Anemia is a frequent manifestation of myelofibrosis (MF) and there is an unmet need for effective treatments in anemic MF patients. The REALISE phase 2 study (NCT02966353) evaluated the efficacy and ...safety of a novel ruxolitinib dosing strategy with a reduced starting dose with delayed up-titration in anemic MF patients. Fifty-one patients with primary MF (66.7%), post-essential thrombocythemia MF (21.6%), or post-polycythemia vera MF (11.8%) with palpable splenomegaly and hemoglobin <10 g/dl were included. Median age was 67 (45-88) years, 41.2% were female, and 18% were transfusion-dependent. Patients received 10 mg ruxolitinib b.i.d. for the first 12 weeks, then up-titrations of up to 25 mg b.i.d. were permitted, based on efficacy and platelet counts. Overall, 70% of patients achieved a ≥50% reduction in palpable spleen length at any time during the study. The most frequent adverse events leading to dose interruption/adjustment were thrombocytopenia (17.6%) and anemia (11.8%). Patients who had a dose increase had greater spleen size and higher white blood cell counts at baseline. Median hemoglobin levels remained stable and transfusion requirements did not increase compared with baseline. These results reinforce the notion that it is unnecessary to delay or withhold ruxolitinib because of co-existent or treatment-emergent anemia.
Background
Children with red blood cell disorders may receive regular transfusions from an early age and consequently accumulate iron. Adequate iron chelation therapy can prevent organ damage and ...delayed growth/development. Deferasirox is indicated for treatment of pediatric patients with chronic iron overload due to transfusional hemosiderosis; however, fewer than 10% of patients in the registration studies were aged 2 to less than 6 years.
Procedure
Deferasirox, a once‐daily oral iron chelator, was evaluated in young pediatric patients with transfusional hemosiderosis during the observational 5‐year ENTRUST study. Patients aged 2 to less than 6 years at enrollment received deferasirox according to local prescribing information, with the primary objective of evaluating safety, specifically renal and hepatic function. Serum ferritin was observed as a surrogate efficacy parameter.
Results
In total, 267 patients (mean age 3.2 years) predominantly with β‐thalassemia (n = 176, 65.9%) were enrolled. Mean ± standard deviation deferasirox dose was 25.8 ± 6.5 mg/kg per day over a median of 59.9 months. A total of 145 patients (54.3%) completed 5 years’ treatment. The proportion of patients with two or more consecutive postbaseline measurements (≥7 days apart) of serum creatinine higher than age‐adjusted upper limit of normal (ULN) and alanine aminotransferase more than five times the ULN was 4.4% (95% confidence interval CI: 2.1–7.9) and 4.0% (95% CI: 1.8–7.4), respectively. Median serum ferritin decreased from 1,702 ng/ml at baseline to 1,127 ng/ml at 5 years. There were no new safety signals.
Conclusions
Safety and efficacy of deferasirox in young pediatric patients in this long‐term, observational study in everyday clinical practice were consistent with the known deferasirox profile.
Background: The Janus kinase (JAK) inhibitor ruxolitinib (RUX) is approved for the treatment of disease-related splenomegaly and symptoms in patients with myelofibrosis (MF). Treatment with RUX has ...been shown to significantly reduce splenomegaly and provide marked improvements in MF-related symptoms and quality-of-life. A number of mutations have been identified with known or likely functional significance in patients with MF (Vannucchi AM, et al. Leukemia. 2013), which may therefore have the potential to affect treatment response. This exploratory analysis aimed to investigate the mutational status of patients in the REALISE trial and to assess the relationship between baseline mutational status and outcome.
Methods: REALISE was a multicenter, open label, single arm phase 2 study (NCT02966353). Eligible patients (N=51) had primary MF, post-essential thrombocythemia (ET) MF or post-polycythemia vera (PV) MF, with palpable (≥5 cm) spleen and hemoglobin level <10 g/dL. Patients started RUX at 10 mg bid with up titrations to 15 or 20 mg bid allowed after 12 weeks based on efficacy and platelet counts. The primary endpoint was achievement of ≥50% reduction in spleen length at Week 24. Secondary endpoints included transfusion requirements/dependence over time, adverse events, and patient-reported outcomes (PRO) (7-point MF score MF-7, MF Symptom Assessment Form MFSAF version 2.0). Next generation sequencing (NGS) analysis using a 236 gene panel (Navigate BioPharma, Carlsbad, CA, USA) was performed on whole blood samples to identify genetic alterations.
Results: NGS analysis data were available for 49/51 patients, median age was 67 years, 67.3% (33/49) had primary MF, 10.2% (5/49) had post-PV MF and 22.4% (11/49) had post-ET MF. DIPSS was available for 45 patients, 16.3% (8/49) were intermediate (Int)-1, 57.1% (28/49) were Int-2 and 18.4% (9/49) were high risk. The most frequent baseline mutations are shown in Figure 1. Classic driver mutations were found in JAK2 (n=33), CALR (n=11) and MPL (n=7), and did not affect response to RUX treatment. Two patients (4.1%) were triple negative for JAK2/CALR/MPL mutations, both responded to RUX treatment. The most commonly found non-driver mutations in patients with ≥50% reduction in spleen length at Week 24 (n=28) were TET2, ASXL1, U2AF1 and SRSF2; in non-responders, the most common non-driver mutations were TP53, FAT1 and ASXL1. The median number of mutations per patient was 2 (range 1-7); 35.7% (10/28) of patients with a response had ≥3 non-driver mutations vs 14.3% (3/21) of non-responders. Overall, no difference was seen in mutational distribution by change in spleen length at Week 24. In general, similar findings were seen for transfusion dependence status at baseline and improvements in symptom score with treatment (Table 1). However, there was a higher incidence of U2AF1 mutation in patients who were transfusion-dependent at baseline vs. non-transfusion dependent patients (4/8 50% vs 3/41 7.3%, respectively). U2AF1 mutation is known to be associated with anemia and/or thrombocytopenia in myelodysplastic syndromes (Li B, et al. Genes Chromosomes Cancer. 2018). Mutations in TP53 were present in 6 patients. One patient showed a response to treatment at Week 24, and 5 were classified as non-responders. None of these 5 patients completed 24 weeks of treatment and 3 died during the study or safety follow-up period. Two progressed to acute myeloid leukemia prior to death. All patients were ≥60 years old, 4 were male and 4 were DIPSS Int-2 risk. Four patients had primary MF, 1 had post-ET MF and 1 had post-PV MF.
Conclusions: Though these data should be interpreted with caution due to the small patient numbers, patients in the REALISE study showed variation in the type and number of genetic alterations with known/likely functional significance in MF. Compared with published mutational data on MF patients treated with RUX (Spiegel, et al. Blood Advances. 2017; Pacilli et al. Blood Cancer Journal. 2018) 12.2% of patients had a TP53 mutation compared to 4% and 4.2% respectively. This molecular difference may reflect the anemic study population. Despite the higher TP53 mutational burden, and alternative dosing strategy, 57.1% (28/49) patients had a response to RUX at Week 24. Although there was no strong association between mutation patterns and response, patients with TP53 mutations tended to have a poor outcome overall.
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Al-Ali:Celgene: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; CTI: Honoraria. Gisslinger:Novartis Pharma GmbH: Consultancy, Honoraria, Research Funding; Roche Austria GmbH: Consultancy; Myelopro GmbH: Consultancy; Celgene GmbH: Honoraria; Pharma Essentia: Other: Personal fees; Janssen-Cilag: Honoraria; AOP Orphan Pharmaceuticals: Consultancy, Honoraria, Research Funding. Passamonti:Janssen: Honoraria, Other: Advisory board , Speakers Bureau; Novartis: Honoraria, Other: Advisory board , Speakers Bureau; Celgene: Honoraria, Other: Advisory board , Speakers Bureau. Foltz:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy; Amgen: Other: Spouse Employment; Incyte: Research Funding; Constellation Pharma: Research Funding. Ross:Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vannucchi:Incyte: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Komatsu:Pharma Essentia: Research Funding, Speakers Bureau; Novartis K.K: Speakers Bureau; Wako Pure Chemical Industries, Ltd.: Research Funding; Takeda Pharmaceutical Company Limited: Research Funding, Speakers Bureau; Fuso Pharmaceutical Industries, Ltd.: Research Funding. Tiwari:Novartis: Employment. Zor:Novartis: Employment. Chaturvedi:Novartis Pharmaceuticals: Employment. Gilotti:Novartis Pharmaceuticals: Employment. Cervantes:Novartis: Honoraria, Speakers Bureau; Celgene: Consultancy, Speakers Bureau.
•Midostaurin in combination with intensive chemotherapy was well-tolerated in fit adult patients with no upper age limit.•The combination showed high response rates irrespective of patient age, ...induction regimen, or the type of anthracycline used in induction.
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The pivotal RATIFY study demonstrated midostaurin (50 mg twice daily) with standard chemotherapy significantly reduced mortality in adult patients (<60 years) with newly diagnosed (ND) FLT3mut acute myeloid leukemia (AML). Considering that AML often present in older patients who show poor response to chemotherapy, this open-label, multicenter phase 3b trial was designed to further assess safety and efficacy of midostaurin plus chemotherapy in induction, consolidation, and maintenance monotherapy in young (≤60 years) and older (>60 years) patients with FLT3mut ND-AML. Compared with RATIFY, this study extended midostaurin treatment from 14 days to 21 days, substituted anthracyclines (idarubicin or daunorubicin), and introduced variation in standard combination chemotherapy dosing (“7+3” or “5+2” in more fragile patients). Total 301 patients (47.2% >60 years and 82.7% with FLT3-ITDmut) of median age 59 years entered induction phase. Overall, 295 patients (98.0%) had at least 1 adverse event (AE), including 254 patients (84.4%) with grade ≥3 AE. The grade ≥3 serious AEs occurred in 134 patients. No difference was seen in AE frequency between age groups, but grade ≥3AE frequency was higher in older patients. Overall, complete remission (CR) rate including incomplete hematologic recovery (CR + CRi) (80.7% 95% confidence interval, 75.74-84.98) was comparable between age groups (≤60 years 83.5%; >60 to ≤70 years 82.5%; in patients >70 years 64.1%) and the type of anthracycline used in induction. CR + CRi rate was lower in males (76.4%) than females (84.4%). Overall, the safety and efficacy of midostaurin remains consistent with previous findings, regardless of age, sex, or induction regimen. The trial is registered at www.clinicaltrials.gov as #NCT03379727.
Objective: The study evaluates the long-term deferasirox treatment of adult and pediatric patients with chronic transfusional iron overload in clinical practice.
Methods: In this non-interventional ...study, patients were observed for up to 3 years from initiation of deferasirox treatment both prospectively and retrospectively for up to 1 year prior to enrollment. The primary end points were the proportion of patients with ≥1 notable increase in serum creatinine (SCr), and ≥1 notable increase in alanine aminotransferase (ALT).
Results: Overall, 120 patients were enrolled and 51 completed the study, with a limited 3-year dropout rate of 12.5% due to adverse events (AEs). Increase in SCr > 33% above baseline and the age-adjusted ULN (upper limit of normal) was observed in 14 patients (95%CI, 7.1-19.2). The ALT levels >5 × ULN was observed in 1 patient. Most frequent AEs reported during treatment with deferasirox include gastrointestinal disturbances.
Conclusions: The long-term treatment with deferasirox was manageable in most transfusion-dependent patients with no unexpected safety findings. Regular monitoring and an adjusted deferasirox dosing strategy per local labels allowed continued iron chelation treatment and control of transfusional iron in the majority of patients on study.
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