Clinical Roundtable Monograph

Chronic lymphocytic leukemia (CLL) is a B-cell leukemia mainly affecting older adults. Historically, CLL has been regarded as an incurable disease, and treatment has been confined to cytotoxic chemotherapy regimens. However, prognosis for patients treated with these agents remained poor, prompting the development of new, targeted agents. The introduction of rituximab, a CD20-targeted monoclonal antibody, revolutionized the treatment for this disease. Rituximab in combination with fludarabine improved response rates and length of progression-free survival. The success of rituximab in this setting has prompted the development of many more investigational agents for CLL, including other antibody agents. However, as with any medication, the potential benefit achieved with CLL therapies is mitigated by the safety risk for the patient. These agents have been associated with adverse events such as immunosuppression, reactivation of cytomegalovirus, and infusion-related reactions that can occur with antibody administration. Adverse events can greatly affect the patient’s quality of life and ability to tolerate therapy. Management of adverse events is a critical component of the overall treatment strategy for CLL, particularly in elderly patients. In this clinical roundtable monograph, 3 expert physicians discuss the latest clinical studies evaluating the treatment of CLL, focusing on the adverse events associated with each agent and the potential interventions that can be used to manage their occurrence. S u p p o r t e d t h r o u g h f u n d i n g f r o m C e p h a l o n O n c o l o g y C L I N I C A L R O U N D T A B L E M O N O G R A P H 2 Clinical Advances in Hematology & Oncology Volume 8, Issue 8, Supplement 17 August 2010 Disclaimer Funding for this Clinical Roundtable Monograph has been provided through funding from Cephalon Oncology. Support of this monograph does not imply the supporter’s agreement with the views expressed herein. Every e!ort has been made to ensure that drug usage and other information are presented accurately; however, the ultimate responsibility rests with the prescribing physician. Millennium Medical Publishing, Inc, the supporter, and the participants shall not be held responsible for errors or for any consequences arising from the use of information contained herein. Readers are strongly urged to consult any relevant primary literature. No claims or endorsements are made for any drug or compound at present under clinical investigation. ©2010 Millennium Medical Publishing, Inc., 611 Broadway, Suite 310, New York, NY 10012. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form. One of the most pivotal practice-changing events in the treatment of chronic lymphocytic leukemia (CLL) has occurred with the introduction of monoclonal antibodies to treat the disease. Although the CD52-targeted monoclonal antibody alemtuzumab was the "rst to be approved for CLL, other antibodies directed against a diverse array of targets are now under evaluation for this disease as well. In addition, alternative treatments are now being explored for patients with relapsed/refractory disease. However, each of these treatments is associated with an adverse event (AE) pro"le, and managing these AEs is an important step in maximizing the bene"t-to-risk ratio for each patient. Studies Involving Monoclonal Antibodies Rituximab Rituximab was only recently approved by the US Food and Drug Administration for the treatment of CLL in combination with other drugs. When given as a single agent, rituximab is not typically associated with a particularly high response rate. #erefore, high-dose rituximab monotherapy has been investigated as a potential alternative to improve response. In a study of 33 patients with either CLL or small lymphocytic leukemia, a thrice weekly dosing schedule of single-agent rituximab was found to be active and well tolerated, producing an overall response rate (ORR) of 45%.1 Similarly, a dose-escalation trial in CLL patients also showed that higher rituximab doses elicited an anti-tumor response.2 In this study, response was shown to be correlated with dose; patients receiving the lowest rituximab doses (500–825 mg/m2) had an ORR of 22%, whereas patients receiving the highest rituximab dose (2,250 mg/m2) had an ORR of 75%. Recently, a report by Adiga and Wiernik showed that highdose (up to 3 g/m2) single-agent rituximab was e!ective in patients with treatment-refractory or poor-prognosis CLL.3 #e ORR reported in this study of 23 patients was 90.9%, with 54.5% of patients achieving a complete response. #e median progression-free survival (PFS) was 12.5 months. #us, together these studies indicate there may be a role for single-agent rituximab, when administered at higher doses, in the treatment of CLL. #e use of rituximab clearly enhances the activity of combination therapy regimens. #e updated results of the CLL8 study, which compared $udarabine/cyclophosphamide (FC) alone with FC plus rituximab (FCR), were presented by Hallek and colleagues.4 #e now proven bene"t in overall survival (OS) conferred by the addition of rituximab continues to reinforce FCR as a standard of care for the treatment of CLL. In addition to the traditional FC chemotherapy regimen, novel combinations with rituximab are being explored as potential treatment regimens. One of these involves lenalidomide, an immunomodulatory agent whose singleagent activity in CLL is itself under investigation.5 For example, one study suggested that lenalidomide treatment was active in patients with high-risk CLL,6 whereas another reported complete and partial responses after lenalidomide treatment in relapsed/refractory CLL.7 However, there is a risk for life-threatening tumor $are with lenalidomide Managing Adverse Events Associated With Monoclonal Antibodies and Other Alternative CLL Therapies Thomas Kipps, MD, PhD C L I N I C A L R O U N D T A B L E M O N O G R A P H Clinical Advances in Hematology & Oncology Volume 8, Issue 8, Supplement 17 August 2010 3 treatment in CLL.8 In an abstract by Ferrajoli and colleagues, the combination of rituximab and lenalidomide was investigated in a prospective, nonrandomized phase II study that included 44 evaluable patients with relapsed CLL.9 #e ORR reported after 12 cycles of therapy was 64%. Although no complete responses were reported after cycle 6, the complete response rate after cycle 12 was 9%. #e near partial response/partial response rates after cycles 6 and 12 were 64% and 54%, respectively. Although the median OS was not reached, the 1-year OS rate was 95%. Neutropenia (31%), fatigue (27%), and fever of unknown origin (18%) were the most common grade 3/4 AEs. Grade 3/4 tumor lysis syndrome occurred in 5% of patients, and 25% of patients had grade 1/2 tumor $are. Although the results of this study are encouraging, they are based on a small patient population that was not randomized to either agent alone, which makes it di%cult to reach a conclusion regarding this combination. However, it appears that the combination of rituximab with lenalidomide can improve response compared with lenalidomide alone. Hillmen and colleagues discussed an open-label phase II trial that evaluated rituximab combined with chlorambucil in previously untreated CLL.10 In this interim analysis, based on the "rst 50 patients enrolled, the ORR (intentto-treat population) was 84%, which was determined to be 17.3% higher than the overall response achieved with chlorambucil alone in a historic control cohort. A total of 25 serious AEs were reported; the majority of these were infections, although febrile neutropenia also occurred. Approximately 40% of patients experienced grade 3/4 neutropenia. Together, the investigators concluded that further evaluation of this combination was warranted in CLL patients. #e use of bendamustine, either alone or combined with rituximab, was explored by Rigacci and colleagues in a multicenter, retrospective study. Here, 173 patients from 16 Italian centers were included; patients had heavily pretreated CLL or another B-cell lymphoma. #e ORR was 73%, with 28% achieving a complete response. Out of 63 patients with CLL, 46 achieved a response. #e OS and PFS rates in CLL patients were 72% and 27%, respectively. Grade 3/4 neutropenia (23%), thrombocytopenia (12%), and anemia (11%) were the most common hematologic toxicities. Other studies explored this combination in more detail in a prospective design,11-14 as discussed by Dr. Stephan Stilgenbauer. In a unique regimen, Del Poeta and colleagues presented data from a study that treated patients with maintenance rituximab following induction $udarabine chemotherapy.15 A total of 120 patients were treated with 6 monthly courses of "rst-line $udarabine, followed a median of 31 days later by 4 weekly doses of maintenance rituximab therapy. CLL patients who underwent consolidation and maintenance therapy showed a longer response duration than those with minimal residual disease who did not undergo maintenance therapy. Although the ORR was very good following consolidation and maintenance therapy, the lack of randomization makes the median PFS and OS rates di%cult to interpret. Ofatumumab Because of the success of rituximab, other CD20-targeted strategies have been developed as potential alternatives.16 #e fully human anti-CD20 monoclonal antibody ofatumumab is the most clinically advanced of these agents. Ofatumumab has been found to induce antibody-dependent cell-mediated cytotoxicity as well as complement-dependent cytotoxicity in CD20-positive B cells.17 Ofatumumab targets a unique epitope within CD20. After a phase I/II clinical study demonstrated that single-agent ofatumumab displayed marked clinical activity in relapsed/refractory CLL,18 its safety and e%cacy was further evaluated in a larger international study in $udarabine-refractory CLL patients with a poor prognosis. In an interim analysis of this international study, single-agent ofatumumab treatment resulted in an overall response up to 47%.19 Because of the studies, ofatumumab was approved for the treatment of CLL refractory to $udarabine and alemtuzumab.20 Although it is currently indicated for use as a singleagent, current e!orts have also focused on the e%cacy and safety of ofatumumab in combination with other agents. Wierda and colleagues reported the results from a multicenter, prospective, parallel-group, randomized phase II clinical trial that evaluated 2 di!erent doses of ofatumumab in combination with $udarabine and cyclophosphamide in 61 patients with previously untreated CLL.21 Patients were treated with six 4-week cycles of ofatumumab plus FC; the "rst cycle of ofatumumab included a dose of 300 mg for all patients, while the remaining cycles administered either 500 mg or 1,000 mg ofatumumab. Both doses of ofatumumab, combined with chemotherapy, were found to be highly active as frontline therapy. #e overall and complete response rates among all patients were 75% and 41%, respectively. #e ORRs for patients in the 500 mg and 1,000 mg arms were 77% and 73%, respectively. Although there was a trend towards a higher rate of complete response in the 1,000 mg arm compared with the 500 mg arm (50% vs 32%), the di!erence between those 2 dosing cohorts did not reach statistical signi"cance. Interestingly, subgroup analysis identi"ed particular characteristics that described those patients who had a higher response to treatment. Patient subgroups that achieved an ORR of greater than 80% included women, patients with lower (<4 mg/L) baseline β2 microglobulin levels, patients with lower (<30,000 cells/ mm3) baseline lymphocyte counts, patients with an unmutated IgVH gene, patients with no cytogenetic abnormalities, and patients who completed all 6 treatment cycles. In this study, ofatumumab combined with FC was well tolerated, with a toxicity pro"le similar to FCR. AEs occurred more C L I N I C A L R O U N D T A B L E M O N O G R A P H 4 Clinical Advances in Hematology & Oncology Volume 8, Issue 8, Supplement 17 August 2010 frequently in the 1,000 mg arm compared with the 500 mg arm. #e most common grade 3/4 AEs reported were cytopenias—including neutropenia (500 mg: 35%; 1,000 mg: 60%), thrombocytopenia (500 mg: 6%; 1,000 mg: 23%), and anemia (500 mg: 6%; 1,000 mg: 20%)—and infections (500 mg: 13%; 1,000 mg: 23%). #e infusion-site reactions that occurred with ofatumumab were all grade 1/2 in severity and were most common after cycles 1 and 2 of treatment. Overall, it was apparent from this study that the combination of ofatumumab with FC was well tolerated and active, warranting further studies comparing the activity of this regimen with that of FCR. GA101 GA101 is a third-generation humanized and glycol-engineered monoclonal antibody directed against CD20 that is being investigated for its activity against B-cell malignancies.22 GA101 binds to the unique epitope of CD20 with high a%nity. #is characteristic allows GA101 to induce antibody-dependent cell-mediated cytotoxicity at a 5to 100-fold greater potency than observed with rituximab.23 In an in vitro preclinical study, Patz and colleagues found that, compared to rituximab, GA101 could induce a higher degree of B-cell depletion in treated whole blood samples (32% vs 11%).24 Furthermore, GA101 was also superior to rituximab in inducing death in isolated CLL samples (21% vs 6%). In addition to this preclinical study, an early phase I dose-escalating clinical study was reported by Morschhauser and colleagues, which evaluated GA101 in relapsed/refractory CLL.25 In this study, GA101 was administered as a single agent to 13 patients with CD20-positive CLL with relapsed/refractory disease for whom no other approved therapy was available. Patients received doses of GA101 that ranged from 400 mg to 2,000 mg on days 1, 8, and 22 and then subsequently every 3 weeks, for a total of 9 infusions. No dose-limiting toxicities were reported, and no dose reductions were required. #e most common AEs were grade 1/2 infusion-related reactions; these occurred most often with the "rst infusion. Grade 3/4 hematologic toxicities that occurred included transient neutropenia (n=9), febrile neutropenia (n=1), and transient thrombocytopenia (n=1). A total of 3 patients experienced serious AEs, including febrile neutropenia, thrombocytopenia, bronchitis, gingivitis, neutropenia, and tumor lysis syndrome. Infections occurred in 10 patients. In all 13 patients, B-cells were almost completely depleted from the "rst infusion; this e!ect remained sustained over the course of treatment. #e ORR was 62%, including 1 patient with a complete response but persistent cytopenias, 7 patients with a partial response, and 5 patients with stable disease. #e duration of response was reported to be over 8 months in some cases. Response to GA101 was not associated with any particular FcγIIIRA genotype, suggesting it may not be in$uenced by polymorphisms that may contribute to rituximab resistance. #e activity of GA101 is notable, particularly in this population of patients with relapsed/refractory CLL, and suggests that further studies of this antibody are needed. Alemtuzumab #e CD52-directed monoclonal antibody alemtuzumab is currently approved for use as a single-agent treatment of CLL.26 Single-agent alemtuzumab was established as a frontline therapy for CLL in a large, randomized study in which it was compared to chlorambucil as "rst-line therapy for 297 patients.27 Compared with chlorambucil, alemtuzumab therapy resulted in a signi"cantly improved PFS (42% reduction in risk of death or progression, hazard ratio [HR], 0.58; P=.0001) and median time to alternative treatment (23.3 vs 14.7 months; HR, 0.54; P=.0001). A signi"cant improvement in overall response was also observed with alemtuzumab compared with chlorambucil (83% vs 55%; P<.0001). #e AE pro"les were largely similar between alemtuzumab and chlorambucil, except for a higher frequency of infusion-related events and cytomegalovirus (CMV) infections with alemtuzumab. An important phase II clinical trial also showed that single-agent alemtuzumab therapy can be used for the treatment of relapsed/refractory CLL.28 In this study, 24 patients who had relapsed from prior therapy with $udarabine were treated with alemtuzumab. A partial response was documented in 33% of patients; no complete responses were reported. #e median time to response was 3.9 months (range, 1.6–5.3 months). Responses were durable, lasting for a median of 15.4 months (range, 4.6 to ≥38.0 months). #e median TTP was 19.6 months (range, 7.7 to ≥42.0 months), and the median patient survival time was 35.8 months (range, 8.8 to ≥47.1 months). A major opportunistic infection occurred in 10 patients on-study. #us, this study showed that alemtuzumab had signi"cant activity in CLL patients with $udarabine-relapsed/refractory disease. Because of its demonstrated bene"t as a single agent, much excitement has surrounded the possibility of combining alemtuzumab with other treatments to increase their e%cacy. Two of these, the combination of $udarabine with alemtuzumab (FluCam) and the combination of $udarabine plus cyclophosphamide with alemtuzumab (FC-Cam),29,30 are discussed in detail by Dr. Stilgenbauer. Additionally, Engert and colleagues reported preliminary results from a phase III trial that compared $udarabine plus alemtuzumab to $udarabine alone as second-line treatment in 335 patients with relapsed/refractory CLL.31 Signi"cantly, the median PFS was prolonged for patients who received the combination therapy compared with single-agent $udarabine (29.6 vs 20.7 months; HR, 1.63; P=.005). However, the signi"cant PFS improvement with $udarabine plus alemtuzumab C L I N I C A L R O U N D T A B L E M O N O G R A P H Clinical Advances in Hematology & Oncology Volume 8, Issue 8, Supplement 17 August 2010 5 was restricted to patients with Rai stage III or IV disease. #e rates of overall response (84.8% vs 68.0%; P<.001) and complete response (30.4% vs 16.4%; P=.002) were also signi"cantly improved among patients who received the alemtuzumab/$udarabine combination. Importantly, the combination treatment was well tolerated, with a similar incidence of grade 3/4 toxicities (including infectious complications) in both treatment arms. Although FCR has established activity for the frontline therapy of patients with CLL, there is a subset of patients who do not respond well to treatment with this regimen. #ese patients exhibit high-risk features, such as elevated serum β2-microglobulin levels and/or those with leukemia cells that have deletions in the short arm of chromosome 17 (17p).4,32 In fact, this cytogenetic abnormality can result in loss of a functional p53 tumor protein, a protein that governs the response of a cell to chemotherapy-induced genotoxic stress, and the loss of which may explain the reduced response to treatment among these patients.33 Unlike with rituximab, the 17p chromosomal deletion does not seem to have the same e!ect on alemtuzumab, as patients with this abnormality generally remain quite responsive to this antibody provided they do not have bulky adenopathy.34-36 #us, Parikh and colleagues evaluated the CFAR regimen, which is comprised of alemtuzumab added to the chemoimmunotherapy regimen of FCR.37 Frontline CFAR was investigated for its ability to improve response and survival in these high-risk patients. #is study included 60 patients with high-risk CLL; all patients had a β2 microglobulin level of 4 mg/L or higher. A median of 4 treatment courses (range, 2–6) of CFAR were administered. #e median OS had not been reached, and the median time to disease progression (TTP) was 38 months. A very high (92%) rate of overall response was achieved; it included a 70% rate of complete response. #e investigators found no signi"cant correlation between the response to CFAR and several disease characteristics, including Rai stage of disease, IgVH mutation status, cytogenetic status, or high-level expression of the ZAP70 or CD38 proteins. However, patients with either the 17p chromosomal deletion or an unmutated IgVH gene experienced a signi"cantly shortened median TTP compared with the overall population (18 months; P=.001 and 33 months; P=.01, respectively). #e incidence of grade 3/4 neutropenia and thrombocytopenia was 31% in patients with either the 17p chromosomal deletion or an unmutated IgVH gene compared with 13% in the overall population; in a historic cohort of high-risk patients treated with FCR, these rates were 31% and 10%. Although 17% of patients experienced a major infection (including pneumonia and sepsis), minor infections (including herpes zoster and urinary tract infections) occurred in 25%. Again, these rates were compared to 15% and 23% in a historic cohort treated with FCR, showing that CFAR therapy resulted in a similar incidence of hematologic toxicity and infection in this patient population. CMV reactivation occurred in 12% of patients despite prophylactic therapy; 1 patient died due to CMV pneumonia. Despite the excellent response to alemtuzumab displayed by these high-risk patients overall, the shortened TTP reached by patients with the 17p chromosomal deletion was discouraging. #e reason for this outcome is unclear, and it remains to be seen if the CFAR regimen provides bene"t over FCR in these high-risk CLL patients. Consolidation therapy with alemtuzumab was explored as a possible treatment option in a phase III, randomized controlled trial of the German CLL Study Group (GCLLSG).38 In this study, patients who achieved a response to chemotherapy (either $udarabine alone or $udarabine combined with cyclophosphamide) were randomized to either treatment with alemtuzumab or observation alone. Of the 21 evaluable patients included in this study, 11 had been randomized to the alemtuzumab arm before the trial was halted prematurely, due to severe infections occurring in 7 of these 11 patients. At 6-month follow-up after randomization, 2 patients in the alemtuzumab arm had achieved a complete response, while 3 patients in the observation arm experienced disease progression. Recently, long-term followup (median follow-up of 48 months) of this study was reported.39 #is follow-up showed that despite the increased toxicity associated with alemtuzumab, patients who were randomized to this treatment experienced a signi"cantly prolonged PFS compared to those patients who received observation alone (P=.004). Despite the small patient population in this study, this di!erence was highly signi"cant. #e Cancer and Lymphoma Group B (CALGB) study 10101 was another trial that evaluated consolidation alemtuzumab therapy, with results "rst reported in 2007.40 Lin and colleagues recently presented "nal toxicity and response data from this study.41 In this phase II trial, 102 previously untreated symptomatic CLL patients received $udarabine plus rituximab induction therapy followed by consolidation therapy with alemtuzumab. Although the initial study design called for all patients to receive alemtuzumab consolidation therapy, a high infection incidence among patients who achieved a complete response to induction therapy caused the protocol to be amended so that only patients who achieved a partial response or stable disease would receive alemtuzumab. After induction therapy, the rates of overall, complete, and partial response were 90%, 29%, and 61%, respectively. Alemtuzumab was administered to 58 patients; of these, 72% completed the planned 6 weeks of treatment. After consolidation therapy, the rates of overall, complete, and partial response were 91%, 66%, and 26%, respectively. Over half (62%) of patients who were in partial response after induction therapy achieved a complete response with alemtuzumab. In an intent-to-treat analysis, 42% of patients achieved minimal residual disease negativity. At a median followC L I N I C A L R O U N D T A B L E M O N O G R A P H 6 Clinical Advances in Hematology & Oncology Volume 8, Issue 8, Supplement 17 August 2010 Roberts and colleagues reported results from M06-873, an ongoing phase I/II dose-escalation trial of ABT-263 in relapsed/refractory CLL.47 #e ORR was 33%; of the 21 evaluable patients included, 2 patients achieved a partial response and 3 patients had an uncon"rmed nodal regression. At the time of the report, the median PFS had not yet been reached. #e most common AEs reported included diarrhea (52%), nausea (44%), vomiting (24%), fatigue (24%), thrombocytopenia (20%), and neutropenia (12%). Dose-limiting toxicities were observed in some patients, prompting the investigators to determine the recommended phase II dosing to be a lead-in dosage of 100 mg for 7 days, followed by 250 mg/day continuous dosing. Based on these promising results, as well as preclinical data suggesting that ABT-263 may act additively or synergistically with other agents used to treat CLL,48 it is actively being explored in possible combination regimens. Gene !erapy Castro and colleagues presented an abstract suggesting that gene therapy could chemosensitize some patients to FCR therapy. #is study relied on evidence that had previously shown that CLL cells containing the 17p chromosomal deletion, when co-cultured in vitro with cells transduced to express the CD40 ligand CD154, could induce expression of the p73 protein.49 Like p53, the p73 protein is a tumor suppressor that can mediate genotoxic stress–related cell death in response to chemotherapy. Additionally, direct transduction of del(17p) CLL cells with an adenovirus encoding CD154 can induce p73 expression in both the transduced as well as bystander CLL cells. Based on this, Castro and colleagues conducted a phase Ib trial in which patients with high-risk CLL who were either $udarabine-refractory or had the 17p chromosomal deletion underwent gene therapy.50 All patients received 3 doses of autologous CLL cells that had been transduced with an adenovirus expressing CD154. Two weeks later, patients were treated with a truncated FCR regimen. Although the CLL cells initially collected from patients were shown to be resistant to $udarabine-induced apoptosis, the CLL cells collected 24 hours or more after the "rst infusion of autologous CLL cells became sensitive to $udarabine. At the time of the report, 2 patients had completed treatment; both achieved a complete response and 1 patient had no detectable minimal residual disease. Additionally, both patients had complete resolution of lymphadenopathy and organomegaly. Both patients had tolerated therapy well with no serious AEs. #e most frequent toxicities reported included transient fever, malaise, and fatigue, all associated with cell transfusion, and cytopenias following FCR treatment. #us, the investigators concluded that CD154 gene therapy via autologous cell delivery could induce in vivo sensitivity to FCR in highrisk patients. up of 34 months, the median PFS was 37 months; the 2-year PFS and OS rates were 73% and 86%, respectively. #ere was no signi"cant di!erence in either PFS or OS between patients who did or did not receive alemtuzumab. During alemtuzumab therapy, grade 3/4 neutropenia and thrombocytopenia occurred in 43% and 19% of patients, respectively. Prior to study amendment, 5 deaths due to infection occurred among patients who achieved a complete response to induction therapy and were subsequently treated with alemtuzumab. One patient who achieved a partial response after induction therapy died due to infection after going on to receive alemtuzumab consolidation therapy. Overall, these results suggest that while patients seem to derive a bene"t from alemtuzumab consolidation therapy, the potential for serious infection is great. TRU-016 TRU-016 is an IgG fusion protein directed against the CD37 antigen, a member of the tetraspanin family that has a predominant expression on normal and malignant B cells. #is agent was developed by humanizing the mousehuman chimeric protein SMIP-016, which in preclinical studies had previously demonstrated antitumor activity in lymphoid malignancies.42 A phase I clinical trial of TRU-016 was reported by Andritsos and colleagues, which demonstrated promising clinical activity in 32 patients with relapsed/refractory CLL.43 #is dose-escalation study employed TRU-016 from 0.03 mg/kg up to a dose of 10 mg/kg; the maximum tolerated dose had not been reached. A total of 12 serious AEs were reported; of these, 3 may have been related to TRU-016 therapy (grade 4 neutropenia, presumed herpes zoster, and immune and idiopathic thrombocytopenic purpura). Clinical activity was evident in patients who received as little as 0.3 mg/kg TRU-016. Responses included 1 partial response in a patient with a 17p chromosomal deletion, 2 patients with complete or partial clearing of leukemia cutis, and an 83% median reduction in peripheral lymphocytosis. Based on these positive results, evaluation of this study population will continue, and future studies investigating TRU-016 are warranted. Studies Involving Alternative Therapies BH3 Mimetics ABT-263 is a novel orally available BH3 mimetic that has been found to have antitumor activity in preclinical studies.44 #e rationale for the use of a BH3 mimetic in hematologic malignancies is based on its ability to antagonize the e!ect of the anti-apoptotic Bcl-2 family member proteins, whose expression is often increased in these cancers.45 Speci"cally, ABT-263 has been shown to potently induce apoptosis in lymphoma cell lines and primary cells (including CLL) that overexpress the Bcl-2 protein.46 C L I N I C A L R O U N D T A B L E M O N O G R A P H Clinical Advances in Hematology & Oncology Volume 8, Issue 8, Supplement 17 August 2010 7 should be used. #ere is also a high incidence (in nearly 50% of patients) of CMV reactivation. #is AE requires recognition either by polymerase chain reaction or clinical suspicion and may require treatment with valganciclovir.