Long-Term Survival With Mylotarg/Transplant in AML

PHILADELPHIA-Remissions induced by gemtuzumab ozogamicin (Mylotarg) monotherapy in patients with first-relapse acute myeloid leukemia (AML) can be prolonged with subsequent therapy. Allogeneic hematopoietic stem cell transplant was particularly effective and even produced some long-term remissions in patients who did not respond to gemtuzumab, Eric Sievers, MD, reported at the 44th Annual Meeting of the American Society of Hematology (ASH abstract 327).

Not a Randomized Trial

The combination of gemtuzumab with allogeneic stem cell transplant appears highly efficacious in patients with first-relapse AML, "with the caveat that this is not a randomized trial, but an observational study of what physicians chose to do with their monotherapy patients in remission," said Dr. Sievers, assistant member, Clinical Research Division, Fred Hutchinson Cancer Research Center.

Allogeneic transplant was relatively safe in patients previously exposed to gemtuzumab, and more than 50% of patients who achieved remission with the combined treatments are alive 2 years post-transplant.

The prognosis for first-relapse AML is historically poor, with response rates to conventional agents of about 30% to 50% and a 6-month median duration of the second remission. Chemotherapy agents are also associated with considerable nonhematologic toxicity.

Dr. Sievers presented long-term follow-up data on patients enrolled in three clinical trials of gemtuzumab, an antibody-targeted chemotherapy consisting of a humanized anti-CD33 antibody linked to calicheamicin, a cytotoxic antibiotic. CD33 is expressed by leukemic blasts in 80% to 90% of patients with AML and is absent from stem cells and nonhematologic tissues, reducing the potential for nonhematologic toxicity.

The aim of the analysis was to determine the best follow-up therapy for patients with relapsed AML treated with gemtuzumab monotherapy. The three multinational trials enrolled a total of 277 patients, all with CD33-positive disease in first untreated relapse.

Patients received gemtuzumab 9 mg/m² in two doses 14 days apart and were evaluated for bone marrow response 28 days after the second infusion. All patients were followed long term to determine safety, disease status, and survival. The study protocol allowed the patients’ physicians to determine what, if any, additional therapy they would receive.

Study Results

An initial response to gemtuzumab (defined as less than 5% marrow blasts) was achieved in 53% of patients. Using the more stringent criteria of hematologic recovery, the overall remission rate was 26%. At 1 year, 22% of patients were alive. "Almost all of the patients who continued in remission received some form of further therapy after gemtuzumab monotherapy," Dr. Sievers said.

Of 71 patients who achieved a response (including partial responses) with gemtu-zumab monotherapy, 20% went on to receive allogeneic transplant, 15% received autologous transplant, 15% had chemotherapy, and about half received no further treatment. Median survival was more than 18 months in patients receiving allogeneic transplant, more than 16 months with autologous transplant, and about 12 months with chemotherapy or no further therapy.

Disease-free survival was notably poor in patients receiving chemotherapy. "Leukemia recurred in almost all patients who did not receive allogeneic transplantation," Dr. Sievers said.

Transplant Candidates

A total of 29 patients received an allogeneic transplant, including 15 who did not respond to gemtuzumab monother-apy. Patients considered as transplant candidates were generally younger and in better health than the cohort as a whole. Transplantation occurred a median of 3 months after gemtuzumab therapy (range, 1 to 8 months). Forty-two months after allogeneic transplant, more than half of the gemtuzumab responders were alive, as were about 20% of the transplanted patients who failed to achieve remission after gemtuzumab induction.

Veno-occlusive Disease

Hepatic veno-occlusive disease/sinusoidal occlusive syndrome (VOD/SOS) occurred at a higher rate following transplant than during the gemtuzumab monotherapy phase of the study.

VOD/SOS developed in 8 (17%) of the 46 patients who underwent any form of transplant. Seven cases occurred following an allogeneic transplant and one after autologous transplant. Five patients died of this complication. In contrast, 3% of patients had VOD/SOS after exposure to gemtuzumab but before receiving any additional therapy, and 1% died of this complication.