Abstract: 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.

Abstract: Introduction: Cytoreductive therapy such as hydroxyurea and interferon is recommended for high-risk polycythemia vera (PV) patients (pts) and is often used as first-line (1L) therapy. Yet, nearly a quarter of pts discontinue 1L therapy due to resistance or intolerance, requiring second-line (2L) therapy. While ruxolitinib (RUX) is an FDA- and EMA-approved agent for treating resistant or intolerant PV, many pts continue 1L therapy in real-world clinical practice. With a primary objective to assess the event-free survival (EFS) of RUX as 2L therapy in high-risk PV pts ("switchers") relative to pts who stay on 1L therapy ("non-switchers") after suboptimal response, we initiated a multinational, retrospective chart review study with a recruitment target of 350 pts across 25 clinical sites in 9 countries. This study is the first of its kind; the current analysis describes the characteristics of an interim sample of RUX switchers and non-switchers following suboptimal response to 1L therapy. Methods: The analysis included an interim sample of eligible pts with data extracted from medical charts from Feb 2020-Jun 2021. Pt eligibility included those ≥18 years old with JAK2 positive PV diagnosed in 2012 or later and a high-risk constellation, suboptimal response to 1L therapy (criteria in Table 1) after ≥12 months of treatment, and ≥6 months of follow-up after suboptimal response except in the event of death. Pts were excluded if they initiated PV treatment other than RUX after suboptimal response. Pts were classified into switchers vs non-switchers based on whether they switched to RUX following first suboptimal response (i.e., index date). Descriptive statistics were used to summarize criteria for suboptimal response, pt characteristics and comorbidities at any time prior to the index date, and PV-related symptoms 12 months prior to the index date (i.e., baseline period). Analyses were conducted separately for switchers and non-switchers. Results: In the interim sample of 137 pts, 44 (32.1%) were classified as switchers and 93 (67.9%) as non-switchers. Switchers tended to be younger at PV diagnosis than non-switchers (mean [SD]: 66.5 [12.0] vs 70.2 [8.5] years) and were more likely to be male (52.3% vs 47.3%). Median (interquartile range) time from PV diagnosis to index date was shorter for switchers than non-switchers (13.6 [12.3-22.3] vs 20.6 [14.7-37.0] months). Distribution of suboptimal response criteria differed for the two groups: "persistence of PV-related symptoms or presence of new PV-related symptoms" was the most common criterion for switchers, reported in 47.7% of pts vs 15.1% of non-switchers, while "the need for ≥3 phlebotomies to maintain hematocrit & lt;45% within 1 year" was most common in non-switchers, reported in 45.2% of pts vs 22.7% of switchers (Table 1). More switchers (54.4%) than non-switchers (31.2%) had a history of thrombosis at time of PV diagnosis. Commonly reported comorbidities included hypertension (43.2% switchers vs 66.7% non-switchers), cardiac conditions (18.2% vs 29.0%), hypercholesterolemia (9.1% vs 25.8%), and diabetes (2.3% vs 16.1%) and tended to be less prevalent in switchers than non-switchers. The most observed PV-related symptoms in the baseline period for both groups were fatigue (18.2% switchers vs 16.1% non-switchers) and pruritus (15.9% vs 14.0%). Fewer switchers (36.4%) than non-switchers (60.2%) received phlebotomies in the baseline period while the mean (SD) number of procedures was similar (3.8 [2.3] vs 3.9 [2.8] ). Spleen size assessment by palpation was available in 13 switchers (29.5%) and 38 non-switchers (40.9%) on index date, with switchers tending to have a lower proportion of normal size (18.2% vs 37.6%) and a higher proportion of mild or moderate splenomegaly (11.4% vs 3.3%). Conclusions: This analysis shows the trending existence of clinical differences between switchers and non-switchers, with a milder comorbidity profile in switchers. Moreover, while switchers experienced similar PV-related symptoms relative to non-switchers at baseline, switchers were more likely to experience persistence of PV-related symptoms or presence of new symptoms as their suboptimal response type. Taken together, these two factors may have influenced clinicians' decisions to switch to RUX or continue 1L therapy. Upon completion, this novel study will examine the potential impact of switching vs non-switching on EFS in this population. Figure 1 Figure 1. Disclosures Koschmieder: Alexion: Other: Travel support; Geron: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support), Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); AOP Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support), Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support), Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Shire: Honoraria, Other; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Karthos: Other: Travel support; Abbvie: Other: Travel support; Baxalta: Membership on an entity's Board of Directors or advisory committees, Other; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; CTI: Membership on an entity's Board of Directors or advisory committees, Other; Image Biosciences: Other: Travel support. Schulte: Novartis: Consultancy. von der Heyde: BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ipsen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees. Busque: Novartis: Consultancy. Boyer-Perrard: Novartis: Consultancy. Devos: Alexion, AstraZeneca Rare Disease Inc.: Consultancy; Novartis: Consultancy; AbbVie: Consultancy; Incyte: Consultancy; Bristol Myers Squibb - Celegene: Consultancy. Passamonti: Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zuurman: Novartis: Current Employment. Paley: Novartis: Ended employment in the past 24 months. Gilotti: Novartis: Current Employment. Cheng: Novartis: Other: I am an employee of Analysis Group, a consulting company that received funding from Novartis for this research study.. Gao: Novartis: Other: I am an employee of Analysis Group, a consulting company that received funding from Novartis for this research study.. Cheng: Novartis: Other: I am an employee of Analysis Group, a consulting company that received funding from Novartis for this research study.. Wu: Novartis: Other: I am an employee of Analysis Group, a consulting company that received funding from Novartis for this research study. Duh: Novartis: Other: I am an employee of Analysis Group, a consulting company that received funding from Novartis for this research study.. Harrison: Incyte Corporation: Speakers Bureau; Geron: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Promedior: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Constellation Pharmaceuticals: Research Funding; Sierra Oncology: Honoraria; Janssen: 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; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Galacteo: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AOP Orphan Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Abstract: Background: Midostaurin, a multikinase inhibitor that directly inhibits FLT3, is approved for the treatment of adult patients (pts) with newly diagnosed, FLT3-mutated AML. In the phase 3 RATIFY study (NCT00651261), younger adults (aged ≤ 60 y) who received midostaurin plus standard chemotherapy (CT) had significant improvements in survival compared with those that received placebo plus standard CT. To further evaluate the safety and efficacy of midostaurin in FLT3-mutated AML, a phase 3b (NCT03379727) study was initiated that allowed enrollment of younger and older (aged & gt; 60 y) pts and variations in CT regimens, including idarubicin or daunorubicin for 7+3 or 5+2. Methods: This is an open-label, single-arm, multicenter study in adults fit for CT with newly diagnosed AML, ECOG performance status (PS) ≤ 2, and a documented FLT3 ITD or TKD mutation. Pts must start their first induction cycle with 7+3 (cytarabine [Ara-C] 100-200 mg/m2/d on days 1-7 + daunorubicin 60-90 mg/m2/d or idarubicin 12 mg/m2/d on days 1-3) or 5+2 (a reduced-dose regimen with these agents) per investigator's discretion and e nroll by day 7 of the first induction cycle. Pts are assigned to the 7+3 group if their Ara-C duration is ≥ 7 days, independent of daunorubicin/idarubicin duration, and to the 5+2 group in other cases. Pts may not switch once started on 7+3 or 5+2. Pts receive Ara-C consolidation (dose per investigator's choice). Midostaurin 50 mg bid is administered on days 8-28 of each 28-day induction/consolidation cycle and daily for ≤ 12 cycles of maintenance. Pts are discontinued from the study if not in either complete remission (CR) or CR with incomplete hematologic recovery (CRi) at the end of induction, relapse during consolidation/maintenance, receive a stem cell transplant (SCT), or experience toxicities leading to discontinuation. The primary and secondary endpoints are safety and the proportion of pts achieving CR/CRi, respectively. Results: Pts were recruited throughout Europe; study enrollment was closed January 28th, 2020, with 318 pts screened and 17 screen failures. Safety and efficacy analyses focused on 301 pts who received treatment and 300 pts who met all study criteria, respectively. The median age (range) was 59 (19-85) y, and 47.2% were aged & gt; 60 y. Most pts had a FLT3-ITD mutation (82.7%), with 17.6% having a FLT3-TKD mutation. At data cut-off on March 31st, 2020, 63 pts were still receiving treatment. All 301 pts entered induction, 69% entered consolidation, and 26% entered maintenance; 28.7% underwent SCT. The majority of pts (80.4%) were treated with midostaurin plus 7+3; 19.6% received 5+2. Approximately 55.1% received idarubicin and 44.9% received daunorubicin for induction. Pts who received daunorubicin for induction were younger (62.2% vs 45.2% were aged & lt; 60 y) and had a lower frequency of ECOG PS=2 (10.4% vs 18.1%) vs those who received idarubicin. Overall, 242 pts achieved CR/CRi (80.7%). The CR/CRi rates in older vs younger pts, female vs male pts, and pts who received daunorubicin vs idarubicin for induction were similar (Table). The majority of SAEs occurred during induction (75, 24.9%) and consolidation (64, 30.6%); there were 5 (6.3%) SAEs during maintenance. The most common AEs were pyrexia, nausea, diarrhea, and febrile neutropenia. Compared with younger pts, older pts had a higher frequency of grade ≥ 3 AEs (78.6% vs 90.8%) and SAEs (35.8% vs 51.4%), AEs leading to dose adjustment/interruption (30.2% vs 43%), and treatment-related AEs (73.6% vs 78.2%), SAEs (15.7% vs 23.9%), and those leading to discontinuation (6.9% vs 11.3%). Compared with younger pts, older pts had a higher frequency of certain grade ≥3 AEs, including severe infections (31.4% vs 45.1%), leukopenia (40.9% vs 49.3%), QT prolongation (3.1% vs 7.7%) , and pulmonary toxicity (3.8% vs 7.7%). There were 30 deaths (10%) reported during the study (7 younger pts, 23 older pts). Of pts who died, 19 were treated with idarubicin (all were older pts) and 11 were treated with daunorubicin for induction. Conclusions: Midostaurin plus CT resulted in high response rates regardless of pt age, sex, induction drug, or alternative CT regimen. The majority of pts received a 7+3 regimen regardless of age. The safety profile of midostaurin plus idarubicin or daunorubicin for induction was generally similar. The safety profile in older and younger pts was consistent with what has been previously reported, with no new safety signals identified. Disclosures Sierra: Jazz Pharmaceuticals: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead-Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Griškevičius:Novartis: Research Funding. Cluzeau:Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Menarini: Consultancy. Luppi:Gilead Sci: Consultancy, Speakers Bureau; Abbvie: Consultancy; Daiichi-Sankyo: Consultancy; MSD: Consultancy; Novartis: Consultancy, Speakers Bureau; Sanofi: Consultancy. Farkas:Abbvie: Honoraria; MSD: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Johnson & Johnson: Honoraria. Bengoudifa:Novartis: Current Employment. Gilotti:Novartis: Current Employment. Hodzic:Novartis: Current Employment. Rambaldi:Roche: Honoraria; MSD: Honoraria; Abbvie: Honoraria; Jazz: Honoraria; Astellas: Honoraria; Omeros: Honoraria; Novartis: Honoraria; Gilead: Honoraria; Bristol-Myers Squibb: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; Pfizer: Honoraria. Venditti:Novartis: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Jazz: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Pfizer: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company).

Abstract: BACKGROUND RUX, a JAK 1/2 inhibitor, is a second-line treatment for symptom management and control of trilineage expansion in patients (pts) with PV who are resistant or intolerant to hydroxyurea (HU). In the RESPONSE study, RUX showed a superior and durable response in controlling hematocrit (HCT) and improving splenomegaly in PV pts resistant or intolerant to HU. RESPONSE-2 (NCT02038036) is a multicenter, open-label, Phase 3 trial comparing RUX with best available therapy (BAT) in HU-resistant/intolerant PV pts without splenomegaly. The primary analysis at Week (Wk) 28 and follow-ups at Wks 80 and 156 proved superiority of RUX over BAT. Here we present the final study results of the 5-year follow-up (Wk 260). METHODS Pts were randomized (1:1) to RUX 10 mg twice daily or BAT; crossover from BAT to RUX was allowed from Wk 28. The final analysis at Wk 260 evaluated durability of HCT control, complete hematologic response (CHR), and safety. Durability of HCT control was defined as absence of phlebotomy eligibility from Wk 8 to Wk 260 with ≤1 phlebotomy eligibility post-randomization to Wk 8. CHR was defined as HCT control with a white blood cell count & lt;10×109/L, platelet count ≤400×109/L. Safety is reported as exposure-adjusted rates per 100 pt-years. Other evaluated endpoints were changes in pt-reported outcomes (PRO) and JAK2 V617F allele burden over time. RESULTS Pts were randomized to RUX (n=74) or BAT (n=75). A total of 59/74 RUX pts and 61/75 BAT pts completed the treatment duration. Among the 75 BAT pts, 58 pts crossed over to RUX, with 38 of them completing the study, allowing for long-term follow-up of 97 pts treated with RUX. Median (range) exposure was 260.0 (0.1 - 273.1) wks in RUX, 28.4 (6.7 - 83.0) wks in BAT, and 224.7 (2.7 - 236.1) wks in crossover arms. At Wk 260, 21.6% of RUX pts (16/74) achieved durable HCT control. The Kaplan-Meier (KM) -estimated median duration of HCT control was not reached (Fig. A). Durable CHR was achieved in 24.3% of RUX pts (18/74; estimated median duration, 34.0 wks). Crossover pts derived RUX benefit by achieving HCT control with HCT levels decreasing over time (median HCT was 46.2% at the crossover baseline and 38.9% at the end of treatment). JAK2 V617F allele burden reduced over time for pts treated with RUX from baseline with a median decrease of 14.8% in RUX (59 evaluable pts) and 13.5% in crossover arms (42 evaluable pts). RUX showed durable improvement in PV-associated symptoms; about 45% of RUX pts continued to achieve ≥50% reduction in MPN-SAF TSS at Wk 260. RUX pts also continued to experience improvements in all 5 dimensions of the EQ-5D-5L assessment. Total number of phlebotomies was 60 in the RUX arm (at Wk 260) vs 106 for BAT (Wk 80). At Wk 260, RUX- (vs BAT-) treated pts required & gt;0 − ≤2 phlebotomies in 16.2% (vs 38.7%), & gt;2 − ≤4 in 9.5% (vs 21.3%), & gt;4 − ≤6 in 5.4% vs (2.7%), and & gt;6 − ≤8 in none (vs 1.3%). The most common AEs ( & gt;5%, exposure-adjusted rate) were anemia, arthralgia, and increased weight in the RUX arm and anemia, and hypertension in pts after crossover. Of note, exposure-adjusted rates of herpes zoster were 3.9 in both RUX (Grade 3/4, 0.9) and crossover pts (no Grade 3/4) and none in the BAT arm. The exposure-adjusted rate of thromboembolic events was higher with BAT than RUX (3.7 vs 1.5). As expected given prior HU exposure, non-melanoma skin cancer was the most common secondary malignancy in RUX (exposure-adjusted rates: randomized, 2.7; crossover, 2.9) and BAT-treated pts (1.9). No RUX pts developed AML, whereas myelofibrosis was reported in 2 pts (exposure-adjusted rate, 0.6%). On-treatment death was reported in 5 pts: 1 each in the RUX arm (metastatic melanoma) and BAT arm (septic shock), and 3 in crossover (1 pt each - cardiac disorder, general health deterioration, and PV progression). The KM-estimated median overall survival was not reached in both RUX (95.8%; 95% CI: 87.4, 98.6) and BAT arms (90.7%; 95% CI: 80.3, 95.7; Fig. B) at ≥260 wks. Transformation-free survival (KM-estimated, 95% CI) in the RUX arm was 94.18% (85.23, 97.78) at ≥260 wks. CONCLUSIONS In line with the RESPONSE study outcomes, final analysis from the 5-yr follow-up of RESPONSE 2 proved superiority of RUX over BAT with a safety profile that remained consistent with previous reports. RUX provided durable HCT control with a decrease in the need for phlebotomies, CHR, improved PV-associated symptoms and PRO scores, with fewer thromboembolic events in PV pts without splenomegaly, who are HU resistant or intolerant. Disclosures Palandri: Novartis: Consultancy, Honoraria. Callum:Canadian Blood Services: Research Funding; Octapharma Canada: Research Funding. Devos:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Vannucchi:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint: Membership on an entity's Board of Directors or advisory committees; Incyte: 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. Zor:Novartis: Current Employment. Gilotti:Novartis: Current Employment. Zhang:Novartis: Current Employment. Griesshammer:Celgene: Honoraria, Speakers Bureau; AOP Orphan: Honoraria, Speakers Bureau; CTI: Honoraria, Speakers Bureau; Shire: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau.

Abstract: The pivotal RATIFY study demonstrated midostaurin (50 mg b.i.d.) with standard chemotherapy significantly reducing mortality in adult patients ( & lt;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 ( & gt;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% & gt;60 years, 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 hematological recovery (CR+CRi) (80.7% [95%CI: 75.74, 84.98]) was comparable between age groups (≤60 years [83.5%] ; & gt;60 to ≤70 years [82.5%]; little less in patients & gt;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, safety and efficacy of midostaurin remains consistent with previous findings, regardless of age, gender, or induction regimen. The trial is registered at clinicaltrials.gov: NCT03379727.

Abstract: 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.