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`Lenalidomide and Rituximab in Waldenstrom’s Macroglobulinemia
`
`Steven P. Treon,1,3 Jacob D. Soumerai,1Andrew R. Branagan,1 Zachary R. Hunter,1ChristopherJ. Patterson,1
`Leukothea Ioakimidis,1Luis Chu,4 Paul Musto,5 Ari D. Baron,6 Johannes C. Nunnink,7
`Joseph J. Kash,8 Terenig O. Terjanian,9 Paul M. Hyman,10 Elena L. Nawfel,11
`David J. Sharon,12 Nikhil C. Munshi,2,3 and Kenneth C. Anderson2,3
`
`Abstract Purpose: Thalidomide and its more potent immunomodulatory derivative lenalidomide enhance
`rituximab-mediated antibody-dependent cell-mediated cytotoxicity. We therefore evaluated
`lenalidomide and rituximab in symptomatic Waldenstrom’s macroglobulinemia (WM) patients
`naive to either agent.
`Experimental Design: Intended therapy consisted of 48 weeks of lenalidomide (25 mg/d for
`3 weeks and then 1week off) along with rituximab (375 mg/m2/wk) dosed on weeks 2 to 5 and
`13 to 16. Sixteen patients were enrolled, 12 of whom were previously untreated.
`Results: Unexpectedly, we observed an acute decrease in hematocrit in 13 of 16 patients
`(median hematocrit decrease, 4.8%), which was attributable to lenalidomide patients and which
`led to cessation of further enrollment on this study. Lenalidomide-related anemia was observed
`even at doses as low as 5 mg/d and occurred in the absence of hemolysis or other cytopenias.
`The overall response and major response (<50% decrease in serum IgM) rates were 50% and
`25%, respectively, on an intent-to-treat basis. With a median follow-up of 31.3 months, 4 of
`8 responding patients have progressed with a median time to progression of 18.9 months.
`Conclusion: Lenalidomide produces unexpected but clinically significant acute anemia in
`patients with WM. In comparison with our previous study with thalidomide and rituximab in an
`analogous patient population, the responses achieved in WM patients with lenalidomide and
`rituximab appear less favorable.
`
`Waldenstrom’s macroglobulinemia (WM) is a B-cell disorder
`characterized primarily by bone marrow infiltration with
`lymphoplasmacytic cells along with demonstration of an IgM
`monoclonal gammopathy (1). This condition is considered to
`
`Authors’ Affiliations: 1Bing Center for Waldenstrom’s Macroglobulinemia and
`2Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute; 3Harvard
`Medical School, Boston, Massachusetts; 4Florida Cancer Specialists, Sarasota,
`Florida; 5Commonwealth Hematology Oncology, Quincy, Massachusetts; 6Pacific
`Hematology Oncology Associates, San Francisco, California; 7University of
`Vermont Cancer Center, Burlington,Vermont; 8Edward Hospital and Health Services
`Cancer Center, Naperville, Illinois; 9Sanford R. Nalitt Institute for Cancer and Related
`Blood Disease, Staten Island, New York; 10Hematology Oncology Associates of
`Western Suffolk PC, Bayshore, New York; 11Harold Alfond Center for Cancer Care,
`Augusta, Maine; and 12Monmouth Medical Center’, Long Branch, NewJersey
`Received 4/4/08; revised 7/10/08; accepted 7/27/08.
`Grant support: Bing Fund for Waldenstrom’s macroglobulinemia, Research Fund
`for Waldenstro« m’s at the Dana-Farber Cancer Institute, and NIH Development
`Award K23CA087977-03 (S.P. Treon).
`The costs of publication of this article were defrayed in part by the payment of page
`charges. This article must therefore be hereby marked advertisement in accordance
`with 18 U.S.C. Section 1734 solely to indicate this fact.
`Note: S.P. Treon, A.R. Branagan, Z.R. Hunter, N.C. Munshi, and K.C. Anderson
`designed and wrote the study. J.D. Soumerai, C.J. Patterson, and L. Ioakimidis
`oversaw the data collection. S.P. Treon, L. Chu, P. Musto, A.D. Baron, J.C. Nunnink,
`J.J. Kash,T.O. Terjanian, P.M. Hyman, E.L. Nawfel, and D.J. Sharon treated the study
`patients and provided study data.
`Requests for reprints: Steven P. Treon, Bing Center for Waldenstrom’s
`Macroglobulinemia, Dana-Farber Cancer Institute, M547, 44 Binney Street, Boston,
`MA 02115. Phone: 617-632-2681; Fax : 617-632-4862; E-mail: steven___treon@
`dfci.harvard.edu.
`F 2009 American Association for Cancer Research.
`doi:10.1158/1078-0432.CCR-08-0862
`
`be lymphoplasmacytic lymphoma as defined by the REAL and
`WHO classification systems (2, 3). Despite advances in therapy,
`WM remains incurable. As such, novel therapeutic agents are
`needed for the treatment of WM.
`One class of therapeutics that has been successfully used in
`patients with WM are monoclonal antibodies. Both rituximab
`and alemtuzumab have been evaluated in WM as single agents
`with major response rates of 30% to 40%, whereas the
`combination of rituximab with chemotherapy has resulted in
`response rates of 70% to 90% (4). With the attainment of
`higher response rates with chemo-antibody therapy, consider-
`ably more short-term and long-term toxicities have been
`reported (4, 5). In an effort to augment monoclonal antibody
`responses in WM patients while averting short-term and long-
`term chemotherapy-induced toxicities, we have sought
`the
`development of immunomodulatory agents for combination
`with rituximab. Thalidomide and its more potent immuno-
`modulatory derivative lenalidomide augment antibody-
`dependent cell-mediated cytotoxicity (5). Moreover,
`these
`agents also lead to expansion of natural killer cells, which
`serve as important effector cells for rituximab activity in
`patients with indolent non-Hodgkin’s lymphoma (6 – 9). As a
`follow-up to these findings, we recently performed a clinical
`trial exploring the combined use of thalidomide and rituximab
`in patients with WM who were naive to either agent (10). The
`results of
`this study demonstrated a higher (70%) major
`(z50% decrease in IgM) response rate than observed previously
`with either thalidomide (20-25%) or rituximab (30-40%)
`alone as upfront therapy in WM patients. Responses in this
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`Cancer Therapy: Clinical
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`Translational Relevance
`
`The intent of this study was to examine the potential for
`the immunomodulator lenalidomide to augment rituximab
`activity in patients with WM. The study showed a unique
`idiopathy for this drug in this patient population, which
`consisted of acute anemia and which persisted despite
`dose reduction and resulted in numerous hospitalizations
`for patients due to anemia complications. This aggravated
`anemia was seen even with dose reduction.We believe that
`this study is very important to alerting clinicians to this nov-
`el and unexpected toxicity, which appears idiopathic to
`WM patients. The mechanism for this finding remains to
`be delineated. The findings of this study are particularly im-
`portant given the relatedness of WM to multiple myeloma
`and the interchange of therapeutics among these disease
`entities by clinicians. Moreover, in comparison with our
`previous study with thalidomide and rituximab in an analo-
`gous patient population, the responses achieved in WM
`patients with lenalidomide and rituximab appear less favor-
`able.We believe that the results of this study will be impor-
`tant not only to clinicians caring for patients with WM but
`also to investigators examining the role of lenalidomide in
`related low-grade B-cell malignancies.
`
`study were durable, with time to progression (TTP) of z38
`months observed among responders. The response rate and TTP
`for combined thalidomide and rituximab therapy was compa-
`rable with that reported with combinations of cytotoxic agents
`or nucleoside analogues and rituximab (4). However, we
`observed a high incidence (44%) of reversible grade z2
`peripheral neuropathy. A higher incidence of peripheral
`neuropathies has also been observed by us in WM patients
`treated with bortezomib in comparison with patients with
`other B-cell malignancies, suggesting a constitutive predisposi-
`tion to neuropathy (11). As such, given the greater immuno-
`modulatory activity as well as diminished neuropathic
`potential for lenalidomide relative to thalidomide, we per-
`formed this phase II study of lenalidomide and rituximab in
`WM patients naive to either agent and reported herein the
`toxicities and activity of this novel combination.
`
`Patients and Methods
`
`Patients with a clinicopathologic diagnosis of WM requiring therapy
`based on the consensus recommendations of the Second International
`Workshop on Waldenstrom’s Macroglobulinemia (12), and who were
`naive to rituximab and lenalidomide, and with CD20+ tumor cells as
`determined by previous bone marrow immunohistochemistry or flow
`cytometry were eligible for this study. To meet eligibility, patients had
`to show a monoclonal IgM protein, minimum IgM level z2 times the
`upper limit of normal, baseline platelet count z25,000/AL, absolute
`neutrophil count z500/AL, serum creatinine <2.5 mg/dL (unless
`nephropathy was attributable to their WM), serum total bilirubin and
`SGOT <2.5 times the upper limit of normal, and Eastern Cooperative
`Oncology Group performance status 0 to 2. No chemotherapy, steroid
`therapy, or radiation therapy within 30 days of study entry was
`permitted. Patients who were pregnant or lactating, had serious
`comorbid disease, had any uncontrolled bacterial, fungal, or viral
`infection, or an active second malignancy were not eligible. All men and
`
`women of reproductive potential were required to agree to use an
`acceptable method of birth control before, during treatment, and for
`6 months after completion of study treatment.
`All patients provided informed written consent and the institutional
`review board approved the protocol. Intended therapy consisted of
`lenalidomide administered at a starting dose of 25 mg/d by mouth for
`3 weeks and then 1 week off on a syncopated schedule as part of a
`4-week cycle. Patients could receive up to 48 weeks of therapy with
`lenalidomide. Dose de-escalation was permitted to 15 mg/d on days of
`treatment. Following enrollment of the first 11 patients, the protocol
`was amended to initiate patients on a start dose of 20 mg/d on the same
`syncopated schedule as before, with dose de-escalation permitted to
`10 mg/d on days of treatment. Following the enrollment of one patient
`at the start dose of 20 mg/d, the protocol was again amended to initiate
`patients at a start dose of 15 mg/d, on the same syncopated schedule as
`before, with dose de-escalation permitted to 5 mg/d on days of
`treatment.
`Rituximab was administered at 375 mg/m2/wk during weeks 2 to 5
`and 13 to 16 for a total of 8 infusions. Patients who did not tolerate the
`first cycle (4 infusions) of rituximab therapy were removed from the
`study and not replaced. Sixteen patients were enrolled in this study,
`which used a Simon two-stage design. Sample size was based on the
`assumption that the expected response rate would be at least 50%.
`Therefore, to have a 95% confidence interval of f20%, a sample size of
`25 was required.
`Response determination. A baseline evaluation was obtained for
`enrollment within 30 days before initiation of
`therapy. Patients
`underwent re-staging studies every 3 months while on therapy and
`thereafter every 3 months until progression of disease. As part of their
`response evaluation, all patients underwent history and physical exam,
`laboratory studies consisting of a complete blood count and
`differential, serum IgM levels, h2-microglobulin levels, and bone
`marrow biopsy and aspiration. Response determinations were made
`using modified consensus panel criteria from the Third International
`Workshop on Waldenstrom’s Macroglobulinemia, and response rates
`determined on an evaluable basis (13). A complete response was
`defined as having resolution of all symptoms, normalization of serum
`IgM levels with complete disappearance of
`IgM paraprotein by
`immunofixation, and resolution of any adenopathy or splenomegaly.
`Patients achieving a major response and a minor response were defined
`as achieving z50% and z25% reduction in serum IgM levels,
`respectively. Patients with stable disease were defined as having <25%
`change in serum IgM levels in the absence of new or increasing
`adenopathy or splenomegaly and/or other progressive signs or
`symptoms of WM. Progressive disease was defined as occurring when
`a >25% increase in serum IgM level occurred from the lowest attained
`response value or progression of clinically significant disease-related
`symptom(s). For patients undergoing plasmapheresis, serum IgM levels
`were used for purposes of assessing response only after steady-state
`attainment (z5 weeks from last plasmapheresis). TTP was calculated
`from the start of therapy using the Kaplan-Meier method.
`Analysis of peripheral blood effector cells. Serial changes in the
`absolute levels of peripheral blood effector cells following lenalidomide
`monotherapy during the first week (and before introduction of
`rituximab to prevent effector cell alterations) were done as described
`previously (10).
`Statistical analysis. Comparison of pretreatment and post-
`treatment variables was done using a two-tailed Student’s t test on
`Microsoft Excel software. P V 0.05 was deemed to be significant for the
`above studies.
`
`Results
`
`Patient and disease characteristics. The clinical features of
`the 16 patients enrolled in this study are summarized in
`Table 1. Of
`the 16 patients enrolled on study, 12 were
`previously untreated. Of the 4 previously treated patients, all
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`Table 1. Baseline characteristics for all 16 patients
`enrolled on study
`
`Gender
`Untreated
`Age (y)
`Prior therapies
`Bone marrow involvement (%)
`Serum IgM (mg/dL)
`h2-Microglobulin (mg/L)
`Hematocrit (%)
`Platelets (k/AL)
`Leukocytes (k/AL)
`
`Median (range)
`
`12 male/4 female
`12/16 (75%)
`65 (49-85)
`0 (0-2)
`37.5 (5-90)
`4,000 (1,180-7,130)
`3.3 (1.8-6)
`32.1 (24-36.6)
`282.5 (78-568)
`6.05 (3-22)
`
`had relapsed to their prior therapy. The median cumulative
`dose of lenalidomide administered for the intended 48-week
`treatment period among all enrolled patients was 455 mg
`(range, 140-5,670), and the median number of weeks on
`lenalidomide therapy was 15.8 (range, 1.1-48). The median
`number of cycles of rituximab among all enrolled patients was
`8 (range, 3-8). Twelve patients were evaluable for response.
`Four patients were unevaluable for response due to their
`premature withdrawal resulting from adverse events associated
`with lenalidomide (n = 3) and rituximab (n = 1).
`Clinical response to therapy. The individual changes in
`serum IgM levels at best response for all evaluable patients
`are shown in Fig. 1. Median serum IgM levels for all evaluable
`patients declined from 2,980 mg/dL (range, 1,180-7,130) to
`1,775 mg/dL (range, 83-4,220) at best response (P = 0.015).
`Pre-therapy, 6 of 12 (50%) showed a serum IgM level z3,000
`mg/dL; at best response, only 3 of 12 (25%) had an IgM level
`z3,000 mg/dL. Overall, 8 of 16 patients enrolled in this study
`showed at least a minor response as their best response. Of
`these patients, 4 of 16 (25%) achieved a major response and
`4 of 12 (25%) achieved a minor response. There were no
`complete responders. Among responding patients, the median
`time to best response was 11.8 months (range, 6-26.4), and the
`median time for a 25% reduction in serum IgM among
`responders was 3.6 months (range, 1.1-7.3). Among major
`responders, the median time to achieving a 50% reduction in
`serum IgM was 4.6 months (range, 2-13). Two patients
`displaying bulky adenopathy (n = 2) and/or splenomegaly
`(n = 1) had complete resolution of their extramedullary disease
`
`Waldenstrom’s Macroglobulinemia
`
`these disease sites following
`after experiencing pain at
`administration of lenalidomide and rituximab.
`Time to progression. The median TTP for all evaluable
`patients was 17.1 months (range, 2-34.3) (Fig. 2). With a
`median follow-up of 31.3 months, 4 of the 8 responding
`patients have progressed. The median TTP for all responding
`patients was 18.9 months (range, 11.4-34.3; Fig. 2).
`Changes in hematologic variables. Pre-therapy, 2 (16.6%)
`and 1 (8.3%) of the 12 evaluable patients showed hematocrit
`V30% and platelet count V100,000/AL, respectively. Following
`therapy, at best response, 1 (8.3%) and none of
`the 12
`evaluable patients showed hematocrit V30% and platelet count
`V100,000/AL, respectively. A significant increase in the median
`hematocrit at best response was noted for the 12 evaluable
`patients from 32.1% (range, 24-36.6%) to 36% (range, 29-
`40.8%) following therapy (P = 0.037). The observed increase in
`median hematocrit with therapy followed cessation and/or dose
`modification of lenalidomide. Pre- and post-therapy, median
`platelet counts remained unaffected by therapy (P = 0.22).
`Toxicities. Premature discontinuation of lenalidomide ther-
`apy occurred in 14 of 16 (88%) patients despite dose reduction
`in 13 of
`these patients and led to cessation of
`further
`enrollment on this study. Discontinuation of lenalidomide
`was based on aggravated anemia or anemia-related complica-
`tions for 13 patients, and/or concurrent myelosuppression
`(neutropenia, n = 1; thrombocytopenia, n = 1), as well as
`development of lenalidomide-related palpitations in 1 patient.
`Acute decreases in hematocrit were observed during first
`2 weeks of lenalidomide therapy in 13 of 16 (81%) patients
`(Fig. 3). Within the first 2 weeks of therapy, the median
`hematocrit declined from 32.3% (range, 26.4-36.6%) to 27.1%
`(range, 24-32.4%). This decline was observed for most patients
`even after 1 week of being on lenalidomide alone and before
`receiving the first rituximab infusion. The median decrease in
`absolute hematocrit values at lowest point in the 2 weeks
`following start of lenalidomide was similar for all three start
`doses examined: -3.15% (25 mg; n = 11), -5.4% (20 mg; n = 1),
`and -3.75% (15 mg; n = 4). The decrease in hematocrit
`observed following initiation of
`lenalidomide therapy was
`deemed to be a factor, at least in part, for the hospitalization of
`4 patients due to congestive heart failure (n = 2), arrhythmia
`(n = 1), and syncope (n = 1). Examination of lactic dehydro-
`genase and reticulocyte counts post-lenalidomide in 4 patients
`who became anemic were unrevealing for hemolysis, and
`a bone marrow biopsy and aspiration done in 2 patients
`
`Fig. 1. Individual changes (%) in serum IgM
`levels at best response following treatment
`with lenalidomide and rituximab.
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`Fig. 2. TTP for (A) all evaluable patients and (B) those who responded to
`lenalidomide and rituximab. Open circles, patients who had not progressed at last
`follow-up.
`
`showed normal or mildly decreased erythroid elements. No
`overt blood loss was seen. Erythropoietin administration was
`required for 10 patients along with transfusional support
`consisting of packed RBC and platelets for 7 and 1 patients,
`respectively, as a consequence of lenalidomide. Although no
`dose reduction in rituximab was permitted on this study,
`premature discontinuation for this treatment occurred in 3
`patients for rituximab-induced symptomatic hyperviscosity
`(n = 2) or anaphylaxis (n = 1). A complete list of all grade
`z2 toxicities and the treatment (lenalidomide, rituximab, or
`both) to which they are possibly, probably, or definitely
`attributed to appears in Table 2.
`Paradoxical
`increases in serum IgM levels. Abrupt and
`paradoxical increases in serum IgM levels have been reported
`with the use of rituximab in patients with WM and can
`aggravate hyperviscosity and contribute to hyperviscosity-
`related symptoms (14, 15). For this reason, plasmapheresis
`was strongly encouraged for patients who had a pre-therapy
`serum viscosity of z3.5 CP. Six patients underwent pre-therapy
`plasmapheresis. During the first four infusions of rituximab, an
`increase in serum IgM above baseline of z25% was observed in
`12 of 16 (75%) patients and prompted the use of plasmaphe-
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`resis in 7 of 16 (44%) patients. This paradoxical spike in serum
`IgM levels was not observed for the 10 patients who received
`the second 4-week course of rituximab, and none required
`plasmapheresis just before or during the second course of
`rituximab treatment. No spike in IgM levels was observed
`during the period patients were on lenalidomide monotherapy
`(during the first week) and only occurred following initiation
`of rituximab therapy.
`Effect of lenalidomide on immune effector cell levels. As part
`of this study, we assessed the effect of lenalidomide as an
`immunomodulating agent by determining changes in absolute
`total T cells (CD3+), natural killer cells
`median levels of
`(CD16+CD56+), helper T cells (CD4+), cytotoxic T cells (CD8+),
`as well as monocytes following 7 days of
`lenalidomide
`monotherapy and before the first rituximab infusion. The
`baseline and day 7 levels for these effector cells are provided in
`Table 3. No significant change in the level of total, CD4 and
`CD8 lymphocyte, natural killer cell, and monocyte peripheral
`blood levels was observed. In addition, no association with
`changes in any effector cell population and response was
`observed.
`
`Discussion
`
`Despite robust expression of CD20 in WM, responses to
`rituximab monotherapy are seen in less than half of treated
`patients, paralleling the experiences reported in other indolent
`non-Hodgkin’s lymphoma (4). Tumor-related variables includ-
`ing CD20 antigen loss, complement resistance antigen expres-
`sion, and tumor burden have been addressed previously by us
`and others and do not account for the heterogeneous response
`observed in WM patients treated with rituximab (16 – 18).
`The possibility that patient-related differences might account
`for the heterogeneity in rituximab response in WM patients
`was suggested by our previous studies, showing a high degree
`of dependence for its activity on polymorphisms present
`within the rituximab binding domain of FcgRIIIA (CD16;
`ref. 19). These studies also implicated antibody-dependent
`
`Fig. 3. Pre-therapy and lowest post-therapy hematocrit for 13 WM patients
`who showed aggravated anemia within a 2-week period of initiation of
`lenalidomide therapy.
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`Clin Cancer Res 2009;15(1) January 1, 2009
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`Table 2. Toxicities experienced by the 16 patients on study deemed to be possibly, probably, or definitely
`related to either lenalidomide, rituximab, or both
`
`Toxicity
`
`Grade 2, n (%)
`
`Grade 3, n (%)
`
`Grade 4, n (%)
`
`Attribution
`
`Waldenstrom’s Macroglobulinemia
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`Allergic reaction
`Anemia
`Arrhythmia
`Back pain
`Chest pain
`Diaphoresis
`Fatigue
`Headache
`Infection
`Leukopenia
`Liver function abnormalities
`Nausea
`Neutropenia
`Peripheral neuropathy
`Pleural effusion
`Pruritus
`Pulmonitis
`Thrombocytopenia
`Tinnitus
`Urinary urgency
`Visual impairment
`
`Abbreviation: NA, not applicable.
`
`1 (6.2)
`8 (50.0)
`2 (12.5)
`1 (6.2)
`NA
`1 (6.2)
`4 (25.0)
`2 (12.5)
`2 (12.5)
`6 (37.5)
`2 (12.5)
`1 (6.2)
`3 (18.7)
`1 (6.2)
`NA
`1 (6.2)
`NA
`1 (6.2)
`2 (12.5)
`1 (6.2)
`1 (6.2)
`
`NA
`1 (6.2)
`1 (6.2)
`NA
`1 (6.2)
`NA
`NA
`NA
`NA
`NA
`NA
`NA
`5 (31.2)
`NA
`1 (6.2)
`NA
`1 (6.2)
`1 (6.2)
`NA
`NA
`NA
`
`NA
`NA
`NA
`NA
`NA
`NA
`NA
`NA
`NA
`NA
`NA
`NA
`NA
`NA
`NA
`NA
`NA
`NA
`NA
`NA
`NA
`
`Rituximab
`Lenalidomide
`Lenalidomide
`Both
`Rituximab
`Lenalidomide
`Lenalidomide
`Rituximab
`Both
`Both
`Both
`Lenalidomide
`Lenalidomide
`Lenalidomide
`Rituximab
`Lenalidomide
`Rituximab
`Lenalidomide
`Lenalidomide
`Lenalidomide
`Rituximab
`
`cell-mediated cytotoxicity function, particularly mediated by
`FcgRIIIA-expressing natural killer cells, as being essential to
`rituximab response in WM patients. We therefore focused our
`efforts on enhancing rituximab efficacy by use of agents, which
`could augment natural killer cell levels as well as antibody-
`dependent cell-mediated cytotoxicity activity. Our previous
`findings showed that thalidomide could enhance circulating
`natural killer cells in MM patients, whereas thalidomide and
`more so its analogue lenalidomide enhanced rituximab-
`mediated antibody-dependent cell-mediated cytotoxicity activ-
`ity (6, 20). As such, we initiated clinical trials first examining
`the activity of thalidomide and thereafter lenalidomide in
`combination with rituximab.
`The results of the present study examining lenalidomide in
`combination with rituximab showed overall and major
`response rates of 50% and 25%, respectively, on an intent-to-
`treat basis. No complete responses were observed. The median
`TTP for responding patients was 18.9 months. Disappointingly,
`
`however, the overall and major response rates as well as the TTP
`observed with lenalidomide and rituximab appeared inferior to
`the results attained in our recent study with thalidomide and
`rituximab in a highly comparable patient population, wherein
`the overall and major response rates were 72% and 64%,
`respectively, and TTP for responding patients was 38.7 months.
`This finding is unexpected, particularly in context of previous
`findings by us and others showing greater immunostimulatory
`properties including enhanced antibody-dependent cell-medi-
`ated cytotoxicity activity for lenalidomide versus thalidomide
`(6, 20). Potential reasons for this discrepancy in activity for
`lenalidomide versus thalidomide could include higher rate
`of premature discontinuation of therapy due to intolerance
`(88% versus 44%) as well as greater nonimmunomodulatory
`mechanisms of action for thalidomide such as phosphodies-
`terase-4 inhibition. Impressive, however, was the observation of
`complete nodal responses in 2 patients with bulky adenopathy,
`which included 1 patient with marked (22 cm) splenomegaly.
`
`Table 3. Changes in peripheral blood effector cell
`patients with WM
`
`levels following 7 days of lenalidomide therapy in 16
`
`Peripheral blood effector cells
`
`Baseline level
`
`Post-7 days lenalidomide
`
`Lymphocytes
`Monocytes
`CD3+
`CD4+
`CD8+
`CD4/CD8 ratio
`CD16+/CD56+
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`1,185 (740-7,260)
`630 (110-1,320)
`827 (310-2,066)
`536 (140-1603)
`273 (131-856)
`1.68 (0.46-6.55)
`208 (37-392)
`
`770 (400-12,560)
`520 (10-1,900)
`436 (284-6,028)
`273 (55-7,132)
`180 (64-1,632)
`1.87 (0.39-9.71)
`259 (4-1,005)
`
`P
`
`0.87
`0.62
`0.89
`0.76
`0.80
`0.94
`0.51
`
`NOTE: Levels were determined before administration of first rituximab infusion. Median (range) for absolute circulating levels of total
`lymphocytes, monocytes, CD3+, CD4+, CD8+, and CD16+/56+ cells.
`
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`Cancer Therapy: Clinical
`
`This finding may hold particular relevance for the investigation
`of lenalidomide and rituximab in patients with other types of
`lymphomas.
`An important recognition in this study was the unexpected
`anemia produced by lenalidomide in patients with WM,
`particularly the acuity in which such decreases in hematocrit
`occurred. The mechanism for this finding remains to be
`clarified but suggests that
`lenalidomide may aggravate an
`underlying constitutional genetic defect perhaps central to the
`pathogenesis of WM itself given the uniqueness of
`this
`toxicity in WM patients. The immunomodulatory derivatives
`of
`thalidomide including lenalidomide and pomalidomide
`are known to dampen both erythroid maturation and/or
`erythroid colony formation in part through down-regulation
`of GATA-1, GATA-2, EKLF, and Gfi-1b (21, 22). Studies
`delineating the relative expression levels of these and other
`red cell transcription factors in stem cells of WM patients
`may help elucidate this idiopathic finding of lenalidomide-
`related anemia in this patient population. Unfortunately,
`despite aggressive dose reduction in lenalidomide, many
`patients did not tolerate lenalidomide because of faltering
`hematocrits at the doses and schedule examined in this study.
`Future trials using lower start doses of
`lenalidomide or
`alternative schedules could be considered in WM patients,
`although in view of the inferior outcomes observed in this
`trial with lenalidomide versus thalidomide with rituximab,
`other combinations should be considered, such as with
`bortezomib.
`
`Lastly, this study underscores the importance of conducting
`clinical trials in patients with various malignancies, because
`unexpected toxicities can often occur even among patients
`considered to have similar diseases. Although lenalidomide is
`known to produce late neutropenia and thrombocytopenia in
`patients with multiple myeloma at the same dose levels and
`schedule used in this study, WM patients experienced unex-
`pected aggravation of anemia as their drug-limiting toxicity.
`Similarly, we and others have reported unexpected or exagger-
`ated toxicities in WM patients with agents commonly employed
`in other related B-cell disorders such as the paradoxical IgM
`spike seen with rituximab or the higher incidence of peripheral
`neuropathy with bortezomib.
`In summary, the results of this study show that lenalidomide
`at conventional dosing and schedule can produce unexpected
`and acute declines in hematocrit in patients with WM, which
`are clinically significant and can result in hospitalizations.
`Moreover, in comparison with thalidomide and rituximab, the
`combination of lenalidomide and rituximab produced inferior
`outcomes in terms of both response rates and TTP in an
`analogous patient population.
`
`Disclosure of Potential Conflicts of Interest
`
`S.P. Treon, N.C. Munshi, and K.C. Anderson are members of the speakers’ bureau
`of and have received research support from Celgene, Inc. S.P. Treon is also a
`member of the speakers’ bureau of and has received research support from
`Genentech, Inc.
`
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