Hematopoietic Cell Transplantation for Waldenstrom Macroglobulinemia

Number: 0833

Table Of Contents

Policy

Scope of Policy

This Clinical Policy Bulletin addresses hematopoietic cell transplantation for Waldenstrom macroglobulinemia.

1. Medical Necessity

   Aetna considers autologous hematopoietic cell transplantation medically necessary as salvage treatment for chemo-sensitive Waldenstrom macroglobulinemia.

2. Experimental, Investigational, or Unproven

   Aetna considers allogeneic hematopoietic cell transplantation experimental, investigational, or unproven for the treatment of Waldenstrom macroglobulinemia because its effectiveness for this indication has not been established.

Background

Waldenstrom macroglobulinemia (WM) is a distinct indolent B-cell lympho-proliferative malignancy characterized by IgM para-proteinemia.  It accounts for 1 to 2 % of hematologic malignancies, with an estimated 1,500 new cases annually in the United States.  The median age of WM patients at presentation is 63 to 68 years; with men comprising 55 to 70 % of cases.  Although the disease is sensitive to chemo-immunotherapy, it remains incurable and affected patients have a median survival of 5 to 10 years.  Risk-stratification in newly diagnosed patients should start with a prognostic evaluation based on the International Prognostic Scoring System for WM to identify those patients in whom particularly poor survival with chemotherapy is expected and in whom alternative treatment strategies, such as hematopoietic cell transplantation (HCT), should be considered.  The hyper-viscosity syndrome associated with WM is a clinical emergency due to elevated levels of IgM resulting in decreased flow and impaired microcirculation of the central nervous system.  Although the diagnosis is established by measuring serum viscosity, clinicians should render the decision to initiate treatment with plasmapheresis on the basis of the patient's symptoms and physical findings (e.g., blurred vision, dizziness, headaches, paresthesia, oro-nasal bleeding, papilledema, retinal vein engorgement and flame-shaped hemorrhages, as well as stupor and coma), rather than on the magnitude of the viscosity measurement (Bachanova and Burns, 2012; Rajkumar, 2012). 

Kyriakou et al (2010a) analyzed the results of ASCT in patients with WM and determined the prognostic factors that have a significant impact on outcome.  These investigators analyzed 158 adult patients with WM reported to the European Group for Blood and Marrow Transplantation (EBMT) between January 1991 and December 2005.  Median time from diagnosis to ASCT was 1.7 years (range of 0.3 to 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 ASCT.  Conditioning regimen was total-body irradiation-based in 45 patients.  Median follow-up for surviving patients was 4.2 years (range of 0.5 to 14.8 years).  Non-relapse mortality (NRM) was 3.8 % at 1 year.  Ten patients developed a secondary malignancy, with a cumulative incidence of 8.4 % at 5 years.  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 ASCT.  The achievement of a negative immune-fixation after ASCT had a positive impact on progression-free survival (PFS) after ASCT.  When used as consolidation at first response, ASCT provided a PFS of 44 % at 5 years.  The authors concluded that ASCT is a feasible procedure in young patients with advanced WM.  Furthermore, they stated that ASCT should not be offered to patients with chemo-resistant disease and to those who received more than 3 lines of therapy.

Ansell et al (2010) provided recommendations on timing and choice of therapy for the management of patients with WM by means of a risk-adapted approach.  Patients with smoldering or asymptomatic WM and preserved hematologic function should be observed without therapy.  Symptomatic patients with modest hematologic compromise and IgM-related neuropathy that require treatment, or hemolytic anemia unresponsive to corticosteroids should receive standard doses of rituximab alone without maintenance therapy.  Patients who have severe constitutional symptoms, profound hematologic compromise, symptomatic bulky disease, or hyper-viscosity should be treated with the DRC (dexamethasone, rituximab, cyclophosphamide) regimen.  Any patient with symptoms of hyper-viscosity should first be treated with plasmapheresis.  For patients who experience relapse after a response to initial therapy of more than 2 years' duration, the original therapy should be repeated.  For patients who had an inadequate response to initial therapy or a response of less than 2 years' duration, an alternative agent or combination should be used.  Autologous stem cell transplant should be considered in all eligible patients with relapsed disease.

Garnier et al (2010) examined the long-term outcome of allogeneic stem cell transplantation (allo-SCT) in WM by studying the records of 24 patients reported in the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) database and 1 transplanted in the bone marrow unit in Hamburg.  Median age at the time of transplant was 48 years (range of 24 to 64).  Patients had previously received a median of 3 lines of therapy (range of 1 to 6) and 44 % of them had refractory disease at time of transplant.  Allogeneic stem cell transplantation after myeloablative (MAC; n = 12) or reduced-intensity conditioning (RIC; n = 13) conditioning yielded an overall response rate of 92 % and immunofixation-negative complete remission (CR) in 50 % of evaluable patients.  With a median follow-up of 64 months among survivors (range of 11 to 149), 5-year OS and PFS rates were 67 % (95 % confidence interval [CI]: 46 to 81) and 58 % (95 % CI: 38 to 75), respectively.  The 5-year estimated risk of progression was 25 % (95 % CI: 10 to 36 %), with only 1 relapse among the 12 patients who entered CR, versus 5 in the 12 patients who did not.  Only 1 of the 6 relapses occurred more than 3 years post-transplant.  The authors concluded that allo-SCT yielded a high rate of CRs and is potentially curative in poor-risk WM.

Kyriakou et al (2010b) presented the long-term outcome of a large series of patients with WM treated with allo-SCT.  A total of 86 patients received allograft by using either MAC (n = 37) or RIC (n = 49) regimens and were retrospectively studied.  The median age was 49 years (range of 23 to 64); 47 patients had received 3 or more previous lines of therapy, and 8 patients had experienced failure on a prior ASCT.  A total of 59 patients (68.6 %) had chemotherapy-sensitive disease at the time of allo-SCT.  Median follow-up of the surviving patients was 50 months (7 to 142).  Non-relapse mortality at 3 years was 33 % for MAC and 23 % for RIC.  The overall response rate was 75.6 %.  The relapse rates (RRs) at 3 years were 11 % for MAC and 25 % for RIC.  Fourteen patients received donor lymphocyte infusions (DLIs) for disease relapse; PFS and OS at 5 years were 56 % and 62 % for MAC and 49 % and 64 % for RIC, respectively.  The occurrence of chronic graft-versus-host disease (cGVHD) was associated with a higher NRM and a lower RR, leading to an improvement in PFS.  The authors concluded that allo-SCT can induce durable remissions in a selected population of young and heavily pre-treated patients with WM.  The low RR, the achievement of additional disease responses after DLIs, and the lower RR in patients developing cGVHD suggested the existence of a clinically relevant graft-versus-WM effect.

Gertz et al (2012) noted that WM is a highly chemo-sensitive lympho-plasmacytic lymphoma with response rates of 90 % to first-line chemotherapy.  The fraction of patients undergoing stem cell transplant for this disorder appears to be lower than that of patients with multiple myeloma.  The indolent nature and favorable genetic profile should make WM an ideal disorder for ASCT, with high response rates that are durable.  These investigators reviewed the literature on ASCT and allo-SCT for WM and concluded that ASCT is effective and under-utilized in the management of this disorder.  On the other hand, allo-SCT should be considered investigational and used only in the context of a clinical trial or when other chemotherapeutic options have been exhausted.

Usmani et al (2011) stated that the optimal management of WM is in evolution, especially since the introduction of novel agents for its sister disease, multiple myeloma.   Literature on the utility of ASCT in WM, albeit mostly retrospective, supports its efficacy for symptomatic disease in eligible patients.  These researchers presented the experience of managing WM at their institution.  They reported that ASCT improved OS/event-free survival (EFS) in both treatment-naive and previously treated WM patients.  Elevated lactate dehydrogenase (LDH) emerged as a poor prognostic factor in both uni-variate and multi-variate analyses.  Based on these data and other series of ASCT experience, it may be feasible to employ this strategy upfront in transplant eligible WM patients when they require a therapeutic intervention for symptomatic disease.

Bachanova and Burns (2012) stated that high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HCT) results in disease-free survival of 45 to 65 % at 5 years, but is unlikely to be curative.  Chemo-sensitive disease at the time of auto-HCT is the most important prognostic factor for response rate and OS.  Allogeneic HCT may offer a unique immune-mediated graft-versus-leukemia (GVL) effect with a plateau in relapse rates and potential for extended disease-free survival.  The authors noted that risk of allogeneic HCT complications is justified in HCT-eligible patients whose expected survival is less than 5 years.

An UpToDate review on "Treatment and prognosis of Waldenstrom macroglobulinemia" (Rajkumar, 2012) states that "There is minimal experience with high dose chemotherapy followed by autologous hematopoietic cell transplantation (HCT) in WM.  Treatment related mortality appears to be less than 10 % and autologous HCT may be able to produce long-term responses even in heavily pretreated patients.  On the other hand, allogeneic HCT, which carries a much higher risk of non-relapse mortality, should NOT be considered outside the context of a clinical trial".

Furthermore, the NCCN’s clinical practice guideline on "Waldenstrom's macroglobulinemia/Lymphoplasmacytic Lymphoma" (Version 1.2013) states that stem cell transplant may be appropriate in selected cases (high-dose therapy with stem cell rescue).  Moreover, allo-SCT should be undertaken in the context of a clinical trial.

Kapoor and colleagues (2016) stated that WM is a non-Hodgkin lymphoma (NHL) characterized by the presence of a CD20 + lymphoplasmacytic bone marrow (BM) infiltrate and serum immunoglobulin M monoclonal protein. Both sporadic and familial forms exist.  A remarkable improvement in outcome of nearly all age groups of WM patients may be primarily a consequence of successful integration of anti-CD20 monoclonal antibody, rituximab, to the conventional chemotherapy.  However, the seminal discoveries of MYD88 (L265P) mutation, present in the vast majority (85 to 100 %), and CXCR4 (WHIM) mutations, identified in nearly 1/3 of patients (who almost exclusively harbor the MYD88 (L265P) variant), have laid a solid foundation for a paradigm shift in the diagnostic and therapeutic approaches towards this rare hematologic malignancy.  Given that 20 to 25 % of patients are asymptomatic at diagnosis and early intervention does not translate into survival benefit, these researchers followed a risk-adapted approach and actively monitor this subset of "smoldering" patients.  Those with low-grade cytopenia can generally be managed with an abbreviated course of rituximab monotherapy, while those with B symptoms, bulky lymphadenopathy, or profound disease-related cytopenia require more aggressive strategies, incorporating several courses of chemo-immunotherapy.  For symptoms associated with hyper-viscosity, prompt plasma exchange is warranted prior to initiation of cytoreductive therapy.  Prospective data are unavailable to a support a unique approach in familial WM or initiation of rituximab maintenance post-induction.  A multitude of potentially effective therapies targeting cell-survival pathways are in development and offer a more precise approach for WM patients.  One such agent, ibrutinib, was recently granted approval.  Off-study, these investigators limit the use of ibrutinib to relapsed-refractory WM patients who harbor MYD88 mutations.  The authors noted that ASCT is another viable option in the relapsed setting for chemo-sensitive transplant-eligible patients.  Unfortunately, despite substantial progress, achieving a minimal residual disease-negative state – a prerequisite for cure – is rare in WM.

Allogeneic Transplantation for Relapsed Waldenstrom Macroglobulinemia

Cornell and colleagues (2017) noted that Waldenstrom macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) is characterized by lymphoplasmacytic proliferation, lymph node and spleen enlargement, bone marrow involvement, and IgM production.  Treatment varies based on the extent and biology of disease.  In some patients, the use of allogeneic hematopoietic cell transplantation (alloHCT) may have curative potential.  These researchers evaluated long-term outcomes of 144 patients who received adult alloHCT for WM/LPL.  Data were obtained from the Center for International Blood and Marrow Transplant Research database (2001 to 2013).  Patients received MAC (n = 67) or RIC (n = 67).  Median age at alloHCT was 53 years, and median time from diagnosis to transplantation was 41 months; 13 % (n = 18) failed prior autologous HCT.  57 % (n = 82) had chemo-sensitive disease at the time of transplantation, whereas 22 % had progressive disease.  Rates of PFS, OS, relapse, and non-relapse mortality at 5 years were 46 %, 52 %, 24 %, and 30 %, respectively.  Patients with chemo-sensitive disease and better pre-transplant disease status experienced significantly superior OS.  There were no significant differences in PFS based on conditioning (MAC = 50 %, versus RIC = 41 %) or graft source.  Conditioning intensity did not impact treatment-related mortality or relapse.  The most common causes of death were primary disease and GVHD.  The authors concluded that  alloHCT yielded durable survival in select patients with WM/LPL.  They stated that strategies to reduce mortality from GVHD and post-transplant relapse are needed to improve this approach.

Furthermore, NCCN’s clinical practice guideline on "Waldenstrom's macroglobulinemia/lymphoplasmacytic lymphoma" (Version 1.2017) still maintains that "According to the NCCN panel, myeloablative or non-myeloablative allogeneic SCT may be considered, but preferably in the context of a clinical trial".

Maffini and colleagues (2018) stated that irrespective of age, patients with aggressive WM who have exhausted chemo-immunotherapy-based approaches may be candidates for allogeneic hematopoietic cell transplantation (allo-HCT), a strategy that has been rarely attempted.  In Seattle, conditioning with a single fraction of low-dose total body irradiation (TBI), combined with a GVHD prophylaxis consisting of cyclosporine and mycophenolate mofetil, led to near-uniform allogeneic engraftment in a canine DLA-identical model.  Clinical trials based on this approach demonstrated rapid engraftment and graft-versus-tumor effects in a wide variety of hematologic malignancies, with higher sustained response rates for patients with indolent diseases.  These researchers presented a retrospective analysis of outcomes among 15 heavily pre-treated and largely chemo-refractory WM patients who received a minimal intensity conditioning regimen consisting of 200 cGy TBI ± fludarabine, in preparation for HLA-matched related or unrelated HCT.  The authors concluded that despite improvements in chemotherapeutic drugs, WM has remained an incurable illness.  However, these investigators and others have shown that allogeneic HCT can achieve cures in nearly 50 % of the patients with advanced WM including those with chemotherapy-resistant disease.  The risk of non-relapse mortality must be carefully evaluated before the procedure.  Moreover, they stated that it is possible that results of allo-HCT can be further improved by transplanting earlier in the disease course when patients are in a better general condition or before they become refractory to chemotherapy or develop secondary cancers.

Sakurai and associates (2020) stated that the role of SCT for patients with WM remains undetermined.  These investigators retrospectively evaluated the outcome of autologous and allogeneic SCT for patients with WM using the registry data-base of the Japan Society for Hematopoietic Cell Transplantation.  A total of 46 patients receiving autologous and 31 receiving allogeneic SCT were analyzed.  The allogeneic SCT group included more patients with advanced disease status at transplant and received more lines of chemotherapy.  The cumulative incidences of non-relapse mortality (NRM) at 1 year were 30.0 % (95 % CI: 14.7 to 46.9 %) in the allogeneic SCT and 0 % in the autologous SCT group.  The estimated 3-year OS and PFS survival rates were 84.5 % (95 % CI: 66.0 to 93.4 %) and 70.8 % (95 % CI: 53.0 to 82.9 %) in the autologous SCT group, and 52.2 % (95 % CI: 32.5 to 68.6 %) and 45.0 % (95 % CI: 26.3 to 62.0 %) in the allogeneic SCT group.  No patients died after the first 2 years following allogeneic SCT.  In uni-variate analyses, disease status at SCT was significantly associated with PFS in autologous SCT, and with OS and PFS in allogeneic SCT.  The authors concluded that these findings suggested that both autologous and allogeneic SCT have potential roles in WM; allogeneic SCT is more curative for WM, but is associated with high NRM.

Parrondo and colleagues (2020) performed a comprehensive literature search using PubMed/Medline and Embase on September 10, 2019.  Data on clinical outcomes related to benefits and harms was extracted independently by 3 authors.  A total of 15 studies (8 autologous hematopoietic cell transplantation (AHCT) [n = 278 patients], 7 allo-HCT [n = 311 patients]) were included in this systematic review/meta-analysis.  Pooled OS, PFS, and NRM rates post-AHCT were 76 % (95 % CI: 65 % to 86 %), 55 % (95 % CI: 42 % to 68 %), and 4 % (95 % CI: 1 % to 7 %), respectively.  Pooled OS, PFS, and NRM rates post-allografting were 57 % (95 % CI: 50 % to 65 %), 49 % (95 % CI: 42 % to 56 %), and 29 % (95 % CI: 23 % to 34 %), respectively.  OS and PFS rates were reported at 3 to 5 years, and NRM was reported at 1 year in most studies.  Pooled ORR (at day 100) post-AHCT and allo-HCT were 85 % (95 % CI: 72 % to 94 %) and 81 % (95 % CI: 69 % to 91 %), respectively.  Pooled complete response rates post-AHCT and allo-HCT were 22 % (95 % CI: 17 % to 28 %) and 26 % (95 % CI: 7 % to 50 %), respectively.  Relapse rates post-AHCT and allo-HCT were 42 % (95 % CI: 30 % to 55 %) and 23 % (95 % CI: 18 % to 28 %), respectively.  The authors concluded that these findings showed that both AHCT and allo-HCT were effective in the treatment of WM.  A 2-fold lower relapse rate but a 7-fold higher NRM was noted for allo-HCT compared with AHCT.  The near 30 % NRM associated with allo-HCT in this analysis raised the question of the wider applicability of allo-HCT for WM.  Moreover, these researchers stated that the ideal population of patients with WM who should undergo hematopoietic cell transplantation will need to be re-examined in the era of novel agents.

BeEAM Conditioning Including High-Dose Bendamustine Before Autologous Stem Cell Transplantation

Heini et al (2023) stated that high-dose chemotherapy (HDCT) with ASCT is an option to consolidate remission in patients with WM, especially in selected younger patients with chemo-sensitive disease.  BEAM, consisting of BCNU, etoposide, cytarabine, and melphalan, is often used as a conditioning regimen.  However, problems with BCNU, including pneumo-toxicity, tolerance, and availability, necessitate the search for alternatives.  In a pilot study, these investigators examined HD-CT with BeEAM, in which BCNU was replaced with high-dose bendamustine as an alternative conditioning regimen in 6 subsequent patients with WM.  Bendamustine treatment was well-tolerated without unexpected toxicities.  The overall response rate (ORR) was 6/6 patients (2 very good partial responses (VGPR) and 4 PR).  After a median follow-up of 72 months, 2 (33 %) patients relapsed.  Median PFS and OS were not reached, and no severe late-onset toxicities were observed so far.  The authors concluded that in this pilot study, BeEAM conditioning before ASCT appeared feasible, safe, and effective in patients with WM.  Moreover, these researchers stated that open questions remain, especially regarding the optimal sequence of therapies and patient selection; they stated that these questions should ideally be addressed in large multi-center studies.

The authors stated that the drawbacks of this study included the small the sample size (n = 6) and its retrospective character, and post-transplant monitoring was carried out in the patients in part in cooperating hemato-oncologic centers.  All toxicities were examined and classified retrospectively.  International Prognostic Scoring System for Waldenstrom’s Macroglobulinemia (ISSWM) grading and remission status also had to be determined retrospectively for most patients, whereby comprehensive serum protein electrophoresis results throughout the study period were missing in some cases.  Due to the afore-mentioned drawbacks and the lack of a control group, no conclusions can be made regarding the effectiveness and long-term effects of BeEAM-HDCT.  However, these findings indicated a favorable outcome and manageable safety profile in WM patients; and given the rarity of WM and the rather rare indication for HDCT/ASCT for this indication, the cohort appeared relevant, although being limited by number.

References