Novel Approaches in the Treatment of Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)
Advances in the Treatment of Acute Myeloid Leukemia
Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults and represents a significant clinical challenge for oncologists. Whereas patients with newly diagnosed AML experience remission rates of 50-80% after combination chemotherapy, 60-80% of patients who do achieve remission eventually relapse. The development of agents that target cell surface antigens is one of the most promising of the new strategies for treating AML. Several discussions at the annual American Society of Hematology meeting focused on one of these agents-gemtuzumab ozogamicin-which has shown to benefit AML patients undergoing first relapse and with lower than usual levels of hematological toxicity. Also presented were several studies of oprelvekin (IL-11), a hematopoietic growth factor effective in preventing chemotherapy-induced thrombocytopenia.
According to Eric L. Sievers, MD, Assistant Professor, University of Washington, Seattle, the CD33 cell surface antigen is a particularly appropriate target for AML therapy because it is present on leukemic blasts in approximately 80-90% of patients. Also, upon binding to an antibody, the antigen enters the cell interior and is therefore ideal for the delivery of a chemotherapeutic agent or toxin.
Gemtuzumab ozogamicin (Mylotarg®) is an antibody-targeted chemotherapy agent approved for the treatment of CD33-positive AML in first relapse. It consists of a humanized anti-CD33 monoclonal antibody conjugated to calicheamicin, a highly potent antitumor antibiotic that cleaves double-stranded DNA. Preclinical studies showed that the drug selectively kills CD33-positive cells in vitro, induces tumor regression in athymic mouse models of leukemia, and inhibits colony formation by leukemic bone marrow specimens.
Phase II Study of Gemtuzumab Ozogamicin
Dr. Sievers discussed the results of a Phase II study in which 142 patients with first relapse AML were treated with two doses of gemtuzumab ozogamicin 9 mg/mІ, 14 days apart. A bone marrow biopsy to assess efficacy was taken 28 days later.
According to Dr. Sievers, the overall remission rate with treatment was 30%. Included in this cohort of responders was a group of patients who became platelet transfusion-independent but did not reach a platelet count of over 100,000/µL (CRp).
There was no significant difference in progression-free survival (PFS) in CR and CRp patients.
Of 15 patients who received hematopoietic stem cell transplant, the probability of relapse-free survival achieved a plateau of 0.7 at 10 months from date of remission. Dr. Sievers commented, "this shows that remission achieved with this agent is reasonably deep, in the sense that these patients are not rapidly relapsing after transplant. Also, re-induction of remission with this agent appears to be associated with sufficiently low toxicity to allow us to deliver transplantation to these patients."
Infusion-related adverse events (overall grades 1-4) were 62% for chills and 61% for fever. Other AEs included hypotension (11%), dyspnea (4%), sepsis (16%), pneumonia (7%), and mucositis (4%). "These compare favorably to high dose cytarabine or regimens containing anthracycline," Dr. Sievers pointed out.
The median total duration of hospitalization was 24 days and 18% of patients required ( 7 days of hospitalization. There were no cases of alopecia or drug-related cardiotoxicity and no clinical evidence of an immune response. Four patients (3%) developed tumor lysis syndrome and 18 patients (13%) died during treatment.
Gemtuzumab Ozogamicin Monotherapy Versus High-Dose Cytarabine Combination Therapy for First Relapse AML
In a further analysis of this study, Dr. Lance Leopold, Wyeth-Ayerst Research, Radnor, Pennsylvania, and colleagues from Wyeth-Ayerst Research and MD Anderson Cancer Center, Houston, Texas, compared the outcomes of the gemtuzumab ozogamicin-treated patients with the outcomes of 128 patients who received high-dose cytarabine (HiDAC)-containing regimens between 1990 and 1999. The HiDAC-containing regimens included = 1.0 g/mІ/dose of cytarabine and combination therapy with fludarabine, topotecan, or idarubicin.
Explaining the rationale of this comparative analysis, Dr. Leopold explained that knowing how to implement therapy for first relapses of AML is problematic. "An important question for physicians treating patients with relapsed AML is whether patients should receive gemtuzumab ozogamicin or more traditional cytarabine-containing regimens."
All patients enrolled in the trials had AML in first relapse with duration of first remission (CR1) = 3 months and no evidence of antecedent hematologic disorders or secondary AML. The primary efficacy endpoints were CR2-defined as < 5% blasts in the bone marrow, = 1,000/?L neutrophils, = 100,000/µL platelets, and platelet transfusion independence-and mortality.
A multivariate logistic regression analysis demonstrated that increasing duration of CR1, decreasing age, and AML treatment regimen were independent predictors of remission (p < 0.05). "The results were the same whether the analysis considered CR patients alone or CR and CRp patients together," Dr. Leopold noted.
After accounting for age, patients with CR1 for 10.5 months or less were more likely to obtain remission after treatment with gemtuzumab ozogamicin than after treatment with the HiDAC-containing regimens. Conversely, patients with CR1 more than 19 months were more likely to obtain remission after treatment with the HiDAC-containing regimens. However, the remission rates for both treatments were statistically the same between 10.5 and 19 months.
Forty-three day mortality rates for the two regimens were similar: 13% for patients treated with gemtuzumab ozogamicin and 17% for those treated with HiDAC combination therapy. However, for older patients (60 years or older), the mortality rates were 13% (10/80) for the gemtuzumab ozogamicin-treated patients and 22% (10/46) for the HiDAC-treated patients. "What you see is that HiDAC produces less mortality in early patients and more mortality in older patients," Dr. Leopold commented.
Summarizing, he stated, "[Gemtuzumab ozogamicin] appears to produce a higher CR and CRp rate than cytarabine combination therapy in first relapse AML patients with short CR1 durations. In addition, it may be preferable in older first relapse AML patients in whom it results in lower mortality. Cytarabine therapy on the other hand appears to be preferable to gemtuzumab ozogamicin for younger patients and in those with longer first CR durations." Dr. Leopold noted that randomized trials to confirm these results are planned and cautioned, "it must be remembered that neither of these regimens are superior in any absolute sense."
Also reported at the meeting was a study in which gemtuzumab ozogamicin was shown to prolong remission in patients with poor prognosis AML or prior stem cell transplant№ and a study in which first relapse AML patients treated with gemtuzumab ozogamicin followed by hematopoietic stem cell transplantation (HSCT) experienced prolonged disease-free survival.І
Expanding Roles for Interleukin 11
Several reports at the ASH meeting featured the use of oprelvekin (recombinant interleukin 11), a growth factor approved for the prevention of severe thrombocytopenia and for reducing the need for platelet infusions in patients with nonmyeloid malignancies following myelosuppressive therapy.
Dr. Larry D. Cripe, Indiana University Medical Center, Indianapolis, and an international team of researchers conducted a Phase II trial to assess the safety and efficacy of oprelvekin in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) after induction chemotherapy for AML with high-dose cytarabine (HiDAC)-containing chemotherapy.
Thirty-four patients (median age 44, range 18 to 53 years) with newly diagnosed AML (5 with secondary AML) were given chemotherapy for ten days and then were administered oprelvekin 50 µg/kg daily starting at day 11 until a sustained platelet count of = 50,000/L was achieved. GM-CSF (250 µg/kg) was begun if marrow aplasia was evident on day 10. All patients had hypercellular marrows at diagnosis.
The median platelet count on day 1 of therapy was 73,000/L (range 11,000-562,000/L. Twenty patients (59%) achieved a CR and the one year survival was estimated at 61%. Oprelvekin was administered for a median of 12 days (range 8-21).
According to the investigators, adverse events were consistent with the expected toxicity of induction chemotherapy with HiDAC. The median time to 20,000/L platelets sustained for 7 days without further platelet transfusion was 25 days (range: 18-36 days), a 6-day decrease from the median time of 31 days (range 19-48) to recovery observed in a cohort of 48 patients treated with a similar induction regimen without oprelvekin or GM-CSF.
In their conclusion, the investigators stated that, "IL-11 may be the first thrombopoietic agent to reduce duration of thrombocytopenia during induction therapy for AML."
Interleukin 11 in Bone Marrow Failure and Stem Cell Transplant
Low platelet counts are a significant and persistent problem for patients with bone marrow failure states, such as that found in myelodysplasia (MDS), aplastic anemia, post-chemotherapy, and graft failure after transplant.
Very little is known about the activity of IL-11 in bone marrow failure states, therefore, Dr. Razelle Kurzrock, Department of Bio-Immunotherapy, M.D. Anderson Cancer Center, Houston, Texas, and colleagues from the University of Texas decided to test oprelvekin in these conditions. However, in pilot studies, the FDA recommended post-chemotherapy doses of 50 µg/kg/day s.c.-intended for only short-term use-produced significant peripheral and pulmonary edema after the prolonged dosing necessary for treating bone marrow failure.
These investigators, then, set out to study the effect of low-dose oprelvekin (10 µg/kg/d) in these patients. Response criteria included doubling of platelets and a rise to more than 50 x 109/L or tripling of platelets and rise to more than 20 x 109/L.
Of the 16 patients evaluable for response (median age 58 years, range 5-84), six (38%) showed a platelet response to oprelvekin and two had a multi-lineage response (one to oprelvekin alone and one to oprelvekin + G-CSF + erythropoietin). Responders included 5 of 11 patients with MDS and 1 of 4 patients with aplastic anemia. Response duration was 12, 13, 14+, 22+, 25 and 30 weeks.
Commenting on the response, Dr. Kurzrock said, "These patients experienced a very significant rise in platelet counts. Not all of them had complete normalization but they went from being quite severely thrombocytopenic to being normal or near normal."
As for the two patients with the multi-lineage response, she noted, "studies of oprelvekin have mainly been done on platelets because that seems to be its predominant effect but there are some lab studies that suggest it may also affect progenitors that are involved in production of white cells and red cells. And two of the patients [in this study] had a response in the white cells and red cells."
Side effects of oprelvekin were mild and included grade 1 peripheral edema, conjunctival injection, or myalgia. Seven patients had no side effects. According to Dr. Kurzrock and colleagues, this study suggests that low dose oprelvekin (10µg/kg/day) can raise platelet counts without significant toxicity, and may be appropriate for selected thrombocytopenic patients with bone marrow failure.
Dr. Kurzrock indicated that further studies of oprelvekin in bone marrow failure states are under way.
1. CMA-676 as monotherapy for patients with poor-prognosis AML. Adam D. Cohen, Selina M. Luger, Patricia A. Mangan, David L. Porter, Ginna G. Laport, Stephen J. Schuster, Donald E. Tsai, Edward A. Stadtmauer. Hematologic Malignancies Program, University of Pennsylvania Cancer Center, Philadelphia, PA, USA. [abstract 1400]
2. Prolonged disease-free survival in patients with acute myeloid leukemia in first relapse treated with gemtuzumab ozogamicin (Mylotarg®, CMA-676) followed by hematopoietic stem cell transplantation. Eric L. Sievers, Richard A. Larson, Elihu Estey, Bob Lowenberg, Harry P. Erba, Martin Gramatzki, Alan List, Jorge Sierra, Edward A. Stadtmauer, Stefano Tarantolo, Mark S. Berger, Lance H. Leopold, Catharine Eten, Mihaela Munteanu, Allegra Stone, Irwin D. Bernstein, Frederick R. Appelbaum. Fred Hutchinson Cancer Research Center, Seattle, WA; University of Chicago, Chicago, IL; MD Anderson Cancer Center, Houston, TX; University Hospital Rotterdam, Rotterdam, The Netherlands; University of Michigan Cancer Center, Ann Arbor, MI; University of Erlangen-Nuremberg, Erlangen, Germany; Arizona Cancer Center, Tuscon, AZ; Hospital de Sant Pau, Barcelona, Spain; University of Pennsylvania Cancer Center, Philadelphia, PA; University of Nebraska, Omaha, NE; Wyeth-Ayerst Research, Radnor, PA. [abstract 1382]