2003 The prognosis of patients suffering from AML with manifestations of accompanying extramedullary leukemia (EML) including myeloid sarcoma (MS) compared to that of AML patients not exhibiting EML manifestations is still an open question as results from previous studies have been contradictory most likely due to selection bias. Here we present an analysis performed in a cohort of 2261 patients representing >90% of all AML patients diagnosed and treated in Denmark during the eleven-year period January 2000 through December 2010. The goal was to investigate the prognostic impact of presence of EML at time of AML diagnosis by a retrospective population- and registry-based analysis Of these patients, 219 (9.7%) showed signs of EML at time of AML presentation. Anatomic sites of EML were: lymph nodes (3.0%), skin (2.7%), spleen (1.7%), oral (1.3%), CNS (0.4%), testes (0.2%), other sites (1.1%), and two or more anatomical sites (0.5%). In 27 cases myeloid sarcoma was not accompanied by AML in the bone marrow and, thus, presented as isolated MS. In total, 1168 of the 2261 (52 %) patients were treated with curative intention. Allogeneic stem cell transplantation (Standard allo in 105 cases, and reduced intensity conditioning (RIC) transplant in 90 cases) was conducted in a total of 195 patients (118 in CR1, 65 in CR2, and 12 during other disease stages). Overall the frequencies of allogeneic transplantations in curatively treated patients were 13.7% in patients with EML and 8.5% in patients without EML. The presence of EML at time of leukemia diagnosis had no statistical significance to probability of obtaining complete remission (CR), nor to duration of overall survival (OS) (Table 1. and Fig. 1). By contrast, well-established prognostic parameters such as presenting cytogenetic abnormalities (categorized according to revised MRC-criteria, D. Grimwade et al. Blood, 2010), age, leukocyte count, and type of leukemia (secondary vs de novo) were all found to be statistically significant to probability of attainment of (CR) and to duration of OS in uni- as well as multivariate analyses. Gender was of borderline statistical significance with respect to probability of attainment of CR and to OS (Table 1).Figure 1Years from AML diagnosisPatients with EML(n = 132)Patients without EML(n = 1007)p-value (log-rank test) = 0.51Figure 1. Years from AML diagnosis. / Patients with EML. / (n = 132). / Patients without EML. / (n = 1007). / p-value (log-rank test) = 0.51Table 1.Factors of significance to probability of attainment of CR and to overall survival (OS)Probability of CR (Logistic regression, nevaluable = 927)Probability of overall survival (Cox regression, nevaluable = 958)VariableOdds ratio (OR)95% CI of ORP valueHazard ratio95% CI of HRP valueEML––0.82––0.54Age1.061.04–1.08<10−41.041.03–1.04<10−4Cytogenetics2.291.63–3.21<10−41.931.65–2.25<10−4Male gender1.481.03–2.070.03––0.06 WBC1.0051.002–1.007<10−41.0011.000–1.0020.02 Secondary2.151.47–3.14<10−41.391.15–1.680.001 Additionally, patients with EML at leukemia presentation who were subjected to an allogeneic stem cell transplantation had a prognosis no different from that of AML patients not exhibiting signs of EML (Fig.2). Analyses of progression free survival are ongoing and will be presented at the meeting.Figure 2Years from AML diagnosisPatients without EML(n = 165)Patients with EML(n = 30)p-value (log-rank test) = 0.75Figure 2. Years from AML diagnosis. / Patients without EML. / (n = 165). / Patients with EML. / (n = 30). / p-value (log-rank test) = 0.75 From this analysis we conclude that presence of EML does not predict for an inferior CR-rate or for shorter survival in AML. We find no clear justification for a more aggressive therapeutic approach or performance of allogeneic stem cell transplantation in AML patients with EML. Therapeutic decisions should be guided by other prognostic parameters, e.g., age and cytogenetic aberrations which are of far greater importance than the presence of EML. Disclosures: No relevant conflicts of interest to declare.
Background: Anemia is one clinically relevant symptom in patients (pts) with myelofibrosis (MF) which is not being addressed by treatment with ruxolitinib (RUX). Single treatment with pomalidomide (POM) improved cytopenia in 14% (POM 0.5 mg QD) and 29% (POM 2 mg QD) of MF pts in our previous MPNSG-0109 trial. Aims: Therefore, we sought to investigate the combination of RUX plus POM in MF with anemia. Methods: MPNSG-0212 (NCT01644110) is a multicenter, open-label, single-arm phase-Ib/II trial with a target population of 90 pts in a twostage design. Pts 1-40 (cohort 1 [co1]) are treated with RUX (10 mg BID) plus low-dose POM (0.5 mg QD), while pts 41-90 (cohort 2 [co2]) receive a step-wise dose increase of POM after 3 and 6 cycles (0.5 -> 1 -> 2 mg QD). Primary endpoints are safety of the combination therapy and anemia response after 12 28-day cycles (according to IWG-MRT and RBC transfusion independency [RBC-TI] criteria). Main inclusion criterion is MF with anemia (Hb <10 g/dL and/or RBC-TD). Pts suitable for allogeneic transplantation and pts with low platelets (<100/nL) are excluded.Results: Data from 59 pts were available for this analysis. Baseline characteristics were as following: Median age 72 yrs (range 49-84), 53% had prior treatment (RUX in 22%, POM in 4%), median Hb level was 8.5 g/dL (range 5.4-11.7), 27% fulfilled the RBC-TD criterion, median spleen size was 17.8 cm (range 12.6-36), 80% had constitutional symptoms, 93% were intermediate-2 (64%) or high-risk (29%) according to DIPSS, and 55% had 1 high molecular risk mutation (ASXL1, SRSF2, EZH2, and/or IDH1/2). Median number of treatment cycles was 12 (range 2-59) in co1 and 11 (range 1-16) in co2. 414 adverse events (AE) were recorded (mostly °I/II). Number or severity of AE were not increased in co2. Most common AE (°I/II) were anemia (34% of pts) and fatigue (29%) in the first weeks of treatment as well as musculoskeletal cramps (25%). Regarding serious AE (SAE), n = 77 were recorded in 64% of pts. No fatal (S)AE occurred in co2. Most common SAE were pneumonia (12%), leukemic transformation (10%), and worsening of general condition (7%). Interruption/termination of RUX and/or POM was rare in co1 and co2. In co1, 18/40 pts (45%) continued treatment beyond cycle 12 because of objective anemia response (7/40, 18%: CI-Hb [Hb increase 2 g/dL] n = 5, PR and RBC-TI n = 1 each) or stable disease in combination with clinical benefit (CB, 11/40, 28%) defined as: Hb increase 1 g/dL and/or doubling of RBC transfusion intervals [n = 4] or improvement of fatigue and/or overall quality of life >25% according to MPN-SAF [n = 7]. Notably, 16 pts of co1 (40%) were on treatment for more than 24 cycles, and mean Hb increased continuously from 8.7 g/dl at baseline to 9.8 g/dL at end of cycle 18 and sustained thereafter at 9.7 g/dL until end of cycle 30 (Figure 1). In co2, 6/19 pts (31%) reached cycle 12 and continued treatment afterwards: 1/6 (17%) experienced RBC-TI, whereas 5 had CB; 16/19 pts (84%) were still on treatment at the time of the analysis with 10/16 p...
Introduction: Momelotinib (MMB) is a potent JAK1, JAK2 and ACVR1 inhibitor with clinical activity against the three hallmark features of myelofibrosis (MF), namely anemia, constitutional symptoms and splenomegaly, across the continuum of intermediate/high risk MF patients whether JAKi--naïve or previously JAKi-treated as demonstrated in the previously conducted Phase 3 SIMPLIFY-1 & -2 clinical trials (S1, S2). S1 was conducted in JAKi-naïve MF patients (n=432) randomized 1:1 to MMB or ruxolitinib (RUX) over a 24-week double-blind dosing period. S2 was conducted in MF patients who experienced hematological toxicity during prior RUX therapy (n=156) randomized 2:1 to MMB or best available therapy (BAT; consisting of RUX in 88% of patients) over a 24-week open-label dosing period. In both trials, following the 24-week randomized treatment (RT) period, patients originally randomized to MMB could continue MMB therapy (MMB→MMB) and those randomized to RUX/BAT were eligible to cross-over to MMB (RUX/BAT→MMB) for additional extended treatment (ET). Over 820 MF patients have received MMB during the compound's clinical development program. Methods: Long term outcome data from S1 and S2 are reported here including survival, response endpoints, and MMB exposure. Overall survival (OS) and leukemia free survival (LFS) were followed for a maximum of approximately 5 years (median of 2.9 years in S1 and 2.3 years in S2). Following participation in S1 and S2, patients were eligible to continue MMB therapy via an extended access protocol (XAP), along with additional Phase 2 MMB subjects. Duration of exposure incorporates XAP data but OS/LFS analyses only include data obtained within S1 and S2. Results: Of the 137 Phase 2 and 3 patients who have enrolled in XAP, 105 remain on MMB with duration on therapy ranging up to 10 years. Across the RT and ET periods of S1 and treatment in XAP, 69% of the 215 JAKi-naïve patients randomized to MMB remained on therapy for ≥ 48 weeks; 44% for ≥ 96 weeks and 30% for ≥ 144 weeks. Of the 104 prior JAKi-exposed subjects randomized to MMB in S2, 47% received MMB (RT, ET and XAP) for ≥ 48 weeks; 25% for ≥ 96 weeks and 17% for ≥ 144 weeks. In both S1 and S2, OS and LFS were similar between treatment groups (stratified HR for OS of 0.99 in S1, 0.96 in S2), demonstrating robust and consistent survival outcomes for patients who commenced JAKi therapy with MMB and those dosed initially with RUX/BAT followed by MMB (Figure 1). In addition, the median OS in S2 (MMB arm of 34.3 months) compares very favorably with previously reported median survival ranging from 13-30 months in patients who have discontinued RUX (Tang, ASH 2019). In S1, splenic response, defined as a reduction in spleen volume of ≥ 35% from baseline at Week 24 was achieved by 26.5% of patients in the MMB group and 29.5% in the RUX group (non-inferiority p<0.001). A total of 35 new responses were noted in the ET phase using the pre-study spleen size as baseline, including responses in 22 RUX→MMB subjects. Overall, 40% of patients randomized to MMB in S1 achieved a splenic response at any time during the study. Robust duration of splenic response was observed in the ET period of both S1 and S2. The ability to achieve or maintain transfusion independence (TI) represents a substantive clinical benefit in light of the progressive myelosuppression associated with MF. In the RT period of both S1 and S2, a greater proportion of subjects receiving MMB compared with the control arm achieved TI at Week 24, defined as no RBC transfusion and no Hgb level below 8 g/dL in of the prior 12 weeks. The proportion who were TI at Week 24 was approximately 70% for MMB vs 54% for RUX in S1, and 44% for MMB vs 27% for BAT/RUX in S2. For MMB→MMB subjects in S1, the RBC transfusion free rate at Week 48 (ET) was approximately 75% and 67% for RUX→MMB. Similarly, in S2, MMB→MMB subjects had an RBC transfusion free rate of approximately 55% and 40% for BAT/RUX→MMB. For the patients who achieved TI at any time during the study, the median duration of TI response by KM estimate was not reached in S1 and was >1 year in S2. Conclusion: In conclusion, further analyses of data from the 550 JAKi-naïve and previously JAKi-treated patients with MF who received MMB in RT and/or ET show robust long-term survival, sustained efficacy and durability of dosing consistent with MMB's differentiated pharmacological profile. These data demonstrate MMB's potential ability to durably address the unmet needs of patients with intermediate/high risk MF. Disclosures Verstovsek: NS Pharma: Research Funding; Promedior: Research Funding; CTI Biopharma Corp: Research Funding; Sierra Oncology: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; PharmaEssentia: Research Funding; AstraZeneca: Research Funding; ItalPharma: Research Funding; Protagonist Therapeutics: Research Funding; Roche: Research Funding; Incyte Corporation: Consultancy, Research Funding; Gilead: Research Funding; Novartis: Consultancy, Research Funding; Genentech: Research Funding; Celgene: Consultancy, Research Funding. Lech-Marańda:Roche, Amgen, Gilead: Speakers Bureau; Roche, Novartis, Takeda, Janssen-Cilag, Amgen, Gilead, AbbVie, Sanofi: Consultancy. Sacha:Incyte: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Adamed: Consultancy, Honoraria; Bristol-Myers Squibb Company: Consultancy, Honoraria, Speakers Bureau. Oh:Constellation: Consultancy; Kartos Therapeutics: Consultancy; Disc Medicine: Consultancy; PharmaEssentia: Consultancy; CTI Biopharma: Consultancy; Incyte Corporation: Consultancy; Gilead Sciences: Consultancy; Novartis: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; Blueprint Medicines: Consultancy. Harrison:Celgene: Honoraria, Research Funding, Speakers Bureau; Sierra Oncology: Honoraria; Janssen: Speakers Bureau; Roche: Honoraria; Promedior: Honoraria; CTI Biopharma Corp: Honoraria, Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; AOP Orphan Pharmaceuticals: Honoraria; Shire: Honoraria, Speakers Bureau; Incyte Corporation: Speakers Bureau. McLornan:NOVARTIS: Honoraria, Speakers Bureau; JAZZ PHARMA: Honoraria, Speakers Bureau; CELGENE: Honoraria, Speakers Bureau. McMullin:Abbvie: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Celgene: Consultancy; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Kowalski:Sierra Oncology Inc.: Current Employment, Current equity holder in publicly-traded company. Smith:Sierra Oncology Inc.: Current Employment, Current equity holder in publicly-traded company. Mesa:Bristol Myers Squibb: Research Funding; Promedior: Research Funding; AbbVie: Research Funding; Sierra Oncology: Consultancy; CTI BioPharma: Research Funding; Samus Therapeutics: Research Funding; Genentech: Research Funding; Incyte: Research Funding; LaJolla Pharmaceutical Company: Consultancy; Novartis: Consultancy.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.