Jack Shiansong Li

Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia

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<0.001). Ibrutinib significantly prolonged overall survival; the estimated survival rate at 24 months was 98% with ibrutinib versus 85% with chlorambucil, with a relative risk of death that was 84% lower in the ibrutinib group than in the chlorambucil group (hazard ratio, 0.16; P=0.001). The overall response rate was higher with ibrutinib than with chlorambucil (86% vs. 35%, P<0.001). The rates of sustained increases from baseline values in the hemoglobin and platelet levels were higher with ibrutinib. Adverse events of any grade that occurred in at least 20% of the patients receiving ibrutinib included diarrhea, fatigue, cough, and nausea; adverse events occurring in at least 20% of those receiving chlorambucil included nausea, fatigue, neutropenia, anemia, and vomiting. In the ibrutinib group, four patients had a grade 3 hemorrhage and one had a grade 4 hemorrhage. A total of 87% of the patients in the ibrutinib group are continuing to take ibrutinib. CONCLUSIONS Ibrutinib was superior to chlorambucil in previously untreated patients with CLL or small lymphocytic lymphoma, as assessed by progression-free survival, overall survival, response rate, and improvement in hematologic variables. (Funded by Pharmacyclics and others; RESONATE-2 ClinicalTrials.gov number, NCT01722487.).

Second-line therapy after nab-paclitaxel plus gemcitabine or after gemcitabine for patients with metastatic pancreatic cancer.

Background:This exploratory analysis evaluated second-line (2L) therapy for metastatic pancreatic cancer in a large phase 3 trial (MPACT).Methods:Patients who received first-line (1L) nab-paclitaxel+gemcitabine (nab-P+Gem) or Gem were assessed for survival based on 2L treatment received. Multivariate analyses tested influence of treatment effect and prognostic factors on survival.Results:The majority of 2L treatments (267 out of 347, 77%) contained a fluoropyrimidine (5-fluorouracil or capecitabine). Median total survival (1L randomisation to death) for patients who received 2L treatment after 1L nab-P+Gem vs Gem alone was 12.8 vs 9.9 months (P=0.015). Median total survival for patients with a fluoropyrimidine-containing 2L therapy after nab-P+Gem vs Gem was 13.5 vs 9.5 months (P=0.012). Median 2L survival (duration from start of 2L therapy to death) was 5.3 vs 4.5 months for nab-P+Gem vs Gem, respectively (P=0.886). Factors significantly associated with longer post-1L survival by multivariate analyses included 1L nab-P+Gem, receiving 2L treatment, longer 1L progression-free survival, and Karnofsky performance status⩾70 and neutrophil-to-lymphocyte ratio⩽5 at the end of 1L treatment.Conclusions:These findings support the use of 2L therapy for patients with metastatic pancreatic cancer. Fluoropyrimidine-containing treatment after 1L nab-P+Gem is an active regimen with significant clinical effect.

Validation of the IPSS-R in lenalidomide-treated, lower-risk myelodysplastic syndrome patients with del(5q).

Validation of the IPSS-R in lenalidomide-treated, lower-risk myelodysplastic syndrome patients with del(5q)

nab -Paclitaxel plus gemcitabine for metastatic pancreatic cancer: a subgroup analysis of the Western European cohort of the MPACT trial

Purpose The global Phase III MPACT trial demonstrated superior efficacy of nab-paclitaxel plus gemcitabine over gemcitabine alone as first-line treatment for metastatic pancreatic cancer. Region was a randomization stratification factor in the MPACT trial. This subgroup analysis of MPACT examined efficacy and safety of patients treated in Western Europe. Patients and methods Patients received nab-paclitaxel plus gemcitabine or gemcitabine alone as first-line treatment for metastatic pancreatic cancer as previously described. A total of 76 patients were included in this analysis (n=38 for each arm). Results Differences between the overall Western European cohort and the intention-to-treat population included lower percentages of male patients (46% and 58%, respectively) and patients with biliary stents (8% and 17%), and higher percentages of patients with Karnofsky performance status of 90–100 (78% and 60%) and primary tumors in the body of the pancreas (48% and 31%). The median overall survival was 10.7 months with nab-paclitaxel plus gemcitabine vs 6.9 months with gemcitabine alone (hazard ratio [HR]: 0.82 [95% confidence interval (CI): 0.48–1.40]; P=0.471). Median progression-free survival was 5.3 vs 3.7 months, respectively (HR: 0.70 [95% CI: 0.37–1.33]; P=0.277). The independently assessed overall response rate was 18% vs 5% (response rate ratio, 3.50 [95% CI: 0.78–15.78]; P=0.076). The most common grade ≥3 adverse events with nab-paclitaxel plus gemcitabine and gemcitabine alone were neutropenia (46% vs 33%, respectively), leukopenia (35% vs 19%), anemia (22% vs 0%), asthenia (21% vs 6%), thrombocytopenia (14% vs 3%), and peripheral neuropathy (13% vs 3%). Conclusion Although a statistically significant difference between the treatment arms was not reached for efficacy endpoints, this study does report treatment benefit and a manageable safety profile associated with nab-paclitaxel plus gemcitabine in patients treated in Western Europe with metastatic pancreatic cancer.

Association of Survival Benefit With Docetaxel in Prostate Cancer and Total Number of Cycles Administered: A Post Hoc Analysis of the Mainsail Study

Importance The optimal total number of docetaxel cycles in patients with metastatic castration resistant prostate cancer (mCPRC) has not been investigated yet. It is unknown whether it is beneficial for patients to continue treatment upon 6 cycles. Objective To investigate whether the number of docetaxel cycles administered to patients deriving clinical benefit was an independent prognostic factor for overall survival (OS) in a post hoc analysis of the Mainsail trial. Design, Setting, and Participants The Mainsail trial was a multinational randomized phase 3 study of 1059 patients with mCRPC receiving docetaxel, prednisone, and lenalidomide (DPL) or docetaxel, prednisone, and a placebo (DP). Study patients were treated until progressive disease or unacceptable adverse effects occurred. Median OS was found to be inferior in the DPL arm compared with the DP arm. As a result of increased toxic effects with the DPL combination, patients on DPL received fewer docetaxel cycles (median, 6) vs 8 cycles in the control group. As the dose intensity was comparable in both treatment arms, we investigated whether the number of docetaxel cycles administered to patients deriving clinical benefit on Mainsail was an independent prognostic factor for OS. We conducted primary univariate and multivariate analyses for the intention-to-treat population. Additional sensitivity analyses were done, excluding patients who stopped treatment for reasons of disease progression and those who received 4 or fewer cycles of docetaxel for other reasons, minimizing the effect of confounding factors. Main Outcomes and Measures Total number of docetaxel cycles delivered as an independent factor for OS. Results Overall, all 1059 patients from the Mainsail trial were included (mean [SD] age, 68.7 [7.89] years). Treatment with 8 or more cycles of docetaxel was associated with superior OS (hazard ratio [HR], 1.909; 95% CI, 1.660-2.194; P < .001), irrespective of lenalidomide treatment (HR, 1.060; 95% CI, 0.924-1.215; P = .41). Likewise, in the sensitivity analysis, patients who received a greater number of docetaxel cycles had superior OS; patients who received more than 10 cycles had a median OS of 33.0 months compared with 26.9 months in patients treated with 8 to 10 cycles; and patients who received 5 to 7 cycles had a median OS of 22.8 months (P < .001). Conclusions and Relevance These findings suggest that continuation of docetaxel chemotherapy contributes to the survival benefit. Prospective validation is warranted.

The impact of lenalidomide exposure on response and outcomes in patients with lower-risk myelodysplastic syndromes and del(5q)

Myelodysplastic syndromes (MDS) are clonal hematopoietic malignancies that primarily affect older adults, with consequent cytopenias, blood product transfusion needs, and truncated survival. Undertreatment of patients with International Prognostic Scoring System (IPSS) Lowor Intermediate (Int)-1-risk MDS and deletion 5q [del(5q)] may lead to insufficient correction of anemia, iron overload, compromised quality of life, and increased morbidity. It is recommended that patients with IPSS-defined lower-risk MDS and del(5q) initiate treatment with lenalidomide at 10 mg/day. Those who develop profound neutropenia or thrombocytopenia should undergo treatment interruption followed by dose reduction to manage adverse events while continuing treatment. It is not known whether initial lenalidomide dose (at 10 or 5 mg), subsequent dose reductions, or cumulative lenalidomide dose affect long-term outcomes in patients with del(5q) MDS. In this retrospective analysis, we combined data from IPSS-defined lower-risk del(5q) MDS patients treated with lenalidomide from study start in the phase 2 MDS-003 study and the phase 3 MDS-004 study to assess the impact of cumulative lenalidomide exposure on red blood cell transfusion independence (RBC-TI) ≥ 26 weeks, cytogenetic response, overall survival, and acute myeloid leukemia (AML)-free survival. In the phase 2, open-label MDS-003 study (NCT00065156), 148 patients received lenalidomide 10mg on days 1–21 (n= 46) or days 1–28 (n= 102) of 28-day cycles. In the phase 3, randomized, double-blind, placebo-controlled MDS-004 study (NCT00179621), 205 patients were centrally randomized using a validated interactive voice response system 1:1:1 to lenalidomide 10mg/day on days 1–21 of 28-day cycles (n= 69), or lenalidomide 5mg/day (n= 69) or placebo (n= 67) on days 1–28 of 28-day cycles. Key inclusion criteria for both studies included IPSS Lowor Int-1-risk del(5q) MDS with or without additional cytogenetic abnormalities, and RBC transfusion-dependent anemia. Outcomes (RBCTI ≥ 26 weeks, cytogenetic response, overall survival, and AML-free survival) were analyzed by initial lenalidomide dose group, total cumulative dose during cycles 1–3, and incidence of dose reductions. Further details on study design can be found in the Supplementary material; full methodology and key results for these studies have been reported previously. A total of 217 patients received an initial dose of lenalidomide 10mg (10 mg dose group) and 69 patients received an initial dose of lenalidomide 5mg (5 mg dose group) in the MDS-003 and MDS-004 studies. Patient baseline characteristics are shown in Supplementary Table 1; details of treatment received can be found in Supplementary Table 2. Overall, RBC-TI ≥ 26 weeks was achieved in 148 patients (51.7%) (Supplementary Table 3); rates of RBCTI ≥ 26 weeks were 57.1% for the 10mg dose group vs. 34.8% for the 5 mg dose group (p < 0.001). Of 181 evaluable patients, 103 (56.9%) achieved cytogenetic response (major or minor responses) (Supplementary Table 3): 65.2% of patients in the 10mg dose group vs. 30.2% in the