Phase I/II study of gemtuzumab ozogamicin added to fludarabine, melphalan and allogeneic hematopoietic stem cell transplantation for high-risk CD33 positive myeloid leukemias and myelodysplastic syndrome

Abstract

We investigated the hypothesis that gemtuzumab ozogamicin (GO), an anti-CD33 immunotoxin would improve the efficacy of fludarabine/melphalan as a preparative regimen for allogeneic hematopoietic stem cell transplantation (HSCT) in a phase I/II trial. Toxicity was defined as grades III-IV organ damage, engraftment failure or death within 30 days. 'Response' was engraftment and remission (CR) on day þ 30. We sought to determine the GO dose (2, 4 or 6 mg m À2 ) giving the best tradeoff between toxicity and response. All patients were not candidates for myeloablative regimens. Treatment plan: GO (day À12), fludarabine 30 mg m À2 (days À5 to À2), melphalan 140 mg m À2 (day À2) and HSCT (day 0). GVHD prophylaxis was tacrolimus and mini-methotrexate. Diagnoses were AML (n ¼ 47), MDS (n ¼ 4) or CML (n ¼ 1). Median age was 53 years (range, 13-72). All but three patients were not in CR. Donors were related (n ¼ 33) or unrelated (n ¼ 19). Toxicity and response rates at 4 mg m À2 were 50% (n ¼ 4) and 50% (n ¼ 4). GO dose was de-escalated to 2 mg m À2 : 18% had toxicity (n ¼ 8) and 82% responded (n ¼ 36). 100-day TRM was 15%; one patient had reversible hepatic VOD. Median follow-up was 37 months. Median event-free and overall survival was 6 and 11 months. GO 2 mg m À2 can be safely added to fludarabine/melphalan, and this regimen merits further evaluation.

Impact of donor source on hematopoietic cell transplantation outcomes for patients with myelodysplastic syndromes (MDS)

“…20 Although these data are reassuring, there are no prospective clinical trials comparing HCT to non-HCT therapies, and there are many unanswered questions that remain regarding the exact role of HCT for patients with MDS. 21 Previous studies comparing MRD and MUD transplantation have yielded conflicting results, with some reporting inferior survival or DFS with MUD HCTs, 22,23 and others reporting similar survival. 24,25 A prior CIBMTR analysis in 2 223 adults with AML demonstrated similar survival among MRD HCT, 8 of 8 MUD HCT, and 7 of 8 MUD HCT recipients.…”

Gemtuzumab Ozogamicin as Part of Reduced-Intensity Conditioning for Allogeneic Hematopoietic Cell Transplantation in Patients with Relapsed Acute Myeloid Leukemia

“…The recent report of de Lima and coworkers suggests that caution is warranted when higher doses of GO are used in this setting. In their attempt to increase the dose of GO in combination with fludarabine and melphalan, they encountered relevant extramedullary toxicity at 2 mg/m 2 in some patients and decided not to further increase the dose of GO in subsequent patients (10). The major difference between the two studies is the predominant use of low and intermediate doses of TBI in our study compared with melphalan in the trial from Houston.…”

“…Although the pathophysiology of GO-induced hepatic damage has not been completely understood, the majority of clinicians avoid the combination of intensive conditioning and GO. Only recently, de Lima and coworkers could nicely show that GO at 2 mg/m 2 can be safely followed by a reduced-intensity conditioning protocol and allogeneic HCT (10). In this trial, the investigators could show the safety and the potential additive effect of a lower dose of GO preceding fludarabine and melphalan.…”

Fludarabine Melphalan reduced-intensity conditioning allotransplanation provides similar disease control in lymphoid and myeloid malignancies: analysis of 344 patients

“…14 In addition, when combined with fludarabine, the combination is highly immunosuppressive, thus providing an excellent platform for rapid engraftment and the GVM effect. Surprisingly, despite its widespread use in both lymphoid 15 and myeloid malignancies, 16 there have been few large studies comparing this commonly used regimen in multiple malignancies.…”