Drug Combination May Benefit Acute Myelogenous Leukemia or Myelodysplastic Syndrome Patients Who Have Poor Prognosis
Patients with newly diagnosed acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) who have poor performance status or a concurrent disease may benefit from combination treatment with azacitidine and vorinostat, according to early results of an ongoing trial.
At the 52nd Annual Meeting of the American Society of Hematology in December, Guillermo Garcia-Manero, M.D., a professor in the Department of Leukemia at MD Anderson, and his colleagues reported the early results of a phase II clinical trial, which is open only to AML and MDS patients with concurrent diseases or with Eastern Cooperative Oncology Group (ECOG) performance status higher than 2. ECOG criteria score patients’ performance status from 0 (fully active) to 4 (completely disabled).
Dr. Garcia-Manero said that newly diagnosed patients with AML or MDS who have a poor ECOG performance status or an additional disease typically survive fewer than 60 days without treatment. However, these patients do not meet the eligibility requirements for most clinical trials and therefore often do not have access to experimental treatments that might prolong survival.
The purpose of the trial was to assess whether AML and MDS patients with concurrent diseases or poor ECOG performance status would benefit from the drug combination of azacitidine and vorinostat, which is known to be safe and active against AML and MDS in patients without such complications.
At a median follow-up of 3.6 months, 20 of 24 patients evaluable for survival had survived past 60 days. Complete remissions (less than 5% blasts in the bone marrow, absolute neutrophil count over 1,000/mL, plate let count over 100,000/mL) were reported for 7 of the 15 patients who could be evaluated for response to the therapy.
“Our findings suggest current eligibility standards that prevent participation by these patients in phase I and phase II clinical trials might be inadequate,” Dr. Garcia-Manero said.
New Targeted Therapy for Hodgkin Lymphoma Shows Promise
In a phase I clinical trial, 38% of patients with relapsed or therapy-resistant lymphoma experienced complete or partial remissions when treated with the antibody-drug conjugate brentuximab vedotin.
“That level of objective response to a drug is impressive for a phase I trial,” said Anas Younes, M.D., a professor and director of clinical and translational research in the Department of Lymphoma/Myeloma at MD Anderson and lead author of the study’s report, which was recently published in the New England Journal of Medicine. “These encouraging results are being confirmed in a large phase II trial.”
Of the 45 patients enrolled in the phase I trial, 42 had Hodgkin lymphoma, 2 had anaplastic large-cell lymphoma, and 1 had angioimmunoblastic T cell lymphoma. The patients had undergone a median of three previous chemotherapy regimens, and 73% of the patients had received autologous stem cell transplants.
Seventeen patients—15 with Hodgkin lymphoma and 2 with anaplastic large-cell lymphoma—had an objective response to treatment. Eleven responders had complete remissions, defined as disappearance of all evidence of the disease. The other 6 responders had partial remissions, defined as a 50% or greater reduction in the cumulative diameters of known malignant lesions and no new lesions.
The drug was given intravenously every 3 weeks, and the maximum tolerated dose was shown to be 1.8 mg/kg of body weight. Side effects at that dose were typically grade 1 or 2 in severity and included fatigue, pyrexia, diarrhea, nausea, neutropenia, and peripheral neuropathy.
Brentuximab vedotin consists of cAC10—a monoclonal antibody that targets the CD30 cell surface protein—and monomethyl auristatin E, an inhibitor of tubulin proteins crucial to the formation of microtubules, which provide structure to cells and are necessary for cell division. CD30 is expressed on Hodgkin lymphoma and anaplastic large-cell lymphoma cells but is normally expressed on only about 1% of T cells and other immune system components; therefore, brentuximab vedotin selectively targets the lymphoma cells.
A unique aspect of Hodgkin lymphoma is that cancer cells make up only about 5% of the tumor while the rest of the tumor is composed of a variety of inflamed cells. “This is the first scientific evidence that if you eliminate a few cancer cells, the entire tumor can be degraded. Eliminate the 5% and the rest goes away,” Dr. Younes said.
“There hasn’t been a new drug considered for Hodgkin lymphoma in 30 years,” Dr. Younes added. “The potential impact of brentuximab vedotin on years of life saved is huge because the median age for patients with this disease is in the 30s.”
Drug Shows Promise Against Treatment-Resistant Chronic Myelogenous Leukemia
Results of a clinical study indicate that the experimental drug ponatinib appears to be effective against treatment-resistant chronic myelogenous leukemia (CML).
Jorge Cortes, M.D., a professor in the Department of Leukemia at MD Anderson, presented these findings at the 52nd Annual Meeting of the American Society of Hematology in December.
CML is caused by the Philadelphia chromosome abnormality, a translocation between chromosomes 9 and 22 that results in the aberrant BCR-ABL gene. The first-line CML treatment imatinib and the second-line treatments nilotinib and dasatinib inhibit tyrosine kinases, a group of enzymes that play a variety of roles in controlling cell growth and differentiation. Although all three drugs inhibit the BCR-ABL protein, none of these drugs is effective against BCR-ABL proteins with the T315I mutation.
In the phase I clinical trial, the tyrosine kinase inhibitor ponatinib produced hematological and cytogenetic responses in patients whose leukemia cells carried the T315I mutation. The trial was open to patients whose disease had not responded to two or more prior treatments with imatinib, dasatinib, or nilotinib or had developed a resistance to at least two of these drugs.
“Ponatinib seems to be filling the gap we had for patients who right now have no good treatments left,” Dr. Cortes said.
Fifty-seven of the 67 patients enrolled at the time of reporting had CML (42 in the chronic phase, 7 in the accelerated phase, and 8 in the blast phase). Three patients had Philadelphia chromosome–positive acute lymphoblastic leukemia, three had acute myelogenous leukemia, and four had other hematological malignancies.
Of the 42 patients with chronic phase CML, 32 were evaluable at the time of reporting. Thirty (90%) of these patients experienced a complete hematological response (normalization of the blood cell counts), and 12 (38%) had complete cytogenetic responses (absence of cells with the Philadelphia chromosome in the bone marrow). All 11 patients with chronic phase CML and the T315I mutation had complete hematological responses; eight of these patients also had complete cytogenetic responses.
The most common adverse events were thrombocytopenia, headache, nausea, arthralgia, fatigue, anemia, increased lipase, muscle spasms, rash, myalgia, and pancreatitis. All dose-limiting toxicities were reversible.Dr. Cortes said patient enrollment has begun at MD Anderson and other institutions for a pivotal phase II trial of ponatinib in patients with treatment-resistant CML.
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Other articles in OncoLog, February 2011 issue: