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Gemtuzumab in pediatric acute myeloid leukemia
GO was 18±5% in the total cohort (Figure 2A). A compar- ison of disease status prior to treatment with GO between patient groups showed that patients who received GO after de novo AML refractory to first late relapse had a probability of 4-year OS of 48±16%; this is significantly higher than in patients with de novo AML refractory to first early relapse (probability of 4-year OS: 12±5%; P=0.03) and patients with de novo AML refractory to second or more relapses/secondary AML (probability of 4-year OS: 10±9%; P=0.02) (Figure 2B). Based on the current retro- spective analysis, factors such as number of cycles and administration of GO as monotherapy or in combination with cytarabine or other agents did not have any signifi- cant influence on survival (Online Supplementary Figure S3A-C).
In the total cohort of patients, 27 (36%) did not receive HSCT after treatment with GO (Table 2) and none of these patients survived (Figure 2C). Of note, most (10 of 15, 67%) patients with de novo AML refractory to second or more relapses/secondary AML, did not receive an HSCT after GO treatment; this is higher than in other groups of patients (Table 2).
From the total group of 76 patients, 49 (64%) received HSCT after GO treatment and their probability of 4-year OS was 27±7%. Thirty (61%) patients with HSCT received GO in combination with cytarabine (data not shown). HSCT after GO was the first HSCT for most of the patients (n=46, 94%), and mean time to transplantation after GO treatment was 41±30 days (range 11-135 days). The probability of 4- year OS in patients who received HSCT early during the first three weeks after GO treatment was 9±9% and patients who received HSCT between three and six weeks after GO administration had a 4-year OS of 40±11% (P=0.06) (Online Supplementary Figure S3D).
Previous treatment with or without FLA/G+DX before GO administration had no influence on the percentage of
HSCT achieved after treatment with GO (FLA/G+DX group: 29 of 43, 67%; no FLA/G+DX or FL/A group: 14 of 21, 67%) (data not shown). However, among transplanted patients, fewer patients with previous FLA/G+DX (7 of 29, 24%) survived compared to the patients without FLA/G+DX or FL/A (6 of 14, 42%) (data not shown). In addition, one patient with de novo AML-M3 refractory to first late relapse is alive after treatment with GO followed by additional chemotherapy and HSCT.
Among 49 patients with subsequent HSCT, 25 (51%) reached CR/CRi before HSCT (Table 2). Out of 19 patients with no response to GO before HSCT, 8 (42%) received additional chemotherapy before HSCT and 3 of them survived. The remaining 11 (58%) patients with no response, received HSCT with no further chemotherapy and 2 of these patients survived (data not shown).
Discussion
The major goal in the treatment of relapsed/refractory pediatric AML is to develop new therapeutic options to achieve complete remission and proceed to HSCT there- after.26 Considering the previous history of intensive chemotherapy and/or previous HSCT in these patients, novel treatment options should be efficient, but must also have acceptable toxicity profiles. However, the introduc- tion of new drugs is challenging. Due to increasing regula- tory challenges and requirements, as well as limited acces- sibility of drugs such as GO, it is more and more time con- suming to open phase III trials. Hence a follow-up trial, that has been planned since 2009 after the end of the phase II trial,18 was not opened until September 2016 and recruited the first patient in August 2017 (EudraCT n.: 2010-018980-41).
In the current analysis, we have evaluated the use of GO
Table 3. Non-hematologic adverse events in 71 patients after the first treatment cycle with gemtuzumab ozogamicin.
AE severity/ consequence
Gastrointestinal
Pain
Infection or fever
in neutropenia
VOD
Infusion-related immunological reactions Exacerbation of the previous conditions Constitutional symptoms Metabolic/laboratory Total, nf (%)
All gradesa Total AEs,
All outcomes n (%)
Grades 1/2 Grades 3 and 4
reversible reversible prolonged progressive fatal n.a.
reversible
AEs Patients AEs Patients AEs Patients AEs Patients AEs Patients AEs Patients
15(15) 11 11 4 4 0 0 0 0 0 0 0 0
00 0 0
00
4(4) 1 1 61(60) 0 0
3(3) 0 0
33 58 46
11
00 22
11
00 1b 1
00
00 00
1c 1
12(12) 7 7
44
00
00
00
2(2) 0 0
2(2) 2 2
00
00
00
00
00
00
00
00
2(2) 2 2
101 (100) 23 (23)
00
70 (69)
00
3 (3)
00
1 (1)
00
1 (1)
1d
2e
0 0
1
2
0 0
3 (3)
AE: adverse events; n: number; n.a.: not applicable; VOD: veno-occlusive disease. aGrading of toxicity and adverse events based on the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.03, revised June 14, 2010. bProgressive fever partly resulted from limiting its treatment due to joint decision to terminate the “active” therapy of the patient. cGO-related VOD led to exacerbation of a pre-existing cardiomyopathy causing death 24 days after the treatment with GO. dTreatment with GO resulted in occur- rence of cytokine syndrome in a patient with pre-existing respiratory distress due to aplasia-associated pneumonia.Following a decrease in level of consciousness,this patient died five days after occurrence of the cytokine syndrome.eTreatment with GO resulted in worsening of previously present pulmonary aspergillosis infection or in worsening of previously observed gastrointestinal toxicity. fAll adverse events in 71 patients were evaluated.
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