Ibrutinib Encouraging in CLL

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-Hodgkin 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 bortezomib 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 rituximab 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.

Daunorubicin-Free Regimen Effective

A study presented at the 54th ASH annual meeting showed 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.

Apixaban Reduced Thromboembolic Events

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.

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.