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Fractionated doses of gemtuzumab ozogamicin in AML
Table 3. Summary of all-causality adverse events of special interest by maximum CTCAE grade (as-treated population*).
Retrospective data, n (%)
Infections: severe (grade ≥3) Hemorrhage: all grades (grade ≥1), total†
Grade 3 Grade 4 Grade 5
GO (n=131)
102 (77.9)
118 (90.1)
23 (17.6)
4 (3.1)
3 (2.3)
6 (4.6)
2 (1.5)
1 (0.8)
2 (1.5)
Control (n=137)
106 (77.4)
107 (78.1)
12 (8.8)
0
1 (0.7)
2 (1.5)
1 (0.7)
1 (0.7)
0
Total (n=268)
208 (77.6)
225 (84.0)
35 (13.1)
4 (1.5)
4 (1.5)
8 (3.0)
3 (1.1)
2 (0.7)
2 (0.7)
VOD: all grades (grade ≥1), total† Grade 3
Grade 4
Grade 5
Control: 3+7 daunorubicin + cytarabine (D+A); CTCAE: Common Terminology Criteria for Adverse Events; GO: gemtuzumab ozogamicin plus D+A; MedDRA: Medical Dictionary for Regulatory Activities; NCI: National Cancer Institute;VOD: veno-occlusive disease; n: number. *Defined as all patients who received at least 1 dose of study medication and reported according to whether or not GO was received. †Adverse events were graded in accordance with the NCI CTCAE v.3.0 and coded by MedDRA v.18.0.
Table 4. Summary of deaths (as-treated population*). Deaths, n (%)
Deaths within 30 days of initiating study treatment
Deaths during safety reporting period† Mechanism(s) of death‡
Disease progression or relapse Septic shock
Infection
Liver toxicity
Hemorrhage
Other
GO (n=131)
5 (3.8)
6 (4.6)
2 (1.5) 2 (1.5) 0
1 (0.8) 3 (2.3) 2 (1.5)
Control (n=137)
3 (2.2)
5 (3.6)
2 (1.5) 2 (1.5) 1 (0.7) 0
1 (0.7)
3 (2.2)
Control: daunorubicin + cytarabine (D+A); GO: gemtuzumab ozogamicin plus D+A; n: number. *Defined as all patients who received at least 1 dose of study medication and reported according to whether or not GO was received. †≤28 days after last dose of any study drug treatment. [GO: daunorubicin, cytarabine and idarubicin (a component of salvage therapy. )] ‡More than 1 mechanism of death could be selected.
and Online Supplementary Table S4); the 2 patients in the control arm received GO during the follow-up phase of the study, as part of the compassionate use program after having relapsed before developing VOD.
All-causality SAEs were reported for 164 (61.2%) patients, including 88 (67.2%) in the GO arm and 76 (55.5%) in the control arm (Online Supplementary Table S5). Among the most commonly reported SAEs were those related to infection: 54 (41.2%) patients in the GO arm and 52 (38.0%) in the control arm (data not shown).
The median number of intensive care unit hospitaliza- tions was similar between the GO and control arms, affecting 25 patients in each arm; median time spent in the intensive care unit was 0.70 (range, 0.3-6.0) weeks and 0.60 (range, 0.1-7.6) weeks, respectively.
A total of 11 (4.1%) patients died during the period in which safety was reported; this included the time from the first dose to 28 days after the last dose of study treat- ment. The number of patient deaths was similar between treatment arms [GO arm, 6 (4.6%); control arm, 5 (3.6%)] (Table 4). The mechanisms of death were mostly similar between the 2 treatment arms, with the largest difference noted for patients for whom the mechanism of death involved hemorrhage [GO arm, 3 (2.3%); control arm, 1 (0.7%)].
Permanent discontinuation of GO and/or chemotherapy due to treatment-emergent AEs occurred in 41 (31.3%)
patients in the GO arm and 10 (7.3%) in the control arm (Online Supplementary Table S6). The most common rea- sons for study drug discontinuation among the 131 patients in the GO arm were thrombocytopenia in 20 (15.3%) patients and hepatobiliary disorders in 8 (6.1%) patients; among the 137 patients in the control arm, no (0%) and 1 (0.7%) patient, respectively, discontinued for the same reasons. Of note, the protocol was amended to withhold GO to patients during consolidation for persist- ing thrombocytopenia below 100x109/L not recovered ≥14 days after the scheduled date of consolidation therapy. Further investigations of the 20 patients in the GO arm who discontinued study drug because of persistent throm- bocytopenia showed that no patients had SAE of hemor- rhage reported.
While the majority of patients experienced severe myelosuppression, with similar rates in both treatment arms (Online Supplementary Table S7), the median time to recovery of platelets was longer for patients in the GO arm than in the control arm for each treatment course (Table 5). Additional analyses conducted to identify severe (grade 3 and 4) persistent thrombocytopenia (i.e. platelet count <50x109/L at 45 days after day 1 of the previous treatment phase in which a patient experienced CRp) showed that more patients had severe persistent throm- bocytopenia in the GO arm (20.4%) than in the control arm (2.0%).
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