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Outcome of APL patients after ATO-based treatment
related to differentiation syndrome were reported in seven patients. As prophylaxis for the differentiation syndrome prednisone at a dose of 0.5 mg/kg of body weight per day was administered from day 1 until the end of induction therapy.2 Toxicities are listed in Table 2. Due to the adverse event, ATRA was withdrawn in five patients, and restarted in four, requiring a dose reduction to 50% in one of the patients. ATO was withdrawn in two patients, and restart- ed in one; additionally, three patients had dose reductions. Most of the patients recovered from the serious adverse events (n=52), although eight patients died. Of the eight fatal serious adverse events, two occurred during induction within 18 days (acute respiratory failure with bilateral pneumonia, n=1; and ischemic cardiomyopathy, n=1) and six occurred in complete remission (infection/sepsis, n=2, bleeding/hemorrhage, n=1; pulmonary edema due to tachycardic atrial fibrillation n=1; progress of an underlying intraabdominal liposarcoma n=1, and hepato-renal syn- drome n=1).
Discussion
This is the largest real-life data analysis of first-line ATO/ATRA treatment in a prospective registry in low- /intermediate-risk APL patients. It confirms a very high response rate as well as excellent overall survival with this new standard of care.2,3 Our data confirm that results can be replicated in a clinical registry, even within the context of non-selected patients and less closely monitored therapy than in the pivotal study. Indeed, on the basis of our registry data, the outcome of patients was identical to that reported after treatment with ATO/ATRA within the APL0406 trial.2,3 In contrast, the outcome of APL patients from previ- ously published registries or population-based studies was inferior to that reported in clinical trials, mainly because of higher early death rates.5-8 However, these registries and population-based studies included results before treatment with ATO/ATRA had been approved by regulatory author- ities.5-8
In our cohort the rate of induction death was extremely low, which might be in part attributable to improved sup- portive care and awareness of APL as a medical emer- gency,18 but also to early treatment with ATO/ATRA itself. Thus, effective strategies due to standardized guidelines along with consultative support and sharing of expertise seem to be well-taken and overcome induction mortality.19 Only two patients died during induction, in one case due to ischemic cardiomyopathy and in the other acute respiratory failure as a result of bilateral pneumonia. More impressive- ly, none of the patients experienced induction death due to bleeding/hemorrhage or infections, which is in sharp con- trast to previously published data on AIDA-based treat- ment.20,21 Nevertheless, we cannot rule out a potential selec- tion bias since patients may also die before diagnosis. High- risk APL (WBC count >10x109/L) at diagnosis is a known risk-factor for a bleeding diathesis.22 The European random- ized intergroup study “APOLLO” is currently investigating idarubicin 12 mg/m2 on days 1 and 3 in addition to oral ATRA 45 mg/m2 twice daily on days 1-28 and ATO 0.15 mg/kg/day intravenously on days 5-28 followed by four cycles of ATO/ATRA consolidation therapy as compared to the standard chemotherapy/ATRA approach (ClinicalTrails.gov identifier: NCT02688140).
The induction death rate in our analysis even compares
favorably with the recently published data from the Swedish Acute Leukemia Registry, which recorded an early death rate of 15% in newly diagnosed, low-/intermediate- risk APL (n=65) for the observation period 2009-2013.8 Thus, early treatment with ATO/ATRA seems to tackle the threat of induction death, again confirming recently pub-
Table 1. Characteristics of the 154 patients with acute promyelocytic leukemia at diagnosis.
Gender: female
N=154 %
75 49
Type of APL
Denovo 140 91 Therapy-related 14 9
ECOG performance status
0 42 27 1 84 55 296 332 432
Missing
Bleeding/hemorrhage Overall
Skin
CNS bleeding Pulmonary Missing
Thrombosis Missing
BCR1/2 BCR3 Missing
Cytogenetics Normal
Sole abnormality Additional abnormalities
- Complex*
- Trisomy 8 Missing
FLT3-ITD positive Missing
FAB subtype M3
M3v Missing
Median ITD allelic ratio
Median age, years N. >70 years
Median WBC, x 109/L Median platelets x 109/L
13 8
59 38 32 21 3 2 1 1 1 1
5 3 5 3
54 35 50 32 50 32
7 5 82 53 43 28
16/43 37 7/43 16 22 14
8/51 16 103 67
138 90 7 5 9 6
Value Range
0.113 0.01-63
53 18-90 20 13%
1.2 0.2-10 41 2-210 10 3.5-14.8
Median hemoglobin, g/dL
Missing 1
Median BM blasts,** %
Missing 23
65 0-95
Median creatinine, mg/dL
Missing 8
0.49-8.14
0.88
APL; acute promyelocytic leukemia; ECOG: Eastern Cooperative Oncology Group; CNS: central nervous system; BCR, breakpoint cluster region; ITD: internal tandem duplication; FAB: French American British; WBC: white blood cell counts; BM: bone marrow. Percentages may not add to 100 because of rounding. *Two or more cyto- genetic abnormalities in addition to t(15;17); **Blast cells included malignant promyelocytes. Percentages may not sum up to 100 due to rounding.
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