Novel Agents Should Have Impact in Lymphocytic Leukemias


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The drug has very high single-agent activity, likely the highest activity of a single agent in the ALL refractory setting.

— Elias Jabbour, MD

Agents with novel mechanisms of action may strongly impact outcomes in chronic lymphocytic leukemia (CLL) and acute lymphocytic leukemia (ALL), if data from early-phase studies presented at this year’s ASCO Annual Meeting are any indication.

There is a clear unmet need for more effective therapies in CLL, said Peter Hillmen, MBChB, PhD, of St. James University Hospital in Leeds, United Kingdom. An effective treatment should target the disease pathophysiologically, he said, as imatinib (Gleevec) does for chronic myelogenous leukemia (CML). Therefore, much emphasis is being placed on understanding the molecular and cellular profiles of CLL, to guide drug development.

Ibrutinib

Advances are also being made by exploring new targets. One such drug making news is the oral agent ibrutinib (PCI-32765), the first drug designed to target Bruton’s tyrosine kinase, a protein that is critical for B-cell receptor signaling in B lymphocytes and essential for CLL cell survival and proliferation. In a single-agent phase II study, ibrutinib produced high response rates in treatment-naive patients with CLL.1

The study included 31 patients previously untreated for CLL. The overall response rate was 75%, including 10% complete and 65% partial responses with daily dosing. The rate of progression-free survival at 15 months was 96%. Investigators had previously reported on the cohort of treatment-refractory patients, 70% of whom responded to the novel drug.2

“All subgroups responded equally well. Overall, the great majority of patients gained benefit from this therapy,” said John C. Byrd, MD, of Ohio State University, Columbus. “This drug is like red wine—with time, it gets better. Responses increase, and many patients are still in follow-up. The continued daily dosing was well tolerated, which allows for extended treatment.”

In a related study by the same investigators, ibrutinib was combined with ofatumumab, an anti-CD20 monoclonal antibody.3 Samantha Jaglowski, MD, also of Ohio State University, reported that the combination produced a 100% response rate in 24 patients with relapsed/refractory CLL, prolymphocytic leukemia, and small lymphocytic leukemis.3 In three patients with Richter’s syndrome, the overall response rate was 67%. At 6.5 months follow-up, only two patients have shown disease progression. “The rapid onset of response, low relapse rate, and favorable safety profile make this noncytotoxic combination worthy of further study,” she said.

Blinatumomab

Encouraging data are also building for the anti-CD19 bi-specific T-cell engager (BiTE) antibody blinatumomab. In a phase II study of 36 patients, blinatumomab produced responses (complete remission or “complete remission with only partial hematologic recovery” [ie, < 5% blasts in the bone marrow, no evidence of circulating blasts or extramedullary disease, and partial recovery of peripheral blood counts]) in 72% of patients with relapsed/refractory B-precursor ALL.4

BiTE antibodies are designed to direct the body’s cytotoxic T cells against tumor cells, enabling T cells to recognize and attack tumor cells in much the same manner as naturally occurring T cells. Blinatumomab targets CD19, which is expressed by 100% of leukemia cells.

Patients received 5 µg/m2/d by continuous infusion during week 1, then 15 µg/m2/d thereafter. A complete remission (or complete remission with partial hematologic recovery) was observed in 72% of all patients and 74% of those receiving the optimal dose. All but two responders achieved a molecular response. Median overall survival in this heavily pretreated population was 9.0 months, and the median duration of hematologic complete response was 8.9 months, reported Max Topp, MD, of the University of Wuerzburg in Germany.

“There was a high remission rate in all patient subgroups, including those with prior allogeneic stem cell transplant and multiple relapses,” Dr. Topp said. Fully reversible central nervous system events leading to treatment interruptions were observed in six patients, including three with seizures and three with encephalopathy; all six patients continued treatment at a lower dose.

Inotuzumab Ozogamycin

Other investigators reported encouraging results with inotuzumab ozogamycin, an anti-CD22 monoclonal antibody conjugated to calecheamicin. In a modified weekly treatment schedule, inotuzumab (1.8 mg/m2 every 3–4 weeks) was associated with a 52% overall response rate in patients with relapsed/refractory ALL.5 Median overall survival was 7 months.

Most drug side effects, including liver function abnormalities, were grade 1 or 2 and reversible. Of 27 evaluable patients, 8 underwent allogeneic stem cell transplant after inotuzumab, and none of these patients developed veno-occlusive disease.

“The drug has very high single-agent activity, likely the highest activity of a single agent in the ALL refractory setting,” commented Elias Jabbour, MD, of The University of Texas MD Anderson Cancer Center, Houston. He noted that plans for further research include a pivotal trial of weekly inotuzumab vs standard of care in relapsed/refractory ALL and an ongoing study of inotuzumab combined with low-intensity chemotherapy in older patients (> 60 years) with the disease. ■

Disclosure: Dr. Hillman has served in a consulting or advisory role for Celgene, Gilead Sciences, Pharmacyclics, and Roche, has received honoraria from Celgene, Genzyme, GlaxoSmithKline, and Roche, and has received research funding from Genzyme, GlaxoSmithKline, and Roche. Dr. Byrd has received research funding from Pharmacyclics. Dr. Jaglowski reported no potential conflicts of interest. Dr. Topp has served in a consulting or advisory role for Micromet. Dr. Jabbour has served in a consulting or advisory role for Pfizer.

References

1. Byrd JC, Furman RR, Coutre SE, et al: The Bruton’s tyrosine kinase inhibitor PCI-32765 in treatment-naive chronic lymphocytic leukemia patients: Interim results of a phase Ib/II study. 2012 ASCO Annual Meeting. Abstract 6507. Presented June 4, 2012.

2. O’Brien S, Burger JA, Blum KA, et al: The Bruton’s tyrosine kinase inhibitor PCI-32765 induces durable responses in relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma: Follow-up of a phase Ib/II study. 53rd American Society of Hematology Annual Meeting. Abstract 983. Presented December 13, 2011.

3. Jaglowski SM, Jones JA, Flynn JM, et al: A phase Ib/II study evaluating activity and tolerability of BTK inhibitor PCI-32765 and ofatumumab in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma and related diseases. 2012 ASCO Annual Meeting. Abstract 6508. Presented June 4, 2012.

4. Topp M, Goekbuget N, Zugmaier G, et al: Effect of anti-CD19 BiTE blinatumomab on complete remission rate and overall survival in adult patients with relapsed/refractory B-precursor ALL. 2012 ASCO Annual Meeting. Abstract 6500. Presented June 4, 2012.

5. Jabbour E, O’Brien SM, Thomas DA, et al: Inotuzumab ozogamycin, a CD22 monoclonal antibody conjugated to calecheamicin, given weekly, for refractory-relapse acute lymphocytic leukemia. 2012 ASCO Annual Meeting. Abstract 6501. Presented June 4, 2012.


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