Novel Therapies for Leukemia Attract Attention at ASCO 2014
By Lynne Lederman, PhD
During this year’s ASCO Annual Meeting, progress in the development of novel therapies for hematologic malignancies was presented. Promising results of 4 leukemia trials presented are highlighted below.
Ibrutinib in CLL: Results from the RESONATE Trial
John C. Byrd, MD, Ohio State University Comprehensive Cancer Center, Columbus, Ohio, presented late-breaking results of the RESONATE trial comparing ibrutinib with ofatumumab in relapsed or refractory chronic lymphocytic leukemia(CLL)/small lymphocytic lymphoma (SLL, the same disease as CLL).1 Results of this trial (NCT01578707), which was funded by Pharmacyclics and Janssen, were published in conjunction with the meeting.2 Patients with CLL or SLL who have a short duration of response to initial therapy, older than age 65 years, or have deletion 17p13.1 have poor outcomes and limited treatment options.
Ibrutinib is a first-in-class, oral, covalent (irreversible) inhibitor of Bruton’s tyrosine kinase, an enzyme that is required for B-cell function. Ibrutinib had previously been designated a breakthrough therapy by the FDA and given accelerated approval on the basis of overall response (OR) in a phase 2 trial for patients with mantle-cell lymphoma in November 2013,3 and for CLL in February 2014, for patients who had received at least one prior therapy.4
RESONATE, a phase 3 open-label trial initiated on the basis of early phase 2 trial results, randomly assigned patients with previously treated, relapsed or refractory CLL or SLL to once daily oral ibrutinib (n=195) or to the anti-CD20 antibody ofatumumab (n=196), an approved, active control agent. The primary endpoint was duration of progression-free survival (PFS); secondary endpoints were duration of overall survival (OS) and OR. During this trial, patients in the ofatumumab group who had disease progression were allowed to cross over to ibrutinib treatment (n=57).
At a median follow-up of 9.4 months, ibrutinib significantly prolonged PFS (median not reached) compared with ofatumumab (median 8.1 months; P<.0001). Ibrutinib reduced the risk of disease progression or death by 78% compared with ofatumumab. OS was not reached in either arm, but was significantly prolonged with ibrutinib compared with ofatumumab (P<.0049), with a 57% reduction in the risk of death in the ibrutinib group, despite the crossover of patients on ofatumumab with progressive disease. The benefits of ibrutinib were not affected by patient age, presence of del 17p, presence of purine analog-refractory disease, or other patient or disease characteristics. As assessed by the independent review committee (IRC) 43% of patients receiving ibrutinib had a partial response compared with 4% receiving ofatumumab; OR was 63% for ibrutinib if partial response with lymphocytosis was not considered to be disease progression. Lymphocytosis was resolved in most patients.
Adverse events (AE) were similar to those previously reported for both agents, e.g., infusion-related reactions for ofatumumab but not ibrutinib. The most frequent AEs for ibrutinib compared with ofatumumab were diarrhea (47.7% vs. 17.8%), fatigue (27.7% vs. 29.8%), and nausea (26.2% vs. 18.3%); the rates of atrial fibrillation were 5.1% vs. 0.5%, and major hemorrhages were 1.0% vs. 1.6%, respectively, although Grade 1 bleeding events were higher with ibrutinib. Patients requiring warfarin but not other types of anticoagulant therapy were excluded from the trial. Neuropathy was higher with ofatumumab (13% vs. 4% for ibrutinib). Rates of renal toxicities and discontinuation were similar for both agents. At the time of the analysis, 86% of patients were still receiving ibrutinib. Richter’s transformation occurred in only 2 patients in each arm.
Dr. Byrd commented that this is the first time that ibrutinib was shown to be superior to a standard comparator agent, and this trial validates ibrutinib as an effective, orally-administered single-agent treatment for patients with relapsed CLL/SLL. Gregory A. Masters, MD, Helen F. Graham Cancer Center, Newark, Delaware and a member of ASCO’s Cancer Communications Committee, commented that it was “impressive to see an OS benefit in CLL. Ibrutinib represents an encouraging option as a drug with a low toxicity profile, and may replace other agents for treatment of this disease.” Phase 3 trials of ibrutinib as first-line therapy for CLL and SLL are ongoing, and in combination with other agents for mantle cell lymphoma and CLL/SLL.
Novel Therapies for Leukemia Attract Attention at ASCO 2014 (continued)
Selective Syk Inhibitor in CLL
Jeff Sharman, MD, Willamette Valley Cancer Institute and Research Center/US Oncology Research, Springfield, Oregon, discussed the results of a phase 2 trial of GS-9973 (NCT01799889), a selective spleen tyrosine kinase (Syk) inhibitor in CLL.5 Syk is a mediator of B-cell receptor (BCR) signaling in normal and malignant B-cells. GS-9973 is an oral, selective Syk inhibitor. This phase 2 trial enrolled 41 patients with CLL as well as patients with other lymphoid malignancies, including follicular lymphoma, mantle cell lymphoma, and diffuse large B cell lymphoma. Most patients with CLL had received prior anti-CD20 antibody and alkylating agents; the majority had received purine analogs; 9 had high risk disease.
Safety data were presented for all patients (n=145), and efficacy data for the CLL patients. At a median duration of exposure of 32 weeks, 19 patients with CLL remain on study. Patient discontinues for AEs were (10%), progressive disease (34%), death (2.4%), or other reason (7.3%). For all patients fatigue and gastrointestinal AEs were common. Mild elevations of bilirubin were an on-target expected lab abnormality. Reversible Grade 3 and 4 elevations in transaminases occurred in 14% of the total population occurring within the first 3 months of therapy; 5 of the 6 patients with CLL in which this occurred were able to resume therapy. Hypertension, which occurred in 24% of patients treated with fostamatinib, another kinase inhibitor, was seen infrequently with GS-9973.
In patients with CLL who did not die or have progressive disease prior to day 29, cytokine and chemokine levels were significantly reduced (P<.0001) at day 8 and day 29 compared with levels at day 1. Lymphocytosis, an expected effect of tyrosine kinase inhibitors, was observed with a peak at day 8, decreasing over 24 weeks, and continuing to improve over time.
Most patients with CLL had a lymph node response; 62% had a response greater than 50%; OR was 49%. The hematologic responses were 25% for hemoglobin, 86% for neutrophils, and 77% for platelets. PFS at 24 weeks, the primary endpoint, was 70%; OR was 49%; median PFS and duration of response were not reached. Future trials will investigate this agent in CLL after relapse following treatment with BCR-targeted therapies.
Efficacy of Blinatumomab in ALL
Outcomes are poor for adult patients with relapsed/refractory acute lymphoblastic leukemia (r/r ALL). Blinatumomab is an investigational bi-specific T-cell engaging (BiTE) antibody that directs cytotoxic T-cells to CD19-expressing target cells. CD19 is expressed on nearly all B-lineage ALL cells (as well as during B-cell development). A prior phase 2 study in 36 patients showed activity of blinatumomab in r/r ALL.
Prof. Dr. Max S. Topp, Wurzburg University Clinic, Wurzburg, Germany, presented the results of a confirmatory open-label, phase 2 trial (NCT01466179; sponsored by Amgen) of blinatumomab in patients with r/r B-precursor ALL (n=189).6 During the first 2 cycles of therapy, 43% of patients had complete remission (CR) or CR with partial hematologic recovery of peripheral blood counts (CRh); 80% of responses were within cycle 1. Thirty-nine percent of patients had no response; 40% received a hematopoietic stem cell transplant after CR/CRh. Median relapse-free survival was 5.9 months; OS was 6.1 months; for patients with CR/CRh, median OS was 9.9 months vs. 2.7 months for those with no CR/CRh.
The most frequent Grade 3 or higher AEs were febrile neutropenia (26%), anemia (15%), and neutropenia (15%); 2% had Grade 3 or higher cytokine release syndrome. Of the 28 patients with fatal AEs, 27 were not in CR/CRh, and 1 died after relapse following CR/CRh. A phase 3 trial in this difficult to treat population is ongoing.
Novel Therapies for Leukemia Attract Attention at ASCO 2014 (continued)
Pan-cyclin-dependent Kinase Inhibitor in AML
Joshua F. Zeidner, MD, The Johns Hopkins Hospital and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, presented results of a phase 2 trial of timed-sequential therapy with flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus “7+3” (cytarabine plus daunorubicin) for adults with newly diagnosed acute myeloid leukemia (AML).7 The trial was supported by the Leukemia and Lymphoma Society, NIH, and NCI.
Most patients with acute myelogenous leukemia (AML) who have a complete response (CR) to induction therapy will relapse; the long-term OS in relapsed/refractory AML is less than 10%. Flavopiridol is a pan-cyclin-dependent kinase inhibitor previously shown to result in high CR rates when followed by cytarabine and mitoxantrone in newly diagnosed, poor-risk AML.
Patients in this trial (NCT01349972) were randomly assigned 2:1 to FLAM (n=109) or 7+3 (n=56). The primary endpoint, CR, was 70% for FLAM and 46% for 7+3 alone (P=.003), and 57% for 7+3 followed by 5+2 (additional cytarabine plus daunorubicin for residual leukemia on day 14, n=14; P=0.08 compared with FLAM). There was no significant difference in OS, relapse rate, or toxicities. There was a great deal of heterogeneity among patients in transplant-related treatments. Follow-up time may be too short to evaluate survival, or FLAM may not improve OS. In an ad hoc analysis, CR rates were highest in patients younger than age 60 years and in those with secondary AML. Dr. Zeidner said they have treated over 150 patients with newly diagnosed secondary AML across 4 studies with FLAM; these patients have a CR rate of 60% to 67%, suggesting these are the patients to focus on in future trials with FLAM.
Patients with CLL, including the elderly and those with poor prognostic features, e.g., deletion 17p13.1, can look forward to more treatment options, including modalities that are orally administered and have reduced toxicities. It remains to be determined which agents and in what combinations will benefit which patient subgroups. Relapsed/refractory ALL and newly diagnosed AML in adults remain difficult to treat and continue to present unmet medical needs.
- Byrd JC, Brown JR, O'Brien SM, et al. Randomized comparison of ibrutinib versus ofatumumab in relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma: Results from the phase III RESONATE trial. J Clin Oncol 2014;32:5s (suppl; abstr LBA7008). http://meetinglibrary.asco.org/content/129571-144.
- Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. New Engl J Med 2014; Online First May 31, 2014;DOI: 10.1056/NEJMoa1400376. http://www.nejm.org/doi/pdf/10.1056/NEJMoa1400376.
- US FDA. Novel New Drugs 2013 Summary. January 2014, http://www.fda.gov/downloads/drugs/developmentapprovalprocess/druginnovation/ucm381803.pdf.
- US FDA. Ibrutinib (Imbruvica). February 13, 2014. http://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm385878.htm.
- Sharman JP, Klein LM, Boxer, M, et al. Phase 2 trial of GS-9973, a selective Syk inhibitor, in chronic lymphocytic leukemia (CLL). J Clin Oncol 2014;32:5s, (suppl; abstr 7007). http://meetinglibrary.asco.org/content/126970-144.
- Topp MA, Goekbuget N, Stein AS, et al. Confirmatory open-label, single-arm, multicenter phase 2 study of the BiTE antibody blinatumomab in patients (pts) with relapsed/refractory B-precursor acute lymphoblastic leukemia (r/r ALL). J Clin Oncol 2014;32:5s, (suppl; abstr 7005^). http://meetinglibrary.asco.org/content/129500-144.
- Zeidner JF, Foster, MC, Blackford A, et al. Randomized multicenter phase II trial of timed-sequential therapy with flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus “7+3” for adults with newly diagnosed acute myeloid leukemia (AML). J Clin Oncol 2014;32:5s, (suppl; abstr 7002). http://meetinglibrary.asco.org/content/125532-144.