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Purpose: The first report from the open-label substudy of the phase III iNNOVATE study (PCYC-1127; NCT02165397) demonstrated that single-agent ibrutinib was efficacious and well tolerated in patients with heavily pretreated, rituximab-refractory Waldenstrom macroglobulinemia. Results from the final analysis are now reported. Patients and Methods: Ibrutinib 420 mg was administered once daily to patients (N = 31) who failed to achieve at least a minor response (MR) or who relapsed = partial response) rates increasing from 61% at 6 months to 77% at 60 months. Median OS was not reached. Seventeen of 21 patients (81%) with baseline hemoglobin

Additional file 2: Table S1. CLL patient and healthy donor characteristics.

Additional file 1. Supplementary methods. Table S1. Baseline covariates before and after weighting. Table S2. Prior medication uses after weighting. Table S3. Treatment emergent AEs (any grade, grade 3 or higher). Figure S1. Outcomes of patients with R/R MCL treated with zanubrutinib in the BGB-3111-AU-003 and BGB-3111-206 trial. (A) DOR in the BGB-3111-AU-003. (B) PFSin the BGB-3111-AU-003. (C) OS in the BGB-3111-AU-003. (D) DOR in the BGB-3111-206. (E) PFS in the BGB-3111-206. (F) OS in the BGB-3111-206. Figure S2. Outcomes of patients with R/R MCL treated with zanubrutinib. (A) DOR. (B) PFS. (C) OS. Figure S3. Outcomes of patients with R/R MCL treated with zanubrutinibas second- versus later-line therapy. (A) DOR before weighting. (B) PFS before weighting. (C) OS before weighting. (D) DOR after weighting. (E) PFS after weighting. (F) OS after weighting.

Additional file 1. SUPPLEMENTARY INFORMATION: Supplemental Methods; Table S1. Patient Disposition; Table S2. Safety Summary; Figure S1. SYMPATICO study schemas; Figure S2. Schema to determine randomized phase 3 dosing; Figure S3. Metabolic laboratory values and abnormalities in one patient with laboratory TLS; Supplementary Figure S4. Overall survival.

Additional file 1: Figure S1. Flow cytometry gating strategy. PBMC from HD or CLL patients were gated on single cells, lymphocytes, live cells, and CD19 + B or CD3 + T cells. The memory phenotype of CD8 + or CD4 + T cells was measured using Na��ve (N, CD27 + CD45RA +), Central memory (CM, CD27 + CD45RA-), effector memory (EM, CD27-CD45RA-), and terminally differentiated effector memory (TEMRA, CD27-CD45RA +) subsets. CD4 + and CD8 + T cells were also tested for the expression of PD-1, TIM3 and LAG3. Flow gating in the bottom row shows representative CD8 + T cell subsets. Figure S2. Generation 0���2 cell proliferation analysis. Proliferation of CD4 + and CD8 + T cells was measured using FlowJo cell proliferation analysis to identify 9 generations of dividing cells. Generation 0 represents undivided cells, and generation 9 represents cells that have undergone at least 8 divisions. The percentage of cells in generations 0, 1, and 2 was added to give a combined total % of cells in generations 0���2, representing undivided or early generation T cells. Figure S3. Stable memory phenotype CD8 + T cell subset frequency in CLL patients on long-term BTKi therapy. PBMC from CLL patients collected prior to treatment (baseline), or after long-term treatment of ibrutinib (n = 7) or zanubrutinib (n = 8) were compared to Healthy Donor (HD, n = 7). Na��ve (N, CD27 + CD45RA +), Central memory (CM, CD27 + CD45RA-), effector memory (EM, CD27-CD45RA-), and terminally differentiated effector memory (TEMRA, CD27-CD45RA +) cells (A-D) were calculated as a percentage of CD8 + T cells. Figure S4. Increased naive CD4 + T cell subset frequency in CLL patients on long-term BTKi therapy. PBMC from CLL patients collected prior to treatment (baseline), or after long-term treatment of ibrutinib (n = 7) or zanubrutinib (n = 8) were compared to Healthy Donor (HD, n = 7). Na��ve (N, CD27 + CD45RA +), Central memory (CM, CD27 + CD45RA-), effector memory (EM, CD27-CD45RA-), and terminally differentiated effector memory (TEMRA, CD27-CD45RA +) cells (A-D) were calculated as a percentage of CD4 + T cells. Figure S5. Ibrutinib inhibits cytokine release in CD4 + T cells from CLL patients in vitro. PBMC from untreated CLL patients (n = 5) were incubated with 1 ��M ibrutinib, zanubrutinib, or acalabrutinib, or DMSO vehicle control for 18 h prior to activation with T cell stimulation beads for 4 h. CD4 + T cell intracellular IFN�� production is shown, and statistical analysis was performed using mixed effects analysis with Tukey���Kramer test for multiple comparisons. Figure S6. Ibrutinib inhibits T cell cytotoxicity, cytokine release and proliferation of healthy donor T cells in vitro. PBMC from Healthy Donor (HD, n = 6) were incubated with 1 ��M ibrutinib, zanubrutinib, or acalabrutinib, or DMSO vehicle control for 18 h prior to activation with T cell stimulation beads for 4 h. CD8 + T cell degranulation (A) intracellular IFN�� production (B) are shown, and statistical analysis was performed using mixed effects analysis with Tukey���Kramer test for multiple comparisons. IL-2, IFN��, TNF�� and IL-4 levels in the supernatant were measured after 24 h of T cell activation bead stimulation of PBMC from HD (n = 4) in the presence of BTKi (C). The sensitivity of the assay was limited to 5000 pg/ml. Data was analysed using RM one-way ANOVA with Fisher���s LSD. Figure S7. Long-term BTKi treatment normalises CD8 + and CD4 + exhaustion marker expression in dividing T cells. Proliferation of PBMC from CLL patients collected at baseline or after long-term treatment of ibrutinib (n = 7) or zanubrutinib (n = 8), and Healthy Donor (HD, n = 7). PD-1, TIM3 and LAG3 cell surface expression (MFI) was measured on total CD8 + and CD4 + T cells (A-F). Data was analysed using Mann���Whitney (HD vs patient sample) or Wilcoxon matched-pairs signed rank (baseline vs treatment sample) tests.

Chaitra Ujjani, 1 Anthony Mato, 2 Brian T Hill, 3 John N Allan, 4 Frederick Lansigan, 5 Ryan Jacobs, 6 Alan Skarbnik, 7 Hande Tuncer, 8 John Pagel, 9 Danielle Brander, 10 Bruce Cheson, 11 Paul Barr, 12 Lindsey E Roeker, 2 Jeffrey Pu, 13 Nirav N Shah, 14 Andre Goy, 15Stephen J Schuster, 16 Nicole Lamanna, 17 Alison Sehgal, 18 Constantine S Tam, 19 Mazyar Shadman 1 1Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 2Division of Hematological Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 3Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA; 4Division of Hematology and Medical Oncology, New York Presbyterian & Weill Cornell, New York, NY, USA; 5Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA; 6Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute, Charlotte, NC, USA; 7Novant Health Cancer Institute, Charlotte, NC 28204, USA; 8Lowell General Hospital, Tufts Medical Center, Boston, MA, USA; 9Center for Blood Disorders and Stem Cell Transplantation, Swedish Cancer Institute, Seattle, WA, USA; 10Division of Hematologic Malignancies and Cellular Therapy, Duke University, Durham, NC, USA; 11Lombardi Comprehensive Cancer Center, Georgetown University Hospital, Washington, DC, USA; 12Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA; 13Division of Hematology/Oncology, SUNY Upstate Medical University, Syracuse, NY, USA; 14Division of Hematology & Oncology, Medical College of Wisconsin, Milwaukee, WI, USA; 15John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, USA; 16Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA; 17Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA; 18University of Pittsburgh Medical Center, Pittsburgh, PA, USA; 19Peter McCallum Cancer Centre, University of Melbourne, East Melbourne, VI, AustraliaCorrespondence: Chaitra UjjaniSeattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, 825 Eastlake Ave E, Mail Stop CE3-300, Seattle, WA, USATel +1 206-606-1955Fax +1 206-606-1130Email ujjani@uw.eduIntroduction: Recent randomized trials have demonstrated the efficacy of ibrutinib-based therapy in the treatment of patients with CLL. In Alliance A041202, a higher than expected number of unexplained deaths were reported with front-line ibrutinib in a patient population aged at least 65 years compared to ECOG 1912, which included patients up to 70 years of age.Methods: Therefore, we conducted a retrospective analysis to investigate whether ibrutinib was associated with a greater mortality in older patients outside of a clinical trial setting. This multicenter analysis was performed by investigators at 20 academic and community practices.Results: Amongst the 391 patients included, there was no correlation between age and response rate, PFS, or OS. However, there was a trend to higher rate of deaths in patients > 65-years-old (8.7% vs 3.8%, p=0.097), with an increased number of early deaths (13 vs 4, p=0.3).Conclusion: These data suggest greater intolerance, and possibly mortality, with ibrutinib in an older population. Patients should be educated regarding the potential complications related to ibrutinib and symptoms of concern to report.Keywords: CLL, ibrutinib, elderly

Background: Patients with diffuse large B-cell lymphoma that is refractory to primary and secondline therapies or that has relapsed after stem-cell transplantation have a poor prognosis. The chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel targets and eliminates CD19-expressing B cells and showed efficacy against B-cell lymphomas in a single-center, phase 2a study. Methods: We conducted an international, phase 2, pivotal study of centrally manufactured tisagenlecleucel involving adult patients with relapsed or refractory diffuse large B-cell lymphoma who were ineligible for or had disease progression after autologous hematopoietic stem-cell transplantation. The primary end point was the best overall response rate (i.e., the percentage of patients who had a complete or partial response), as judged by an independent review committee. Results: A total of 93 patients received an infusion and were included in the evaluation of efficacy. The median time from infusion to data cutoff was 14 months (range, 0.1 to 26). The best overall response rate was 52% (95% confidence interval, 41 to 62); 40% of the patients had complete responses, and 12% had partial responses. Response rates were consistent across prognostic subgroups. At 12 months after the initial response, the rate of relapse-free survival was estimated to be 65% (79% among patients with a complete response). The most common grade 3 or 4 adverse events of special interest included cytokine release syndrome (22%), neurologic events (12%), cytopenias lasting more than 28 days (32%), infections (20%), and febrile neutropenia (14%). Three patients died from disease progression within 30 days after infusion. No deaths were attributed to tisagenlecleucel, cytokine release syndrome, or cerebral edema. No differences between response groups in tumor expression of CD19 or immune checkpoint- related proteins were found. Conclusions: In this international study of CAR T-cell therapy in relapsed or refractory diffuse large B-cell lymphoma in adults, high rates of durable responses were produced with the use of tisagenlecleucel.

Background: Mantle cell lymphoma (MCL), a rare and aggressive disease, accounts for approximately 5% of all B-cell non-Hodgkin’s lymphomas. Evidence on the burden of this disease, for patients and healthcare providers, is scarce. Methods: Four systematic literature reviews were developed to identify epidemiological, real-world clinical, economic and humanistic burden data on patients with MCL. Electronic databases searched included MEDLINE and Embase, NHS EED and Econlit. Results: Eight epidemiological studies, 19 clinical burden, 2 economic impact and 0 quality of life studies were identified. The range of standardized MCL incidence rates was 0.1–1.27/100,000. Overall survival rates of patients at 3 years differed by age at diagnosis (≤65 years: 76–81%, >65 years: 46–64%) and disease stage (stage I: 73–80%, stage IV: 48–53%). Outcomes were poorer in previously treated patients, and those with later stage or blastoid disease, and improved with more recent diagnosis/treatment. Hospitalization is a major contributor to healthcare cost and differs by therapy toxicity. Conclusions: We identified significant data gaps for many G20 countries for epidemiology, real-world clinical, economic and humanistic burden. These literature reviews demonstrate the ongoing unmet need for MCL patients globally. Future research to further understand the real-world impact of MCL is needed along with new therapeutic options to improve patient outcomes.

Patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) with deletion 17p [del(17p)] have poor outcomes with chemoimmunotherapy. Ibrutinib is indicated for the treatment of CLL/SLL, including del(17p) CLL/SLL, and allows for treatment without chemotherapy. This integrated analysis was performed to evaluate outcomes in 230 patients with relapsed/refractory del(17p) CLL/SLL from three ibrutinib studies. With a median of 2 prior therapies (range, 1-12), 18% and 79% of evaluable patients had del(11q) or unmutated IGHV, respectively. With a median follow-up of 28months, overall response rate was 85% and estimated 30-month progression-free and overall survival rates were 57% [95% confidence interval (CI) 50-64] and 69% (95% CI 61-75), respectively. Patients with normal lactate dehydrogenase or no bulky disease had the most favourable survival outcomes. Sustained haematological improvements in haemoglobin, platelet count and absolute neutrophil count occurred in 61%, 67% and 70% of patients with baseline cytopenias, respectively. New onset severe cytopenias and infections decreased in frequency over time. Progression-free and overall survival with ibrutinib surpass those of other therapies for patients with del(17p) CLL/SLL. These results provide further evidence of the robust clinical activity of ibrutinib in difficult-to-treat CLL/SLL populations.

Although chromosome 17p abnormalities and TP53 mutations are purported to be poor prognostic indicators in chronic lymphocytic leukemia (CLL), the significance of p53 expression in CLL has not been defined in patients uniformly treated with chemoimmunotherapy, nor has its utility in combination with other novel prognostic markers, such as IgVH mutation status (IgVH MS) or ZAP-70 expression, been evaluated. Therefore, we studied p53 expression by immunohistochemistry (IHC), using the bone marrow specimens from 222 CLL patients (pts) enrolled in the phase II evaluation of the fludarabine, cyclophosphamide and rituximab (FCR) regimen. ZAP70 expression and IgVH MS were assessed in 208 and 108 patients, respectively. 168 CLL pts had concurrent classical cytogenetic analysis. p53 expression correlated with abnormal karyotype (p=0.002) and adversely affected overall survival independent of ZAP70 expression and IgVH MS (p

PURPOSE CAPTIVATE ( NCT02910583 ), a randomized phase II study, evaluates minimal residual disease (MRD)-guided treatment discontinuation following completion of first-line ibrutinib plus venetoclax treatment in patients with chronic lymphocytic leukemia (CLL). METHODS Previously untreated CLL patients age < 70 years received three cycles of ibrutinib and then 12 cycles of combined ibrutinib plus venetoclax. Patients in the MRD cohort who met the stringent random assignment criteria for confirmed undetectable MRD (Confirmed uMRD) were randomly assigned 1:1 to double-blind placebo or ibrutinib; patients without Confirmed uMRD (uMRD Not Confirmed) were randomly assigned 1:1 to open-label ibrutinib or ibrutinib plus venetoclax. Primary end point was 1-year disease-free survival (DFS) rate with placebo versus ibrutinib in the Confirmed uMRD population. Secondary end points included response rates, uMRD, and safety. RESULTS One hundred sixty-four patients initiated three cycles of ibrutinib lead-in. After 12 cycles of ibrutinib plus venetoclax, best uMRD response rates were 75% (peripheral blood) and 68% (bone marrow). Patients with Confirmed uMRD were randomly assigned to receive placebo (n = 43) or ibrutinib (n = 43); patients with uMRD Not Confirmed were randomly assigned to ibrutinib (n = 31) or ibrutinib plus venetoclax (n = 32). Median follow-up was 31.3 months. One-year DFS rate was not significantly different between placebo (95%) and ibrutinib (100%; arm difference: 4.7% [95% CI, –1.6 to 10.9]; P = .15) in the Confirmed uMRD population. After ibrutinib lead-in tumor debulking, 36 of 40 patients (90%) with high tumor lysis syndrome risk at baseline shifted to medium or low tumor lysis syndrome risk categories. Adverse events were most frequent during the first 6 months of ibrutinib plus venetoclax and generally decreased over time. CONCLUSION The 1-year DFS rate of 95% in placebo-randomly assigned patients with Confirmed uMRD suggests the potential for fixed-duration treatment with this all-oral, once-daily, chemotherapy-free regimen in first-line CLL.

CAPTIVATE (NCT02910583) is an international phase 2 study in patients aged ≤70 years with previously untreated chronic lymphocytic leukemia (CLL). Results from the cohort investigating fixed-duration (FD) treatment with ibrutinib plus venetoclax are reported. Patients received 3 cycles of ibrutinib lead-in then 12 cycles of ibrutinib plus venetoclax (oral ibrutinib [420 mg/d]; oral venetoclax [5-week ramp-up to 400 mg/d]). The primary endpoint was complete response (CR) rate. Hypothesis testing was performed for patients without del(17p) with prespecified analyses in all treated patients. Secondary endpoints included undetectable minimal residual disease (uMRD) rates, progression-free survival (PFS), overall survival (OS), and safety. Of the 159 patients enrolled and treated, 136 were without del(17p). The median time on study was 27.9 months, and 92% of patients completed all planned treatment. The primary endpoint was met, with a CR rate of 56% (95% confidence interval [CI], 48-64) in patients without del(17p), significantly higher than the prespecified 37% minimum rate (P < .0001). In the all-treated population, CR rate was 55% (95% CI, 48-63); best uMRD rates were 77% (peripheral blood [PB]) and 60% (bone marrow [BM]); 24-month PFS and OS rates were 95% and 98%, respectively. At baseline, 21% of patients were in the high tumor burden category for tumor lysis syndrome (TLS) risk; after ibrutinib lead-in, only 1% remained in this category. The most common grade ≥3 adverse events (AEs) were neutropenia (33%) and hypertension (6%). First-line ibrutinib plus venetoclax represents the first all-oral, once-daily, chemotherapy-free FD regimen for patients with CLL. FD ibrutinib plus venetoclax achieved deep, durable responses and promising PFS, including in patients with high-risk features.

Limited information is available on the efficacy of front‐line bendamustine and rituximab (BR) in chronic lymphocytic leukemia (CLL) with reduced renal function or coexisting conditions. We therefore analyzed a cohort of real‐world patients and performed a matched adjusted indirect comparison with a cohort of patients treated with ibrutinib. One hundred and fifty‐seven patients with creatinine clearance (CrCl) 6 were treated with BR. The median age was 72 years; 69% of patients had ≥2 comorbidities and the median CrCl was 59.8 mL/min. 17.6% of patients carried TP53 disruption. The median progression‐free survival (PFS) was 45 months; TP53 disruption was associated with a shorter PFS (P = 0.05). The overall survival (OS) at 12, 24, and 36 months was 96.2%, 90.1%, and 79.5%, respectively. TP53 disruption was associated with an increased risk of death (P = 0.01). Data on 162 patients ≥65 years treated with ibrutinib were analyzed and compared with 165 patients ≥65 years treated with BR. Factors predicting for a longer PFS at multivariable analysis in the total patient population treated with BR and ibrutinib were age (HR 1.06, 95% CI 1.02‐1.10, P, Bendamustine and Rituximab was a relatively effective first‐line regimen in real‐world untreated CLL patients with reduced renal function or coexisting conditions without TP53 disruption.In a matched‐adjusted indirect comparison with a cohort of CLL patients treated upfront, ibrutinib provided longer PFS than bendamustine and rituximab in those with advanced stage.

Patients with chronic lymphocytic leukemia or small lymphocytic lymphoma whose tumors carry deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Zanubrutinib is a selective next-generation Bruton tyrosine kinase inhibitor. We evaluated the safety and efficacy of zanubrutinib 160 mg twice daily in treatment-naïve patients with del(17p) disease enrolled in a dedicated, nonrandomized cohort (Arm C) of the phase 3 SEQUOIA trial. A total of 109 patients (median age, 70 years; range, 42 – 86) with centrally confirmed del(17p) were enrolled and treated. After a median of 18.2 months (range, 5.0 – 26.3), seven patients had discontinued study treatment due to progressive disease, four due to an adverse event, and one due to withdrawal of consent. The overall response rate was 94.5% with 3.7% of patients achieving complete response with or without incomplete hematologic recovery. The estimated 18-month progression-free survival rate was 88.6% (95% CI, 79.0 – 94.0) and the estimated 18-month overall survival rate was 95.1% (95% CI, 88.4 – 98.0). Most common all-grade adverse events included contusion (20.2%), upper respiratory tract infection (19.3%), neutropenia/neutrophil count decreased (17.4%), and diarrhea (16.5%). Grade ≥ 3 adverse events were reported in 53 patients (48.6%), most commonly neutropenia (12.9%) and pneumonia (3.7%). An adverse event of atrial fibrillation was reported in three patients (2.8%). Zanubrutinib was active and well tolerated in this large, prospectively enrolled treatment cohort of previously untreated patients with del(17p) chronic lymphocytic leukemia/small lymphocytic lymphoma. This trial was registered at ClinicalTrials.gov as #NCT03336333.

The management of CML in pregnancy is challenging with the need to balance disease control against potential teratogenic effects of TKI therapy. In this multi-center case-cohort study of 16 women in chronic phase, CML ceased TKI treatment pre- or post-conception during their first pregnancy. Thirteen patients were on imatinib; 9 ceased their TKI prior to conception and 7 ceased at pregnancy confirmation. Twelve patients had achieved either MMR or better at time of TKI cessation. Eleven women lost MMR during pregnancy and two patients lost CHR. Fourteen women reestablished MMR on TKI recommenced. The depth molecular response prior to conception appeared to correlate well with restoration of disease control on TKI recommencement though duration of MMR did not appear to be as important. While interruption of TKI treatment for pregnancy usually leads to loss of molecular response, loss of hematological response is uncommon and disease control is reestablished with resumption of therapy in the majority of women. Refereed/Peer-reviewed

Duvelisib (also known as IPI-145) is an oral, dual inhibitor of phosphatidylinositol 3-kinase δ and γ (PI3K-δ,γ) being developed for treatment of hematologic malignancies. PI3K-δ,γ signaling can promote B-cell proliferation and survival in clonal B-cell malignancies, such as chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). In a phase 1 study, duvelisib showed clinically meaningful activity and acceptable safety in CLL/SLL patients. We report here the results of DUO, a global phase 3 randomized study of duvelisib vs ofatumumab monotherapy for patients with relapsed or refractory (RR) CLL/SLL. Patients were randomized 1:1 to oral duvelisib 25 mg twice daily (n = 160) or ofatumumab IV (n = 159). The study met the primary study end point by significantly improving progression-free survival per independent review committee assessment compared with ofatumumab for all patients (median, 13.3 months vs 9.9 months; hazard ratio [HR] = 0.52; P < .0001), including those with high-risk chromosome 17p13.1 deletions [del(17p)] and/or TP53 mutations (HR = 0.40; P = .0002). The overall response rate was significantly higher with duvelisib (74% vs 45%; P < .0001) regardless of del(17p) status. The most common adverse events were diarrhea, neutropenia, pyrexia, nausea, anemia, and cough on the duvelisib arm, and neutropenia and infusion reactions on the ofatumumab arm. The DUO trial data support duvelisib as a potentially effective treatment option for patients with RR CLL/SLL. This trial was registered at www.clinicaltrials.gov as #NCT02004522.

Hairy cell leukemia is an uncommon hematologic malignancy characterized by pancytopenia and marked susceptibility to infection. Tremendous progress in the management of patients with this disease has resulted in high response rates and improved survival, yet relapse and an appropriate approach to re-treatment present continuing areas for research. The disease and its effective treatment are associated with immunosuppression. Because more patients are being treated with alternative programs, comparison of results will require general agreement on definitions of response, relapse, and methods of determining minimal residual disease. The development of internationally accepted, reproducible criteria is of paramount importance in evaluating and comparing clinical trials to provide optimal care. Despite the success achieved in managing these patients, continued participation in available clinical trials in the first-line and particularly in the relapse setting is highly recommended. The Hairy Cell Leukemia Foundation convened an international conference to provide common definitions and structure to guide current management. There is substantial opportunity for continued research in this disease. In addition to the importance of optimizing the prevention and management of the serious risk of infection, organized evaluations of minimal residual disease and treatment at relapse offer ample opportunities for clinical research. Finally, a scholarly evaluation of quality of life in the increasing number of survivors of this now manageable chronic illness merits further study. The development of consensus guidelines for this disease offers a framework for continued enhancement of the outcome for patients.

Chronic lymphocytic leukemia (CLL) primarily affects older persons who often have coexisting conditions in addition to disease-related immunosuppression and myelosuppression. We conducted an international, open-label, randomized phase 3 trial to compare two oral agents, ibrutinib and chlorambucil, in previously untreated older patients with CLL or small lymphocytic lymphoma. Background Chronic lymphocytic leukemia (CLL) primarily affects older persons who often have coexisting conditions in addition to disease-related immunosuppression and myelosuppression. We conducted an international, open-label, randomized phase 3 trial to compare two oral agents, ibrutinib and chlorambucil, in previously untreated older patients with CLL or small lymphocytic lymphoma. METHODS We randomly assigned 269 previously untreated patients who were 65 years of age or older and had CLL or small lymphocytic lymphoma to receive ibrutinib or chlorambucil. The primary end point was progression-free survival as assessed by an independent review committee. RESULTS The median age of the patients was 73 years. During a median follow-up period of 18.4 months, ibrutinib resulted in significantly longer progression-free survival than did chlorambucil (median, not reached vs. 18.9 months), with a risk of progression or death that was 84% lower with ibrutinib than that with chlorambucil (hazard ratio, 0.16; P