Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell Lymphoma (original) (raw)

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N Engl J Med. Author manuscript; available in PMC 2015 Jul 24.

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PMCID: PMC4513941

NIHMSID: NIHMS558061

Michael L. Wang, M.D., Simon Rule, M.D., Peter Martin, M.D., Andre Goy, M.D., Rebecca Auer, M.D., Ph.D., Brad S. Kahl, M.D., Wojciech Jurczak, M.D., Ph.D., Ranjana H. Advani, M.D., Jorge E. Romaguera, M.D., Michael E. Williams, M.D., Jacqueline C. Barrientos, M.D., Ewa Chmielowska, M.D., John Radford, M.D., Stephan Stilgenbauer, M.D., Martin Dreyling, M.D., Wieslaw Wiktor Jedrzejczak, M.D., Peter Johnson, M.D., Stephen E. Spurgeon, M.D., Lei Li, Ph.D., Liang Zhang, M.D., Ph.D., Kate Newberry, Ph.D., Zhishuo Ou, M.D., Nancy Cheng, M.S., Bingliang Fang, Ph.D., Jesse McGreivy, M.D., Fong Clow, Sc.D., Joseph J. Buggy, Ph.D., Betty Y. Chang, Ph.D., Darrin M. Beaupre, M.D., Ph.D., Lori A. Kunkel, M.D., and Kristie A. Blum, M.D.

Departments of Lymphoma and Myeloma (M.L.W., J.E.R., L.Z., K.N., Z.O.), Stem Cell Transplantation and Cellular Therapy (M.L.W.), Experimental Radiation Oncology (L.L.), and Thoracic and Cardiovascular Surgery (B.F.), University of Texas M.D. Anderson Cancer Center, and Baylor College of Medicine (N.C.) — both in Houston; the Department of Haematology, Derriford Hospital, Plymouth (S.R.), Department of Haemato-Oncology, Barts Health National Health Service (NHS) Trust, London (R.A.), Christie NHS Foundation Trust and the University of Manchester, Manchester (J.R.), and Cancer Research UK Centre, University of Southampton, Southampton (P.J.) — all in the United Kingdom; the Division of Hematology–Oncology, Weill Cornell Medical College, New York (P.M.); Chronic Lymphocytic Leukemia Research and Treatment Program, Division of Hematology and Medical Oncology, Department of Medicine, Hofstra North Shore–Long Island Jewish Medical Center, New Hyde Park, NY (J.C.B.); the John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ (A.G.); the Department of Medicine, Division of Hematology and Oncology, University of Wisconsin, Madison (B.S.K.); the Department of Hematology, Jagiellonian University, Krakow (W.J.), Oddzial Kliniczny Onkologii Centrum Onkologii, Bydgoszcz (E.C.), and Medical University of Warsaw, Warsaw (W.W.J.) — all in Poland; the Department of Medicine, Division of Oncology, Stanford University Medical Center, Stanford (R.H.A.), and Pharmacyclics, Sunnyvale (J.M., F.C., J.J.B., B.Y.C., D.M.B., L.A.K.) — both in California; University of Virginia School of Medicine, Charlottesville (M.E.W.); Universitätsklinikum Ulm, Klinik für Innere Medizin II, Ulm (S.S.), and Klinikum der Universität München–Campus Grosshadern, Munich (M.D.) — both in Germany; Oregon Health and Science University, Portland (S.E.S.); and the Division of Hematology, Ohio State University Comprehensive Cancer Center, Columbus (K.A.B.).

Address reprint requests to Dr. Wang at the University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 429, Houston, TX 77030, or at gro.nosrednadm@gnawim.

Supplementary Materials

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Abstract

BACKGROUND

Bruton's tyrosine kinase (BTK) is a mediator of the B-cell–receptor signaling pathway implicated in the pathogenesis of B-cell cancers. In a phase 1 study, ibrutinib, a BTK inhibitor, showed antitumor activity in several types of non-Hodgkin's lymphoma, including mantle-cell lymphoma.

METHODS

In this phase 2 study, we investigated oral ibrutinib, at a daily dose of 560 mg, in 111 patients with relapsed or refractory mantle-cell lymphoma. Patients were enrolled into two groups: those who had previously received at least 2 cycles of bortezomib therapy and those who had received less than 2 complete cycles of bortezomib or had received no prior bortezomib therapy. The primary end point was the overall response rate. Secondary end points were duration of response, progression-free survival, overall survival, and safety.

RESULTS

The median age was 68 years, and 86% of patients had intermediate-risk or high-risk mantle-cell lymphoma according to clinical prognostic factors. Patients had received a median of three prior therapies. The most common treatment-related adverse events were mild or moderate diarrhea, fatigue, and nausea. Grade 3 or higher hematologic events were infrequent and included neutropenia (in 16% of patients), thrombocytopenia (in 11%), and anemia (in 10%). A response rate of 68% (75 patients) was observed, with a complete response rate of 21% and a partial response rate of 47%; prior treatment with bortezomib had no effect on the response rate. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months (95% confidence interval [CI], 15.8 to not reached), the estimated median progression-free survival was 13.9 months (95% CI, 7.0 to not reached), and the median overall survival was not reached. The estimated rate of overall survival was 58% at 18 months.

CONCLUSIONS

Ibrutinib shows durable single-agent efficacy in relapsed or refractory mantle-cell lymphoma. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01236391.)

Mantle-cell lymphoma is a distinct subtype of non-Hodgkin's lymphoma that has an aggressive clinical course and a poor prognosis.1 Current frontline combination chemotherapies2 and intensive chemoimmunotherapy followed by stem-cell transplantation have improved the outcome for patients with this disease.3,4 Although these regimens have high initial response rates, most patients eventually have a relapse and die from mantle-cell lymphoma. More effective agents are needed.

Constitutive activation of B-cell receptor signaling appears to be essential for the survival and proliferation of malignant B cells, an observation that has led to the design of inhibitors of B-cell receptor–associated kinases.3-5 Bruton's tyrosine kinase (BTK) has been identified as an essential component of the B-cell–receptor signaling pathway.6-9 An antigen-driven origin of mantle-cell lymphoma has been suggested,10 and genomic and expression profiling of samples from patients with mantle-cell lymphoma has identified proteins upstream of BTK, such as the spleen tyrosine kinase Syk, as important contributors to the growth and survival of mantle-cell lymphoma cells.11

Ibrutinib (PCI-32765) is an oral covalent inhibitor of BTK that significantly reduced the tumor burden in a rodent treatment and prevention model of mantle-cell lymphoma.12 In early-stage clinical trials, ibrutinib has shown antitumor activity in B-cell cancers.13-15 In a phase 1 study, ibrutinib induced a response in seven of nine patients with relapsed or refractory mantle-cell lymphoma; investigation of the side effects and efficacy at various doses in this study established 560 mg as the phase 2 dose.14 On the basis of these results, we conducted a phase 2, open-label trial to assess the efficacy and safety of ibrutinib at a daily dose of 560 mg in patients with relapsed or refractory mantle-cell lymphoma.

Methods

PATIENTS

Eligible patients had a confirmed diagnosis of mantle-cell lymphoma with cyclin D1 overexpression or translocation breakpoints at t(11;14) and measurable disease (lymph-node diameter, ≥2 cm). Patients had received at least one but no more than five previous lines of treatment, with no partial or better response to the most recent treatment regimen or with disease progression after the most recent regimen.

Other eligibility criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less (scores range from 0 to 5, with 0 indicating asymptomatic and higher numbers indicating increasing disability) and adequate organ function. An absolute neutrophil count of at least 0.75×109 per liter and a platelet count of at least 50×109 per liter were required unless the patient had bone marrow involvement by lymphoma.

STUDY DESIGN AND TREATMENT

This international open-label, phase 2 study was conducted at 18 sites. Patients with mantle-cell lymphoma were enrolled without randomization and were classified as either having received treatment with bortezomib (≥2 cycles) or not having received such treatment (<2 complete cycles or no prior bortezomib therapy). Single-agent bortezomib is a treatment approved by the Food and Drug Administration for patients with mantle-cell lymphoma that has progressed after at least one initial treatment. Therefore, a defined cohort of patients with prior bortezomib treatment was included in this study, and the combination of the two cohorts was representative of a broad population of patients with relapsed or refractory mantle-cell lymphoma. Patients received single-agent ibrutinib administered orally at a daily dose of 560 mg until progression of disease or until unacceptable levels of adverse events occurred. All the patients provided written informed consent.

The institutional review board at each site approved the study protocol, which was conducted according to the principles of the Declaration of Helsinki and the International Conference on Harmonisation Guidelines for Good Clinical Practice. The protocol, including the statistical analysis plan, is available with the full text of this article at NEJM.org.

STUDY OVERSIGHT

The academic authors were responsible for designing the study protocol and statistical analysis plan together with the sponsor, Pharmacyclics. The investigators and their respective research teams collected all the data, and the sponsor confirmed the accuracy of the data and compiled them for summation and analysis. Statistical analyses were performed by the biometrics group at Janssen Research and Development and were independently confirmed and validated by a separate statistical group at Pharmacyclics. The investigators had full access to the data and analyses for the compilation of this report. Manuscript drafts were prepared by all the authors, with editorial assistance from a professional medical writer paid by the sponsor. All the authors vouch for the accuracy and completeness of the data reported and for the adherence of the study to the protocol, and all the authors made the decision to submit the manuscript for publication.

ASSESSMENTS

The primary end point was the rate of overall response, defined as either a partial response or a complete response according to the Revised International Working Group Criteria for non-Hodgkin's lymphoma.16 In addition, a response evaluation based on computed tomographic (CT) and positron-emission tomographic (PET) scans, bone marrow–biopsy specimens, gastrointestinal biopsy specimens (if a gastrointestinal biopsy was performed), and clinical data was conducted by an independent central review vendor (BioClinica). Tumor assessment was performed during screening with the use of CT scans of the chest, abdomen, pelvis, and any other disease sites (e.g., neck); PET scans; and bone marrow biopsy. CT scanning was repeated at cycles 3, 5, and 7 and then every three cycles until disease progression. A PET scan was mandatory for confirmation of a complete response.

The secondary end points included response duration, measured from the time when the criteria for a response were met until the first date on which recurrent or progressive disease was objectively documented; progression-free survival, measured as the time from the first administration of the study drug until lymphoma progression or death from any cause; overall survival, measured from the time of the first administration of the study drug until the date of death; and safety. Safety was assessed on the basis of the frequency and severity of adverse events. Adverse events were graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0.17 The safety assessment was based on reported adverse events, clinical laboratory tests (hematologic testing, serum chemical testing, and urinalysis), measurements of weight and vital signs, physical examinations, and ECOG performance status.

PERIPHERAL-BLOOD LYMPHOCYTE COUNTS

In chronic lymphocytic leukemia, ibrutinib causes a transient increase in blood lymphocytes that is concurrent with a reduction in lymph-node size.15 Whether a similar phenomenon occurs in patients with mantle-cell lymphoma was investigated by counting and characterizing peripheral-blood lymphocytes after treatment with ibrutinib (see the Supplementary Appendix, available at NEJM.org). The effect of ibrutinib on cytokine expression was also evaluated in a subset of patients (see the Supplementary Appendix).

STATISTICAL ANALYSIS

The sample for this study was 115 patients; we planned to include 65 patients with no prior treatment with bortezomib and 50 with prior bortezomib treatment. With the use of Simon's two-stage design18 (see the study protocol), the study was designed to check the efficacy of the drug in a small group of patients before enrolling the entire planned study population. If an appropriate number of patients had a response in the first stage (see below), then we would continue enrollment; if the level of response did not meet our success criteria for clinical benefit, the study would be terminated for that group.

For the cohort of patients without prior treatment with bortezomib, a two-stage design was planned to test the null hypothesis that the response rate would be 20% or less (i.e., before the investigators could proceed to stage 2 of the study, at least 6 of 25 patients had to have a response). We calculated that a sample of 65 patients would provide 91% power to test a difference in the response rate of 20% versus 40% at a one-sided alpha level of 0.01. For the cohort of patients with prior bortezomib treatment, a two-stage design was planned to test the null hypothesis that the response rate would be 15% or less (i.e., before the investigators could proceed to stage 2 of the study, at least 5 of 25 patients had to have a response). We calculated that a sample of 50 patients would provide 80% power to test a difference in the response rate of 15% versus 35% at a one-sided alpha level of 0.01.

In each cohort, an interim analysis for futility was conducted on the basis of the stopping rules for Simon's two-stage design.18 On the basis of this interim analysis, enrollment in both study cohorts was allowed to continue, per protocol.

The final analysis was planned to be performed approximately 8 months after the last patient was enrolled in the study. Frequency tables were used to summarize categorical variables. The distribution of time-to-event end points, including response duration, progression-free survival, and overall survival, were estimated with the use of the Kaplan–Meier method.19 All statistical tests were based on a two-sided alpha level of 0.05.

RESULTS

PATIENTS AND TREATMENT

From February 15, 2011, through March 21, 2012, a total of 115 patients with relapsed or refractory mantle-cell lymphoma were enrolled without randomization. We classified patients into two groups: patients with prior bortezomib treatment (50 patients) or no prior bortezomib treatment (65 patients, including 58 who had never received bortezomib and 7 who had received fewer than two cycles). The baseline characteristics of the patients in the two groups are provided in Table 1.

Table 1

Demographic and Baseline Clinical Characteristics.*

Of the 115 enrolled patients, 3 (2 patients with prior bortezomib treatment and 1 without prior treatment) did not receive the study drug owing to rapid disease progression, and 1 was not treated for administrative reasons. A total of 111 patients received at least one dose of ibrutinib, and the median number of cycles administered in the overall study population was 9 (range, 1 to 24).

With an estimated median follow-up of 15.3 months (range, 1.9 to 22.3), 46 patients were still receiving treatment, and 65 had discontinued therapy. Reasons for treatment discontinuation included progression of disease in 50 patients (including 2 patients who discontinued treatment within 30 days after the first dose and 1 with un-confirmed progression of disease), patient or investigator decision for 7 patients (including 1 patient who proceeded to stem-cell transplantation), and adverse events in 8 patients (including 2 patients with subdural hematomas, and 1 each with pneumonia, an elevated bilirubin level, sepsis, metastatic adenocarcinoma, respiratory failure, and cardiac arrest) (Table S1 in the Supplementary Appendix).

SAFETY

With continuous ibrutinib treatment, the majority of the adverse events observed were grade 1 or 2. The most common nonhematologic adverse events occurring in more than 20% of patients were diarrhea (in 50% of patients), fatigue (in 41%), nausea (in 31%), peripheral edema (in 28%), dyspnea (in 27%), constipation (in 25%), upper respiratory tract infection (in 23%), vomiting (in 23%), and decreased appetite (in 21%) (Table 2). The most common infection of grade 3, 4, or 5 was pneumonia (in 6% of patients) (Table S2 in the Supplementary Appendix). Serum IgM, IgG, and IgA levels did not change during treatment (data not shown). A decrease in neutrophils, platelets, or hemoglobin level was reported in less than 19% of patients.

Table 2

Adverse Events.*

Grade 3 and 4 hematologic adverse events included neutropenia (in 16% of patients), thrombocytopenia (in 11%), and anemia (in 10%). Grade 3 bleeding events occurred in five patients, with no grade 4 or 5 hemorrhagic events (Table S2 in the Supplementary Appendix). Four patients had subdural hematomas (grade 1 in one patient, grade 2 in one, and grade 3 in two); all were associated with falls, head trauma, or both. In addition, all four patients were receiving either aspirin or warfarin within 2 days before or on the date of occurrence of these events.

An adverse event leading to discontinuation of therapy occurred in 8 patients (7%) (Table S1 in the Supplementary Appendix). A total of 16 patients (14%) died during the trial, with 12 deaths due to disease progression and 4 due to an adverse event (2 deaths from pneumonia, 1 from sepsis, and 1 from a cardiac arrest that was deemed not to be drug-related).

EFFICACY

In the 111 patients who had received ibrutinib, the estimated median follow-up was 15.3 months (range, 1.9 to 22.3). The response rate for all patients was 68%, with 47% of patients having a partial response and 21% having a complete response (Table 3). The response to ibrutinib did not vary on the basis of baseline characteristics or the presence of risk factors associated with treatment failure with chemotherapy (Fig. 1). Of 43 patients with lymph nodes that were at least 5 cm in diameter, 27 (63%) had a response to treatment (Fig. S1 in the Supplementary Appendix). Response rates were similar in the two cohorts, and 17 of 27 patients (63%) previously treated with lenalidomide had a response to ibrutinib. The overall response rate and the complete response rate also improved over time with continued therapy.

Overall Response Rates According to Subgroup

This forest plot of data for all treated patients shows the overall response rate according to demographic and clinical characteristics and risk factors. The 95% confidence intervals (CIs) are based on normal approximation to the binomial distribution. The simplified Mantle-Cell Lymphoma International Prognostic Index (MIPI) score ranges from 0 to 11 and was derived with the use of the four prognostic factors of age, Eastern Cooperative Oncology Group (ECOG) performance-status score, lactate dehydrogenase level, and white-cell count at baseline. The index classifies patients as having low-, intermediate-, or high-risk disease, as defined by scores of 0 to 3, 4 or 5, and 6 to 11, respectively. ECOG performance-status scores range from 0 to 5, with 0 indicating asymptomatic, 1 symptomatic but ambulatory, and 2 symptomatic and in bed less than half the day; a score of more than 2 indicates only limited self-care and in bed more than half the day (3), completely disabled and confined to bed or chair (4), or dead (5). Advanced disease was defined as involvement of bone marrow, extranodal sites, or both; and refractory disease as a lack of at least a partial response to the last therapy before study entry. High-intensity therapy was defined as stem-cell transplantation; treatment with hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD); or treatment with a hyper-CVAD–like regimen.

Table 3

Best Response to Therapy.*

For the 75 patients who had a response at the time of data analysis, the estimated median response duration was 17.5 months (range, 0.0 to 19.6; 95% confidence interval [CI], 15.8 to not reached) (Fig. 2A and Table 3). The median time to a response was 1.9 months (range, 1.4 to 13.7), and the median time to a complete response was 5.5 months (range, 1.7 to 11.5). The estimated median progression-free survival among all treated patients was 13.9 months (range, 0.7 to 21.4; 95% CI, 7.0 to not reached) (Fig. 2B and Table 3). The median progression-free survival for patients who had a partial response as the best response was 17.5 months, and the median progression-free survival for those who had a complete response was not reached. The median overall survival for this study was also not reached (estimated overall survival rate of 58% at 18 months) (Fig. 2C and Table 3).

Duration of Response, Progression-free Survival, and Overall Survival

Panel A shows the duration of the response (shown as the percentage of patients alive without progression of disease) for the 75 patients who had a response; the estimated median duration was 17.5 months. For the 43 patients in the cohort without prior bortezomib treatment who had a response, the estimated median duration was 15.8 months. For the 32 patients in the cohort with prior bortezomib treatment who had a response, the median duration was not reached. Panel B shows progression-free survival for all 111 treated patients, according to cohort. In this analysis, data from the 1 patient who received subsequent anticancer therapy before progression of disease were censored at the time of the start of that therapy. For all patients, the estimated median progression-free survival was 13.9 months; for the 63 patients without prior borte zomib treatment and for the 48 with prior bortezomib treatment, the estimated median progression-free survival was 7.4 and 16.6 months, respectively. Panel C shows the results of the overall-survival analysis performed at the time of the primary analysis of progression-free survival, when 70 patients (63%) were alive. The median overall survival was not reached.

The efficacy data, which were further evaluated by an independent review committee, showed a response rate of 69%, with a complete response rate of 21% and a partial response rate of 48%. For 95% of patients with an investigator-assessed response, the response was confirmed by the independent review committee. The median response duration estimated by the independent review committee was 19.6 months.

MANTLE-CELL LYMPHOMA CELLS IN PERIPHERAL BLOOD

Ibrutinib has been shown to inhibit the adhesion of chronic lymphocytic leukemia cells20 and mantle-cell lymphoma cells21 in vitro, suggesting the potential to mobilize cells from tissues to the peripheral blood. The findings in a mouse model bearing human mantle-cell lymphoma cells en-grafted in subcutaneously implanted human fetal bone22 were consistent with these observations, revealing a substantial increase in mantle-cell lymphoma cells in the peripheral blood 10 days after ibrutinib treatment, followed by a decrease to near baseline by day 28 (data not shown). A total of 34% of patients had a transient increase in the absolute lymphocyte count (≥50% increase from baseline and >5000 cells per cubic millimeter) during the course of ibrutinib treatment, with the peak count occurring at a median of 4 weeks after the initiation of treatment (Fig. S2 in the Supplementary Appendix). Toward the end of the second cycle, the elevated lymphocyte levels decreased substantially and tapered off during cycle 4 or 5.

Peripheral-blood mononuclear cells obtained from patients before treatment and 1 week after treatment were subjected to triple staining for CD19, CD5, and CD3 and analyzed by means of flow cytometry. The increase in periph eral-blood lymphocytes included primarily CD19+CD5+CD3− lymphocytes (data not shown). The peripheral-blood CD19+CD5+CD3− cells showed a pattern of light-chain restriction, which was consistent with the presence of mantle-cell lymphoma cells in the peripheral blood, after 1 week of ibrutinib therapy. Ibrutinib treatment also led to a decrease in the secretion of macrophage inflammatory proteins 1_α_ (CCL3) and 1_β_ (CCL4), macrophage-derived chemokine (CCL22), and tumor necrosis factor α in most of the patients who were evaluated (Fig. S2 in the Supplementary Appendix).

DISCUSSION

This study shows the therapeutic activity of the oral BTK inhibitor ibrutinib in patients with relapsed or refractory mantle-cell lymphoma. Single-agent ibrutinib induced a high response rate (68%) and durable responses, given the relatively short period of follow-up (estimated median duration of response, 17.5 months) and the fact that patients who had a response included those who had risk factors for a poor outcome.

Safety data showed that grade 3 and 4 adverse events were uncommon with ibrutinib therapy (Table S3 in the Supplementary Appendix). Four patients had subdural hematomas during the study. The risk of subdural hematoma is known to increase with age, head trauma, falls, anticoagulant and antiplatelet therapies, and cardiovascular disease.23 Multiple factors contributing to subdural hematoma were identified in all four patients. Only one of the four had a low platelet count that required platelet transfusions. Subsequent studies have excluded the use of warfarin in clinical trials of ibrutinib; however, other anticoagulant agents are permitted. Randomized trials are required to determine whether bleeding associated with ibrutinib is increased in this patient population.

With respect to efficacy, a response rate of 68% and a complete response rate of 21% (complete response rate of 37% among the 51 patients who had been receiving treatment the longest) are high response rates for a single agent in this patient population. Previously, such a high rate of complete response in this population with substantial previous treatment has been achieved only with intensive chemotherapy regimens, such as ESHAP (etoposide, methylprednisolone sodium succinate, cytarabine, and cisplatin),24 MINE (mesna, ifosfamide, mitoxantrone [Novantrone], and etoposide),25 hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone),26 and R-ICE (rituximab, ifosfamide, carboplatin, and etoposide),27 all of which are myelotoxic. In contrast, conventional-dose salvage regimens achieve only modest response rates and short remissions.28,29

In conclusion, the BTK inhibitor ibrutinib is a highly active new agent showing durable single-agent activity in relapsed and refractory mantle-cell lymphoma. The favorable toxicity profile suggests that ibrutinib provides the opportunity for treatment with less intensive and more effective regimens than those currently available.

Supplementary Material

Supplementary File 1

Supplementary File 2

Supplementary File 3

Acknowledgments

Supported by Pharmacyclics and Janssen Biotech and by phil-anthropic funding provided to the M.D. Anderson Cancer Center by Edward Crutchfield.

Dr. Wang reports receiving grant support through his institution from Pharmacyclics and Janssen Biotech. Dr. Rule reports receiving consulting fees from Roche, Napp Pharmaceuticals, GlaxoSmithKline, and Celgene, and lecture fees from Roche, Napp Pharmaceuticals, and Johnson & Johnson. Dr. Martin reports receiving lecture fees from Janssen Biotech. Dr. Goy reports receiving payment for board membership from Millennium, Pharmacyclics, Johnson & Johnson, Seattle Genetics, Pfizer, and Celgene, and lecture fees from Millennium. Dr. Auer reports receiving payment for board membership from Gilead, consulting fees from Celgene, lecture fees from Roche, and travel support through her institution from Roche. Dr. Kahl reports receiving payment for board membership from Roche, Seattle Genetics, Millennium, and Cell Therapeutics, and consulting fees from Pharmacyclics, Gilead, Infinity Pharmaceuticals, and Genentech. Dr. Advani reports receiving grant support through his institution from Seattle Genetics and Genentech. Dr. Williams reports receiving consulting fees from Pharmacy-clics and grant support through his institution from Pharmacyclics and Janssen Biotech. Dr. Barrientos reports receiving consulting fees from Gilead and grant support through her institution from Abbott and Gilead. Dr. Radford reports receiving consulting fees from Millennium, Roche, Novartis, and GlaxoSmithKline, receiving lecture fees from Seattle Genetics, receiving payment for the development of educational presentations from Millennium, holding stock in GlaxoSmithKline and AstraZeneca, receiving grant support through his institution from Millennium and Amgen, and providing expert advice for Millennium and Mundipharma in licensing submissions to the European Medicines Agency. Drs. Stilgenbauer, McGreivy, Clow, Buggy, Chang, Beaupre, and Kunkel report being employees of and holding stock and stock options in Pharmacyclics. Dr. Dreyling reports receiving payment for board membership and lectures fees from Janssen Biotech, as well as grant support through his institution from Janssen Biotech. Dr. Jedrzejczak reports receiving consulting fees from Novartis, Janssen Biotech, and Amgen, lecture fees from Celgene and Novartis, and travel support from Roche and Pierre Fabre. Dr. Johnson reports receiving consulting fees from Janssen Biotech and Boehringer Ingelheim, lecture fees from Pfizer and Millennium, and grant support through his institution from Janssen Biotech. No other potential conflict of interest relevant to this article was reported.

We thank the investigators and coordinators at each of the clinical sites; the patients who participated in this trial and their families; the employees of Pharmacyclics who contributed to the design and implementation of this trial; Shuling Hwang, M.D., and Mei Cheng, Ph.D., for assistance with data collection and analyses; Namit Ghildyal, Ph.D., and Alison Sikora, Ph.D., for editorial assistance with an earlier version of the manuscript; and Nicolaus Wagner-Bartak, M.D., for critical expertise in interpreting the positron-emission tomographic and computed tomographic scans.

Footnotes

Presented in part at the Annual Meeting of the American Society of Hematology, San Diego, CA, December 11–13, 2011; and in part at the Annual Meeting of the American Society of Hematology, Atlanta, December 8–11, 2012.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

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