Page 82 - 2021_12-Haematologica-web

S. Kayser et al.
described.12,13 Data collection and analysis were approved by the local Institutional Review Boards.
Treatment
All patients were treated with ATO/ATRA as induction thera- py and with up to four consolidation cycles of ATO/ATRA.2 Eight patients additionally received 12 mg/m2 idarubicin (for up to 4 days) and two patients received 100 mg/m2 cytarabine for up to 2 days during induction with ATO/ATRA because of WBC counts rising above 10x109/L. One elderly patient (age, 72 years) was initially treated with decitabine (38 mg/day) for 5 days and was then switched to two cycles of ATO/ATRA after genetic analysis revealed t(15;17). Response was assessed according to Cheson et al.10
Statistical analyses
Survival endpoints including overall survival and cumulative incidence of death in complete remission were defined according to the revised recommendations of the International Working Group.10 Induction death was defined as death occurring at any time during induction therapy before the achievement of com- plete remission. Comparisons of patients’ characteristics were per- formed with the Kruskal-Wallis rank sum test for continuous vari- ables and Fisher exact test for categorical variables. The median follow-up time was computed using the reverse Kaplan-Meier estimate.14 The Kaplan-Meier method was used to estimate the distribution of overall survival.15 Confidence interval (CI) estimates for survival curves were based on the cumulative hazard function using the Greenwood formula for variance estimation. Log-rank tests were employed to compare survival curves between groups. The cumulative incidence of death in complete remission and the standard error were computed using the method described by Gray16 and included only patients attaining complete remission. All statistical analyses were performed with the statistical soft- ware environment R, version 3.3.1, using the R packages, and sur- vival, version 2.39-5.17
Results
In total, data on 154 low-/intermediate-risk APL patients, reported within the NAPOLEON registry between 2013 and 2019 within two large European study groups were included. The median age of these patients was 53 years (range, 18-90 years); 13% (n=20) were older than 70 years. APL was de novo in 91% (n=140) and therapy-related in 9% (n=14). Primary malignancies included solid cancers in 12 patients (breast cancer, n=5; female genital tract, n=2; prostate cancer, lung cancer, colon cancer, intraabdominal liposarcoma, and epidermoid cancer, n=1 each) and lym- phoma in two patients. All patients received chemotherapy and/or radiation as treatment for the prior malignancy/neo- plasm and were in remission at the time of APL diagnosis. The median latency period between diagnosis of the pri- mary malignancy/neoplasm and the occurrence of therapy- related APL was 2.80 years (range, 1.68-7.70 years).
Information on extramedullary disease was available for 131 patients and was present in two (1.5%) patients (skin manifestation, hepatosplenomegaly; n=1 each). Comorbidities were present in 48 (58%) of 83 patients and included arterial hypertension (n=25), pulmonary disease (n=12; mild, n=5, moderate/severe, n=7), gastro-intestinal disease (n=9), renal disease (n=8; mild, n=4, moderate/severe, n=4), diabetes (n=8), psychiatric distur- bance (n=8), cardiac/arrhythmias (n=6), rheumatologic dis-
order (n=5), hepatic disease (n=3, mild, n=1, moderate/severe, n=2), cerebrovascular disease (n=3), and immunosuppression due to human immune-deficiency virus infection (n=2).
In all patients APL was confirmed by cytogenetics and/or FISH/RT-PCR. Information on cytogenetics was available for 132 (86%) patients. In seven (5%) patients t(15;17) could only be detected by FISH and/or RT-PCR, while cytogenet- ics showed a normal karyotype. In 82 (66%) of the remain- ing 125 patients, the balanced t(15;17) translocation was the sole abnormality, whereas in 43 (34%) patients, the translo- cation was accompanied by additional cytogenetic abnor- malities, most frequently t(15;17) within a complex kary- otype, i.e., ≥2 cytogenetic abnormalities in addition to t(15;17) (n=16) or trisomy 8 (n=7).
Regarding FLT3-ITD mutational status, information was available for 51 (33%) of the 154 patients. Of those, eight (16%) patients were FLT3-ITD-positive. Information on the PML-RARA transcript isoform (breakpoint cluster region, BCR) was available for 104 (67%) patients and 50 had the short isoform (BCR3). The patients’ baseline characteristics are shown in Table 1.
Response to induction therapy
Overall, 152 patients (99%) achieved complete remission, whereas two patients (1%) experienced induction death within 18 days after starting therapy due to acute respirato- ry failure with bilateral pneumonia in one case and ischemic cardiomyopathy in the other. Both patients had de novo APL, Eastern Cooperative Oncology Group perform- ance status ≤2 and no signs of hemorrhage or thrombosis at initial presentation. They were 64 and 75 years old. Cytogenetics in both cases revealed t(15;17) as the sole abnormality; no concurrent FLT3-ITD was present.
None of the patients was refractory to treatment. In uni- variable analysis age above 70 years had no impact on response to induction therapy (P=0.24).
Survival analysis
The median follow-up for survival was 2 years (95% CI: 1.61-2.30 years). Overall, the estimated 1-year and 2-year overall survival rates were 97% (95% CI: 94-100%) and 95% (95% CI: 91-99%), respectively (Figure 1). The overall survival rate was significantly lower in elderly patients (>70 years) than in younger patients (P<0.001) (Figure 2).
None of the patients relapsed after ATO/ATRA treat- ment, thus overall survival and event-free survival were identical. Six (4%) patients died in remission at a median of 0.95 years after diagnosis (range, 0.18-2.38 years). Of these patients, three were below 70 years old. Causes of death were sepsis (n=2), bleeding/hemorrhage (n=1), pulmonary edema due to tachycardic atrial fibrillation (n=1), progress of an underlying intra-abdominal liposarcoma (n=1) as well as hepato-renal syndrome (n=1). The cumulative incidence of death in complete remission was significantly higher in older patients than in younger patients (P=0.001) (Figure 3). So far, none of the patients has developed a secondary neo- plasm after treatment with ATO/ATRA.
Toxicity
A total of 118 serious adverse events were reported in 60 patients, mainly infections (n=31), hepatobiliary events (n=21), neurotoxicity/neuropathy (n=9, including headache in 2 patients), and cardiac events (n=6, including QTc pro- longation in 2 patients). Serious adverse events classified as
3102
haematologica | 2021; 106(12)