You are here

Meeting Highlights

American Society of Hematology 2017

The 59th American Society of Hematology (ASH) Annual Meeting, held December 9–12, drew approximately 25,000 hematology professionals to Atlanta. We review below sessions on Hodgkin’s lymphoma, diffuse large B-cell lymphoma, venous thromboembolism, hemo­philia, sickle cell disease, and chronic lymphocytic leukemia.

Brentuximab Vedotin Plus Doxorubicin, Vinblastine, and Dacarbazine as Front-Line Therapy Demonstrates Superior Modified Progression-Free Survival Versus ABVD in Patients With Previously Untreated Stage III or IV Hodgkin’s Lymphoma: The Phase 3 Echelon-1 Study

  • Joseph M. Connors, MD, Division of Medical Oncology and Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, Canada

Results of the multinational, phase 3 Echelon-1 study establish brentuximab vedotin (BV) (Adcetris, Seattle Genetics) plus doxorubicin, vinblastine, and dacarbazine (AVD) as a new first-line option for patients with advanced-stage Hodgkin’s lymphoma (HL), Dr. Connors said in an ASH press briefing.

Dr. Connors noted that the combination of doxorubicin (formerly referred to by the now-discontinued brand name Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD) has been the standard treatment for HL since the 1970s. While other strategies aimed at improving outcomes have all induced severe side effects in phase 1 research, adding the anti-CD30 antibody BV, a microtubule-disrupting agent, to ABVD produced a complete response rate of 96% with 100% five-year overall survival in 26 patients. BV was also well tolerated.

In the open-label Echelon-1 study, first-line treatment for stage III or IV HL was administered with ABVD or BV plus AVD in a 1:1 randomization among 1,334 patients with up to 50 months of follow-up. The primary endpoint was modified progression-free survival (mPFS) at two years assessed by independent review.

Mean patient age was 68 years in the BV-plus-AVD group and 63 years in the ABVD group, and approximately 58% of the patients in both groups were men. In the BV-plus-AVD group, mPFS was 82.1%; in the ABVD group, it was 77.2% (hazard ratio, 0.77; 95% confidence interval, 0.60–0.98; P = 0.0348). Subsequent anticancer therapy was required by 18% of patients in the BV-plus-AVD group and by 22% of patients in the ABVD group. Subsequent chemotherapy was required by 33% fewer patients in the BV-plus-AVD group, and 33% fewer received high-dose chemotherapy with transplant in that group.

Although grade 3 or higher neutropenia or febrile neutro­penia rates were higher in the BV-plus-AVD group, prophylactic use of granulocyte-colony stimulating factor (G-CSF) therapy lowered rates to levels comparable with that of ABVD after the interim safety analysis. In addition, patients receiving BV-plus-AVD had higher rates of treatment-emergent peripheral neuropathy than patients in the ABVD arm (67% versus 43%), with most grade 1 (64%) or grade 2 (29%) in severity. Resolution or improvement by at least one grade was reported in 67% of those with peripheral neuropathy in the BV-plus-AVD group. Drug discontinuation rates for peripheral neuropathy were 7% in the BV-containing arm and 2% in the ABVD arm. Interstitial lung disease of grade 3 or higher, associated generally with bleomycin, occurred in less than 1% of patients receiving BV plus AVD and in 3% of patients receiving ABVD.

“Brentuximab vedotin in combination with AVD was more effective than ABVD for the front-line treatment of advanced-stage Hodgkin’s lymphoma,” Dr. Connors concluded, adding that chances of being cured with the addition of BV increased as early as the first round of treatment. G-CSF primary prophylaxis is recommended for all patients. He noted that the regimen allows bleomycin to be omitted, and that toxicities are manageable.

Primary Analysis of JULIET: A Global, Pivotal, Phase 2 Trial of CTL019 in Adult Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma

  • Stephen J. Schuster, MD, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania

Analysis of JULIET trial results reveals a high percentage of durable response to tisagenlecleucel (Kymriah [formerly CTL019], Novartis) in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). In an ASH press briefing, Dr. Schuster said the trial also showed that global distribution of tisagenlecleucel, the first chimeric antigen receptor T-cell therapy to be approved, is feasible.

He noted that responses to salvage therapy in this poor-­prognosis relapsed/refractory population are historically low (8% complete response [CR], 18% partial response [PR]). Median overall survival is just four months. High-dose chemotherapy followed by autologous stem cell transplant is the standard of care. Approximately 50% of patients are ineligible for transplant, and about another 25% respond to chemotherapy and can go on to transplantation. Among these patients, approximately 10% are cured and 15% relapse. Most patients who relapse have no further options. In a phase 2 study of tisagenlecleucel, all CRs (57%) were sustained at a median follow-up of 29 months.

Manufacturing of tisagenlecleucel with cryopreserved apheresis was centralized in the pivotal JULIET trial. The drug was distributed to 27 sites in 10 countries in North America, Europe, Australia, and Asia. Investigators enrolled 99 patients with DBLCL who were ineligible for transplant or who had disease that had progressed after two or more lines of prior chemotherapy. Twenty-six percent of patients were treated on an outpatient basis.

The primary endpoint of overall response rate (ORR) (CR plus PR) in 81 evaluable patients was 53% with CR in 40% (P < 0.0001). At three months (n = 81), ORR was 38% and CR was 32%. At six months (n = 46), the rates were 37% and 30%, respectively. Dr. Schuster commented that the “durability of response is shown by the stability between three- and six-month response rates.” In addition, 74% of responders were relapse-free at six months. While in response, no patients proceeded to transplant. Most adverse events occurred shortly after infusion and included cytokine release syndrome (58%) and neuro­toxicities (21%). No deaths were attributed to adverse events.

“Analysis confirms the durable clinical benefit previously observed in the single-center University of Pennsylvania trial,” Dr. Schuster said. “We are going to be able to offer patients who don’t respond to standard therapies a form of therapy that may, after a single treatment, relieve symptoms and save lives.”

A Randomized, Open-Label, Blinded-Outcome Assessment Trial Evaluating the Efficacy and Safety of LMWH/Edoxaban Versus Dalteparin For Venous Thromboembolism Associated With Cancer: The Hokusai VTE-Cancer Study

  • Gary E. Raskob, PhD, University of Oklahoma College of Public Health, Oklahoma City, Oklahoma

In the Hokusai VTE-Cancer study, oral edoxaban (Savaysa, Daiichi Sankyo) was noninferior to subcutaneous dalteparin (Fragmin, Pfizer) for the endpoint of venous thromboembolism (VTE) or major bleeding. While recurrent thromboembolism was reduced with edoxaban, major bleeding increased to a similar degree, Dr. Raskob said. At an ASH late-breaking clinical trial session, he pointed out that roughly one in five individuals with cancer develop thromboembolism, a rate higher than in patients without cancer. Bleeding also occurs more often in cancer patients, he said, and can both interfere with cancer therapy and contribute to mortality and morbidity.

Major practice guidelines, including those from the American College of Chest Physicians, American Society of Clinical Oncology, and European Society for Medical Oncology, recommend low-molecular-weight heparin (LMWH) as initial and long-term therapy for VTE, but subcutaneous injections can be burdensome and limit adoption of therapy. Direct oral anticoagulants, such as edoxaban, may be an attractive alternative for these patients, Dr. Raskob said.

The 1,050 patients enrolled in the Hokusia VTE-Cancer study represented a wide range of cancer types and chemotherapy regimens; approximately 10% had hematologic cancers and the rest had solid tumors. All were being treated for VTE (at 114 centers in 13 countries). Half were randomly assigned to receive LMWH (dalteparin 200 IU/kg daily for one month, then 150 IU/kg thereafter), and half were assigned to receive edoxaban (60 mg daily) for up to 12 months. All patients were followed for 12 months or until study closure (minimum, nine months). The primary outcome was first recurrent VTE or major bleeding event at 12 months.

Dr. Raskob reported that the primary outcome rate was significantly lower in the edoxaban group than in the dalteparin group (12.8% versus 13.5%) (hazard ratio, 0.97; 95% confidence interval, 0.70–1.36; P = 0.018). The recurrent VTE rates for edoxaban and dalteparin were 6.5% and 10.3%, respectively. The major bleeding rates were 6.3% and 3.2%, respectively. Most bleeding was in the upper gastrointestinal tract and occurred in patients with gastrointestinal cancers, Dr. Raskob said. While the major bleeding rate was higher for edoxaban, bleeds in the dalteparin group tended to be more severe. Event-free survival was identical for both groups.

“Oral edoxaban is noninferior to subcutaneous dalteparin for the primary outcome of recurrent venous thromboembolism or major bleeding,” Dr. Raskob said. He explained that the results do not necessarily apply to all direct oral anticoagulants because some act through different mechanisms or are metabolized differently than edoxaban. “For the vast majority of patients with cancer-associated venous thromboembolism, treatment with oral edoxaban can replace the injectable dalteparin,” he concluded.

HAVEN 2 Updated Analysis: Multicenter, Open-Label Phase 3 Study to Evaluate Efficacy, Safety, and Pharmacokinetics of Subcutaneous Emicizumab Prophylaxis in Pediatric Patients With Hemophilia A With Inhibitors

  • Guy Young, MD, University of Southern California Keck School of Medicine, Children’s Hospital Los Angeles, Los Angeles, California

In children with hemophilia A who develop resistance to standard intravenous (IV) therapy, once-weekly subcutaneous (SC) administration of emicizumab (Hemlibra, Genentech) effectively prevents bleeds, according to nine-week results of the HAVEN 2 trial presented at an ASH press conference.

In patients with hemophilia A, the most common form of the disease, levels of blood-clotting protein factor VIII are extremely low, leading to debilitating bleeding events, with joint pain and eventual joint disease in the absence of factor VIII infusions. In about 30% of patients, however, neutralizing alloantibodies (known as inhibitors) bind to the infused factor VIII and render it useless. Morbidity increases and health-related quality of life declines. The condition is currently treated through immune tolerance induction or bypassing agents requiring frequent IV infusions, often with long-term use of central venous access devices in children, with concomitant infections and thrombosis. The unmet need in this population, Dr. Young said, is to alleviate the burden of both the disease and the treatment.

Emicizumab, a humanized, bispecific, monoclonal antibody, is not affected by inhibitors and replaces the function of factor VIII by bridging activated factor IX and factor X.

Children in HAVEN 2 (N = 60, 100% male) all have inhibitors to factor VIII infusions. They are receiving episodic or prophylactic treatment with bypassing agents. They are being treated with SC emicizumab at 3 mg/kg per week for four weeks and 1.5 mg/kg per week thereafter. The primary analysis will be conducted 52 weeks after the last patient is enrolled. Safety will be monitored for 24 additional weeks (on or off study drug). Dosing intervals of two and four weeks will be tested in future trials.

At baseline, 95% of the boys had severe disease. The median number of bleeds per patient in the 24 weeks preceding the trial was six (range, 0–155). In addition, more than one-third of the patients (38.3%) had “target joints” (joints with frequent bleeding episodes).

Emicizumab treatment was effective in this population. Among 57 evaluable patients, 94.7% reported zero bleeds needing treatment, and 98.2% had no treated joint bleeds. Among the 23 patients with at least 12 weeks of follow-up (range, 12.7–41.6 weeks), only three patients reported treated bleeds (one each in the joint, muscle, and hip). All three were safely treated with recombinant factor VIIa, a standard of care for this population. The annualized bleeding rate in this group was 0.2, a 99% reduction compared with prior bypass agent prophylaxis.

Health-related quality of life for patients and burden for caregivers versus prior bypassing agents were both substantially improved.

Ten of the 40 adverse events (67.7%) were considered treatment-related. All were local injection-site reactions: six of them serious and four of grade 3 or higher. No thromboembolic or thrombotic microangiopathy events were reported.

“Emicizumab successfully prevented or reduced bleeds,” Dr. Young concluded. “The once-weekly treatment is so much easier for the patients. This treatment has a tremendous impact on patients’ lives.”

Achievement of Normal Circulating Factor VIII Activity Following BMN 270 AAV5-FVIII Gene Transfer: Interim, Long-Term Efficacy and Safety Results From a Phase 1/2 Study in Patients With Severe Hemophilia A

  • K. John Pasi, MD, Barts and the London School of Medicine and Dentistry, London, United Kingdom

In a first-in-human phase 1/2 study, patients with hemo­­philia A who underwent an investigational, single-infusion gene therapy using an AAV-factor VIII vector (valoctocogene roxaparvovec [formerly BMN 270], BioMarin) have experienced sustained and clinically relevant factor VIII activity for more than 1.2 years after treatment. Valoctocogene roxaparvovec is a functional copy of the gene responsible for producing factor VIII; this gene is mutated in hemophilia A patients. The results have profoundly reduced self-reported bleeding and exogenous factor VIII use in these patients, Dr. Pasi said. He also said that hemophilia A, an X-linked, single-gene disorder of factor VIII, is an ideal candidate for gene therapy.

The current treatment standard for severe hemophilia A (factor VIII level of less than 1 IU/dL) of using factor VIII replacement products is expensive and demanding, requiring multiple intravenous infusions per week. While several gene therapies have demonstrated success for hemophilia B, the rarer form of the disease, gene therapy for hemophilia A has been considered more challenging because it is associated with a more complex and much larger gene.

Participants had received up to 185 factor VIII infusions to prevent bleeds in the year prior to study enrollment, with up to 41 breakthrough bleeding episodes per year despite prophylactic treatment. Patients received one of four valoctocogene roxaparvovec doses based on factor VIII activity at three weeks, with doses increased if their factor VIII level was less than 5 IU/dL.

Dr. Pasi reported results from two of the valoctocogene roxaparvovec doses (6E13 vg/kg, n = 7; 4E13 vg/kg, n = 6). Within several weeks of treatment, all patients began producing factor VIII. By 20 weeks after the infusion, factor VIII levels in those receiving the higher dose had plateaued in the normal range and remained there. Among those receiving the lower dose, factor VIII levels increased steadily to a median of 34 IU/dL by week 20. In three patients who had been followed for 32 weeks, the factor VIII median was 51 IU/dL, which is within the normal range. Dr. Pasi observed that with 1.5 years of follow-up, 6E13 vg/kg achieved levels within the normal range of factor VIII activity, with a median of 90 IU/dL at 78 weeks. With up to one year of follow-up, 4E13 vg/kg achieved levels approaching or within the lower end of the normal range of factor VIII activity, with a median of 49 IU/dL at 48 weeks (n = 3). The increases, given that pretreatment factor VIII levels were less than 1 IU/dL, were dramatic, he said.

In those patients with post-infusion factor VIII levels greater than 5%, the annualized bleed rate in the 6E13 group went from 16.5 episodes to zero, and from eight to zero episodes in the 4E13 group. Similarly, in those with post-infusion factor VIII levels greater than 5%, median annual factor VIII use dropped from 138.5 infusions to zero in the 6E13 group and from 155.5 infusions to zero in the 4E13 group.

Valoctocogene roxaparvovec was well tolerated, Dr. Pasi said, and no patients developed inhibitors to factor VIII. Two serious adverse events included pyrexia with myalgia and headache during infusion and a planned total knee replacement for chronic arthropathy. Nonserious liver enzyme elevations of limited duration (0.4–15.4 weeks) were observed in 10 of 15 patients. In addition, all patients who received 6E13 remain off steroids, and only one 4E13 patient remains on steroids. Dr. Pasi said that adverse events were not qualitatively different between the 6E13 and 4E13 cohorts.

“Both doses of valoctocogene roxaparvovec eliminated occurrence of spontaneous bleeds and provided factor VIII coverage, eliminating the need for factor VIII, even in cases of major trauma or surgery,” he concluded.

Long-Term Follow-Up in ZUMA-1: A Pivotal Trial Of Axicabtagene Ciloleucel in Patients With Refractory Aggressive Non-Hodgkin’s Lymphoma

  • Sattva S. Neelapu, MD, The University of Texas MD Anderson Cancer Center, Houston, Texas

More than half of patients with fast-growing and refractory aggressive non-Hodgkin’s lymphoma were alive at least one year after a single infusion of axicabtagene ciloleucel (Yescarta, Kite Pharma, Inc.) in the pivotal ZUMA-1 trial. Axicabtagene ciloleucel is a chimeric antigen receptor (CAR) T-cell therapy that targets the CD19 protein often found on lymphoma cells, Dr. Neelapu said in an ASH press briefing. A patient’s own T cells are harvested for CAR T-cell therapies, and then reengineered to target specific proteins on leukemia and lymphoma cell surfaces. They are then reintroduced to the patient’s immune system, Dr. Neelapu explained.

The phase 1/2 ZUMA-1 study, conducted at 22 sites, is the largest study of a CAR T-cell therapy to date. ZUMA-1 includes seven phase 1 patients and 101 phase 2 patients (median age, 58 years; age range, 23–76 years; 68% men), all of whom had not responded to their last chemotherapy or had relapsed after it. Patients were a year or less post-autologous stem cell transplant and had received prior anti-CD20 monoclonal antibody and anthracycline treatment. Seventy percent of the patients had received three or more prior therapies.

The objective response rate in the 108 patients was 82%, including 58% with a complete response (CR) after a median follow-up of 15.4 months. Forty-three percent (three of seven) of the phase 1 patients have achieved a CR, which is ongoing at 24 months. In the updated analysis, 23 of 60 patients with either a partial response (11 of 35) or stable disease (12 of 25) at the first tumor assessment (one month post-infusion) subsequently achieved a CR up to 15 months after infusion without additional therapy.

Median duration of response has not been reached in those with a CR and is 11.1 months in the overall group. Among the 56% of patients remaining alive, 42% are progression-free, Dr. Neelapu said.

Most patients (97%) had a grade 3 or higher adverse event, with cytokine release syndrome, neurological toxicities, neutro­penia, anemia, and thrombocytopenia most common in the pivotal portion of ZUMA-1. Within six months after the primary analysis, 10 patients experienced a serious adverse event, with manageable infections in eight patients. In the updated analysis, no new-onset cytokine release syndrome or neurological events related to axicabtagene ciloleucel were observed.

Investigators found, after analyzing tumor tissue biopsied before and after treatment in patients who relapsed, that more than two-thirds of tumors showed evidence of programmed death ligand-1 expression that was likely inhibiting the function of the infused T cells. Follow-up studies are now under way.

“Axi-cel [axicabtagene ciloleucel] is highly effective in patients with large B-cell lymphoma who otherwise have no curative options,” Dr. Neelapu said.

Initial Results From a Cohort in a Phase 2a Study Evaluating Adolescents With Sickle Cell Disease Treated With Multiple Doses of GBT440, an HbS Polymerization Inhibitor

  • Carolyn C. Hoppe, MD, Children’s Hospital Oakland, Oakland, California

Improvements in total severity scores suggest that voxelotor (formerly GBT440, Global Blood Therapeutics, Inc.) may be a disease-modifying therapy for patients with mildly symptomatic sickle cell disease. That conclusion emerged from interim study findings, Dr. Hoppe said in an ASH press briefing.

Voxelotor, an investigational first-in-class hemoglobin oxygen affinity modulator, inhibits the intracellular polymerization of sickle hemoglobin that makes red blood cells less deformable, leading to hemolytic anemia, vaso-occlusion and symptoms of fatigue, pain crisis, and potentially fatal organ damage.

Dr. Hoppe reported on a phase 2a, open-label, 24-week study designed to assess the efficacy of voxelotor in pediatric patients with sickle cell disease as measured by improvements in anemia. Prior voxelotor testing, she noted, had only been among adults. The current trial included 24 adolescents (ages 12–17 years) with sickle cell disease. All received voxelotor 900 mg daily.

The efficacy analysis was conducted among 12 patients (half were female) who had undergone 16 weeks of treatment. Most (11 of 12) had the HbSS genotype. Forty-one percent of the children had experienced one to four vaso-occlusive crises in the prior year, and 55% had been vaso-occlusive crisis-free. Eleven had been receiving hydroxyurea, the standard of care.

Hemoglobin responses greater than 1 g/dL at week 16 were achieved by 55% (six of 11) of the patients. Ten of 12 patients showed a reduction in total severity score from baseline, and five of 12 had a mean total severity score of zero at week 16. One patient sustained a score of zero from baseline to week 16.

Voxelotor was well tolerated with most adverse events grade 1 or 2 in severity (nausea, 12.5%; headache, 8.3%; rash, 8.3%). No drug-related serious adverse events or study drug discontinuations were reported.

“Voxelotor 900 mg for 16 weeks in sickle cell disease adolescents, most of whom were receiving hydroxyurea, demonstrated consistent and sustained efficacy on hemoglobin levels and measures of hemolysis,” Dr. Hoppe said. The findings also suggest that voxelotor’s safety and tolerability profile are consistent with that demonstrated among adults in the earlier study.

Results of the Randomized, Double-Blind, Placebo-Controlled, Phase 3 Hercules Study Of Caplacizumab in Patients with Acquired Thrombotic Thrombocytopenic Purpura

  • Marie Scully, MD, Department of Hematology, University College London Hospitals NHS Trust, London, United Kingdom

Results of the phase 3 HERCULES study confirm that treatment with caplacizumab (investigational, Ablynx) reduces the time to platelet count response, resulting in faster resolution of acquired thrombotic thrombocytopenic purpura (aTTP). The findings, Dr. Scully said in a late-breaking clinical trial presentation, confirm the promising data from earlier-stage research.

Acquired thrombocytopenic purpura, an acute life-threatening thrombotic microangiopathy, Dr. Scully noted, occurs when antibodies block the activity of ADAMTS-13, an enzyme that cleaves von Willebrand factor, a key blood-clotting protein. Disseminated microthrombi deprive tissues of oxygen, causing end-organ damage with greater than 90% mortality in the absence of treatment. The current treatment for aTTP is daily plasma exchange to remove autoantibodies, and corticosteroids and/or rituximab (Rituxan, Genentech) to inhibit autoantibody formation. Mortality is 10% to 20%, and the disease recurs within weeks after the cessation of plasma exchanges. “The unmet medical need remains high,” Dr. Scully said.

The anti-von Willebrand nanobody caplacizumab inhibits the formation of microthrombi by blocking the binding of von Willenbrand factor to platelets, Dr. Scully explained. It was tested in the double-blind, multinational HERCULES study, which included 145 patients suffering acute episodes of aTTP despite standard care. Half were given caplacizumab and the other half placebo. Treatment was administered intravenously before plasma exchange, with daily doses given subcutaneously for the duration of the daily plasma exchange, and 30 days thereafter. Treatment could be extended for up to an additional four weeks if the underlying disease was ongoing. Patients were monitored for safety for at least 28 days post-treatment. The primary endpoint was time to platelet count response (initial platelet count 150 × 109/L or greater with subsequent cessation of daily plasma exchange within five days).

Dr. Scully reported a platelet normalization rate ratio of 1.55 for patients receiving caplacizumab (95% confidence interval, 1.10–2.20; P < 0.01). The first key secondary endpoint of aTTP-related death, recurrence, or major thromboembolic event was reported at rates of 49.3% for placebo (n = 73) and 12.7% (n = 72) for the caplacizumab group. The recurrence rate of aTTP was 38.4% and 4.2% in the placebo and caplacizumab groups, respectively. Similar percentages of patients in the placebo (8.2%) and caplacizumab (8.5%) groups experienced at least one emergent major thromboembolic event. Deaths attributed to aTTP were reported at a rate of 4.1% in the placebo group and 0% in the caplacizumab group.

In addition, patients in the caplacizumab group experienced improvements in the relative reduction of days of plasma exchange (–38%), plasma volume (–41%), days in intensive care (–65%), and days in the hospital (–31%).

Rates of treatment-emergent adverse events leading to discontinuation were 12.3% and 7.0% in the placebo and caplacizumab groups, respectively. The safety profile of caplacizumab was in line with prior study reports, Dr. Scully said. She concluded, “Caplacizumab addresses the pathophysiological platelet aggregation that leads to the formation of microthrombi and the resultant mortality and morbidity seen in aTTP.”

Venetoclax Plus Rituximab Is Superior to Bendamustine Plus Rituximab in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia: Results From Preplanned Interim Analysis of the Randomized Phase 3 Murano Study

  • John F. Seymour, MBBS, PhD, Peter MacCallum Center and Royal Melbourne Hospital, Melbourne, Australia

MURANO, the first phase 3 study of venetoclax (Venclexta, AbbVie) in relapsed/refractory chronic lymphocytic leukemia (CLL), shows a profound improvement in progression-free survival (PFS) versus standard bendamustine chemotherapy with rituximab (Rituxan, Genentech), with consistent effects across all risk subsets, Dr. Seymour said in a late-breaking clinical trial press briefing.

With historical overall response rates of 59%, complete response rates of 9%, a median PFS rate of 15.2 months, and overall survival of 33.9 months,1 the conventional chemo­immunotherapy combination of bendamustine and rituximab is suboptimal, Dr. Seymour noted. Venetoclax is an orally administered, highly selective, potent BCL-2 inhibitor with activity even in patients with poor prognostic features. Phase 1b research with venetoclax combined with rituximab, however, demonstrated an acceptable safety profile with high rates of complete response and minimal residual disease (MRD) negativity, and with durable disease control after drug cessation.

MURANO investigators enrolled 389 patients (median age, 65 years) whose CLL had persisted or recurred after at least one previous course of treatment, including chemotherapy. Half of the patients were randomly assigned to a regimen of six monthly doses of venetoclax (400 mg daily) plus rituximab (375 mg/m2 day 1 of cycle 1; 500 mg/m2 day 1 of cycles 2–6) and half received six cycles of bendamustine (70 mg/m2 days 1 and 2 of cycles 1–6) plus rituximab. Patients assigned to the venetoclax arm continued to use venetoclax alone for two years or until CLL returned. The primary endpoint was investigator-assessed PFS.

After a median follow-up of 23.8 months (range, 0–37.4 months), median PFS was not reached in the venetoclax group and was 17 months in the bendamustine group (hazard ratio [HR], 0.17; 95% confidence interval [CI], 0.11–0.25; P < 0.0001). In the venetoclax group, 65 patients completed two years of treatment without progression. Overall survival at two years was 91.9% and 86.6% in the venetoclax and bendamustine groups, respectively (HR, 0.48; 95% CI, 0.25–0.90; P = 0.0186). The improvements, Dr. Seymour said, were “clinically meaningful.”

“Safety was consistent with known safety profiles in patients with relapsed/refractory CLL,” he said. Serious adverse events were reported in similar proportions in both groups (46% for venetoclax plus rituximab; 43% for bendamustine plus rituximab), with grade 3 and grade 4 event rates of 82% and 70%, respectively.

“MURANO results suggest that venetoclax plus rituximab should be considered as a standard therapeutic option in patients with relapsed/refractory CLL, replacing chemo­therapy,” Dr. Seymour concluded. The results also indicate that the preferred treatment would be with venetoclax in combination with rituximab, he said.


  1. Fischer K, Cramer P, Busch R, et al. Bendamustine combined with rituximab in patients with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol 2011;29(26):3559–3566.
Author bio: 

The author is a freelance writer living in New York City.