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Fractionated doses of gemtuzumab ozogamicin in AML
Table 5. Time to recovery of platelets and persistent thrombocytopenia (as-treated population*). GO
Control
2/101 (2.0) Consolidation
Patient with persistent thrombocytopenia† Overall, n‡/N (%)§ǁ
By treatment phase
Time to platelet recovery to 50x109/L Patients recovered n‡/N (%)¶
Median recovery time,#d
Time to platelet recovery to 100x109/L Patients recovered, n‡/N (%)¶
Median recovery time,#d
Induction
Course 8/108 (7.4)
109/131 (83.2) 34.0
99/131 (75.6)
35.0
22/108 (20.4) Consolidation
Induction
Course 1/101 (1.0)
118/137 (86.1) 29.0
111/137 (81.0)
30.0
Course 1 8/94 (8.5)
92/97 (94.8) 32.0
71/97 (73.2)
35.0
Course 2 10/76 (13.2)
80/82 (97.6) 36.5
70/82 (85.4)
43.0
Course 1 0/94 (0)
86/97 (88.7) 27.0
80/97 (82.5)
28.0
Course 2 2/85 (2.4)
85/89 (95.5) 30.0
82/89 (92.1)
32.0
Control: daunorubicin + cytarabine (D+A); CRp: complete remission with incomplete platelet recovery; GO: gemtuzumab ozogamicin plus D+A. *Defined as all patients who received at least 1 dose of study medication and reported according to whether or not GO was received.†Persistent thrombocytopenia was defined as platelet count not recov- ered to 50x109/L at 45 days after day 1 of the respective treatment phase in patients experiencing CRp. ‡n: number of patients with events. §Overall number of patients with per- sistent thrombocytopenia after any phase. ǁN: number of patients evaluable for thrombocytopenia was used as the denominator for calculating the percentage of patients with persistent thrombocytopenia. Patients evaluable for thrombocytopenia were those who received each of the courses and had platelet laboratory results collected during the retrospective data collection. N: number of patients who received each of the courses of treatment. #Based on Kaplan-Meier estimate.
ity rate between the 2 arms. The rationale for fractionated GOdosedat3mg/m2ondays1,4,and7,asusedin ALFA-0701, is further supported by results of the IPD-MA, which showed less early mortality with the 3 mg/m2 dose compared to 6 mg/m2.8 Furthermore, study NCRI AML17, in which a single dose of 6 mg/m2 of GO was used in combination with induction chemotherapy, provided no advantage in response, disease-free survival, or OS com- pared with a 3-mg/m2 dose; however, in this study, the 30- and 60-day mortality was significantly higher in the patients receiving 6 mg/m2.8,10
Regarding AEs of special interest for GO, in the GO arm, there was no increase in either the incidence of severe infection or the percentage of patients who died of infection. Hemorrhage, VOD, and the number of patients who discontinued the study drug(s) because of AEs were increased with GO. The most frequent AE that led to per- manent discontinuation of study drug in the GO arm (in 20 patients) was persistent thrombocytopenia, influenced in part by a protocol amendment recommending discon- tinuation of GO in case of persistent thrombocytopenia. Thus, physicians should be aware of thrombocytopenia
associated with GO and provide supportive care as required. Similarly, physicians must be aware of the risk of VOD with GO, particularly the increased risk of VOD, either preceding or following HSCT, and closely monitor for clinical signs such as hepatomegaly, rapid weight gain, and ascites, elevations in alanine aminotransferase, aspar- tate aminotransferase, total bilirubin, and alkaline phos- phatase.
In conclusion, the final results of this study indicate that GO added to standard chemotherapy significantly pro- longs EFS in patients with newly diagnosed de novo AML and has an acceptable safety profile. This combination may expand front-line treatment options for this difficult- to-treat patient population.
Funding
The authors would like to thank the Acute Leukemia French Association, which sponsored this study in collaboration with the Centre Hospitalier de Versailles (CHV); Pfizer acquired the study data and usage rights from CHV in March 2013. Editorial support was provided by Susan Reinwald, PhD, of Complete Healthcare Communications, LLC, and was sponsored by Pfizer.
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