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Editorials
Gemtuzumab ozogamicin in acute myeloid leukemia: act 2, with perhaps more to come
Johann Hitzler1 and Elihu Estey2
1Division of Hematology/Oncology, The Hospital for Sick Children and Developmental and Stem Cell Biology, The Hospital for Sick Children Research Institute, Toronto, ON, Canada and 2Division of Hematology University of Washington Medical Center and Clinical Research Division Fred Hutchinson Cancer Research Center Seattle, WA, USA
E-mail: eestey@u.washington.edu doi:10.3324/haematol.2018.205948
This editorial discusses two papers, both published in this issue of Haematologica, that expand our knowledge regarding gemtuzumab ozogamicin (GO), both in adults with newly-diagnosed acute myeloid leukemia (AML) and in children with relapsed AML. GO combines the toxin calicheamicin with an antibody to CD33, an antigen found on the surface of hematopoietic cells, including in some instances “stem cells” (Figure 1).1 The relative lack of CD33 expression on the surface of non-hematopoietic cells, except for macrophages lining hepatic sinusoids (Kupffer cells), limits the drug’s principal toxicity to blood forming cells and to a lesser extent Kupffer cells; the latter toxicity results in a sinusoidal obstructive syndrome, most often seen after allogeneic hematopoietic cell transplant (HCT) but largely preventa- ble.2 On September 1, 2017, having originally approved but subsequently withdrawn approval for GO, the US Food and Drug Administration (FDA) re-approved use of GO combined with daunorubicin and cytosine arabi- noside (ara-C) given as standard “7+3” for treatment of adults with newly-diagnosed CD33-positive AML, who constitute the great majority of patients with the disease, thus officially ushering in GO’s second act. (https://www.fda.gov/drugs/informationondrugs/approved- drugs/ucm574518.htm). Several months later, the European Medicines Agency (EMA) approved GO for the same indi- cation (https://www.ema.europa.eu/medicines/human/ EPAR/mylotarg-0#authorisation-details-section). The FDA also gave notice of its approval of GO for use as single agent in relapsed or refractory AML and in children.
Both the FDA and EMA approvals primarily rested on a French trial (ALFA-0701) randomizing newly diagnosed patients aged 50-70 years to receive 7+3 ± GO 3 mg/m2 on days 1, 4, and 7.3 In a break with precedent, which we dis- cuss below, approval was based on prolongation of event- free survival (EFS) rather than “overall” survival (hereafter “survival”); the benefit was limited to patients with “favor- able” or “intermediate” cytogenetics. Median survival in patients remaining alive was 20 months. It is known, however, that the risk of relapse or death declines precip- itously only once 2-3 years have elapsed since achieve- ment of CR.4 Hence the update of the ALFA-0701 trial reported by Lambert et al. in the current issue of Haematologica is particularly noteworthy given the medi- an follow up of 47 months in the 7+3+GO group and 41 months in the controls.5 The essential findings of the orig- inal study remain unchanged, validating the FDA and EMA decisions to grant approval for GO.
Another report in the current issue of Haematologica by Niktoreh et al. from the Berlin-Frankfurt-Münster study group notes that when GO was given on a “compassion-
ate” basis, either alone or with cytarabine, treatment
resulted in sufficient reduction in blast count to permit
6 64% of 76 children aged under 18 years to receive HCT.
At four years, probability of survival was 18±5%: 27±7% in the HCT and 0% in the non-HCT group. Although there is less experience with GO in children than in adults, this report follows a randomized trial of chemotherapy with or without addition of GO (one dose of 3 mg/m2 given on the first and fourth course of chemotherapy) con- ducted in over 500 children by the Children’s Oncology Group (COG).7 Results were analogous to those reported in ALFA-0701: a greater effect on EFS than on survival and largely limited to individuals with intermediate or favor- able cytogenetics. Both the COG study and the study reported here by Niktoreh et al.6 justify the FDA’s approval of GO in children. The value of GO in relapsed pediatric AML will be clarified by the authors’ ongoing prospective randomized controlled trial (EudraCT Number: 2010- 018980-41).
For many years, an increase in survival had been the sole basis for approval of new drugs in AML. This was sensi- ble, since once failure to enter CR or relapse from CR had occurred, survival was typically limited to 2-3 months. Hence EFS and survival were largely synonymous. However today, the ability to keep people alive once these events have occurred has improved. Probably this is main- ly due to improved supportive care, particularly better anti-fungal agents, but also reflects better “salvage” thera- pies. For example, the NCRI/MRC group in the UK report- ed that AML patients with intermediate-risk cytogenetics who did not receive HCT in first complete remission (CR1), nonetheless had similar survival as patients receiv- ing HCT in CR1.8 This was a result of the ability to achieve, and then perform HCT in CR2 in the patients in whom relapse occurred after failure to perform HCT in CR1. The severance of EFS time from survival time has important implications. Once an event (no CR or relapse) occurs in a patient randomized to one arm of a phase III trial, there is no assurance that the salvage therapy or sup- portive care received will be identical to that received by a patient who has an event in the other arm of the trial. Hence what began as a randomized trial degenerates into an observational study, with all the attendant biases. Thus EFS, the primary end point in the ALFA-0701 trial, may be more reliable than survival as an indicator of the efficacy of an intervention such as GO.9
While there was an improvement in survival in the GO arm of ALFA-0701 and in the individual patient meta- analysis performed by Hills et al.,10 that included ALFA- 0701, these improvements were not “statistically signifi- cant”, unlike those in EFS, using P<0.05 as the criterion for
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