PMID 27789362

3. Kyriakou C, Canals C, Cornelissen JJ, et al. Allogeneic stem-cell transplantation in patients with Waldenstrom macroglobulinemia: report from the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. Nov 20 2010;28(33):4926-4934. PMID 20956626

4. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Waldenstrom's Macroglobulinemia/Lymphoplasmacytic Lymphoma. Version 1.2017. https://www.nccn.org/professionals/physician_gls/pdf/waldenstroms.pdf. Accessed January 4, 2018.

5. Kapoor P, Ansell SM, Fonseca R, et al. Diagnosis and management of Waldenstrom macroglobulinemia: Mayo Stratification of Macroglobulinemia and Risk-Adapted Therapy (mSMART) Guidelines 2016. JAMA Oncol. Sep 1 2017;3(9):1257-1265. PMID 28056114

6. Leblond V, Kastritis E, Advani R, et al. Treatment recommendations from the Eighth International Workshop on Waldenstrom's Macroglobulinemia. Blood. Sep 8 2016;128(10):1321-1328. PMID 27432877

7. Talaulikar D, Tam CS, Joshua D, et al. Treatment of patients with Waldenstrom macroglobulinaemia: clinical practice guidelines from the Myeloma Foundation of Australia Medical and Scientific Advisory Group. Intern Med J. Jan 2017;47(1):35-49. PMID 28076910

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
38232
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Q0083
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S2140
S2142