Edward A. Stadtmauer

Efficacy and Safety of Gemtuzumab Ozogamicin in Patients With CD33-Positive Acute Myeloid Leukemia in First Relapse

PURPOSE Three open-label, multicenter trials were conducted to evaluate the efficacy and safety of single-agent Mylotarg (gemtuzumab ozogamicin; CMA-676; Wyeth Laboratories, Philadelphia, PA), an antibody-targeted chemotherapy agent, in patients with CD33-positive acute myeloid leukemia (AML) in untreated first relapse. PATIENTS AND METHODS The study population comprised 142 patients with AML in first relapse with no history of an antecedent hematologic disorder and a median age of 61 years. All patients received Mylotarg as a 2-hour intravenous infusion, at a dose of 9 mg/m(2), at 2-week intervals for two doses. Patients were evaluated for remission, survival, and treatment-emergent adverse events. RESULTS Thirty percent of patients treated with Mylotarg obtained remission as characterized by 5% or less blasts in the marrow, recovery of neutrophils to at least 1,500/microL, and RBC and platelet transfusion independence. Although patients treated with Mylotarg had relatively high incidences of myelosuppression, grade 3 or 4 hyperbilirubinemia (23%), and elevated hepatic transaminase levels (17%), the incidences of grade 3 or 4 mucositis (4%) and infections (28%) were relatively low. There was a low incidence of severe nausea and vomiting (11%) and no treatment-related cardiotoxicity, cerebellar toxicity, or alopecia. Many patients received Mylotarg on an outpatient basis (38% and 41% of patients for the first and second doses, respectively). Among the 142 patients, the median total duration of hospitalization was 24 days; 16% of patients required 7 days of hospitalization or less. CONCLUSION Administration of the antibody-targeted chemotherapy agent Mylotarg to patients with CD33-positive AML in first relapse induces complete remissions with what appears to be a favorable safety profile.

Lenalidomide after stem-cell transplantation for multiple myeloma

BACKGROUND Data are lacking on whether lenalidomide maintenance therapy prolongs the time to disease progression after autologous hematopoietic stem-cell transplantation in patients with multiple myeloma. METHODS Between April 2005 and July 2009, we randomly assigned 460 patients who were younger than 71 years of age and had stable disease or a marginal, partial, or complete response 100 days after undergoing stem-cell transplantation to lenalidomide or placebo, which was administered until disease progression. The starting dose of lenalidomide was 10 mg per day (range, 5 to 15). RESULTS The study-drug assignments were unblinded in 2009, when a planned interim analysis showed a significantly longer time to disease progression in the lenalidomide group. At unblinding, 20% of patients who received lenalidomide and 44% of patients who received placebo had progressive disease or had died (P<0.001); of the remaining 128 patients who received placebo and who did not have progressive disease, 86 crossed over to lenalidomide. At a median follow-up of 34 months, 86 of 231 patients who received lenalidomide (37%) and 132 of 229 patients who received placebo (58%) had disease progression or had died. The median time to progression was 46 months in the lenalidomide group and 27 months in the placebo group (P<0.001). A total of 35 patients who received lenalidomide (15%) and 53 patients who received placebo (23%) died (P=0.03). More grade 3 or 4 hematologic adverse events and grade 3 nonhematologic adverse events occurred in patients who received lenalidomide (P<0.001 for both comparisons). Second primary cancers occurred in 18 patients who received lenalidomide (8%) and 6 patients who received placebo (3%). CONCLUSIONS Lenalidomide maintenance therapy, initiated at day 100 after hematopoietic stem-cell transplantation, was associated with more toxicity and second cancers but a significantly longer time to disease progression and significantly improved overall survival among patients with myeloma. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00114101.).

Multicenter Phase II Study of Bortezomib in Patients With Relapsed or Refractory Mantle Cell Lymphoma

PURPOSE Evaluate response rate, duration of response (DOR), time-to-progression (TTP), overall survival (OS), and safety of bortezomib treatment in patients with relapsed or refractory mantle cell lymphoma (MCL). PATIENTS AND METHODS Bortezomib 1.3 mg/m(2) was administered on days 1, 4, 8, and 11 of a 21-day cycle, for up to 17 cycles. Response and progression were determined using International Workshop Response Criteria, both using data from independent radiology review and by the investigators. Primary efficacy analyses were based on data from independent radiology review. RESULTS In total, 155 patients were treated. Median number of prior therapies was one (range, one to three). Response rate in 141 assessable patients was 33% including 8% complete response (CR)/unconfirmed CR. Median DOR was 9.2 months. Median TTP was 6.2 months. Results by investigator assessments were similar. Median OS has not been reached after a median follow-up of 13.4 months. The safety profile of bortezomib was similar to previous experience in relapsed multiple myeloma. The most common adverse events grade 3 or higher were peripheral neuropathy (13%), fatigue (12%), and thrombocytopenia (11%). Death from causes that were considered to be treatment related was reported for 3% of patients. CONCLUSION These results confirm the activity of bortezomib in relapsed or refractory MCL, with predictable and manageable toxicities. Bortezomib provides significant clinical activity in terms of durable and complete responses, and may therefore represent a new treatment option for this population with usually very poor outcome. Studies of bortezomib-based combinations in MCL are ongoing.

Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma.

This phase 3, multicenter, randomized (1:1), double-blind, placebo-controlled study evaluated the safety and efficacy of plerixafor with granulocyte colony-stimulating factor (G-CSF) in mobilizing hematopoietic stem cells in patients with multiple myeloma. Patients received G-CSF (10 microg/kg) subcutaneously daily for up to 8 days. Beginning on day 4 and continuing daily for up to 4 days, patients received either plerixafor (240 microg/kg) or placebo subcutaneously. Starting on day 5, patients began daily apheresis for up to 4 days or until more than or equal to 6 x 10(6) CD34(+) cells/kg were collected. The primary endpoint was the percentage of patients who collected more than or equal to 6 x 10(6) CD34(+) cells/kg in less than or equal to 2 aphereses. A total of 106 of 148 (71.6%) patients in the plerixafor group and 53 of 154 (34.4%) patients in the placebo group met the primary endpoint (P < .001). A total of 54% of plerixafor-treated patients reached target after one apheresis, whereas 56% of the placebo-treated patients required 4 aphereses to reach target. The most common adverse events related to plerixafor were gastrointestinal disorders and injection site reactions. Plerixafor and G-CSF were well tolerated, and significantly more patients collected the optimal CD34(+) cell/kg target for transplantation earlier compared with G-CSF alone. This study is registered at www.clinicaltrials.gov as #NCT00103662.

Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma

An obstacle to cancer immunotherapy has been that the affinity of T-cell receptors (TCRs) for antigens expressed in tumors is generally low. We initiated clinical testing of engineered T cells expressing an affinity-enhanced TCR against HLA-A*01-restricted MAGE-A3. Open-label protocols to test the TCRs for patients with myeloma and melanoma were initiated. The first two treated patients developed cardiogenic shock and died within a few days of T-cell infusion, events not predicted by preclinical studies of the high-affinity TCRs. Gross findings at autopsy revealed severe myocardial damage, and histopathological analysis revealed T-cell infiltration. No MAGE-A3 expression was detected in heart autopsy tissues. Robust proliferation of the engineered T cells in vivo was documented in both patients. A beating cardiomyocyte culture generated from induced pluripotent stem cells triggered T-cell killing, which was due to recognition of an unrelated peptide derived from the striated muscle-specific protein titin. These patients demonstrate that TCR-engineered T cells can have serious and not readily predictable off-target and organ-specific toxicities and highlight the need for improved methods to define the specificity of engineered TCRs.

A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma

Carfilzomib is a next-generation, selective proteasome inhibitor being evaluated for the treatment of relapsed and refractory multiple myeloma. In this open-label, single-arm phase 2 study (PX-171-003-A1), patients received single-agent carfilzomib 20 mg/m(2) intravenously twice weekly for 3 of 4 weeks in cycle 1, then 27 mg/m(2) for ≤ 12 cycles. The primary endpoint was overall response rate (≥ partial response). Secondary endpoints included clinical benefit response rate (≥ minimal response), duration of response, progression-free survival, overall survival, and safety. A total of 266 patients were evaluable for safety, 257 for efficacy; 95% were refractory to their last therapy; 80% were refractory or intolerant to both bortezomib and lenalidomide. Patients had median of 5 prior lines of therapy, including bortezomib, lenalidomide, and thalidomide. Overall response rate was 23.7% with median duration of response of 7.8 months. Median overall survival was 15.6 months. Adverse events (AEs) were manageable without cumulative toxicities. Common AEs were fatigue (49%), anemia (46%), nausea (45%), and thrombocytopenia (39%). Thirty-three patients (12.4%) experienced peripheral neuropathy, primarily grades 1 or 2. Thirty-three patients (12.4%) withdrew because of an AE. Durable responses and an acceptable tolerability profile in this heavily pretreated population demonstrate the potential of carfilzomib to offer meaningful clinical benefit. This trial was registered at www.clinicaltrials.gov as #NCT00511238.

Conventional-Dose Chemotherapy Compared with High-Dose Chemotherapy plus Autologous Hematopoietic Stem-Cell Transplantation for Metastatic Breast Cancer

BACKGROUND We conducted a randomized trial in which we compared high-dose chemotherapy plus hematopoietic stem-cell rescue with a prolonged course of monthly conventional-dose chemotherapy in women with metastatic breast cancer. METHODS Women 18 to 60 years of age who had metastatic breast cancer received four to six cycles of standard combination chemotherapy. Patients who had a complete or partial response to induction chemotherapy were then randomly assigned to receive either a single course of high doses of carboplatin, thiotepa, and cyclophosphamide plus transplantation of autologous hematopoietic stem cells or up to 24 cycles of cyclophosphamide, methotrexate, and fluorouracil in conventional doses. The primary end point was survival. RESULTS The median follow-up was 37 months. Of 553 patients who enrolled in the study, 58 had a complete response to induction chemotherapy and 252 had a partial response. Of these, 110 patients were assigned to receive high-dose chemotherapy plus hematopoietic stem cells and 89 were assigned to receive conventional-dose chemotherapy. In an intention-to-treat analysis, we found no significant difference in survival overall at three years between the two treatment groups (32 percent in the transplantation group and 38 percent in the conventional-chemotherapy group). There was no significant difference between the two treatments in the median time to progression of the disease (9.6 months for high-dose chemotherapy plus hematopoietic stem cells and 9.0 months for conventional-dose chemotherapy). CONCLUSIONS As compared with maintenance chemotherapy in conventional doses, high-dose chemotherapy plus autologous stem-cell transplantation soon after the induction of a complete or partial remission with conventional-dose chemotherapy does not improve survival in women with metastatic breast cancer.

High-dose chemotherapy with autologous hematopoietic stem-cell support for breast cancer in North America.

PURPOSE To identify trends in high-dose therapy with autologous hematopoietic stem-cell support (autotransplants) for breast cancer (1989 to 1995). PATIENTS AND METHODS Analysis of patients who received autotransplants and were reported to the Autologous Blood and Marrow Transplant Registry. Between January 1, 1989 and June 30, 1995, 19,291 autotransplants were reviewed; 5,886 were for breast cancer. Main outcomes were progression-free survival (PFS) and survival. RESULTS Between 1989 and 1995, autotransplants for breast cancer increased sixfold. After 1992, breast cancer was the most common indication for autotransplant. Significant trends included increasing use for locally advanced rather than metastatic disease (P < .00001) and use of blood-derived rather than marrow-derived stem cells (P < .00001). One-hundred-day mortality decreased from 22% to 5% (P < .0001). Three-year PFS probabilities were 65% (95% confidence intervals [Cls], 59 to 71) for stage 2 disease, and 60% (95% Cl, 53 to 67) for stage 3 disease. In metastatic breast cancer, 3-year probabilities of PFS were 7% (95% Cl, 4 to 10) for women with no response to conventional dose chemotherapy; 13% (95% Cl, 9 to 17) for those with partial response; and 32% (95% Cl, 27 to 37) for those with complete response. Eleven percent of women with stage 2/3 disease and less than 1% of those with stage 4 disease participated in national cooperative group randomized trials. CONCLUSION Autotransplants increasingly are used to treat breast cancer. One-hundred-day mortality has decreased substantially. Three-year survival is better in women with earlier stage disease and in those who respond to pretransplant chemotherapy.

Final report of the efficacy and safety of gemtuzumab ozogamicin (Mylotarg) in patients with CD33-positive acute myeloid leukemia in first recurrence

In this study, the authors analyzed the efficacy and safety of gemtuzumab ozogamicin (GO) (Mylotarg®), an antibody‐targeted chemotherapy for CD33‐positive acute myeloid leukemia (AML).

Alemtuzumab in Previously Treated Chronic Lymphocytic Leukemia Patients Who Also Had Received Fludarabine

PURPOSE This phase II pilot study determined the efficacy and safety of alemtuzumab (Campath-1H; Burroughs Wellcome, United Kingdom) in patients with chronic lymphocytic leukemia (CLL), all of whom had previously received fludarabine and other chemotherapy regimens. PATIENTS AND METHODS Twenty-four patients were treated with intravenous alemtuzumab at six centers in the United States. The target dose of 30 mg over 2 hours, three times weekly, was administered for up to 16 weeks. Responses were evaluated by an independent panel of experts using 1996 National Cancer Institute-sponsored Working Group criteria. Safety assessments included analysis of lymphocyte subpopulations. Antimicrobial prophylaxis was not mandatory. RESULTS Eight patients (33%) achieved a major response (all partial remissions), with a median time to response of 3.9 months (range, 1.6 to 5.3 months). The median duration of response was 15.4 months (range, 4.6 to >or= 38.0 months), the median time to disease progression was 19.6 months (range, 7.7 to >or= 42.0 months), and the median survival time was 35.8 months (range, 8.8 to >or= 47.1 months). Acute infusion-related events, mainly grades 1 and 2, were most common and most severe in the first week. Ten patients (eight nonresponders and two responders) experienced major infections on-study. Pneumocystis carinii pneumonia was reported in two patients on-study; neither had received prophylaxis. Median CD4+ and CD8+ counts decreased and then began to increase by the end of the study, with further recovery by 1-month follow-up. One of 53 samples obtained from 10 patients had a low titer of alemtuzumab antibodies. CONCLUSION Alemtuzumab has significant activity in poor-prognosis, fludarabine-treated CLL patients. However, because of a relatively high incidence of opportunistic infections accompanying profound lymphopenia, future protocols should include mandatory prophylaxis.