Gemtuzumab in Children with Relapsed and Refractory Acute Myeloid Leukemia Treated on Compassionate-Use Basis: A Report of the AML-BFM Study Group
Authors: Rasche Mareike , Lerius Beate , Creutzig Ursula , Zimmermann Martin , Zwaan C. Michel , Reinhardt Dirk 
Published: October 2019

Abstract
BACKGROUND:
Long-term survival in pediatric acute myeloid leukemia (AML) improved remarkably during the last decades. However, children with refractory disease or relapsed AML still suffer from exceedingly poor outcome, especially those who relapse within one year of diagnosis with very limited treatment options. Gemtuzumab ozogamicin (GO) is an anti-CD33 antibody linked to calicheamicin, a potent cytotoxic agent. Developed for targeted treatment of CD33-positive AML, studies in adults showed its efficacy in relapsed and refractory AML. We performed this retrospective analysis of patients with highly advanced pediatric AML, receiving GO as compassionate use.
PATIENTS AND METHOD:
In total, 96 children <18 years diagnosed from 1995 to 2014 with multiple relapsed or refractory AML received GO as compassionate use. Eighty-eight patients had sufficient data available for this retrospective analysis, evaluation of adverse effects during first cycle of GO was based on medical reports of 83 patients. Sixty-one patients were treated in refractory disease or early first relapse, but also including 7 patients with 2 relapses within the first year after diagnosis. Nine patients were in 2nd relapse (>1year from diagnosis) and one patient in 3rdrelapse, four children had AML as secondary malignancy. Fourteen children have been already transplanted once, one child twice before GO therapy. Fourty-seven children received monotherapy with GO, 35 children were treated combined with cytarabine and 3 children received other combinations with other agents (3 unknown). Fifty-three patients received one cycle, 34 received 2 cycles of GO, however one patient received 4 cycles of monotherapy. Of note, eight patients have been previously reported elsewhere (Zwaan et al., Br J Haematol. 2010). Time of database lock was 07/2016 with a median follow-up of 9.8 years for the surviving patients.
RESULTS:
Safety profile was comparable to other pediatric studies. Adverse effects during first cycle of treatment consisted mostly of fever in neutropenia (n=49), less frequently infections (n=9) or allergic reactions (n=18). A few patients reported about mild gastrointestinal symptoms, which was not clearly related to GO due to combination therapy. Two patients suffered from sepsis. Veno-occlusive disease (VOD) of the liver occurred in three patients, one of those had a previous VOD, but all of them have been treated successfully with defibrotide. No lethal event was observed during treatment with GO. One patient developed a VOD during subsequent transplantation despite of prophylactic use of defibrotide. Sixty patients were evaluable for response assessment of the bone marrow. Twenty-eight children showed a response with a blast reduction to 5% or less in the bone marrow samples after treatment (46%). Fourteen out of these patients, received GO combined with cytarabine, 12 patients had monotherapy, and two other combinations. Subsequently, 53 children proceeded to stem cell transplantation (SCT) (one patient unknown). Of note, 13 out of those, received further chemotherapy before HSCT was performed. In details, 47 patients proceeded to first SCT, whereas 5 patients received 2ndSCT (one unknown). Time to transplantation varied (<3 weeks, n=14; 3 to 6 weeks, n=28; >6 weeks, n=11 patients [median time to transplantation after GO: 30 days]). The probability of 4-year overall survival after treatment with GO of all patients (n=88) was 21±4%. In patients treated with monotherapy it was 18±6%. Eighteen patients of this cohort are still alive at time of database lock.
CONCLUSION:
To our knowledge, this analysis is the largest pediatric cohort of patients, treated with GO in a very advanced disease. The results of this retrospective trial indicate efficacy of GO, while having an acceptable toxicity profile, even in heavily pretreated patients. It can induce blast reduction and even survival in patients, who have no further conventional treatment options. Further randomized studies are necessary to learn more about efficacy and side effects in a relapse setting, especially for therapeutic implications in future.

Disclosures
Rasche: Jazz Pharma: Other: Travel accomodation. Zwaan:Pfizer: Research Funding; Pfizer: Consultancy. Reinhardt:Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Jazz Pharma: Other: Travel Accomodation.