Ruxolitinib in patients with polycythemia vera resistant and/or intolerant to hydroxyurea:European observational study

Background: Hydroxyurea (HU) is a commonly used first-line treatment in patients with polycythemia vera (PV). However, approximately 15%–24% of PV patients report intolerance and resistance to HU. Methods: This phase IV, European, real-world, observational study assessed the efficacy and safety of ruxolitinib in PV patients who were resistant and/or intolerant to HU, with a 24-month follow-up. The primary objective was to describe the profile and disease burden of PV patients. Results: In the 350 enrolled patients, 70% were &gt;60 years old. Most patients (59.4%) had received ≥1 phlebotomy in the 12 months prior to the first dose of ruxolitinib. Overall, 68.2% of patients achieved hematocrit control with 92.3% patients having hematocrit &lt;45% and 35.4% achieved hematologic remission at month 24. 85.1% of patients had no phlebotomies during the study. Treatment-related adverse events were reported in 54.3% of patients and the most common event was anemia (22.6%). Of the 10 reported deaths, two were suspected to be study drug-related. Conclusion: This study demonstrates that ruxolitinib treatment in PV maintains durable hematocrit control with a decrease in the number of phlebotomies in the majority of patients and was generally well tolerated.</p

The Association between Patient Characteristics and the Efficacy and Safety of Selinexor in Diffuse Large B-Cell Lymphoma in the SADAL Study.

Selinexor, an oral selective inhibitor of nuclear export, was evaluated in the Phase 2b SADAL study in patients with diffuse large B-cell lymphoma (DLBCL) who previously received two to five prior systemic regimens. In post hoc analyses, we analyzed several categories of patient characteristics (age, renal function, DLBCL subtype, absolute lymphocyte count, transplant status, number of prior lines of therapy, refractory status, Ann Arbor disease stage, and lactate dehydrogenase) at baseline, i.e., during screening procedures, to determine their potential contributions to the efficacy (overall response rate [ORR], duration of response [DOR], overall survival [OS]) and tolerability of selinexor. Across most categories of characteristics, no significant difference was observed in ORR or DOR. OS was significantly longer for patients ULN. The most common adverse events (AEs) across the characteristics were thrombocytopenia and nausea, and similar rates of grade 3 AEs and serious AEs were observed. With its oral administration, novel mechanism of action, and consistency in responses in heavily pretreated patients, selinexor may help to address an important unmet clinical need in the treatment of DLBCL

The Association between Patient Characteristics and the Efficacy and Safety of Selinexor in Diffuse Large B-Cell Lymphoma in the SADAL Study.

Selinexor, an oral selective inhibitor of nuclear export, was evaluated in the Phase 2b SADAL study in patients with diffuse large B-cell lymphoma (DLBCL) who previously received two to five prior systemic regimens. In post hoc analyses, we analyzed several categories of patient characteristics (age, renal function, DLBCL subtype, absolute lymphocyte count, transplant status, number of prior lines of therapy, refractory status, Ann Arbor disease stage, and lactate dehydrogenase) at baseline, i.e., during screening procedures, to determine their potential contributions to the efficacy (overall response rate [ORR], duration of response [DOR], overall survival [OS]) and tolerability of selinexor. Across most categories of characteristics, no significant difference was observed in ORR or DOR. OS was significantly longer for patients ULN. The most common adverse events (AEs) across the characteristics were thrombocytopenia and nausea, and similar rates of grade 3 AEs and serious AEs were observed. With its oral administration, novel mechanism of action, and consistency in responses in heavily pretreated patients, selinexor may help to address an important unmet clinical need in the treatment of DLBCL

The Association between Patient Characteristics and the Efficacy and Safety of Selinexor in Diffuse Large B-Cell Lymphoma in the SADAL Study.

Selinexor, an oral selective inhibitor of nuclear export, was evaluated in the Phase 2b SADAL study in patients with diffuse large B-cell lymphoma (DLBCL) who previously received two to five prior systemic regimens. In post hoc analyses, we analyzed several categories of patient characteristics (age, renal function, DLBCL subtype, absolute lymphocyte count, transplant status, number of prior lines of therapy, refractory status, Ann Arbor disease stage, and lactate dehydrogenase) at baseline, i.e., during screening procedures, to determine their potential contributions to the efficacy (overall response rate [ORR], duration of response [DOR], overall survival [OS]) and tolerability of selinexor. Across most categories of characteristics, no significant difference was observed in ORR or DOR. OS was significantly longer for patients ULN. The most common adverse events (AEs) across the characteristics were thrombocytopenia and nausea, and similar rates of grade 3 AEs and serious AEs were observed. With its oral administration, novel mechanism of action, and consistency in responses in heavily pretreated patients, selinexor may help to address an important unmet clinical need in the treatment of DLBCL

Lenalidomide maintenance therapy in previously treated chronic lymphocytic leukaemia (CONTINUUM): a randomised, double-blind, placebo-controlled, phase 3 trial

BACKGROUND: The efficacy and safety of lenalidomide as maintenance therapy after chemotherapy-based second-line therapy in patients with chronic lymphocytic leukaemia is unknown. Although kinase inhibitors can improve outcomes for some patients with relapsed and refractory disease, not all patients have access to these novel drugs. In this study, we aimed to assess the efficacy and safety of lenalidomide as maintenance therapy in patients with previously treated chronic lymphocytic leukaemia. METHODS: This randomised, double-blind, placebo-controlled, phase 3 trial (CONTINUUM) was done at 111 hospitals, medical centres, and clinics in 21 countries. Patients were eligible if they had chronic lymphocytic leukaemia; were aged 18 years or older; had been treated with two lines of therapy (with at least a partial response after second-line therapy); had received a purine analogue, bendamustine, anti-CD20 antibody, chlorambucil, or alemtuzumab as first-line or second-line treatment; and had an Eastern Cooperative Oncology Group performance score of 0-2. Eligible patients were randomly assigned (1:1) by an interactive voice-response system to receive either oral lenalidomide (2·5 mg/day) or matching oral placebo capsules (2·5 mg/day) for 28-day cycles, until disease progression or unacceptable toxicity. Lenalidomide dose escalation (to 5 mg or 10 mg per day) was permitted if the drug was well tolerated. Patients, investigators, and those completing data analyses were masked to treatment allocation. Randomisation was stratified by age, response to second-line therapy, and prognostic factors. Co-primary endpoints were progression-free survival and overall survival; the primary endpoint was later changed to overall survival after the data cutoff for this analysis. Secondary endpoints were time from randomisation to second disease progression or death (PFS2),32 tumour response (improvement in response and duration of response), safety, and health-related quality of life (HRQoL). Efficacy analyses were done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00774345, and is closed to accrual, but follow-up is ongoing. FINDINGS: Between Feb 16, 2009 and Sept 29, 2015, 314 patients with chronic lymphocytic leukaemia were enrolled and randomly assigned to receive either lenalidomide (n=160) or placebo (n=154). With a median follow-up of 31·5 months (IQR 18·9-50·8), there was no significant difference in overall survival between the lenalidomide and the placebo groups (median 70·4 months, 95% CI 57·5-not estimable [NE] vs NE, 95% CI 62·8-NE; hazard ratio [HR] 0·96, 95% CI 0·63-1·48; p=0·86). Progression-free survival was significantly longer in the lenalidomide group (median 33·9 months, 95% CI 25·5-52·5) than in the placebo group (9·2 months, 7·4-13·6; HR 0·40, 95% CI 0·29-0·55; p<0·0001). PFS2 was significantly longer in the lenalidomide group than in the placebo group (median 57·5 months [47·7-NE] vs 32·7 months [26·4-49·0]; HR 0·46, 95% CI 0·29-0·70; p<0·01). Improved responses from baseline were observed in ten (6%) of 160 lenalidomide-treated patients versus four (3%) of 154 placebo-treated patients (p=0·12). Median time to improved response was 12·2 weeks (IQR 7·2-22·5) in the lenalidomide group versus 76·3 weeks (20·2-182·6) in the placebo group. Duration of improved response was not estimable in either group (95% CI 22·9-NE in the lenalidomide group vs NE-NE for placebo). There were no clinically meaningful differences in HRQoL between lenalidomide-treated patients and placebo-treated patients, as measured by FACT-Leu and EQ-5D, during maintenance treatment. In the safety population, the most common grade 3 or 4 adverse events included neutropenia (94 [60%] of 157 patients in the lenalidomide group vs 35 [23%] of 154 patients in the placebo group), thrombocytopenia (26 [17%] vs ten [6%]), and diarrhoea (13 [8%] vs one [<1%]). There were five fatal adverse events (three [2%] patients in the lenalidomide group and two [1%] patients in the placebo group). INTERPRETATION: Lenalidomide might delay time to subsequent therapy and does not adversely affect response to subsequent therapy. Chemoimmunotherapy followed by lenalidomide maintenance could be an effective treatment option for patients with chronic lymphocytic leukaemia who do not have access to kinase inhibitors

Ruxolitinib for the treatment of inadequately controlled polycythemia vera without splenomegaly: 80-week follow-up from the RESPONSE-2 trial

RESPONSE-2 is a phase 3 study comparing the efficacy and safety of ruxolitinib with the best available therapy (BAT) in hydroxyurea-resistant/hydroxyurea-intolerant polycythemia vera (PV) patients without palpable splenomegaly. This analysis evaluated the durability of the efficacy and safety of ruxolitinib after patients completed the visit at week 80 or discontinued the study. Endpoints included proportion of patients achieving hematocrit control (< 45%), proportion of patients achieving complete hematologic remission (CHR) at week 28, and the durability of hematocrit control and CHR. At the time of analysis, 93% (69/74) of patients randomized to ruxolitinib were receiving ruxolitinib; while in the BAT arm, 77% (58/75) of patients crossed over to ruxolitinib after week 28. No patient remained on BAT by week 80. Among patients who achieved a hematocrit response at week 28, the probability of maintaining response up to week 80 was 78% in the ruxolitinib arm. At week 80, durable CHR was achieved in 18 patients (24%) in the ruxolitinib arm versus 2 patients (3%) in the BAT arm. The safety profile of ruxolitinib was consistent with previous reports. These data support that ruxolitinib treatment should be considered also as a standard of care for hydroxyurea-resistant/hydroxyurea-intolerant PV patients without palpable splenomegaly.status: publishe

Ruxolitinib for the treatment of inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): a randomised, open-label, phase 3b study

Background In the pivotal RESPONSE study, ruxolitinib, a Janus kinase (JAK)1 and JAK2 inhibitor, was superior to best available therapy at controlling haematocrit and improving splenomegaly and symptoms in patients with polycythaemia vera with splenomegaly who were inadequately controlled with hydroxyurea. In this study, we assessed the efficacy and safety of ruxolitinib in controlling disease in patients with polycythaemia vera without splenomegaly who need second-line therapy. Methods RESPONSE-2 is a randomised, open-label, phase 3b study assessing ruxolitinib versus best available therapy in patients with polycythaemia vera done in 48 hospitals or clinics across 12 countries in Asia, Australia, Europe, and North America. Eligible patients (aged 6518 years) with polycythaemia vera, no palpable splenomegaly, and hydroxyurea resistance or intolerance were stratified by their hydroxyurea therapy status (resistance vs intolerance) and randomly assigned (1:1) by an interactive response technology provider using a validated system to receive either oral ruxolitinib 10 mg twice daily or investigator-selected best available therapy (hydroxyurea [at the maximum tolerated dose], interferon or pegylated interferon, pipobroman, anagrelide, approved immunomodulators, or no cytoreductive treatment). Investigators and patients were not masked to treatment assignment; however, the study sponsor was masked to treatment assignment until database lock. The primary endpoint was the proportion of patients achieving haematocrit control at week 28. Analyses were done according to an intention-to-treat principle, including data from all patients randomly assigned to treatment. This study is registered with ClinicalTrials.gov (NCT02038036) and is ongoing but not recruiting patients. Findings Between March 25, 2014, and Feb 11, 2015, of 173 patients assessed for eligibility, 74 patients were randomly assigned to receive ruxolitinib and 75 to receive best available therapy. At randomisation, best available therapy included hydroxyurea (37 [49%] of 75 in the best available therapy group), interferon or pegylated interferon (ten [13%] of 75), pipobroman (five [7%] of 75), lenalidomide (one [1%] of 75), no treatment (21 [28%] of 75), and other (one [1%] of 75). Haematocrit control was achieved in 46 (62%) of 74 ruxolitinib-treated patients versus 14 (19%) of 75 patients who received best available therapy (odds ratio 7\ub728 [95% CI 3\ub743\u201315\ub745]; p<0\ub70001). The most frequent haematological adverse events of any grade were anaemia (ten [14%] of 74 in the ruxolitinib group vs two [3%] of 75 in the best available therapy group) and thrombocytopenia (two [3%] vs six [8%]). No cases of grade 3\u20134 anaemia or thrombocytopenia occurred with ruxolitinib; one patient (1%) reported grade 3\u20134 anaemia and three patients (4%) reported grade 3\u20134 thrombocytopenia in the group receiving best available therapy. Frequent grade 3\u20134 non-haematological adverse events were hypertension (five [7%] of 74 vs three [4%] of 75) and pruritus (0 of 74 vs two [3%] of 75). Serious adverse events occurring in more than 2% of patients in either group, irrespective of cause, included thrombocytopenia (none in the ruxolitinib group vs two [3%] of 75 in the best available therapy group) and angina pectoris (two [3%] of 74 in the ruxolitinib group vs none in the best available therapy group). Two deaths occurred, both in the best available therapy group. Interpretation RESPONSE-2 met its primary endpoint. The findings of this study indicate that ruxolitinib could be considered a standard of care for second-line therapy in this post-hydroxyurea patient population. Funding Novartis