Background: Ponatinib is effective in adults with Philadelphia positive (Ph+) leukemias but only few case reports are available regarding the use of this so far not-licensed drug in children and adolescents. Aims: To describe the profile of tolerance and efficacy of compassionate use of ponatinib in children and adolescents with Ph+ leukemias. Methods: Data from 11 children with chronic myeloid leukemia (CML) registered to the I-CML-Ped-Study and from 3 children with Ph+ acute lymphoblastic leukemia (Ph+ ALL) treated with ponatinib were retrospectively collected. Results: In 11 girls and 3 boys (median age 14 years, range: 4.5-17) ponatinib was used as a second (n = 2), third (n = 5), fourth (n = 2), fifth (n = 3), sixth (n = 1) or eighth (n = 1) treatment line. Ponatinib was administered as single therapy in 7 patients while the 7 remaining patients (advanced phases CML n = 5, Ph+ ALL n = 2) received additional chemotherapy. The status of the disease when ponatinib was started was: CML advanced phases (accelerated phase, n = 2; blast crisis, n = 6), CML without achievement of major molecular response (MMR, n = 2), T315I mutation (n = 1) and in Ph+ ALL patients molecular relapse (n = 2) or marrow relapse (n = 1). Six patients were previously transplanted. Ponatinib was used as a bridge to transplant in 5 cases. Dose administered ranged between 15-41 mg/m 2 (median: 27 mg/m 2 ) and median duration of ponatinib treatment was 2.5 months (range: 0.5-14 months). Treatment responses in the 8 patients in CML-advanced phases were: no response (n = 2), complete hematologic response (n = 1), MMR (n = 3), MR4.5 (n = 1) or unknown (n = 1). In patients in CML chronic phase, achievement of MMR was obtained in 2 of the patients without prior achievement of MMR while no response was observed in the patient with mutation T315I. Two of the 3 patients with Ph+ ALL achieved MR4.5 and MR5 while the remaining patient did not respond. Grade 1 to 4 side effects were recorded in 5 of 7 patients treated with ponatinib alone; toxicity grade 3-4 was reported in 2 patients (hematologic toxicity). No vascular event related to ponatinib was observed. Summary/Conclusion: With the limitation of the retrospective nature of this study, ponatinib may be a reasonable additional treatment option for children with Ph+ leukemias who failed to several lines of therapy.
Introduction Treatment-free remission (TFR) is increasingly considered as treatment goal for patients with chronic myeloid leukemia (CML), but information on the disposition and outcome of TFR in clinical practice is scarce. Here we report the characteristics of patients with CML in deep molecular remission (DMR) and/or after an attempt of TFR reported by 33 German hematologists. Methods Data were collected retrospectively by means of a questionnaire. Patients were eligible if they had either discontinued tyrosine kinase inhibitor (TKI) therapy or had achieved DMR of at least MR4 (BCR-ABL ≤0.01%) prior to the time-point of data collection. Results 797 patients were included in the analysis, out of which 281 patients had been discontinued from TKI treatment. TKI discontinuation rates among practices were variable, ranging from 0-36 patients. Mean time from TKI initiation to discontinuation was 7.2 years, mean duration of MR4 before TFR was 3.5 years. At the time of entering TFR, most patients (90.8%) had achieved a deep molecular response (≥MR4). BCR-ABL monitoring during TFR was performed heterogeneously: Within the first six months of TFR, 58.6% of the practices reported mean monitoring intervals of <6 weeks, while 20.7% employed intervals >8 weeks. After entering TFR, 53.2% of patients remained in MR4 or better. TKI treatment was re-initiated in 108 patients, mainly for loss of major molecular remission. Conclusions These clinical data from a German real-life population show that TKI discontinuation is feasible in clinical practice. Outcomes appear to be comparable to those reported in clinical trials, but molecular monitoring in TFR is rather variable.
Background:In 2009 we started a registry to evaluate the course of MDS in routine care in Germany.Aims:The aim of the current evaluation was to analyze factors associated with the need for red blood cell transfusions in patients (pts) with IPSS low and intermediate‐1 (int‐1) risk at diagnosis and in the course of the disease.Methods:2,447 patients (pts) with MDS were included in the regular care MDS‐registry from July 2009 till December 2016, provided that the diagnosis was confirmed by bone marrow biopsy and the pts had given their written informed consent. Baseline parameters at diagnosis and the clinical course were quarterly documented in an online database (IoStudy by Iomedico) by 90 centers all over Germany.imageResults:At the data‐cut in April 2017 1,240 of 2,428 evaluable pts (50.7%) had a low‐ (612 pts/49,4%) or an int‐1 ‐risk MDS (628 pts. /50.6%). The median age of the lower risk pts was 74 years (range 26–94), 484 (39%) were women and the median time of observation was 25 months (mo, range 0–97, mean 30,62mo). At diagnosis 114 (18.6%) low‐ and 169 (26.9%) int‐1‐ risk pts were transfusion‐dependent (TD). The median time to become TD was significantly different (log rank (Mantel‐Cox) p = <0.01) between low‐ (28mo, SD 4.030, 95% CI 20.1 – 35.9) and int‐1‐ risk pts (9mo, SD 1.380, 95% CI 6.295 – 11.705). Survival (OS) was estimated by Kaplan‐Meier curves for pts without TD mean 82,661mo (SD 1,813mo, 95%>CI 79,108 ‐ 86,214) and pts with TD mean 51,261mo (SD 1,453mo, 95%>CI 48,413 ‐ 54,109)(fig. 1A). Furthermore, OS after becoming TD was estimated by a time‐to‐TD stratified Kaplan‐Meyer curve (fig. 1B), that shows a significant difference (0.00 Log Rank, Mantel‐Cox). In an univariate analysis the following baseline parameters were significantly associated with a shorter duration to become TD: age ≥80years, hemoglobin (hb), count of reticulocytes, LDH, endogenous erythropoietin level (epo), ferritin, and fibrosis in bone marrow histology. The following parameters were not associated: sex, thrombocyte‐, leucocyte‐ and granulocyte‐count, folic‐acid‐, vitamin B12 level, and CRP. Del‐5q and trisomy 8 were the only cytogenetic abnormalities significantly associated with a shorter duration to become TD. In a cox regression analysis (table 1) hb and epo were significant only.imageSummary/Conclusion:The sooner pts becomes TD in the course of MDS, the poorer is the prognosis. It should be tested if a therapy that respites TD can prolong OS.Supported by an unrestricted grand from Celgene, Munich, Germany
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