July 2014 Edition Vol.11, Issue 7

Novel Therapies for Leukemia Attract Attention at ASCO 2014

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.

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