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Sunday, July 6, 2014

ONLINE FIRST: Adult ALL: Studies Show Promise of Both Blinatumomab and Ponatinib



CHICAGO – A large, multicenter study confirms the significant single-agent activity of blinatumomab in difficult-to-treat patients with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL).


Reporting the study here at the American Society of Clinical Oncology Annual Meeting (Abstract 7005), Max S. Topp, MD, of the University Hospital of Würzburg in Germany, said that outcomes are poor for adults with relapsed/refractory ALL, with median overall survival typically five to eight months, and that blinatumomab, an investigational bi-specific T-cell engaging (BiTE) antibody that directs cytotoxic T-cells to CD19-expressing target cells, has shown anti-leukemia activity in this group of patients.


He noted that in a previous exploratory study of 36 adults with relapsed/refractory B-precursor ALL, more than two-thirds of patients had a complete remission (CR), and median relapse-free survival (RFS) was 7.6 months and median overall survival (OS) was 9.8 months. About 17 percent of patients had to have dose interruptions or discontinuations due to neurologic events.


At the ASCO meeting, Topp presented the results of a large, confirmatory Phase II study to evaluate blinatumomab’s efficacy and toxicity The study enrolled 189 patients, median age of 39, with Philadelphia chromosome-negative ALL who, less than 12 months before, had their first relapse and were refractory to post-hematopoietic stem cell transplantation (HSCT). More than one-third of the patients had at least two salvage therapies.


Blinatumomab was given continuously through intravenous infusion for four weeks on and two weeks off for up to five cycles. Cycle 1 included 9 μg per day of blinatumomab on days 1-7, and then 28 μg per day. Patients received blinatumomab for a median of two cycles. The primary endpoint was CR or CR with partial hematological recovery (CRh) within the first two cycles.


A total of 43 percent of patients achieved a CR or CRh. The majority of responses (80%) occurred within the first cycle. CRs/CRhs were seen in all subgroups, but were more prominent in patients with less than 50 percent bone marrow blasts, Topp reported.


Median RFS and OS were 5.9 and 6.2 months, respectively. In a landmark analysis, after two treatment cycles overall survival was 9.9 months among patients who achieved a CR/CRh.


Adverse Events

Regardless of causality, the most frequent adverse events were pyrexia (occurring in 59% of patients), headache (35%), and febrile neutropenia (29%). The most frequent grade 3 or higher adverse events were febrile neutropenia (26%), anemia (15%), and neutropenia (15%); two percent had grade 3 or higher cytokine release syndrome (CRS).


The most common grade 3 or higher nervous system disorders were headache, encephalopathy, and ataxia. Only three patients had grade 5 adverse events considered treatment-related, including sepsis and candida infection.

Twenty eight patients died, but 27 of them did not have a CR/CRh while on the study, Topp noted. One patient died of a fatal adverse event after relapse following an initial CR/CRh.


In conclusion, he said, “the present study confirmed the anti-leukemia single-agent activity of blinatumomab in a difficult-to-treat population with relapsed/refractory ALL, with a CR/CRh rate of 43 percent. Responses were observed in all subgroups of patients. Adverse events were consistent with previous blinatumomab treatment experience in the setting of relapsed/refractory ALL.”


Fatal events were only seen in those with uncontrollable leukemia, he added.


Topp noted that a randomized, open-label Phase III trial of blinatumomab in this patient population is currently underway.


Asked for his opinion of the study, Mikkael Sekeres, MD, Director of the Leukemia Program at Cleveland Clinic Taussig Cancer Institute and Chair of the Hematology/Oncology Pharmacy & Therapeutics Committee and OT’s Clinical Advisory Editor for Hematology/Oncology, said, “This BiTE antibody is an important treatment. This trial adds to data and confirms what has been seen previously. In adult, relapsed/refractory Philadelphia-negative B-cell ALL, we typically see response rates of 30 to 40 percent for CR or near CR.


“This report of a CR of 43 percent for single-agent therapy is a high response rate in patients who were previously treated -- particularly when a large percentage of them had prior salvage therapies.”


Discussant: Blinatumomab Has Been Around for a While

The Discussant for the study, Crystal Mackall, MD, Head of the Pediatric Oncology Branch of the National Cancer Institute, said, “Blinatumomab is not new to the community. We were impressed with first clinical trial in 2011 that demonstrated an incredible 80 percent rate of minimal residual disease [MRD]-negative CR in adults with B-cell ALL.


“These patients were molecularly refractory and largely had MRD. Many experienced prolonged survival, some following consolidation with HSCT. This is an agent that is able to eradicate chemo-resistant leukemia. This new trial is the first opportunity for us to see what blinatumomab can do in patients with high-burden ALL. It found a quite impressive 43 percent CR rate, and 82 percent had MRD negativity, which is a deep response.”


She noted that the responders with less than 50 percent bone marrow blasts had superior survival: “This agent is active in inducing remission, but has not shown ability to be curative as a single agent. The response rate varies greatly depending on the burden of leukemia. Those with greater than 50 percent leukemia had a lower response rate. If you’re thinking about using blinatumomab, probably you would want to use it in patients with a lower burden of disease.”


Toxicity was “quite acceptable,” Mackall continued, with most of the toxicity reported due to the underlying leukemia. She noted that cytokine release syndrome (CRS) is not uncommon with the use of blinatumomab, and said that because CRS tends to be worse with higher burden disease, it was surprising that there was actually not even more CRS in the patients in the study.


This diminished incidence may be related to alterations in dose, she speculated: During the first week, patients received a lower dose of blinatumomab than in the original study. “Does this offset efficacy? Would a higher dose be more efficacious or tolerable in patients with higher disease burden?” she asked.


Regarding neurotoxicity, Mackall said it was reassuring it was all reversible: “Neurotoxicity with blinatumomab may be related to CRS. Reversible neurologic toxicity is commonly associated with CRS from CAR T cell therapy. Essentially everyone -- 20 of 24 patients -- had their neurologic abnormalities resolved.”


She said she wondered what residual neurotoxicity there might be that did not resolve, but said it was likely reversible and would not pose a problem for this drug.


“Emerging data seem to clearly demonstrate that blinatumomab serves as an effective bridge to transplant in patients with chemo-resistant B-ALL,” Mackall said. “The data suggest that it is more effective in lower-burden disease. My guess is that the ongoing registration trial will be able to replicate these impressive response rates.


“The overlying question is whether blinatumomab can achieve a cure in a significant fraction of patients,” she continued. “Many of these patients will require consolidation for a cure.” HSCT may not be an option for some older and heavily pretreated patients, she noted.


Looking at future uses of the drug, Mackall asked, “Could blinatumomab be used to improve cure rates or preclude the need for a transplant if it was incorporated into the upfront regimen? Could the drug be used preemptively after allogeneic transplant to prevent relapse?”


Combination of ALL Chemotherapy with Ponatinib

In another report at the meeting, a combination of chemotherapy with the tyrosine kinase inhibitor (TKI) ponatinib showed high response rates and indications that it may be an effective treatment for patients with Philadelphia-positive (Ph+) ALL (Abstract 7064).  


The third-generation TKI ponatinib is a potent BCR-ABL inhibitor, said Susan O’Brien, MD, Professor of Medicine and Chief of the Section of Acute Lymphocytic Leukemia at the University of Texas MD Anderson Cancer Center, who reported the data.


“Ponatinib suppresses T315I clones, commonly causing relapse in Ph+ ALL. It has high activity and acceptable single-agent toxicity.”


Complete cytogenetic response (CCyR) rates range from 40 to 50 percent in patients who do not respond to use of two or three TKIs and in those with the T315I mutation, she explained. Combinations of ALL chemotherapy and ponatinib are likely to be associated with better response rates, lower relapse rates, and a higher likelihood of eradication of minimal residual leukemia.


For the study, she and her colleagues enrolled 37 newly diagnosed Philadelphia-positive ALL patients, median age of 51, into a Phase II study of a combination of hyperCVAD with ponatinib in frontline therapy. The patients received eight cycles of hyperCVAD every 21 days. Ponatinib was given at 45 mg daily for the first 14 days of cycle 1, and then continuously for the subsequent cycles.


Patients who had a complete response received maintenance with ponatinib at 45 mg daily with vincristine/prednisone monthly for two years followed by ponatinib indefinitely. Patients received a median of six cycles, and 12 patients are currently receiving maintenance in complete remission. “All patients were in CR after cycle 1,” O’Brien said. “CCyR rates were 94 percent after one cycle and 100 percent after two cycles.”


Virtually all patients (95%) achieved a major molecular response and nearly 75 percent had a complete molecular response (CMR). Similarly, almost all patients (97%) were MRD negative. Eight patients had an autologous stem cell transplant (ASCT) after a median of four courses.


Grade 3 or higher toxicities included infections during induction, increased liver function tests, thrombotic events, myocardial infarction, skin rash, and pancreatitis.


The results showed that with a median follow-up of 13 months, 31 patients are alive and in complete remission. The one-year progression-free survival rate is an estimated 100 percent and one-year overall survival is 86 percent.


At the last follow-up, O’Brien reported, seven patients are alive post-ASCT, and 15 patients on ponatinib are alive. Of the other nine surviving patients, seven were switched to dasatinib, one to imatinib, and one patient is no longer receiving treatment. “Due to the vascular events observed, some patients were switched to alternative TKIs,” she said. In the remaining patients, the ponatinib dose was modified to 30 mg daily during consolidation, with subsequent reduction to 15 mg in patients in CMR.


In conclusion, O’Brien said, “HyperCVAD with ponatinib is highly effective in patients with Ph+ ALL, with high molecular response rates and durable responses.”


Also commenting on this study, Sekeres said, “This large study looked at the newest TKI approved for chronic myeloid leukemia. Now ponatinib is being applied to ALL. It shows a high response rate in patients who don’t typically have high responses -- in particular, an extremely high CCyR rate.


“Ponatinib may represent a new standard in treating these patients. ALL experts need to think more about combining new agents with established therapies.”