DECIDING ON INITIATING TREATMENT
As part of the Second International Workshop on Waldenström Macroglobulinemia, a consensus panel was organized to recommend criteria for the initiation of therapy in patients with WM.127 The panel recommended that initiation of therapy should not be based on the IgM level per se, as this may not correlate with the clinical manifestations of WM. The consensus panel did, however, agree that initiation of therapy is appropriate for patients with constitutional symptoms, such as recurrent fever, night sweats, fatigue as a consequence of anemia, or weight loss. Progressive symptomatic lymphadenopathy and/or splenomegaly provide additional reasons to begin therapy. Anemia with a hemoglobin value of 10 g/dL or less or a platelet count of 100 × 109/L or less owing to marrow infiltration, also justifies treatment. Certain complications, such as hyperviscosity syndrome, symptomatic sensorimotor peripheral neuropathy, systemic amyloidosis, renal insufficiency, or symptomatic cryoglobulinemia, may also be indications for therapy.16,127
The International Workshops on Waldenström Macroglobulinemia have also formulated consensus recommendations for both initial therapy and therapy for refractory disease based on the best available evidence. The most recent recommendations emerged from the Seventh International Workshop on Waldenström Macroglobulinemia.128 Individual patient considerations, including the presence of cytopenias, need for more rapid disease control, age, and candidacy for autologous transplant therapy, should be taken into account in making the choice of the drugs to use. For patients who are candidates for autologous stem cell transplantation, which typically is reserved for those patients younger than 70 years of age, the panel recommended that exposure to alkylating agents or nucleoside analogues should be limited. The use of nucleoside analogues should be approached cautiously in patients with WM as there appears to be an increased risk for the development of disease transformation, as well as myelodysplasia and acute myelogenous leukemia.
Oral alkylating drugs, alone and in combination therapy with glucocorticoids, have been extensively evaluated in the treatment of WM. Chlorambucil has been administered on both a continuous (i.e., daily dose schedule) and an intermittent schedule. Patients receiving chlorambucil on a continuous schedule typically receive 0.1 mg/kg per day, whereas on the intermittent schedule patients typically receive 0.3 mg/kg for 7 days, every 6 weeks. In a prospective randomized study, no significant difference in the overall response rate between these schedules was observed,129 although the median response duration was greater for patients receiving intermittent-dose versus continuous-dose chlorambucil (46 vs. 26 months). Despite the favorable median response duration in this study for use of the intermittent schedule, no difference in the median overall survival was observed. Moreover, an increased incidence for development of myelodysplasia and acute myelogenous leukemia with the intermittent (three of 22 patients) versus the continuous (zero of 24 patients) chlorambucil schedule prompted the preference for use of continuous chlorambucil dosing. The use of glucocorticoids in combination with alkylating agent therapy has also been explored. Chlorambucil (8 mg/m2) plus prednisone (40 mg/m2) given orally for 10 days, every 6 weeks, resulted in a major response (i.e., reduction of IgM by more than 50 percent) in 72 percent of patients.130 Alkylating agent regimens employing melphalan and cyclophosphamide in combination with glucocorticoids also have been examined.131,132 This approach produced slightly higher overall response rates and response durations, although the benefit of these more complex regimens over chlorambucil remains to be demonstrated. Pretreatment factors associated with shorter survival in the entire population of patients receiving single-agent chlorambucil were age older than age 60 years, male sex, hemoglobin less than 10 g/dL, leukocytes less than 4 × 109/L, and platelets less than 150 × 109/L. Organomegaly, signs of hyperviscosity, renal failure, monoclonal IgM level, blood lymphocytosis, and percentage of marrow lymphoid cells were not significantly correlated with survival.133 Additional factors to be taken into account in considering alkylating agent therapy for patients with WM include necessity for more rapid disease control given the slow response, as well as consideration for preserving stem cells in patients who are candidates for autologous stem cell transplantation therapy. A large randomized study showed an inferior response rate and time to progression in WM patients receiving chlorambucil versus fludarabine, as well as a higher incidence of secondary malignancies in the former. Neutropenia was, however, more pronounced in those patients on fludarabine.134
Nucleoside Analogue Therapy
Cladribine administered as a single agent by continuous intravenous infusion, by 2-hour daily infusion, or by subcutaneous bolus injections for 5 to 7 days has resulted in major responses in 40 to 90 percent of patients who received primary therapy, whereas in the previously treated patients, responses have ranged from 38 to 54 percent.135,136,137,138,139,140,141 Median time to achievement of response in responding patients following cladribine ranged from 1.2 to 5 months. The overall response rate with daily infusion of fludarabine, administered mainly on 5-day schedules, in previously untreated and treated patients, ranged from 38 to 100 percent and 30 to 40 percent, respectively,142,143,144,145,146,147 similar to the responses to cladribine. Median time to achievement of response for fludarabine (3 to 6 months) was also similar to cladribine. In general, response rates and durations of responses have been greater for patients receiving nucleoside analogues as initial therapy, although in several studies in which both untreated and previously treated patients were enrolled, no difference in the overall response rate was reported.
Myelosuppression commonly occurs following prolonged exposure to either of the nucleoside analogues. A sustained decrease in both CD4+ and CD8+ T lymphocytes, measured 1 year following initiation of therapy, is notable.135,136,137 Treatment-related mortality as a consequence of myelosuppression and/or opportunistic infections attributable to immunosuppression occurred in up to 5 percent of all treated patients in some series with nucleoside analogues.
Factors predicting for a better response to nucleoside analogues include younger age at start of treatment (<70 years), higher pretreatment hemoglobin (>95 g/L), higher platelet count (>75 × 109/L), disease relapsing off therapy, and a long interval between first-line therapy and initiation of a nucleoside analogue in relapsing patients.135,140,146 There are limited data on the use of an alternate nucleoside analogue in previously treated patients among whom disease relapsed or who had resistance when not on cladribine or fludarabine therapy.148,149 Three of four (75 percent) patients responded to cladribine after progression following an unmaintained remission to fludarabine, whereas only one of 10 (10 percent) with disease resistant to fludarabine responded to cladribine.148 A response in two of six patients (33 percent) and disease stabilization in the remaining patients to fludarabine, in spite of an inadequate response or progressive disease, following cladribine therapy has been reported.149
Harvesting autologous blood stem cells succeeded on the first attempt in 14 of 15 patients who did not receive nucleoside analogue therapy as compared to two of six patients who received a nucleoside analogue.150 A sevenfold increase in transformation to an aggressive lymphoma and a threefold increase in the development of myelodysplasia or acute myelogenous leukemia were observed among patients who received a nucleoside analogue versus other therapies for their WM.151 A meta-analysis of several trials in which patients were treated with nucleoside analogues in WM patients, included patients who had previously received an alkylating agent, and showed a crude incidence of approximately 8 percent for development of disease transformation and of approximately 5 percent for development of myelodysplasia or acute myelogenous leukemia.152 None of the risk factors—that is, gender, age, family history of WM, or B-cell malignancies, typical markers of tumor burden and prognosis, type of nucleoside analogue therapy (cladribine vs. fludarabine), time from diagnosis to nucleoside analogue use, nucleoside analogue treatment as primary or salvage therapy, or treatment with an oral alkylator (i.e., chlorambucil)—predicted for the occurrence of transformation or development of myelodysplasia or acute myelogenous leukemia in patients treated with a nucleoside analogue.152
CD20-Directed Antibody Therapy
Rituximab is a chimeric monoclonal antibody that targets CD20, a widely expressed antigen on lymphoplasmacytic cells in WM.153 Several retrospective and prospective studies indicated that rituximab, when used at standard doses (i.e., 4 weekly intravenous infusions of 375 mg/m2) induced major responses in approximately 30 percent of previously treated and untreated patients.154,155 Even patients who achieved minor responses benefited from rituximab by improved hemoglobin and platelet counts, and reduction of lymphadenopathy and/or splenomegaly.154 The median time to treatment failure in these studies was found to range from 8 to 27+ months. Patients on an extended rituximab schedule consisting of four weekly courses at 375 mg/m2 per week, repeated 3 months later by another 4-week course have demonstrated major response rates of approximately 45 percent, with time to progression estimates of 16+ to 29+ months.156,157
In many WM patients, a transient increase or flare of the serum IgM may occur immediately following initiation of rituximab treatment.156,158,159 Such an increase does not herald treatment failure and most patients will return to their baseline serum IgM level by 12 weeks. Some patients continue to show a prolonged increase in IgM despite an apparent reduction in their marrow tumor cells. However, patients with baseline serum IgM levels of greater than 50 g/dL or serum viscosity of greater than 3.5 cp may be particularly at risk for a hyperviscosity-related event and plasmapheresis should be considered in these patients in advance of rituximab therapy.158 Because of the decreased likelihood of response in patients with higher IgM levels, as well as the possibility that serum IgM and blood viscosity levels may abruptly rise, rituximab monotherapy should not be used as sole therapy for the treatment of patients at risk for hyperviscosity signs and symptoms.128,156,157
Time to response after rituximab is slow and exceeds 3 months on the average. The time to best response in one study was 18 months.157 Patients with baseline serum IgM levels of less than 60 g/dL are more likely to respond, regardless of the underlying marrow involvement by tumor cells.156,157 An analysis of 52 patients who were treated with single-agent rituximab found the objective response rate was significantly lower in patients who had either low serum albumin (<35 g/L) or a serum monoclonal protein greater than 40 g/L.160 The presence of both adverse prognostic factors was associated with a short time to progression (3.6 months). Patients who had normal serum albumin and relatively low serum monoclonal protein levels derived a substantial benefit from rituximab with a time to progression exceeding 40 months.
A correlation between polymorphisms at position 158 in the FcγRIIIa receptor (CD16), an activating Fc receptor on important effector cells that mediate antibody-dependent cell-mediated cytotoxicity, and rituximab response was observed in WM patients.161 Individuals may encode either the amino acid valine or phenylalanine at position 158 in the FcγRIIIa receptor. WM patients who carried the valine amino acid (either in a homozygous or heterozygous pattern) had a fourfold higher major response rate (i.e., 50 percent decline in serum IgM levels) to rituximab versus those patients who expressed phenylalanine in a homozygous pattern.
Both bortezomib and carfilzomib have been evaluated in prospective studies in patients with WM, although the latter only in combination therapy (discussed below). In a retrospective study, 10 patients with refractory or relapsed WM were treated with bortezomib administered intravenously at a dose of 1.3 mg/m2 on days 1, 4, 8, and 11 in a 21-day cycle for a total of four cycles. Most patients had been exposed to all active agents for WM and eight patients had received three or more regimens. Six of these patients achieved a partial response which occurred at a median of 1 month. The median time to progression in the responding patients is expected to exceed 11 months. Peripheral neuropathy occurred in three patients and one patient developed severe paralytic ileus in this series.162 In a prospective study among 27 relapsed or refractory patients who received up to eight cycles of bortezomib at 1.3 mg/m2 on days 1, 4, 8, and 11, median serum IgM levels declined significantly from 4.7 g/dL to 2.1 g/dL.33 The overall response rate was 85 percent, with 10 and 13 patients achieving a minor (≥25 percent) and major (≥50 percent) decrease in IgM level. Responses occurred at a median of 1.4 months. The median time to progression for all responding patients in this study was 7.9 (range: 3.0 to 21.4+) months, and the most common grades III/IV toxicities were sensory neuropathies (22.2 percent), leukopenia (18.5 percent), neutropenia (14.8 percent), dizziness (11.1 percent), and thrombocytopenia (7.4 percent). Sensory neuropathies resolved or improved in nearly all patients following cessation of therapy. Twenty-seven patients with both untreated (44 percent) and previously treated (56 percent) disease received bortezomib, using the standard schedule until they either demonstrated progressive disease or two cycles beyond a complete response or stable disease.163 The overall response rate was 78 percent, with major responses observed in 44 percent of patients. Sensory neuropathy occurred in 20 patients following two to four cycles of therapy. Among the 20 patients developing a neuropathy, 14 showed resolution or improvement 2 to 13 months after therapy.
Because rituximab is not myelosuppressive, its combination with chemotherapy has been explored. A regimen of rituximab, cladribine, and cyclophosphamide used in 17 previously untreated patients resulted in a partial response in 94 percent of WM patients, including a complete response in 18 percent.164 No patient had relapsed with a median followup of 21 months. The combination of rituximab and fludarabine used in 43 patients of whom 32 (75 percent) were previously untreated, led to an overall response rate of 95.3 percent, with 83 percent of patients achieving a major response (i.e., 50 percent reduction in disease burden).165 The median time to progression was 51.2 months in this series, and was longer for those patients who were previously untreated and for those achieving a very good partial remission (i.e., 90 percent reduction in disease) or better. Hematologic toxicity was common: grade 3 neutropenia and thrombocytopenia observed in 27 and four patients, respectively. Two deaths occurred in this study from pneumonia. Secondary malignancies including transformation to aggressive lymphoma and development of myelodysplasia or acute myelogenous leukemia were observed in six patients in this series. The addition of rituximab to fludarabine and cyclophosphamide has also been explored in previously treated patients, of whom four of five patients had a response.166 In another combination study, rituximab along with pentostatin and cyclophosphamide given to 13 patients with untreated and previously treated WM or LPL resulted in a major response in 77 percent of patients.167 The combination of rituximab, dexamethasone, and cyclophosphamide was used as primary therapy to treat 72 patients with WM in whom a major response was observed in 74 percent of patients in this study, and the 2-year progression-free survival was 67 percent.168 Therapy was well tolerated, although one patient died of interstitial pneumonia.
Two studies examined cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in combination with rituximab (R-CHOP). In a randomized trial involving 69 patients, most of whom had WM, the addition of rituximab to CHOP resulted in a higher overall response rate (94 percent vs. 67 percent) and median time to progression (63 vs. 22 months) in comparison to patients treated with CHOP alone.169 R-CHOP was also used in 13 WM patients, 10 of whom had relapsed or refractory disease.170 Among 13 evaluable patients, 10 patients achieved a major response (77 percent), including three complete and seven partial remissions. Two other patients achieved a minor response. In a retrospective study of symptomatic WM patients who received either R-CHOP; rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP); or cyclophosphamide, prednisone, and rituximab (R-CP) and were similar in most pretreatment variables, the overall response rates to therapy were comparable among all three treatment groups—R-CHOP (96 percent), R-CVP (88 percent), and R-CP (95 percent)—although there was a trend for more complete remissions among patients treated with R-CVP and R-CHOP.171 Adverse events attributed to therapy showed a higher incidence for neutropenic fever and treatment related neuropathy for R-CHOP and R-CVP versus R-CP. The results of this study suggest that in WM, the use of R-CP may provide analogous treatment responses to more intense cyclophosphamide-based regimens while minimizing treatment-related complications. The extended alkylator bendamustine has also been evaluated in combination with rituximab in both untreated, as well as previously treated WM patients. A randomized study by the German STiL Group examined bendamustine plus rituximab (BR) versus R-CHOP in patients with untreated, indolent B-cell lymphomas including WM.172 Patients with WM in this study showed similar overall responses (96 percent vs. 94 percent), although progression-free survival was significantly longer (69 vs. 29 months) in patients who received BR versus R-CHOP. Treatment was also better tolerated in patients receiving BR. In the relapsed or refractory setting, an overall response rate of 83 percent was observed with bendamustine in combination with a CD20 monoclonal antibody.173 The median time to progression was 13 months in this study. Prolonged myelosuppression was more common in patients who received prior nucleoside analogues.
The use of two cycles of oral cyclophosphamide along with subcutaneous cladribine to 37 patients with previously untreated WM led to a partial response in 84 percent of patients and the median duration of response was 36 months.164 Fludarabine in combination with intravenous cyclophosphamide resulted in partial responses in six of 11 (55 percent) WM patients with either primary refractory disease or who had relapsed on treatment.174 The combination of fludarabine plus cyclophosphamide was also evaluated in 49 patients, 35 of whom were previously treated. Seventy-eight percent of the patients achieved a response, and the median time to treatment failure was 27 months.175 Hematologic toxicity was frequent, and three patients died of treatment-related toxicities. Two important findings in this study were the development of acute leukemia in two patients, histologic transformation to diffuse large B-cell lymphoma in one patient, and two cases of solid malignancies (prostate and melanoma), as well as failure to mobilize stem cells in 4 of 6 patients.
The combination of bortezomib, dexamethasone, and rituximab (BDR) as primary therapy in patients with WM resulted in an overall response rate of 96 percent, and a major response rate of 83 percent.176 The incidence of grade 3 neuropathy was approximately 30 percent, but was reversible in most patients following discontinuation of therapy. An increased incidence of herpes zoster was also observed prompting the prophylactic use of antiviral therapy. Alternative schedules for administration of bortezomib (i.e., once weekly at higher doses) in combination with rituximab in patients with WM have achieved overall response rates of 80 to 90 percent.177,178 The European Myeloma Network (EMN) recently showed that transitioning bortezomib from twice weekly intravenous dosing during the first cycle to weekly administration thereafter reduced grade 3 neuropathy to less than 10 percent in patients treated with BDR.179 There have been no studies addressing the safety and efficacy of subcutaneous bortezomib use in WM.
Carfilzomib which is associated with a low risk of treatment-related peripheral neuropathy has been evaluated in combination with rituximab and dexamethasone (CaRD) in WM patients.34 Carfilzomib was administered intravenously at 20 mg/m2 (cycle one), then 36 mg/m2 (cycles two to six), together with dexamethasone (20 mg) on days 1, 2, 8, and 9 as part of a 21-day cycle. As part of this regimen, rituximab 375 mg/m2 was given on days 2 and 9 every 21 days. Maintenance therapy was given 8 weeks following induction therapy with intravenous carfilzomib (36 mg/m2) and dexamethasone (20 mg) administered on days 1 and 2 and rituximab 375 mg/m2 on day 2 every 8 weeks for up to eight cycles. Overall response rate with this regimen was 87.1 percent (one complete response, 10 very good partial responses, 10 partial responses, and six minimal responses) and was not impacted by MYD88L265P or CXCR4WHIM mutation status. With a median followup of 15.4 months, 20 patients remained progression free. Grade 2 or higher toxicities included asymptomatic hyperlipasemia (41.9 percent), reversible neutropenia (12.9 percent), and cardiomyopathy in one patient (3.2 percent) with multiple risk factors. Treatment-related neuropathy, which was grade 2, occurred in one patient (3.2 percent). Declines in serum IgA and IgG were common, and some patients required intravenous gammaglobulin therapy for recurring sinus and bronchial infections.
The use of Ibrutinib was recently approved by the FDA for the treatment of symptomatic patients with WM. Ibrutinib targets BTK, a target of ibrutinib that is activated by MYD88L265P.43 In a multicenter study that examined the role of ibrutinib in previously treated (median: two prior therapies, 40 percent refractory) WM patients, the overall response rate was 91 percent.180 Patients on this study received 420 mg/day of ibrutinib by mouth. Posttherapy, median serum IgM levels declined from 3610 to 915 mg/dL; hemoglobin rose from 10.5 to 13.5 g/dL; and marrow involvement declined from 60 percent to 25 percent. Decreased or resolved adenopathy was observed in 60 percent of patients with extramedullary disease, and five of nine patients with IgM-related peripheral neuropathy had symptomatic improvement. The 24-month estimate for progression-free and overall survival was 70 percent and 95 percent, respectively. Although major response rates were lower in patients with MYD88WT and CXCR4WHIM mutations, it is not recommended that genotyping be used to select which patients should go on ibrutinib until further data is available. Grade 2 or higher treatment-related toxicities included neutropenia (25 percent) and thrombocytopenia (14 percent), which were more common in heavily pretreated patients; atrial fibrillation associated with a prior history of arrhythmia (5 percent); and bleeding associated with procedures and marine oil supplements (3 percent). Serum IgA and IgG levels were unchanged following treatment with ibrutinib, and treatment-related infections were infrequent.
Everolimus is an oral inhibitor of the mammalian target of rapamycin (mTOR) pathway that is active in WM. A multicenter study examined everolimus in 60 previously treated patients that showed an overall response rate (ORR) of 73 percent, with 50 percent of patients attaining a major response.181 The median progression-free survival in this study was 21 months. Grade 3 or higher related toxicities were observed in 67 percent of patients, with cytopenias constituting the most common toxicity. Pulmonary toxicity occurred in 5 percent of patients, and dose reductions as a result of toxicity occurred in 52 percent of patients. A clinical trial examining the activity of everolimus in 33 previously untreated patients with WM has also been reported that included serial marrow biopsies in response assessment.182 The ORR in this study was 72 percent, including partial or better responses in 60 percent of patients. However, discordance between serum IgM levels upon which consensus criteria for response are based, and marrow disease response were common and complicated response assessment. In a few patients, discontinuation of everolimus led to rapid increases in serum IgM levels, and symptomatic hyperviscosity. Grade 2 or higher hematologic and nonhematologic toxicities in this study that were related to everolimus were predominately hematologic, including anemia (40 percent), thrombocytopenia (12 percent), and neutropenia (18 percent). Nonhematologic toxicities included oral ulcerations (27 percent), which improved with oral dexamethasone swish and spit solution, and pneumonitis (15 percent), which led to treatment discontinuation.
A large retrospective study examined the categorical responses outcome of rituximab-naïve patients who were either observed or received maintenance rituximabwere.183 Categorical responses improved after induction therapy in 42 percent of patients who received maintenance rituximab versus 10 percent in patients on observation. Additionally, both progression-free survival (56.3 vs. 28.6 months) and overall survival (>120 vs. 116 months) were longer in patients who received maintenance rituximab. Improved progression-free survival was evident despite previous treatment status or induction with rituximab, either alone or in combination therapy. Best serum IgM response was also lower and hematocrit higher in those patients who received maintenance rituximab. Among patients who received maintenance rituximab therapy, an increased number of infectious events, predominantly grade 1 or 2 sinusitis and bronchitis were observed, along with lower serum IgA and IgG levels. A prospective study examining the role of maintenance rituximab was also initiated by the German STiL group.184 In this study, patients received up to six cycles of bendamustine and rituximab, and responders randomized to either observation or maintenance rituximab every 2 months for 2 years. Enrollment for this study is complete and response outcome for maintenance rituximab therapy is awaited.
HIGH-DOSE THERAPY AND STEM CELL TRANSPLANTATION
The European Bone Marrow Transplant Registry reported the largest experience for both autologous as well as allogeneic stem cell transplantation (SCT) in WM.185,186 Among 158 WM patients receiving an autologous SCT, which included primarily relapsed or refractory patients, the 5-year progression-free and overall survival rate was 39.7 percent and 68.5 percent, respectively.185 Nonrelapse mortality at 1 year was 3.8 percent. Chemorefractory disease, and the number of prior lines of therapy at time of the autologous SCT were the most important prognostic factor for progression-free and overall survival. In the allogeneic SCT experience from the European Bone Marrow Transplant, the long-term outcome of 86 WM patients was reported.186 A total of 86 patients received allograft by either myeloablative or reduced-intensity conditioning. The median age of patients in this series was 49 years, and 47 patients had three or more previous lines of therapy. Eight patients failed prior autologous SCT. Fifty-nine patients (68.6 percent) had chemotherapy-sensitive disease at the time of allogeneic SCT. Nonrelapse mortality at 3 years was 33 percent for patients receiving a myeloablative transplant, and 23 percent for those who received reduced-intensity conditioning. The overall response rate was 75.6 percent. The relapse rates at 3 years were 11 percent for myeloablative, and 25 percent for reduced-intensity conditioning recipients. Five-year progression-free and overall survival for WM patients who received a myeloablative allogeneic SCT were 56 percent and 62 percent, respectively, and for patients who received reduced intensity conditioning were 49 percent and 64 percent, respectively. The occurrence of chronic graft-versus-host disease was associated with improved progression-free survival, and suggested the existence of a clinically relevant graft-versus-WM effect in this study.