February 2013, Vol 2, No 1
Personalized Medicine Highlights From ASH 2012Uncategorized
Hematologic oncology is a fertile field for exploration of new targets for drug therapy. Below are summaries of presentations from the 54th Annual Meeting of the American Society of Hematology (ASH) on some new targeted therapies for hematologic malignancies currently in phase 2 testing.
Quizartinib: FLT3 Inhibitor in AML
Quizartinib, an investigational oral FLT3 inhibitor, achieved high response rates in a difficult-to-treat cohort of patients with acute myelogenous leukemia (AML), and some of the responses were durable, according to results of a phase 2 trial.
The FLT3 mutation is found in up to one-third of patients with AML and portends more aggressive disease and treatment failure on standard therapies. Although other FLT3 inhibitors have been studied in AML, quizartinib is the most potent of these in humans, said lead author Mark J. Levis, MD, the Sidney KimmelComprehensive Cancer Center at Johns Hopkins Medicine in Baltimore, MD.
The phase 2 trial enrolled 2 cohorts of patients with a total number of 271 patients. Cohort 1 included patients aged 60 years or older with the FLT3 mutation who failed on standard chemotherapy or who had a recent first relapse. Cohort 2 included patients over age 18 years who presented with relapsed or refractory AML and had been given salvage chemotherapy after failure on prior treatment or had relapsed after a stem cell transplant. The majority of patients in both cohorts had the FLT3 mutation.
Levis reported results from 137 patients (99 with FLT3 mutations and 38 without) in cohort 2. The complete response rate was 46% in patients with an FLT3-positive mutation and 32% in FLT3-negative patients. Median overall survival was 22.9 weeks for FLT3-positive patients and 25.6 weeks for FLT3-negative patients. Quizartinib enabled 37% of all patients to go on stem cell transplant.
The most common treatment-emergent adverse events were nausea (53%), vomiting (41%), febrile neutropenia (38%), diarrhea (37%), anemia (34%), Q-T interval prolongation (27%), and fatigue (24%).
Cohort 1 results, presented by Jorge Cortes, MD, MD Anderson Cancer Center, Houston, TX, showed that complete responses were achieved in more than 50% of FLT3-positive elderly patients. These results were considered clinically meaningful and allowed some patients to be bridged to stem cell transplant. Also, slightly fewer than one-third of FLT3-negative patients achieved a complete response. The side effect profile of quizartinib was similar to that in cohort 2.
The investigators concluded that quizartinib may be an option for elderly AML patients who require further therapy. A phase 3 trial is planned.
Pomalidomide Plus Carfilzomib Looks Promising in Relapsed/Refractory Myeloma
The combination of pomalidomide, carfilzomib, and dexamethasone achieved high response rates and delayed disease progression in heavily pretreated patients with multiple myeloma, according to results of a phase 1/2 trial. Study subjects had been previously treated with a median of 6 lines of therapy (range, 1-15). All were relapsed/refractory to lenalidomide and/or bortezomib.
Overall response rate (ORR) was 50% (15/30), with 37% achieving a partial response, 13% achieving at least a very good partial response, and 67% attaining clinical benefit (minor response or better), reported Jatin Shah, MD, MD Anderson Cancer Center, Houston, TX.
Median progression-free survival was 7.4 months, and overall survival at 1 year was 90%. â€śThe combination has encouraging preserved response rates and survival independent of FISH [fluorescence in situ hybridization]/cytogenetic risk status,â€ť he commented.
The most common toxicities were neutropenia (84%), anemia (63%), and thrombocytopenia (57%). Febrile neutropenia occurred in 6%. Hematologic toxicities were reversible and manageable.
The maximum tolerated dose of the regimen was carfilzomib 20/27 mg/m2, pomalidomide 4 mg, and dexamethasone 40 mg in relapsed/refractory myeloma. Enrollment is ongoing in a phase 2 study of 82 patients.
Daratumumab Moving Forward in Myeloma
Daratumumab, a monoclonal antibody that binds to CD38, is moving forward in studies of multiple myeloma. In a phase 1/2 study in 32 patients, clinical benefit was achieved in almost half the heavily pretreated relapsed/refractory population. Torben Plesner, MD, of Vejle Hospital in Vejle, Denmark, reported that 47% of patients demonstrated a reduction in the amount of monoclonal protein in the blood or urine, which corresponded to a 13% partial response rate, 19% minor response rate, and 16% stable disease rate. A reduction in plasma cell infiltration of the bone marrow was also observed. The maximum tolerated dose of the drug has not been established.
Daratumumab infusion was surprisingly well tolerated. A dose-dependent reduction in natural killer cells was observed on treatment but was reversible upon treatment discontinuation.
Brentuximab Vedotin Prolongs Survival in Hodgkin Lymphoma
Several studies at ASH validated the use of brentuximab vedotin in Hodgkin lymphoma and suggested that indications for the drug may be expanded. Treatment with brentuximab after autologous stem cell transplant prolonged overall survival in relapsed/refractory HodgÂkin lymphoma patients in a retrospective study that compared 102 patients treated with brentuximab versus 756 age-matched patients on standard therapy.
A statistically significant overall survival benefit for brentuximab versus standard therapy was observed: median overall survival of 91.49 versus 27.99 months, respectively (P<.0001). Neither age nor sex had an impact on overall survival, said lead author Meghan S. Karuturi, MD, MD Anderson Cancer Center, Houston, TX.
Among complete responders to brentuximab, positron emission tomography (PET) negativity after 7 cycles of treatment was correlated with longer progression-free survival (P<.013). PET status (negative vs positive) after both 4 and 7 cycles was significantly associated with improved progression-free and overall survival, she reported.
Blinatumomab in Relapsed/Refractory ALL
Blinatumomab is a bispecific T-cell engager antibody that engages T cells and tumor cells, placing the T cells within reach to inject toxins into the tumor cell, triggering apoptosis. Blinatumomab directs the T cells to target cells that express CD19, a protein on the surface of most B-cellâ€“derived leukemias and lymphomas.
Blinatumomab induced a high complete remission (CR) rate and prolonged overall survival in adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) in a phase 2 single-arm study. The study established a dose regimen of 5 mcg/m2/day for week 1, followed by 15 mcg/m2/day thereafter. The most common adverse events were pyrexia, fatigue, headache, tremor, and leukopenia. Medically important, but fully reversible, adverse events included cytokine release syndrome and central nervous system events.
Lead author Max S. Topp, MD, Wuerzburg University Medical Center, Germany, reported â€śunprecedentedâ€ť single-agent activity of blinatumomab among 36 patients enrolled in the phase 2 trial. CR was 69%. Molecular remission was achieved in 88% of hematologic responders. Median overall survival was 9.8 months, and median relapse-free survival was 9.8 months.
A phase 2 trial has been launched in adults with relapsed/refractory B-cell ALL.
Inotuzumab in ALL
Inotuzumab is an antibody-antigen complex that binds to CD22 cells, releasing calicheamicin inside the tumor cell. Calicheamicin is a potent cytotoxic agent that binds to DNA, inducing double-stranded DNA breaks leading to apoptosis of the cell.
Single-agent inotuzumab achieved an encouraging ORR of 57% in the treatment of relapsed/refractory ALL in a phase 2 trial. Response was independent of treatment schedule and correlated with clearance of leukemia cells from the bone marrow. The weekly schedule will be used in subsequent clinical trials, said lead author Susan Oâ€™Brien, MD, MD Anderson Cancer Center, Houston, TX.
Additional studies of inotuzumab are under way. One is a pivotal trial of the weekly schedule versus the best standard of care in relapsed/refractory ALL, and inotuzumab is also being studied in combination with low-intensity chemotherapy in elderly patients with ALL.
Patients with refractory or relapsed CD22-positive ALL (n=89) were enrolled in this phase 2 trial. The first 10 patients were aged 18 years or older, and then the trial was opened to children. More than 90% of patients had CD22-expressing ALL. Weekly and monthly schedules were studied using the same total dose of inotuzumab for both schedules. Patients could be treated for up to 8 cycles.
ORR of 57% was similar in the arms (weekly vs monthly schedule). CR was 18% in both arms; CR with the exception of platelets was 29% in the monthly arm and 30% in the weekly arm. Resistance was identified in 39% and 38% of patients, respectively, and 2 deaths occurred in each arm in less than 4 weeks. Cytogenetic CR was seen in 89% and 90% of patients, respectively. Overall, 63% and 70% of patients, respectively, were minimal residual disease negative.
Median progression-free survival was 4.9 months, with a progression-free survival rate of 21% at 1 year. Median overall survival is 5.6 months; 20% are alive at 1 year, with no difference between the treatment arms.
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