Chronic Lymphocytic Leukemia

December 18, 2017

Verastem announced results from the phase III DUO study evaluating the efficacy and safety of duvelisib in patients with relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). In the study, 319 patients were randomized 1:1 to receive either duvelisib 25mg orally twice daily or ofatumumab monotherapy, an approved standard of care treatment for use in CLL/SLL, per its label with an initial infusion of 300 mg followed by seven weekly infusions and four monthly infusions of 2,000mg. The DUO study met its primary endpoint with oral duvelisib monotherapy achieving a statistically significant improvement in median PFS (mPFS) compared to ofatumumab in patients with relapsed or refractory CLL/ SLL per a blinded Independent Review Committee (IRC) using iwCLL or revised IWG Response Criteria (modified iwCLL/ IWG; 13.3 months vs 9.9 months, respectively; HR=0.52; p<0.0001), representing a 48% reduction in the risk of progression or death. Similar efficacy of duvelisib was observed regardless of whether patients had 17p deletion (del[17p]). The primary outcome of mPFS via IRC review in the del[17p] subpopulation significantly favored duvelisib over ofatumumab (12.7 months vs 9.0 months, respectively; HR=0.41; p=0.0011), representing a 59% reduction in the risk of progression or death. Per investigator assessment, duvelisib demonstrated a mPFS of 17.6 months, compared to 9.7 months for ofatumumab (HR=0.40, p<0.0001). Duvelisib maintained a PFS advantage in all patient subgroups analyzed as a subset of pre-specified sensitivity analyses. Verastem plans to submit a NDA to the FDA requesting full approval of duvelisib for the treatment of patients with relapsed or refractory CLL/SLL, and accelerated approval for the treatment of patients with relapsed or refractory FL. The company expects to submit the duvelisib NDA during the first quarter of 2018.

January 23, 2017

AbbVie issued results of a phase Ib/II PCYC-1102 trial and PCYC-1103 extension study of single-agent Imbruvica (ibrutinib) for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Patients received either 420mg or 840mg once daily until disease progression or unacceptable toxicity. In this analysis, 89% of treatment-naïve (TN) and relapsed/refractory (R/R) patients with CLL/SLL, including those with high-risk disease, showed a complete or partial response. Among R/R patients, 34% had del17p, 35% had del11q, 47% had del13q, and 78% had unmutated IGVH. Almost one-third of patients (29%) who received ibrutinib as their first treatment for the disease achieved a complete response (CR), and patients lived without disease progression longer when treatment was started earlier in the course of the disease. In the five years of follow-up, the overall response rate (ORR) in patients treated with Imbruvica was 89%, with 14% of patients achieving CR [87% ORR with 29% CR in TN patients (n=31) and 89% ORR with 10% CR in R/R patients (n=101)]. Median time on study was 62 months for TN patients and 49 months for R/R patients. At five years, progression-free survival (PFS) was 92% in TN patients and 43% in R/R patients, and overall survival (OS) was 92% for TN patients and 57% for R/R patients. Median PFS was not reached in the TN group and was 52 months for previously treated R/R patients. Median OS was not reached for TN or R/R patients. 

January 18, 2016

Genentech reported results of a phase II study of venetoclax for chronic lymphocytic leukemia (CLL). The study met its primary endpoint, with an overall response rate (ORR) of 79.4% with venetoclax, as assessed by an independent review committee (IRC). In addition, 7.5% of people achieved a complete response with or without complete recovery (complete response without normal blood counts) in the bone marrow. Forty-five people had an assessment for minimal residual disease (MRD) in the blood. Notably 18 people (17% of the total, 21% of responders) achieved MRD-negativity, meaning no cancer could be detected using a specific test. Ten of these 18 people also had bone marrow assessments and six were MRD-negative. At one year, 84.7% of all responses and 94.4% of MRD-negative responses were maintained. The one-year progression-free survival (PFS) and overall survival (OS) rates were 72% and 86.7%, respectively. No unexpected safety signals were reported. AbbVie has submitted an NDA for venetoclax to the FDA. Venetoclax received Breakthrough Therapy designation from the FDA earlier this year for the treatment of people with relapsed or refractory CLL harboring the 17p deletion. AbbVie also has submitted a marketing authorization application (MAA) to the EMA. Submissions to other regulatory authorities around the world are planned in 2016.

December 14, 2015

Janssen-Cilag International issued results of a randomized, multicenter, open-label, phase III trial of ibrutinib (IMBRUVICA) for treatment-naïve chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) in patients aged 65 or older. Patients were randomized to receive either ibrutinib 420mg orally, once daily until progression or toxicity or chlorambucil 0.5 to 0.8mg/kg on days one and 15 of each 28-day cycle for up to 12 cycles. The primary endpoint of the study was PFS as assessed by an IRC according to the International Workshop on Chronic Lymphocytic Leukaemia (iWCLL) 2008 criteria, with modification for treatment-related lymphocytosis. The Independent Review Committee (IRC) found ibrutinib significantly prolonged PFS compared with chlorambucil. The hazard ratio (HR) was 0.16 (95% CI, 0.09-0.28; P<0.001), which represents a reduction in the risk of progression or death by 84% v. chlorambucil (median not reached v. 18.9 months); the PFS rate at 18 months was 90% for ibrutinib v. 52% for chlorambucil. Ibrutinib also significantly prolonged OS (HR=0.16: 95% CI, 0.05, 0.56; P=0.001) with a 24-month survival rate of 98%, compared to 85% for patients in the chlorambucil arm. Additionally, ibrutinib was associated with a significantly higher ORR (86% v. 35%; P<0.001) as assessed by the IRC and significantly increased the rate of sustained improvements in both haemoglobin and platelets. The RESONATE-2 results are the basis for a Type II variation application to the EMA seeking to broaden the existing marketing authorization for IMBRUVICA to include previously untreated patients with CLL. Janssen affiliates market IMBRUVICA in EMEA (Europe, Middle East and Africa) as well as the rest of the world, except for the U.S., where Janssen Biotech, Inc. and Pharmacyclics co-market it.

April 27, 2015

Novartis reported results of a phase III study of Arzerra (ofatumumab) plus chlorambucil in patients with chronic lymphocytic leukemia (CLL) for whom fludarabine-based therapy was considered inappropriate, mainly due to advanced age or the presence of comorbidities. This prospective, randomized, open-label, phase III study included 447 patients with previously untreated CLL. Patients were randomized 1:1 to treatment with up to 12 cycles of ofatumumab in combination with chlorambucil or up to 12 cycles of chlorambucil alone. In the study, median PFS was improved by 71% in the group receiving ofatumumab plus chlorambucil compared to the chlorambucil alone group (22.4 months v. 13.1 months, respectively; HR 0.57 [95% CI 0.45, 0.72]; p<0.0001). Improvement in PFS was observed in most subgroups irrespective of age, gender, disease stage and prognostic factors. Additionally, patients in the combination arm also experienced significantly longer TTNT when compared to chlorambucil alone (39.8 months v. 24.7 months, respectively; HR 0.49 [95% CI: 0.36, 0.67]; p<0.0001). Patients in the combination arm had a higher ORR (82% of patients v. 69% of patients, respectively; odds ratio 2.16 [95% CI: 1.36-3.42]; p=0.001), with a better CR rate (14% of patients v. 1% of patients, respectively). Compared to those on chlorambucil alone, patients in the combination arm had a duration of response of 22.1 months v. 13.2 months (HR 0.56 [95% CI: 0.43, 0.74]; p<0.001). More patients in the group receiving ofatumumab plus chlorambucil (50%) experienced adverse events (AEs) of grade three or greater compared to chlorambucil alone (43%), with neutropenia being the most common adverse event (26% v. 14%). Grade 3/4 infusion-related reactions (IRRs) were reported in 10% of patients receiving ofatumumab plus chlorambucil, leading to drug withdrawal in 3% of patients and hospitalization in 2% of patients. No fatal IRRs were reported. These phase III data formed the basis for regulatory approvals in the U.S. and E.U. in 2014.

March 2, 2015

Pharmacyclics reported results of the phase I portion of a phase I/IIb study of IMBRUVICA (ibrutinib). Treatment with IMBRUVICA was associated with an 88% overall response rate (ORR), with a median time on study of 23.3 months, in 16 patients with relapsed/refractory (R/R) high-risk chronic lymphocytic leukemia (CLL). These patients had a median of five prior therapies and 63% were high-risk del 17p CLL patients. The estimated median progression-free survival (PFS) at 24 months was 76.6%. All patients had previously undergone allogeneic stem cell transplant. Pharmacyclics now is enrolling the phase II portion at the recommended phase II dose of 420mg.

October 13, 2014

Erytech reported results of a phase III study of Graspa for acute lymphoblastic leukemia (ALL). The three-arm, controlled, multicenter trial enrolled 80 children and adults. The first two arms compared Graspa to native E. Coli L-asparaginase, both in combination with standard chemotherapy, in a 1-to-1 randomization in patients without prior allergies to L-asparaginase. The third arm was an open-label assessment of Graspa for patients who have experienced allergic reactions related to asparaginase in their first-line treatment. None of the 26 patients in the Graspa arm experienced an allergic reaction v. 12 of the 28 (42.9%) patients treated with reference L-asparaginase in the control group (p<001). In the Graspa group, asparaginase levels were maintained above 100 IU/l for an average of 20.5 days with up to two injections during the first month of treatment (induction phase) v. 9.2 days in the control group with up to eight injections of reference L-asparaginase (p<001). At the end of the induction phase, 15 patients (71.4%) in the Graspa arm show complete remission v. 11 patients (42.3%) in the control arm. Erytech intends to submit an application to the European Marketing Authorization in the first half of 2015.

June 16, 2014

AbbVie issued results of phase Ib trials of ABT-199/GDC-0199 in combination with rituximab for relapsed/refractory chronic lymphocytic leukemia (CLL) and various subtypes of non-Hodgkin’s lymphoma (NHL). The phase I, open-label, multicenter, international trial of ABT-199/GDC-0199 in patients with relapsed/refractory CLL and NHL enrolled 78 patients in the CLL arm and 62 patients in the NHL arm of the trial. In the CLL arm, due to concerns of TLS, the initial dose was reduced from 50mg to 20mg and daily dosing was modified to a weekly rampup period to the final dose of 400mg. A ramp-up period with weekly dose increases occurred from 20mg, 50mg, 100mg, 200mg to the final recommended phase II dose (RPTD) of 400mg. The overall response rate (ORR) was 77%, with 23% achieving complete response (CR). Of the 18 CR/CRi patients (complete response with incomplete blood count recovery), 11 were evaluated for minimal residual disease (MRD) and six were found to be MRD negative. The ORR for patients with 17p deletion and F-refractory CLL was 79% and 76%, respectively. ABT- 199/GDC-0199 as a monotherapy in patients with relapsed/refractory CLL harboring the 17p deletion is under investigation in an ongoing phase II clinical trial.

April 28, 2014

GlaxoSmithKline and Genmab released results of a phase III study of Arzerra (ofatumumab), in combination with chlorambucil for previously untreated patients with chronic lymphocytic leukemia (CLL). Results from the randomized, open-label, parallel-arm, pivotal phase III study evaluating the combination of ofatumumab and chlorambucil (N=221) v. chlorambucil alone (N=226) demonstrated statistically significant improvement in median PFS in patients randomized to ofatumumab and chlorambucil compared to patients randomized to chlorambucil alone (22.4 months v. 13.1 months, respectively) (HR=0.57 [95% CI, 0.45, 0.72] <0.001). The majority of adverse reactions (ARs) were Grade 2 or lower in both treatment arms. The most common (>/=5% in the ofatumumab plus chlorambucil arm and also >/=2% more than in the chlorambucil monotherapy arm) non-infusion-related ARs (all grades) as reported by investigators within 60 days following the last treatment were neutropaenia (27% ofatumumab + chlorambucil, 18% chlorambucil), asthaenia (8%, 5%), headache (7%, 3%), leukopaenia (6%, 2%), herpes simplex (6%, 4%), lower respiratory tract infection (5%, 3%), arthralgia (5%, 3%) and upper abdominal pain (5%, 3%).

April 15, 2013

Pharmacyclics reported results from a phase II trial of ibrutinib for relapsed and refractory chronic lymphocytic leukemia (CLL). This study enrolled 53 subjects with CLL, 24 who were treatment naïve and 29 who had a deletion of chromosome 17p. Subjects received ibrutinib for six months. Results showed ibrutinib demonstrated rapid and sustained disease control in blood, lymph nodes, spleen and bone marrow. After six months, 95% of patients experienced a reduction in lymph node size and all showed reduction in spleen enlargement, with a median reduction of 55%. In 26 patients, for whom a bone marrow biopsy was done, tumor infiltration decreased by 82%. The Progression Free Survival probability for these patients at 12 months was estimated to be 94%. Ibrutinib was well tolerated. The most frequent adverse events were diarrhea, fatigue and rash. Based on this data, the FDA has designated ibrutinib as a Breakthrough Therapy in CLL patients with deletion 17p.

November 12, 2012

MorphoSys and Xencor released results from a phase I/IIa trial of MOR208 (MOR00208/XmAb5574) for the treatment of tumor activity. This dose-ranging study enrolled patients with high-risk, heavily pretreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Subjects received doses ranging from MOR208 0.3mg/kg to 12mg/kg as an intravenous infusion on days 1, 4, 8, 15 and 22 in cycle one, and on days 1, 8, 15 and 22 in cycle two. Overall response rate by International Working Group on CLL (IWCLL) 2008 criteria was 11%, which utilizes more rigorous CT scan reduction of internal lymph nodes not previously required in older historic studies. Using IWCLL 1996 response criteria resulted in a response rate of 42%. MORE208 was well tolerated and found safe. The most frequent adverse events were mild to moderate infusion reactions usually with the first dose. Based on these results, MorphoSys plans to commence phase II studies of MOR208 in B-cell malignancies in the near future.

December 14, 2009

Roche reported positive long-term results from a phase III trial of Rituxan plus fludarabine and cyclophosphamide chemotherapy for the treatment of Chronic Lymphocytic Leukemia (CLL). This randomized study, dubbed CLL8, enrolled 817 subjects with previously untreated CD20-positive CLL. The subjects received fludarabine and cyclophosphamide chemotherapy alone at standard doses (FC arm) or FC plus rituximab, administered intravenously at 375 mg/m2 on day 0 at the first cycle and 500 mg/m2 on day 1 for all subsequent cycles, every 28 days (FCR arm). Three-year follow up data showed that 87.2% of subjects in the FCR arm were still alive after more than three years (37.7 months) compared to 82.5% of the FC alone treatment arm (p≡0.012). The median survival has not yet been reached. In addition, at this time point (37.7 months), subjects in the FCR arm had a median progression-free survival of 51.8 months compared to 32.8 months for those who received FC alone (p<0.001).

October 5, 2009

Genzyme issued positive interim results from a phase III trial of Campath for the treatment of chronic lymphocytic leukemia (CLL). This multicenter, international, open-label, randomized study, dubbed CAM314, enrolled 335 subjects with progressive Rai stage I-IV CLL. The trial was designed to compare Campath plus Fludara (FluCAM) to Fludara alone in terms of progression free survival. In the FluCAM arm, subjects received Campath in escalating doses of 3, 10, 30 mg IV (days 1-3 up to 14 days). They then received Fludara at 30 mg/m2 IV (days 1-3) followed by Campath 30 mg IV (days 1-3) every 28 days for up to 6 cycles. Subjects in the Fludara arm received Fludara at 25 mg/m2 IV daily for 5 consecutive days (days 1-5) every 28 days for up to 6 cycles. Treatment with FluCAM resulted in a significant increase in progression free survival versus Fludara alone (p<0.0173).

January 7, 2008

Cephalon reported positive results from a phase III trial of Treanda for the treatment of chronic lymphocytic leukemia (CLL). This randomized, international, multicenter, open-label study enrolled three-hundred and five subjects. It was designed to compare Treanda to chlorambucil. The subjects received Treanda (100 mg /M2 on days one and two) or chlorambucil (0.8 mg/kg on days one and fifteen) for up to six treatment cycles. The co-primary endpoints, overall response rate and progression-free survival, were both achieved. Overall response rate was significantly higher with Treanda than with chlorambucil (68% versus 39%; p<0.0001) with a strong complete response rate of 30% compared to 2%, a nodular partial response of 10% compared to 3%, and a partial response of 28% compared to 34%, respectively. Treanda significantly improved progression-free survival compared to chlorambucil (median 21.7 months versus 9.3 months, respectively; p<.0001). The median duration of response in the Treanda arm was 18.9 months compared to 6.1 months in the chlorambucil arm. An NDA is currently under review by the FDA.

Gloucester reported positive preliminary results from a phase II trial of romidepsin for the treatment of cutaneous t-cell lymphoma (CTCL) at the American Society of Hematology (ASH) Annual Meeting. Subjects enrolled in this non-randomized, open-label, single-arm international study received romidepsin at a dose of 14 mg/m(2), intravenously over four hours, on days one, eight and fifteen of a twenty-eight day cycle. The duration was six cycles, although those subjects who had an objective response or stable disease were eligible to continue therapy until disease progression. Of seventy- three evaluable subjects, an overall response rate of 37% was reported, with four complete responses, twenty-three partial responses and forty reports of stable disease. Six subjects had progressive disease. Of the subjects with severe pruritus at baseline, 37% reported significant relief. In addition, 38% of the subjects who exhibited any pruritus at baseline reported significant relief from symptoms. Treatment was determined to be safe and well tolerated. Based on the results, this phase II trial continues as planned.

Medarex and Bristol-Myers Squibb announced mixed top-line results from three phase III registrational trials (008, 022, 007) evaluating ipilimumab monotherapy for the treatment of metastatic melanoma. These international trials included an open-label, single arm trial (008) evaluating overall response rate in one hundred and fifty-five subjects who progressed on or following standard treatment; a randomized, double-blind trial (022) evaluating the efficacy of three dose levels of ipilimumab in two hundred and sixteen subjects who were previously treated, relapsed or failed to respond to experimental treatment or were unable to tolerate currently approved therapies; and a randomized, double-blind, placebo-controlled trial (007) in one-hundred and sixteen subjects comparing the safety of ipilimumab, with or without prophylactic oral budesonide (primarily evaluating the rate of grade 2+ diarrhea). The results from study 008, conducted under a SPA, did not meet the primary endpoint, which was to rule out a best objective response rate of less than ten percent. However, the totality of data from the trials included a clear dose response effect observed in study 022 and best objective response rates across the three studies ranging from mid-single digits to mid-teens as determined by independent radiology review. The objective responses included complete and partial responses. Medarex and BMS were planning to meet with the regulatory authorities and file for US approval by the first half of 2008.

October 1, 2007

Celgene released positive results from two ongoing phase II trials of Revlimid for the treatment of Chronic Lymphocytic Leukemia (CLL) at the 12th International Workshop on Chronic Lymphocytic Leukemia. The first trial enrolled 45 CLL subjects who had at least two prior therapies. The subjects received 25 mg of Revlimid orally once daily for 21 days in a four-week cycle. The overall response rate was 58%, of whom 18% achieved a complete remission and 40% partial remission. The median time to best response was 5.9 months and the median progression free survival was 19.4 months. Of subjects with poor prognostic factors, 44% showed a clinical response, while 30% of those with fludarabine refractory disease showed a clinical response. Treatment was generally well tolerated, with no unexpected adverse events. The second trial enrolled 44 subjects with CLL who had received prior purine analog-based combinations. Revlimid 10 mg orally once daily was administered for four weeks, followed by dose escalation by 5 mg every 28 days to a maximum dose of 25mg/day. The overall response rate was 34%, among which 7% achieved a complete remission, 2% achieved a nodular partial remission and 25% achieved a partial remission. Stable disease was observed in 23% of the subjects. The median response duration to date is 12-plus months. Based on the results, Celgene plans to move forward with the development of Revlimid for the treatment of CLL.

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