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, paresthesias, 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).
The gold standard treatment for WM at diagnosis is still unknown. In asymptomatic patients with low tumor burden, watchful waiting is appropriate. On the other hand, in symptomatic patients that require treatment, chemo-immunotherapy with rituximab in association with chlorambucil; cyclophosphamide, vincristine and prednisolone (CVP); cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP); fludarabine-containing regimens or bendamustine is recommended. While maintenance therapy has been incorporated into the management of other indolent forms of non-Hodgkin lymphoma principally based upon its ability to prolong time to progression in these subtypes, there are limited data regarding the use of maintenance therapy in WM and no randomized trials. High-dose chemotherapy with autologous stem cell transplantation (ASCT) is useful in relapsed/refractory patients. New drugs such as bortezomib, lenalidomide, humanized monoclonal antibody anti-CD20 or anti-CD22 are tested in relapse and front-line patterns, with encouraging results. The main objectives of treatment of WM are 2-fold: (i) to control symptoms and (ii) prevent end organ damage. Treatment preferences are usually based on age, the severity of symptoms, eligibility for ASCT, presence of co-morbidities, and patient preferences. The specific regimen chosen depends upon patient characteristics and tumor burden. For the hyper-viscosity syndrome, the only effective treatment is the removal of IgM from the circulation via plasmapheresis. The large size of the IgM molecule restricts it mainly to the intra-vascular space such that it can be rapidly removed with plasmapheresis resulting in prompt alleviation of symptoms. For patients who present with symptoms due to hyper-viscosity, or who develop hyper-viscosity during treatment, immediate institution of therapeutic plasmapheresis is required. Red blood cell transfusions should be avoided, if possible, prior to plasmapheresis since they might further increase serum viscosity. After patients have completed plasmapheresis, chemotherapy can be initiated to control the malignant clone (Chiappella et al, 2011; 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.