A wealth of abstracts were presented at the 54th Annual Meeting of the American Society of Hematology (ASH), held in Atlanta, Georgia, on December 8-11, 2012. More than 18,000 hematologists and other healthcare professionals from around the world gathered to discuss the latest clinical developments in research, therapies, and practice strategies. Attendees had the opportunity to review thousands of selected scientific abstracts. Following are some of the highlights from the ASH annual meeting.
According to expert opinion, ibrutinib is one of the most important treatments to emerge in the past 3 decades. This investigational agent has the promise to change the natural history of chronic lymphocytic leukemia (CLL) and lymphomas, if the results of several phase 2 trials are confirmed in the phase 3 studies currently in progress.
Ibrutinib, an investigational Bruton’s tyrosine kinase (BTK) inhibitor, achieved excellent results in clinical trials of patients with CLL, indolent non-Hodg-kin lymphoma, and mantle cell lymphoma (MCL)
“Rarely does a drug come along that helps patients this much. This drug is highly effective and very well tolerated. We are looking forward to Pharmacyclics bringing this drug forward. The quicker we get this drug across the finish line, the better,” stated John C. Byrd, MD, the D. Warren Brown Chair of Leukemia Research and director of the Division of Hematology at the Ohio State University Comprehensive Cancer Center in Columbus.
Byrd presented the results of a phase 2 trial of 116 patients with CLL/small lymphocytic leukemia (SLL) including elderly treatment-naive, relapsed/refractory, and high-risk relapsed/refractory patients.1 At 26 months, single-agent ibrutinib achieved excellent progression-free survival (PFS) both in elderly treatment-naive individuals (estimated PFS, 96%) and in those with relapsed/refractory high-risk CLL/SLL (estimated PFS, 75%).
Ibrutinib is also being studied in combination with rituximab in CLL and lymphoma. A separate phase 2 study in 40 patients with high-risk CLL treated with the combination of ibrutinib plus rituximab achieved an overall response rate of 83% and no evidence of disease progression in 38 of 40 patients, who are continuing on therapy.2
“These patients typically have inferior outcomes compared with low- and intermediate-risk patients,” stated Jan Burger, MD, PhD, lead author of this phase 2 trial and associate professor at the University of Texas MD Anderson Cancer Center in Houston. “This study shows profound activity for this combination in high-risk patients with CLL. The overall response rate is favorable compared with standard treatment, and the toxicity compares favorably to other treatment options.”
Interim results of an international phase 2 study of ibrutinib in relapsed/refractory MCL were extremely positive, according to another presentation at the 54th ASH annual meeting by Michael Wang, MD, also of the MD Anderson Cancer Center.3 The phase 2 study enrolled 115 patients (65 bortezomib naive and 50 bortez- omib exposed) with relapsed/refractory MCL. In these difficult-to-treat patients, ibrutinib achieved an overall response rate of 70% and a complete response rate of 20%, which increased to 50% at 14 months.
“With other molecular compounds, response rates in this group of patients are about 30% and progression-free survival is about 6 months. The difference between ibrutinib and other molecular compounds is outrageous,” stated an expert not involved in these studies, Martin Dreyling, MD, of the University of Munich, Germany.
A separate study presented at ASH by Wyndham Wilson, MD, PhD, of the National Cancer Institute in Bethesda, Maryland, showed that ibrutinib achieved an overall response rate of about 28% in 70 patients with relapsed diffuse large B-cell lymphoma (DLBCL).4 However, when patients were stratified according to genetic expression, response rates in activated B-cell (ABC)-like DLBCL were 40% (this group has the worst prognosis) and in germinal center B-cell–like DLBCL were 5.3%.
These results in the ABC subgroup of patients with relapsed DLBCL are considered unprecedented. Wilson and his coinvestigators concluded that future clinical trials of ibrutinib in DLBCL should be confined to the ABC subtype.
References 1. Byrd JC, Furman RR, Coutre S, et al. The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib (PCI-32765) promotes high response rate, durable remissions, and is tolerable in treatment naïve (TN) and relapsed or refractory (RR) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) patients including patients with high-risk (HR) disease: new and updated results of 116 patients in a phase Ib/II study. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 189. 2. Burger JA, Keating MJ, Wierda WG, et al. The Btk inhibitor ibrutinib (PCI-32765) in combination with ri- tuximab is well tolerated and displays profound activity in high-risk chronic lymphocytic leukemia (CLL) patients. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 187. 3. Wang M, Rule SA, Martin P, et al. Interim results of an international, multicenter, phase 2 study of Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib (PCI-32765), in relapsed or refractory mantle cell lymphoma (MCL): durable efficacy and tolerability with longer follow-up. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 904. 4. Wilson WH, Gerecitano JF, Goy A, et al. The Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib (PCI-32765), has preferential activity in the ABC subtype of relapsed/refractory de novo diffuse large B-cell lymphoma (DLBCL): interim results of a multicenter, open-label, phase 2 study. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 686.
A study presented at the 54th ASH annual meeting showed that daunorubicin could be safely omitted from an induction regimen without compromising survival in children with standard-risk acute lymphocytic leukemia (ALL). Daunorubicin is already omitted in this setting at many cancer centers in the United States and Europe, but until now there has been little evidence to support this practice. The French Acute Lymphoblastic Leukemia (FRALLE) 2000-A study is the first randomized controlled trial in the modern era to provide scientific evidence to support daunorubicin-free induction therapy.
The current cure rate for standard-risk ALL in pediatric patients is 90%. For many years, daunorubicin—an anthracycline that is associated with myelosuppression and potential long-term cardiac damage—was part of the induction protocol. However, this practice was based on only 3 studies that were more than 20 years old.
An anthracycline-free induction regimen can achieve the same positive outcomes without putting children at risk for both myelosuppression and cardiac toxicities associated with daunorubicin, said lead author Andre Baruchel, MD, head of the Department of Pediatric Hematology at the Robert Debré University Hospital in Paris, France. “These data can potentially benefit children with ALL in 2 important ways. First, we now have strong evidence that reducing the amount of chemotherapy initially administered to these children with standard-risk ALL [the majority of ALL patients] does not have a negative effect on their immediate outcome. Perhaps more importantly, we know and anticipate that removing harmful chemotherapy from their treatment can help minimize their risk of experiencing cardiac damage later in life.”
The FRALLE 2000-A study, conducted at 20 centers in France and 1 center in Belgium, randomized 1128 pediatric patients with standard-risk B-cell ALL to 2 treatment arms: arm A (n = 560) received standard-dose daunorubicin during induction therapy, and arm B (n = 568) did not. The induction regimen included vincristine, dexamethasone, and asparaginase. Patients received doxorubicin during delayed intensification (ie, the last treatment phase before maintenance therapy) and standard 24-month maintenance therapy from December 2000 through June 2010. Five-year event-free survival (EFS) and overall survival (OS) were evaluated during that period. Standard-risk ALL of the B-cell lineage was defined as children between 1 and 10 years of age and white blood cell count <50 g/L. Five-year EFS was 92.9% in arm A and 93.3% in arm B. OS rates were 97.2% for arm A and 98.2% for arm B. The amount of minimal residual disease (MRD) was similar in both arms: MRD ≥1% was observed in 1.8% of arm A and in 1.9% of arm B; MRD ≥0.1% was seen in 6.5% and 9.3%, respectively. The rates of cumulative incidence of relapse and site of relapse were also similar in both arms.
“These results show similar efficacy rates in children with standard-risk ALL for induction regimens with and without daunorubicin,” Baruchel emphasized.
Reference Baruchel A, Petit A, Leblanc T, et al. Daunorubicin or not during the induction treatment of childhood standard-risk B-cell precursor acute lymphoblastic leukemia (SR-BCP-ALL): the randomized Fralle 2000-A protocol. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 135.
For many years, rituximab-CHOP (the combination of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone, also known as R-CHOP) has been considered the treatment of choice for indolent lymphoma. Following on the heels of several positive studies, the combination of bendamustine-rituximab is gaining favor in Europe and the United States as a replacement for the more toxic R-CHOP regimen.
A poster presentation showed that in Germany, R-CHOP accounted for 16% of patients with indolent lymphoma, while bendamustine was included in first-line therapy in 71% of patients, according to lead author Wolfgang Knauf, MD, professor of hematology at Onkologische Gemeinschaftspraxis, Frankfurt, Germany. Rituximab was included as first-line therapy in 94% of patients, and it was combined with bendamustine in 66% of patients.
“R-CHOP is dead. The registry data we present is a description of what is happening in Germany,” Knauf said. The registry is in the process of recruiting 1000 patients with indolent lymphoma, 1000 with chronic myelogenous leukemia, and 1000 with aggressive lymphoma. Knauf presented data on 645 patients with indolent lymphoma at the 54th ASH annual meeting.
In terms of second-line therapy, Knauf said that bendamustine is now used more often than CHOP. Of 121 patients treated with second-line therapy, rituximab was used in 102 patients, bendamustine was used in 82 patients, and the combination was used in 72 patients. By contrast, R-CHOP was used in 9 patients.
Some experts in the United States agreed that bendamustine-based therapy is poised to replace R-CHOP for the treatment of lymphoma, based on promising progression-free survival data reported last year in the Study Group on Indolent Lymphomas (StiL) trial. However, R-CHOP will continue to have a role in select patients, they predicted.
Reference Knauf WU, Abenhardt W, Nusch A, et al. Bendamustine-rituximab (BR) replaces R-CHOP as “standard of care” in the treatment of indolent non-Hodgkin lymphoma in German hematology outpatient centres. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Poster 3666.
An investigational oral proteasome inhibitor known as MLN9708 had such promising results in phase 1 and 2 trials that it is currently in phase 3 testing. If results are positive, the drug is expected to be approved as soon as 2014. MLN9708 is an oral drug taken once weekly, and will be an alternative to bortezomib, the first proteasome inhibitor developed for multiple myeloma. Bortezomib is administered by intravenous infusion or subcutaneous injection. MLN9708 appears to have a more favorable adverse-effect profile than bortezomib; specifically, peripheral neuropathy has been greatly reduced with the oral agent in trials thus far.
To put this into context, bortezomib given intravenously twice weekly has been associated with peripheral neuropathy in 30% to 40% of patients, compared with rates of about 10% to 15% for MLN9708 in preliminary trials. Shaji Kumar, MD, of the Mayo Clinic, Rochester, Minnesota, presented results of the phase 1/2 trial at the 54th ASH annual meeting after a median of 6 cycles of therapy.
The study had 2 parts. Phase 1 enrolled 15 patients and established 4 mg orally once weekly as the maximum tolerated dose of the investigational agent. Phase 2 included 55 patients with newly diagnosed multiple myeloma. MLN9708 4 mg was given on days 1, 8, and 15, in combination with lenalidomide 25 mg once daily on days 1 to 21 and dexamethasone 40 mg on days 1, 8, 15, and 22.
Twenty patients went on to attempt stem-cell harvesting for transplant. The other 30 remained on therapy at the time of ASH.
Minor adverse events were reported in 40% of patients, including fatigue, nausea, and rash. Seven patients discontinued treatment due to adverse events.
The major serious adverse events of grade 3 or higher were gastrointestinal upset and skin rash (about 5% of patients for each adverse event). Two grade 4 events occurred: end-stage renal disease in 1 patient, which was attributed to the disease itself, and deep vein thrombosis in 1 patient. One patient died from pneumonia.
Mild grade 1 neuropathy occurred in 8.45%, and grade 3 neuropathy developed in only 2.07%.
The overall response rate was 92%; 55% had very good partial response and 23% had complete response. Longer treatment increased the depth of response. For those patients who finished 12 cycles of therapy, the complete response rate increased to 67%, while 33% had very good partial response.
Reference Kumar SK, Berdeja JG, Niesvizky R, et al. A phase 1/2 study of weekly MLN9708, an investigational oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma (MM). Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 332.
In the randomized, placebo-controlled Apixaban After the Initial Management of Pulmonary Embolism and Deep Vein Thrombosis With First-Line Therapy–Extended Treatment (AMPLIFY-EXT) trial, oral apixaban taken for another year after a standard course of treatment for venous thromboembolism (VTE) reduced the risk of fatal and nonfatal recurrent VTE without increasing the risk of major bleeding. Extended treatment with oral apixaban was associated with death or recurrent VTE in about 4% of patients who received either 2.5-mg or 5-mg doses of the drug, compared with 12% in the group assigned to placebo.
“Both doses of anticoagulant reduced the risk of recurrent fatal or nonfatal VTE by about 80%, and the rates of major bleeding on apixaban were low and comparable to those in the placebo group. The number of patients needed to treat [NNT] to prevent 1 episode of recurrent or nonfatal VTE is only 14, while the NNT to cause 1 episode of major or clinically relevant nonmajor bleeding is 200,” stated lead author Giancarlo Agnelli, MD, of the University of Perugia, Italy. Warfarin is standard treatment for VTE, and after patients discontinue warfarin the risk of recurrent VTE ranges from 6% to 10% in patients without reversible risk factors, he explained.
Apixaban is a new oral Xa inhibitor that is rapidly absorbed, with the kidney excreting about 25%. Unlike warfarin, no monitoring is necessary with apixaban.
In the AMPLIFY-EXT trial, patients with deep vein thrombosis or VTE treated for 6 to 12 months with anticoagulant therapy were randomized to receive either apixaban 2.5 mg or 5 mg twice daily versus placebo. Patients were treated for 12 additional months, and safety was assessed at 30 days after treatment initiation.
Recurrence of VTE or all-cause death was 3.8% for the 2.5-mg dose of apixaban, 4.2% for the 5-mg dose, and 11.6% for placebo, for a risk reduction of 65%.
Recurrent VTE or VTE-related deaths were 1.7%, 1.7%, and 8.8% for the 2.5-mg dose, the 5-mg dose, and placebo, respectively. Myocardial infarction, stroke, or cardiovascular-related deaths were reported in 2.1%, 2.3%, and 10%, respectively.
The rates of major bleeding were 0.2% for the 2.5-mg dose, 0.1% for the 5-mg dose, and 0.5% for placebo. The rates of clinically relevant nonmajor bleeding were 3%, 4.2%, and 2.3%, respectively.
Agnelli said the optimal treatment duration for apixaban has not yet been determined. In the AMPLIFY-EXT trial, patients were treated for 1 year and achieved risk reduction in recurrent VTE without an increase in major bleeding, but further study of a longer treatment duration would be needed to establish a benefit.
Going forward, the 2.5-mg dose will be preferred, because the 5-mg dose did not provide further benefit. Apixaban will be reviewed by the US Food and Drug Administration in the future. l
Reference Agnelli G, Buller HR, Cohen A, et al. Two doses of apixaban for the extended treatment of venous thromboembolism. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract LBA-1.
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