Mini-review Stem cell transplantation (SCT) for Waldenstrom s macroglobulinemia (WM)

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1 (2002) 29, Nature Publishing Group All rights reserved /02 $ Mini-review Stem cell transplantation (SCT) for Waldenstrom s macroglobulinemia (WM) Department of Blood and Marrow Transplantation at the University of Texas MD Anderson Cancer Center, Houston, TX, USA Summary: Waldenstrom s macroglobulinemia (WM) is a lowgrade lymphoplasmacytoid malignancy of unknown etiology. It primarily affects elderly patients and is characterized by a monoclonal IgM component, varying degrees of cytopenias, lymphadenopathy and manifestations related to hyperviscosity syndromes. WM is usually treated with single agent nucleoside analogues or alkylating agents that often provide high response rates and durable remissions. Recurrence of the disease after primary therapy is not uncommon, and resistance to both alkylating agents and nucleoside analogs eventually emerges. Small numbers of patients have undergone high-dose chemotherapy (HDC) with either autologous (n = 24) or allogeneic (n = 6) stem cell transplantation (SCT) as treatment for this disease. Most patients in both groups achieved remission. Results are promising and a more in-depth analysis of possible applications of this treatment modality is attempted with this minireview. (2002) 29, DOI: /sj/bmt/ Keywords: Waldenstrom s macroglobulinemia; stem cell transplantation; high-dose chemotherapy Waldenstrom s macroglobulinemia (WM) is a rare lowgrade lymphoplasmacytoid malignancy, characterized by the presence of an IgM paraprotein. WM typically affects elderly individuals, with a median age at presentation of 65 years. The disease usually has a long natural history and the patients often survive more than 5 years after the initial diagnosis. 1 Patients with WM may present with hyperviscosity syndrome, cryoglobulinemia, cold agglutinin disease, peripheral neuropathy, amyloidosis as well as lymphadenopathy and symptoms related to the cytopenias. Adverse prognostic factors in patients with WM have been analyzed in several studies and include low albumin level, increased Correspondence: Dr S Giralt, Department of Blood and Marrow Transplantation, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA age, cytopenias, the presence of cryoglobulinemia and elevated serum beta 2 microglobulin. 2 5 Treatment is generally employed when patients become symptomatic. 1 Alkylating agents, such as chlorambucil and cyclophosphamide, with or without corticosteroids, together with plasmapheresis have been the mainstay of therapy to reduce tumor burden as well as the symptoms related to hyperviscosity. More recently, the nucleoside analogues fludarabine and cladribine have been used either as single agents or in combination as frontline therapy for the disease. 1 Interferon-, anti-cd20 monoclonal antibodies as well as thalidomide have also shown activity in relapsed patients. 6 8 Patients with WM generally respond to initial therapy with either alkylating agents or nucleoside analogs. Response to treatment is considered complete when the serum monoclonal protein disappears as assessed by immunofixation and there is complete resolution of lymphadenopathy and splenomegaly with less than 20% lymphocytes in the bone marrow. Complete remissions are rare and all responding patients will eventually relapse. Reinduction of remission is possible, but eventually resistance to both alkylating agents as well as nucleoside analogs develops. Thus for practical purposes WM remains an incurable disease. High-dose chemotherapy (HDC) followed by stem cell transplantation (SCT) has been used in refractory or highrisk patients Patients with disease resistant to conventional chemotherapy have achieved durable responses after HDC followed by autologous or even allogeneic SCT. In this review we summarize the published experience with SCT in WM patients, and provide guidelines with regard to the current and possible future role of this therapeutic modality in the treatment of WM. Autologous stem cell transplantation for Waldenstrom s macroglobulinemia Twenty-four patients with WM have undergone HDC and autologous SCT and have been reported in the literature and are summarized in Table ,15 Median age was 51 (range 30 71). Fourteen patients were transplanted in a refractory or relapsed status of their disease and the remaining 10 were transplanted at a time when the disease was chemosensitive. Most patients were treated within the first

2 944 Table 1 Characteristics of 24 patients with WM who underwent HDC supported by autologous SCT Ref. Patient Age median Time to Disease status Preparative regimen Response FU in months Outcome No. (range) transplant (range) (years) (45 69) 4 (3 9) Multiple relapse untreated 3 MEL 200 (2 patients) 2 PR 15+, 9 1 AW, 1 progressed, died Mel 140+TBI (1 patient) 1PR 6 progressed died 1st remission 2 MEL 200 2PR 12+, 5+ 2AW Progressive disease 1 MEL CR 52+ 1AW (39 61) 1 year 1st remission 3 CY TBI PR 1, CR (3 30) 7 AW 1ry refractory 4 CY TBI PR Unknown Unknown 1st remission MEL 200 PR 1,CR 4 Unknown Unknown Unknown Refractory Bu MEL120 CR AW Refractory MEL 140 CR AW (30 58) 0.9 1ry refractory Thiotepa Bu CY PR AW 0.8 Refractory relapse Thiotepa Bu CY NA 1 1 early death 10 VP-16 CY TBI PR ry AML, died 1 CY TBI PR AW MEL = melphalan; CY = cyclophosphamide; TBI = total body irradiation; Bu = busulfan; VP-16 = etoposide; PR = partial remission; CR = complete remission; ED = early death; AW = alive and well; 1ry = primary; 2ry = secondary. year of initial diagnosis. The preparative regimens consisted primarily of high-dose melphalan or TBI in combination with an alkylating agent. Twenty-three of the 24 reported patients were reported to have achieved remission and only one treatment-related death was noted. The median follow-up of the surviving patients was 15 months but at least two patients were reported as alive 4.5 and 12 years post transplant without disease recurrence (Table 1). (GVHD), while two patients were reported to be alive in remission for an extended period of time after transplant (Table 2). There is also anecdotal experience from Seattle with three WM patients receiving low-dose TBI as preparative regimen who responded to treatment; however, followup is still short (personal communication with Dr David Maloney). Allogeneic stem cell transplantation for Waldenstrom s macroglobulinemia Six patients with WM who underwent an allogeneic SCT have been reported in the literature and are summarized in Table 2. 11,14,16 The median age of these patients was 45 (range 30 62) years. All patients were heavily pretreated due to refractory or relapsed disease. The median time from diagnosis to transplant was 3.1 years (range 1.3 7). Four subjects received a full myeloablative regimen, three with a TBI-containing approach and one using thiotepa, busulfan and cyclophosphamide. Two patients received a reduced intensity or non-myeloablative regimen consisting of fludarabine with cyclophosphamide or melphalan. Two patients died from complications of graft-versus-host disease Discussion It is obvious that there is only limited experience with HDC and SCT in WM, therefore, the role of this procedure in the therapy of this disease is unknown. The only conclusion that can be derived from the published data is that the procedure is feasible in some patients, that autologous transplant seems to be generally safe and well tolerated, and that both autografts and allografts can be associated with longterm remissions even in patients whose disease is refractory to alkylating agents and nucleoside analogs. Thus although feasible, HDC and SCT should be considered investigational and limited to clinical trials. There are several questions that should be addressed in the course of clinical investigation: Table 2 Six patients with WM who underwent HDC supported by allogeneic SCT Ref. Patients Age Time to Disease status Regimen Best response Follow-up Adverse events transplant (months) (years) Thiotepa Bu CY, NE 1 Early death Refractory relapse TLI CY VP16 TBI PR 6 Died of GVHD FAMP CY NR 36 Graft failure, died of disease Sensitive relapse Chlorambucil CY TBI PR 112+ None, AW Refractory relapse CY TBI CR 34+ None, AW Refractory relapse FAMP MEL140 PR 5+ None, AW Bu = busulfan; Cy = cyclophosphamide; TLI = total lymphoid irradiation; FAMP = fludarabine; ED = early death; GVHD = graft-versus-host disease.

3 (1) Should high-dose chemotherapy and stem cell transplantation be explored as frontline therapy for Waldenstrom s Macroglobulinemia? WM typically affects elderly individuals. It is estimated that around 20% of the patients will die of unrelated causes. 3 Up to 90% of patients respond to first line single agent treatment (chlorambucil or nucleoside analogue) and nearly half of patients respond to single agent salvage treatment. 4,17 21 Median survival after diagnosis has been estimated to be more than 5 years. 1 However, there are several prognostic models that have identified groups of patients who have limited survival. 2 5 In the largest report to date, Morel et al 22 were able to identify age, cytopenias and albumin as important prognostic factors, and validated these factors in an independent population. Patients with low risk disease (ie less than 65 years of age, no cytopenias, and normal albumin) had an expected survival rate at 5 years of 92% vs 27% for patients with high-risk disease. The primary limitation of this and other prognostic models is that such guides were derived from patients who received alkylating agent-based therapy; therefore the utility of these models in the era of nucleoside analogs is unknown. Nevertheless, in other lymphoid malignancies where nucleoside analogs have been effective, prognostic factors for survival to alkylating agents have been similar for therapy with nucleoside analogs. 23,24 Thus, it is reasonable to explore high-dose chemotherapy in patients with WM who have poor risk features, particularly young patients with cytopenias and low albumin levels. However, until more experience is obtained, HDC and SCT for WM should only be explored in the context of well-designed clinical trials. (2) What stem cell source should be used when exploring HDC and SCT as consolidation therapy for patients with WM? Should we only try autologous SCT with HDC as consolidation treatment in newly diagnosed WM patients with poor prognostic features or should we also try allogeneic SCT when there is a donor available? Based on the limited current experience with HDC and SCT in WM only autografting should be explored as consolidation therapy for an initial remission in patients with WM. Experience to date in patients mostly with relapsing disease, has demonstrated that non-relapse mortality for autografting in WM is low ( 5%), and long-term remissions in relapsing or refractory patients can be achieved. The applicability and feasibility of autografting in patients with high-risk WM, is still unclear, since the feasibility of collecting enough stem cells, particularly after prior exposure to nucleoside analogs is as yet unknown. There are studies indicating that prior nucleoside analog exposure, negatively affects stem cell collection. 25,26 A recent retrospective study from Europe regarding mobilization of autologous peripheral blood SC in CLL patients with prior treatment with fludarabine, indicates that patients who had received fludarabine in combination with other chemotherapy regimens, or in patients who received the last dose of fludarabine within 2 months of stem cell collection, peripheral blood stem cell content was reduced, whereas administration of single agent fludarabine early in the disease course did not hamper successful collection. 27 The effect of cladribine on stem cell collection has also not been well explored, but potentially could also affect stem cell collections even with limited exposure. The use of allogeneic transplantation as a consolidation treatment in high-risk patients might become an issue in certain cases. However, existing data do not support the hypothesis that the potential benefits of a graft-versusmacroglobulinemia effect would overcome the risk of the severe adverse outcomes of GVHD or severe life-threatening infections, in patients having achieved remission of their disease. (3) Should high-dose chemotherapy and stem cell transplantation be explored as salvage therapy for Waldenstrom s macroglobulinemia? Response to first line treatment is a strong predictive factor for survival in WM, the median survival for patients not responding to therapy is less than 3.5 years. 3,4 Review of the published literature suggests that SCT can be used with success in WM and that this therapeutic option can be offered to patients relapsing or not responding to initial therapy. In this situation, HDC and SCT should preferentially be offered in the context of a clinical trial. The type of transplant will depend on the ability to collect autologous stem cells and the availability of an HLA compatible donor. However, the optimal cell source is unknown at this time. Although published experience suggests a graft-versus-wm effect, 11,14 this has not been documented in series of patients. The morbidity and mortality of allogeneic transplantation is always higher than autologous transplantation. Although non-ablative transplantation has been shown to reduce morbidity and mortality significantly in patients with low-grade lymphomas and other hematologic malignancies, this procedure does not eliminate the occurrence of acute or chronic GVHD that still impact tremendously on the quality of life post transplant At this time, based upon current results, if autologous stem cells can be collected autografting would be our favored approach in patients with primary refractory disease. If an adequate number of autologous stem cells cannot be collected, allografting is a reasonable alternative if an HLAcompatible donor is found. Data on allografting are still very limited and the risks outweigh the potential benefits of choosing an allogeneic transplant in refractory patients where autologous SCT is feasible. On the other hand, HDC alone has been shown to overcome disease resistance in WM patients (Table 1) and this should be our first choice in these cases. The majority of patients with WM will fall into the group of patients who respond to the first line therapy and relapse a few years later. Their chances of responding to salvage therapy are good. Prognostic factors for salvage therapy have not been developed, but are likely to parallel those for initial therapy and could be used to segregate patients into more or less aggressive treatment strategies. As with most lymphoid malignancies, response to salvage therapy has been shown to be an important prognostic factor for survival. Patients failing salvage therapy with 945

4 946 alkylators, have only a 21% chance of responding to nucleoside analogues, and a median survival of 13 months. 1 Review of the current transplant experience would suggest that these patients would be appropriate candidates for HDC and SCT in the context of a clinical trial as long as their performance status was adequate and they had an adequate source of stem cells. Transformation into a more aggressive histology although rare, has usually been associated with a poor outcome, and could also be considered as an appropriate indication to explore more aggressive therapy with SCT. For refractory disease patients, however, allografting may be the only treatment modality available, since autologous stem cells may not be available, and other therapy is unlikely to produce meaningful remissions. In low-grade lymphoma, patients with chemorefractory relapses had a substantial chance of long-term disease control after allografting, underscoring the relevance of the graft-versuslymphoma effect in this disease. 32,33 However, although classified as a low-grade lymphoid malignancy, neither the existence nor the relevance of a graft-versus- Waldenstrom s effect has been clearly demonstrated to date. Future prospects The fact that WM is a rare disease makes it difficult to perform prospective studies. Recent advances in other lymphoid malignancies like multiple myeloma or other low-grade lymphomas allows us to make new therapeutic approaches. The use of anti-cd20 and thalidomide are good examples. 7,8 The use of anti-cd20 in conjunction with HDC, or the use of thalidomide as maintenance post transplant might improve outcomes in WM patients. The optimal preparative regimen for patients undergoing autologous SCT has not yet been identified, nor is the intensity of the preparative regimen in the allogeneic SCT standard. However, using reduced intensity regimens in the allogeneic setting may induce donor cell engraftment with limited toxicities and may allow us to use this as a platform for further immune-mediated anti-macroglobulinemia effects. Consistent reporting and accumulation of sporadic WM cases treated with HDC, and participation of new cases in multi-institutional treatment protocols, might help us make advances in this area. Moreover, advances in the understanding of the molecular and genetic basis of the disease could also incorporate more intelligent diseasespecific treatments in the setting of SCT. Conclusion Waldenstrom s macroglobulinemia is a rare disease of elderly individuals. Historically, SCT is a treatment for younger patients without other medical conditions. Recent advances in supportive care, as well as the use of peripheral blood as a stem cell source has extended the use of SCT to patients with advanced ages and significant co-morbidities. The limited available data for SCT in WM patients should encourage investigators to prospectively study the role of HDC and SCT in WM. As with other indolent lymphoid malignancies, development of surrogate markers and endpoints will be essential to be able to better study the role and effects of HDC and SCT in patients with WM. References 1 Dimopoulos MA, Panayiotidis P, Moulopoulos LA et al. Waldenstrom s macroglobulinemia: clinical features, complications, and management. J Clin Oncol 2000; 18: Gobbi PG, Bottini R, Montecucco C et al. Study of prognosis in Waldenstrom s macroglobulinemia: a proposal for a simple binary classification with clinical and investigational utility. Blood 1994; 83: Facon T, Brouillard M, Duhamel A et al. 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