‘Paradigm-Shifting’ Results in Treatment of Hematologic Disorders

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Lucy A. Godley, MD, PhD

Ruxolitinib may be a valuable new treatment option in patients with polycythemia vera. This is just the first-in-class for JAK inhibitors; it will be very exciting to see the development of other JAK inhibitors.

—Lucy A. Godley, MD, PhD

The three leukemia/lymphoma studies selected from the many 2014 ASCO Annual Meeting abstracts for presentation at the recent Best of ASCO meeting in Chicago “are really paradigm-shifting,” noted Lucy A. Godley, MD, PhD, of the University of Chicago. These studies, she said, “give great promise for new therapies” for patients with acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), and polycythemia vera.

Blinatumomab Activity Confirmed

A large phase II trial confirmed the antileukemia activity of single-agent blinatumomab among difficult-to-treat patients with relapsed/refractory B-precursor acute lymphoblastic leukemia. Within the first two cycles of treatment (continuous intravenous infusion, 4 weeks on 2 weeks off), 43% of patients achieved complete remission or complete remission with partial hematologic recovery. “For treating patients who had refractory ALL, this is a remarkable percentage,” Dr. Godley commented.

“Blinatumomab, an investigational bispecific T-cell engaging (BiTE) antibody that directs cytotoxic T cells to CD19-expressing target cells, has shown antileukemia activity in an exploratory study in adult relapsed/refractory B-precursor ALL,” according to the ASCO abstract.1

Blinatumomab “brings cytotoxic T cells into physical proximity and really to touching B cells,” Dr. Godley explained. “And these cytotoxic T cell use perforin [a cytolytic protein] and other enzymes to kill that B cell within minutes, at least when that has been measured in vitro. It’s a very novel mechanism of action and really brings great promise to our ALL patients.”

Bridge to Stem Cell Transplant

The study was open to adults (≥ 18 years old) with Philadelphia chromosome–negative B-precursor ALL who had primary refractory disease, early relapse (duration of first remission ≤ 12 months), relapse within 12 months of allogeneic hematopoietic stem cell transplantation, or any relapse or refractory disease after first salvage therapy. “Importantly here, patients had to have more than 10% bone marrow blasts at the time of going on the study and had to be well-performing patients,” Dr. Godley said.

The median age of the 189 study participants was 39 years (range, 18–79), and 63% were male. A total of 39% had received two or more salvage therapies, and 34% had undergone prior allogeneic stem cell transplant.

“One of the critical elements of this abstract,” Dr. Godley stated, is where the responses were seen. “These responses were seen largely in patients who had lower disease burden—less than 15% bone marrow blasts at the time of enrollment in the study. Patients who had greater than 75% bone marrow blasts really did not do well. So this generates ideas of how blinatumumab will be most effective moving forward.”

The most effective way to use blinatumumab may be “to bridge patients to first or potentially second allogeneic stem cell transplant,” she noted.

The most frequently reported adverse events were pyrexia (59%), headache (35%), and febrile neutropenia (29%). The most frequent grade ≥ 3 adverse events were febrile neutropenia (26%), anemia (15%), and neutropenia. The most common grade ≥ 3 nervous system disorders were headache (4%), encephalopathy (3%), and ataxia (2%). Three patients had grade 5 adverse events that were considered treatment-related, two with sepsis and one with Candida infection.

“A randomized, open-label phase III study of blinatumomab in this patient population is currently underway,” Dr. Godley said. “Some larger questions that arise from this work come when we think about how can we move the drug from a relapse setting into the front-line setting.”

Ruxolitinib for Hematocrit Control

Maintaining hematocrit control is a key therapeutic goal in patients with polycythemia vera, and ruxolitinib (Jakafi) was shown to be superior to best supportive therapy in controlling hematocrit without phlebotomy and reducing spleen volume in the phase III RESPONSE trial. “RESPONSE is the first phase III study to evaluate a JAK inhibitor in treating [polycythemia vera],” according to the Annual Meeting abstract.2 Ruxolitinib is a JAK1/JAK2 inhibitor approved by the U.S. Food and Drug Administration for patients with intermediate- or high-risk myelofibrosis.

Phlebotomy-dependent patients with splenomegaly (≥ 450 cm3) who were resistant to or intolerant of hydroxyurea were randomly assigned 1:1 to ruxolitinib at 10 mg twice a day or investigator-selected best available therapy (eg, interferon, anagrelide, pipobroman [Vercyte], an immunomodulatory drug, or observation). The initial randomization assigned 110 patients to treatment with ruxolitinib and 112 to best available therapy, but 108 best available therapy patients (96%) discontinued randomized treatment and 96 crossed over to ruxolitinib. By contrast, 17 ruxolitinib patients (15%) discontinued treatment.

‘Hands-Down Winner’

The primary endpoint was the proportion of patients who achieved both hematocrit control without phlebotomy from week 8 to week 32 (with ≤ 1 phlebotomy from week 0 to week 8) and a ≥ 35% reduction in spleen volume at week 32. “The primary response was the ability of patients to not need transfusions any more. The primary endpoint was achieved in 21% of ruxolitinib patients compared to only 1% of patients receiving best available therapy,” Dr. Godley stated (P < .0001). At least one component of the primary endpoint was achieved by 77% of patients assigned to ruxolitinib.

The duration of response “was off-the-scale positive,” Dr. Godley added. At week 48, 91% of ruxolitinib patients maintained their response.

Complete hematologic response was achieved in 23.5% of ruxolitinib patients vs 9% of the best available therapy group (P = .003). Among the 26 patients who achieved a complete hematologic response, 23 (88.5%) maintained it at week 48. In addition, ≥ 50% improvement in a 14-item myeloproliferative neoplasm symptom score was achieved by 49% of patients receiving ruxolitinib at week 32 vs 5% of best available therapy recipients. “Treatment with ruxolitinib wins hands-down over best available therapy,” Dr. Godley declared.

Ruxolitinib was generally well tolerated. “Most adverse events were grade 1/2, and few patients developed grade 3/4 cytopenias,” Dr. Godley reported. She pointed out that “a few more events of nonmelanoma skin cancer” occurred among patients receiving ruxolitinib. Four patients receiving ruxolitinib had nonmelanoma skin cancer (grade 3/4 in 3), vs two patients receiving best available therapy (grade 3/4 in 1). Seven patients in the ruxolitinib group developed herpes zoster infections (no grade 3/4), whereas none of the patients in the best available therapy group did.

In conclusion, Dr. Godley said that the “data demonstrate that ruxolitinib may be a valuable new treatment option in this population of patients with polycythemia vera. This is just the first-in-class for JAK inhibitors,” she noted. “It will be very exciting to see the development of other JAK inhibitors.”

Ibrutinib for Second-Line CLL/SLL

The 391-patient RESONATE study found that ibrutinib (Imbruvica) significantly improved response, progression-free survival, and overall survival compared to ofatumumab (Arzerra) in second-line chronic lymphocytic leukemia/small lymphocytic leukemia.3 (The study was reported in detail in the June 25 issue of The ASCO Post.)

“This study establishes ibrutinib as an effective, new single-agent therapy” for patients with CLL/SLL “and the new standard of care,” Dr. Godley stated. She noted that mutations have been identified in all six study patients who were resistant to ibrutinib, along with two different mechanisms of resistance. “It will be very interesting to see, as so many more patients are going to be treated now, if these two mechanisms of resistance persist,” Dr. Godley remarked. ■

Disclosure: Dr. Godley reported no potential conflicts of interest.


1. Topp MS, 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). ASCO Annual Meeting. Abstract 7005. Presented June 3, 2014.

2. Verstovek S, Kiladjian J-J, Greisshammer M, et al: Results of a prospective, randomized, open-label phase 3 study of ruxolitinib (RUX) in polycythemia vera (PV) patients resistant to or intolerant of hydroxyurea (HU): The RESPONSE trial ASCO Annual Meeting. Abstract 7026. Presented June 3, 2014.

3. Byrd JC, Brown JR, O’Brien SM, et al: Randomized comparison of ibrutinib versus ofatumumab in relapsed or refractory (R/R) chronic lymphocytic lymphoma: Results from the phase III RESONATE trial. ASCO Annual Meeting. Abstract LBA7008. Presented June 3, 2014.