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Thalidomide-dexamethasone compared with melphalan-prednisolone in elderly patients with multiple myeloma

We compared thalidomide-dexamethasone (TD) with melphalan-prednisolone (MP) in 289 elderly patients with multiple myeloma (MM). Patients received either thalidomide 200 mg plus dexamethasone 40 mg, days 1 to 4 and 15 to 18 on even cycles and days 1 to 4 on odd cycles, during a 28-day cycle or to melphalan 0.25 mg/kg and prednisolone 2 mg/kg orally on days 1 to 4 during a 28- to 42-day cycle. Patients achieving stable disease or better were randomly assigned to maintenance therapy with either thalidomide 100 mg daily and 3 MU interferon alpha-2b thrice weekly or to 3 MU interferon alpha-2b thrice weekly only. TD resulted in a higher proportion of complete and very good remissions (26% vs 13%; P= .006) and overall responses (68% vs 50%; P= .002) compared with MP. Time to progression (21.2 vs 29.1 months; P= .2), and progression-free survival was similar (16.7 vs 20.7 months; P= .1), but overall survival was significantly shorter in the TD group (41.5 vs 49.4 months; P= .024). Toxicity was higher with TD, particularly in patients older than 75 years with poor performance status. The study was registered at ClinicalTrials.gov as NCT00205751.

Light Chain–Induced Acute Renal Failure Can Be Reversed by Bortezomib-Doxorubicin-Dexamethasone in Multiple Myeloma: Results of a Phase II Study

PURPOSE To assess the efficacy of bortezomib-doxorubicin-dexamethasone (BDD) therapy in patients with multiple myeloma with light chain-induced acute renal failure. PATIENTS AND METHODS Sixty-eight patients with light chain-induced acute renal failure and glomerular filtration rate (GFR) less than 50 mL/min received bortezomib (1.0 mg/m(2) on days 1, 4, 8, and 11), doxorubicin (9 mg/m(2) on days 1 and 4), and dexamethasone (40 mg on days 1, 4, 8, and 11); if well tolerated after two cycles, bortezomib could be increased to 1.3 mg/m(2) and doxorubicin administered on days 1, 4, 8, and 11. RESULTS By intent-to-treat analysis a myeloma response was obtained in 72% of 18 previously and 50 not previously treated patients (complete response [CR]/near CR [nCR], 38%; very good partial response [VGPR], 15%; partial response [PR], 13%; minor response [MR], 6%). Renal response was achieved in 62% of patients (renal CR, 31%; renal PR, 7%; renal MR, 24%). Median GFR increased from 20.5 to 48.4 mL/min. GFR improvement correlated with tumor response; the greatest increase to 59.6 mL/min was seen in the group of patients with CR/nCR/VGPR. Median progression-free survival was 12.1 months. One- and 2-year survival rates were 72% and 58%, respectively. Survival did not differ between patients with and without renal response but was inferior in previously treated patients (P < .001). In multivariate analysis, baseline GFR and tumor response correlated with renal response, and pretreatment status, lactate dehydrogenase, and myeloma response correlated with survival. The most common grade 3 or 4 toxicities were infection (19.1%), thrombocytopenia (14.7%), neutropenia (14.7%), fatigue/weakness (10.3%), and polyneuropathy (8.8%). CONCLUSION BDD induced a high rate of myeloma and renal responses, and treatment was well tolerated.

Thalidomide maintenance treatment increases progression-free but not overall survival in elderly patients with myeloma

Background Thalidomide maintenance therapy after stem cell transplantation resulted in increased progression-free survival and overall survival in a few trials, but its role in non-transplant eligible patients with multiple myeloma remains unclear. This study assessed the impact of thalidomide-interferon in comparison to interferon maintenance therapy in elderly patients with multiple myeloma. Design and Methods Of 289 elderly patients with multiple myeloma who were randomized to thalidomide-dexamethasone or melphalan-prednisolone induction therapy, 137 finally completed 9 cycles of induction therapy with stable disease or better and thereby qualified for maintenance treatment. Of these, 128 have been randomized to either thalidomide-interferon or interferon alone. Primary study endpoints were progression-free survival and response rates; secondary endpoints were overall survival, toxicity and quality of life. Results Thalidomide-interferon maintenance therapy led to a significantly longer progression-free survival compared to interferon (27.7 vs. 13.2 months, P=0.0068), but overall survival was similar in both groups (52.6 vs. 51.4 months, P=0.81) and did not differ between patients aged 75 years or older, or younger patients (P=0.39). Survival after disease progression tended to be shorter in patients on thalidomide-interferon maintenance therapy (P=0.056). Progression-free survival and overall survival tended to be shorter in patients with adverse cytogenetic (FISH) findings compared to the standard risk group but differences were not significant (P=0.084 and P=0.082, respectively). Patients on thalidomide-interferon presented with more neuropathy (P=0.0015), constipation (P=0.0004), skin toxicity (P=0.0041) and elevated creatinine (P=0.026). Conclusions Thalidomide plus interferon maintenance therapy increased progression-free survival but not overall survival and was associated with slightly more toxicity than maintenance with interferon alone. (ClinicalTrials.gov Identifier: NCT00205751).

Distinct clinical characteristics of myeloproliferative neoplasms with calreticulin mutations

Somatic insertions/deletions in the calreticulin gene have recently been discovered to be causative alterations in myeloproliferative neoplasms. A combination of qualitative and quantitative allele-specific polymerase chain reaction, fragment-sizing, high resolution melting and Sanger-sequencing was applied for the detection of three driver mutations (in Janus kinase 2, calreticulin and myeloproliferative leukemia virus oncogene genes) in 289 cases of essential thrombocythemia and 99 cases of primary myelofibrosis. In essential thrombocythemia, 154 (53%) Janus kinase 2 V617F, 96 (33%) calreticulin, 9 (3%) myeloproliferative leukemia virus oncogene gene mutation-positive and 30 triple-negative (11%) cases were identified, while in primary myelofibrosis 56 (57%) Janus kinase 2 V617F, 25 (25%) calreticulin, 7 (7%) myeloproliferative leukemia virus oncogene gene mutation-positive and 11 (11%) triple-negative cases were identified. Patients positive for the calreticulin mutation were younger and had higher platelet counts compared to Janus kinase 2 mutation-positive counterparts. Calreticulin mutation-positive patients with essential thrombocythemia showed a lower risk of developing venous thrombosis, but no difference in overall survival. Calreticulin mutation-positive patients with primary myelofibrosis had a better overall survival compared to that of the Janus kinase 2 mutation-positive (P=0.04) or triple-negative cases (P=0.01). Type 2 calreticulin mutation occurred more frequently in essential thrombocythemia than in primary myelofibrosis (P=0.049). In essential thrombocythemia, the calreticulin mutational load was higher than the Janus kinase 2 mutational load (P<0.001), and increased gradually in advanced stages. Calreticulin mutational load influenced blood counts even at the time point of diagnosis in essential thrombocythemia. We confirm that calreticulin mutation is associated with distinct clinical characteristics and explored relationships between mutation type, load and clinical outcome.

Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: interim results from a phase 3, randomised, double-blind, placebo-controlled trial

Summary Background Bendamustine and rituximab (BR) has been a standard of care for the management of patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). We evaluated the efficacy and safety of adding idelalisib, a first-in-class targeted PI3Kδ inhibitor, to BR in patients with R/R CLL Methods This trial was a global, multicenter, double-blind, placebo -controlled trial in adult patients (≥18 years) with R/R CLL requiring treatment for their disease. Patients had to have measurable lymphadenopathy (≥1 nodal lesion ≥2.0 cm in the longest diameter and ≥1.0 cm in the longest perpendicular diameter) by computer tomography or magnetic resonance imaging, disease progression within <36 months since last prior therapy, a Karnofsky Performance Status score ≥60 and adequate bone marrow, liver and kidney function. Key exclusion criteria included histological transformation to an aggressive lymphoma (eg, Richter transformation) or disease refractory to bendamustine. Patients were randomised 1:1 using a central interactive web response system that assigned a unique treatment code for each patient, to receive intravenous BR infusions for a maximum of 6 cycles in addition to blinded study drug matching the assigned treatment of either twice-daily oral idelalisib 150 mg or placebo administered continuously until disease progression or intolerable study drug-related toxicity. Randomisation was stratified based on high-risk features (IGHV, del(17p)/TP53 mutation) and refractory vs relapsed disease. The primary endpoint was progression-free survival (PFS) assessed by an independent review committee in the intent-to-treat population. Overall survival was a key secondary endpoint. Crossover was not permitted to the idelalisib arm at progression. The trial is ongoing (ClinicalTrials.gov # NCT01569295). Findings Between 26 June 2012 and 21 August 2014, 416 patients with R/R CLL were enrolled; 207 patients were randomised to the idelalisib and 209 to the placebo arm. After the prespecified interim analysis, the Independent Data Monitoring Committee (IDMC) recommended discontinuation and unblinding of the trial due to efficacy. Updated data are presented in this manuscript with a cutoff date of 07 October 2015. Median (95% CI) PFS was 20·8 (16·6, 26·4) and 11·1 (8·9, 11·1) months in the idelalisib and placebo arms, respectively (hazard ratio [HR], 0·33; 95% CI, 0·25, 0·44; P<0·0001) at a median (Q1, Q3) follow-up of 14 (7, 18) months. The most frequent grade 3 or greater AEs were neutropenia (124/207 [60%]) and febrile neutropenia (48/207 [23%]) in the idelalisib arm and neutropenia (99/209 [47%]) and thrombocytopenia (27/209 [13%]) in the placebo arm. Serious AEs included febrile neutropenia, pneumonia and pyrexia and were common in both treatment arms. An increased risk of infection was observed in the idelalisib vs placebo arm. Interpretation Idelalisib plus BR is superior to BR alone, improving PFS and OS. This regimen represents an important new treatment option for patients with R/R CLL.

Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1): an international, randomised, phase 3 trial

BACKGROUND Available therapies for myelofibrosis can exacerbate cytopenias and are not indicated for patients with severe thrombocytopenia. Pacritinib, which inhibits both JAK2 and FLT3, induced spleen responses with limited myelosuppression in phase 1/2 trials. We aimed to assess the efficacy and safety of pacritinib versus best available therapy in patients with myelofibrosis irrespective of baseline cytopenias. METHODS This international, multicentre, randomised, phase 3 trial (PERSIST-1) was done at 67 sites in 12 countries. Patients with higher-risk myelofibrosis (with no exclusions for baseline anaemia or thrombocytopenia) were randomly assigned (2:1) to receive oral pacritinib 400 mg once daily or best available therapy (BAT) excluding JAK2 inhibitors until disease progression or unacceptable toxicity. Randomisation was stratified by risk category, platelet count, and region. Treatment assignments were known to investigators, site personnel, patients, clinical monitors, and pharmacovigilance personnel. The primary endpoint was spleen volume reduction (SVR) of 35% or more from baseline to week 24 in the intention-to-treat population as assessed by blinded, centrally reviewed MRI or CT. We did safety analyses in all randomised patients who received either treatment. Here we present the final data. This trial is registered with ClinicalTrials.gov, number NCT01773187. FINDINGS Between Jan 8, 2013, and Aug 1, 2014, 327 patients were randomly assigned to pacritinib (n=220) or BAT (n=107). Median follow-up was 23·2 months (IQR 14·8-28·7). At week 24, the primary endpoint of SVR of 35% or more was achieved by 42 (19%) patients in the pacritinib group versus five (5%) patients in the BAT group (p=0·0003). 90 patients in the BAT group crossed over to receive pacritinib at a median of 6·3 months (IQR 5·8-6·7). The most common grade 3-4 adverse events through week 24 were anaemia (n=37 [17%]), thrombocytopenia (n=26 [12%]), and diarrhoea (n=11 [5%]) in the pacritinib group, and anaemia (n=16 [15%]), thrombocytopenia (n=12 [11%]), dyspnoea (n=3 [3%]), and hypotension (n=3 [3%]) in the BAT group. The most common serious adverse events that occurred through week 24 were anaemia (10 [5%]), cardiac failure (5 [2%]), pyrexia (4 [2%]), and pneumonia (4 [2%]) with pacritinib, and anaemia (5 [5%]), sepsis (2 [2%]), and dyspnoea (2 [2%]) with BAT. Deaths due to adverse events were observed in 27 (12%) patients in the pacritinib group and 14 (13%) patients in the BAT group throughout the duration of the study. INTERPRETATION Pacritinib therapy was well tolerated and induced significant and sustained SVR and symptom reduction, even in patients with severe baseline cytopenias. Pacritinib could be a treatment option for patients with myelofibrosis, including those with baseline cytopenias for whom options are particularly limited. FUNDING CTI BioPharma Corp.

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 ≥18 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 7·28 [95% CI 3·43-15·45]; p<0·0001). 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 3-4 anaemia or thrombocytopenia occurred with ruxolitinib; one patient (1%) reported grade 3-4 anaemia and three patients (4%) reported grade 3-4 thrombocytopenia in the group receiving best available therapy. Frequent grade 3-4 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.

Phase III Open-Label Randomized Study of Cytarabine in Combination With Amonafide L-Malate or Daunorubicin As Induction Therapy for Patients With Secondary Acute Myeloid Leukemia

PURPOSE Secondary acute myeloid leukemia (sAML), defined as AML arising after a prior myelodysplastic syndrome or after antineoplastic therapy, responds poorly to current therapies. It is often associated with adverse karyotypic abnormalities and overexpression of proteins that mediate drug resistance. We performed a phase III trial to determine whether induction therapy with cytarabine and amonafide L-malate, a DNA intercalator and non-ATP-dependent topoisomerase II inhibitor that evades drug resistance mechanisms, yielded a superior complete remission rate than standard therapy with cytarabine and daunorubicin in sAML. PATIENTS AND METHODS Patients with previously untreated sAML were randomly assigned at a one-to-one ratio to cytarabine 200 mg/m(2) continuous intravenous (IV) infusion once per day on days 1 to 7 plus either amonafide 600 mg/m(2) IV over 4 hours on days 1 to 5 (A + C arm) or daunorubicin 45 mg/m(2) IV over 30 minutes once per day on days 1 to 3 (D + C arm). RESULTS The complete remission (CR) rate was 46% (99 of 216 patients) in A + C arm and 45% (97 of 217 patients) in D + C arm (P = .81). The 30- and 60-day mortality rates were 19% and 28% in A + C arm and 13% and 21% in D + C arm, respectively. CONCLUSION Induction treatment with A + C did not improve the CR rate compared with D + C in patients with sAML.

SIMPLIFY-1: A Phase III Randomized Trial of Momelotinib Versus Ruxolitinib in Janus Kinase Inhibitor–Naïve Patients With Myelofibrosis

Purpose We evaluated the efficacy and safety of momelotinib, a potent and selective Janus kinase 1 and 2 inhibitor (JAKi), compared with ruxolitinib, in JAKi-naïve patients with myelofibrosis. Patients and Methods Patients (N = 432) with high risk or intermediate-2 risk or symptomatic intermediate-1 risk myelofibrosis were randomly assigned to receive 24 weeks of treatment with momelotinib 200 mg once daily or ruxolitinib 20 mg twice a day (or per label), after which all patients could receive open-label momelotinib. The primary end point was a ≥ 35% reduction in spleen volume at 24 weeks of therapy. Secondary end points were rates of symptom response and effects on RBC transfusion requirements. Results A ≥ 35% reduction in spleen volume at week 24 was achieved by a similar proportion of patients in both treatment arms: 26.5% of the momelotinib group and 29% of the ruxolitinib group (noninferior; P = .011). A ≥ 50% reduction in the total symptom score was observed in 28.4% and 42.2% of patients who received momelotinib and ruxolitinib, respectively, indicating that noninferiority was not met ( P = .98). Transfusion rate, transfusion independence, and transfusion dependence were improved with momelotinib (all with nominal P ≤ .019). The most common grade ≥ 3 hematologic abnormalities in either group were thrombocytopenia and anemia. Grade ≥ 3 infections occurred in 7% of patients who received momelotinib and 3% of patients who received ruxolitinib. Treatment-emergent peripheral neuropathy occurred in 10% of patients who received momelotinib (all grade ≤ 2) and 5% of patients who received ruxolitinib (all grade ≤ 3). Conclusion In JAKi-naïve patients with myelofibrosis, 24 weeks of momelotinib treatment was noninferior to ruxolitinib for spleen response but not for symptom response. Momelotinib treatment was associated with a reduced transfusion requirement.

Results of the PERSIST-1 phase III study of pacritinib (PAC) versus best available therapy (BAT) in primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF), or post-essential thrombocythemia-myelofibrosis (PET-MF).

LBA7006 Background: PAC is a potent JAK2 inhibitor without significant JAK1 inhibition with minimal myelosuppression in early-phase studies in MF. METHODS The efficacy and safety of daily oral PAC was compared to BAT (2:1 randomization stratified for risk and platelet count). The 10 endpoint was the proportion of ITT patients (pts) achieving ≥ 35% spleen volume reduction (SVR) at week (wk) 24 by centrally reviewed MRI or CT. Secondary endpoints included the proportion achieving ≥ 50% reduction in total symptom score (TSS) at wk 24 using the MPN Symptom Assessment Form. RESULTS Patients:327 were enrolled (PAC:220, BAT:107), 62% with 10 MF. Median time from diagnosis was 1.12 years (PAC 0.99, BAT 1.60): 32% and 15% had a platelet counts < 100,000/µL or <50,000/ µL; 75% were JAK2V617F positive. EFFICACY The median duration of treatment was 16.2 months PAC and 5.9 months BAT. Sixty-two percent of BAT patients received active disease directed therapy. The SVR rates at week 24 were 19.1% for PAC vs. 4.7% for BAT (p=0.0003) in ITT and 25% vs. 5.9% (p=0.0001) in the evaluable population. 79% of BAT patients crossed over to PAC; 21% had achieved a >35% reduction in spleen volume at data cutoff. TSS composite V1 + V2 response rates were 24.5%for PAC vs. 6.5% for BAT (p<0.0001) by ITT, and were 40.9% vs. 9.9% in evaluable pts (p<0.0001). Efficacy with baseline cytopenias: In pts with <100,000 and <50,000 platelets/μ/L, the SVR rates were 16.7% for PAC vs. 0% for BAT (p=0.009), and 22.9% vs. 0% (p=0.045) by ITT and 23.5% vs. 0% (p=0.007) and 33.3% vs. 0% (p=0.037) in evaluable pts. In RBC transfusion dependent pts, 25.7% of PAC pts became RBC independent vs. 0% of BAT pts (p=0.043). SAFETY The most common adverse events (AE) for PAC were diarrhea, nausea, and vomiting; (grade 3 were <5%, <1%, <1% respectively). Hematologic AEs were similar between PAC and BAT. CONCLUSIONS This study demonstrated PAC was well tolerated and induced significant and sustained SVR and symptom control even in patients with severe thrombocytopenia. PAC therapy resulted in RBC transfusion independence in a significant proportion of pts. CLINICAL TRIAL INFORMATION NCT01773187.