scholarly journals Indirect Treatment Comparisons of the Effect of Fedratinib Versus Navitoclax Plus Ruxolitinib on Spleen Volume and Symptoms in Patients with Myelofibrosis and Prior Ruxolitinib Treatment

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4626-4626
Author(s):  
Pranav Abraham ◽  
Xiaomeng Liao ◽  
Manoj Chevli ◽  
Sarah Smith
Keyword(s):  
Platelet Count ◽  
High Risk ◽  
Sample Size ◽  
Response Rates ◽  
Janus Kinase ◽  
Spleen Volume ◽  
Treatment Comparison ◽  
Previously Treated ◽  
Indirect Treatment ◽  
Ecog Ps

Abstract Introduction: Myelofibrosis (MF) is a serious and life-threatening myeloproliferative neoplasm that is characterized by stem cell-derived clonal myeloproliferation, bone marrow fibrosis, anemia and splenomegaly. The Janus kinase (JAK) pathway is the critical pathway in its pathogenesis. Ruxolitinib, a JAK1/2 inhibitor, was the first US Food and Drug Administration (FDA)-approved therapy for intermediate- and high-risk MF. However, there remains a high unmet need for alternative treatment options for patients who discontinue (41.1%-60.9% of patients discontinue after 3 months and 48.4%-73.0% after 6 months) (Fonseca E, et al. Blood 2013;122. Abstract 2833) or are no longer responding to ruxolitinib therapy (Bose P, Verstovsek S. Leuk Lymphoma 2020;61:1797-1809). The efficacy and safety of fedratinib, a JAK2 inhibitor approved by the FDA in 2019, was investigated post ruxolitinib in the single-arm trial JAKARTA-2 (NCT01523171) (Harrison CN, et al. Lancet Haematol 2017;4:e317-324; Harrison CN, et al. Am J Hematol 2020;95:594-603). New clinical evidence for treating a similar population with navitoclax plus ruxolitinib was presented at the American Society of Hematology Annual Meeting in 2020 (Pemmaraju N, et al. Blood 2020;136(suppl 1):49-50). The efficacy of fedratinib relative to navitoclax plus ruxolitinib in patients with MF previously treated with ruxolitinib has not yet been evaluated. Objective: To explore the comparative efficacy of fedratinib versus navitoclax plus ruxolitinib in patients with MF previously treated with ruxolitinib for the 2 binary endpoints of ≥ 35% spleen volume reduction (SVR) from baseline to the end of cycle 6 (EOC6; 24 weeks) and ≥ 50% reduction in total symptom score (TSS) from baseline to the EOC6. Methods: Evidence for fedratinib was informed by JAKARTA-2 patient-level data, and evidence for navitoclax plus ruxolitinib was informed by known reported evidence from the REFINE study (NCT03222609) (Pemmaraju N, et al. Blood 2020;136(suppl 1):49-50; Harrison CN, et al. J Clin Oncol 2019;37 (suppl 15). Abstract 7057). The suitability of these studies for indirect treatment comparison (ITC) was assessed by considering the comparability of study design, population, intervention, and outcomes. Given the lack of a common comparator in the identified studies, unanchored ITCs were performed for SVR using matching-adjusted indirect comparison (MAIC) and simulated treatment comparison (STC) methods. Univariable and multivariable regression models were used to identify potential prognostic factors to adjust for in the ITCs. Additionally, all reported Dynamic International Prognostic Scoring System (DIPSS)-Plus criteria were considered. Where sample size was too small, response rates (number of responders divided by total number of patients) were compared naively. Results: A subgroup of 58 JAKARTA-2 patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1 and intermediate-2 or high-risk disease most closely aligned with the REFINE population was used in the analyses. Baseline mean platelet count was similar between subgroups. Across the analyses performed, results suggested fedratinib consistently increased the odds/risk of a spleen response compared with navitoclax plus ruxolitinib (Table). The MAIC, matching on ECOG PS, suggested that the odds of having an SVR for patients in the fedratinib group was 2.19 times (95% confidence interval [CI], 1.26 to 3.66) that of the navitoclax plus ruxolitinib group, and the risk of having an SVR for patients in the fedratinib group was 17.59% higher (95% CI, −2.14 to 36.97). The results from the MAIC that additionally matched on all possible DIPSS-Plus criteria (age, hemoglobin, and platelet count) were consistent. Results from the 2 methods (MAIC and STC) were also consistent. For TSS reduction, the sample size (N = 20) in REFINE was considered too small to perform a meaningful ITC; however, the absolute response rates for TSS reduction were similar across the 2 groups (29% [16/56] in the fedratinib group and 30% [6/20] in the navitoclax plus ruxolitinib group). Conclusion: In the population of patients with MF previously treated with ruxolitinib, these analyses suggest treatment with fedratinib was associated with a greater proportion of patients achieving a spleen response compared with navitoclax plus ruxolitinib. Limited data were available for comparison of TSS. Figure 1 Figure 1. Disclosures Abraham: Bristol Myers Squibb: Current Employment. Liao: BMS: Consultancy. Chevli: Bristol-Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Smith: Sarah Smith is an employee of BresMed. BresMed received consultancy fees from BMS/Celgene for the reasearch in this abstract. She did not receive direct payment as a result of this work outside of her normal salary payments.: Consultancy.

scholarly journals The Effect of Fedratinib, a Selective Inhibitor of Janus Kinase 2 (JAK2), on Weight and Metabolic Parameters in Patients with Intermediate (INT)- or High-risk Myelofibrosis (MF)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 16-17
Author(s):  
Douglas Tremblay ◽  
Lara Cavalli ◽  
Sibabrata Raja Banerjee ◽  
Shelonitda Rose ◽  
John Mascarenhas
Keyword(s):  
Weight Gain ◽  
High Risk ◽  
Fasting Glucose ◽  
Albumin Level ◽  
Metabolic Parameters ◽  
Phase Iii ◽  
Spleen Volume ◽  
Publicly Traded ◽  
Starting Dose ◽  
Previously Treated

BACKGROUND: MF is characterized by stem cell-derived clonal myeloproliferation, abnormal cytokine expression, marrow fibrosis, splenomegaly, and shortened survival. Fedratinib (FEDR) is an oral, selective JAK2 inhibitor approved in the United States (US) for treatment (Tx) of INT-2 or high-risk MF. Ruxolitinib (RUX) is a JAK1/2 inhibitor approved in the US and European Union for Tx of INT- or high-risk MF. Clinical experience indicates that weight gain during RUX Tx is both common and substantial (mean increase ~4 kg from baseline [BL] in the COMFORT-I and COMFORT-II studies); begins during early Tx (~6-8 weeks from initiation) and continues throughout the course of Tx; and cannot be solely attributable to resolution of MF symptoms (eg, early satiety, abdominal discomfort) or splenomegaly (Mesa 2015; Sapre 2019; Molle 2020). The impact of FEDR on weight and metabolic parameters is of interest. FEDR was investigated in the randomized, placebo (PBO)-controlled, phase III JAKARTA trial in patients (pts) with JAK-inhibitor-naïve MF, and in the single-arm, phase II JAKARTA2 trial in pts with MF previously treated with RUX. OBJECTIVE: Evaluate changes in weight, BMI, and metabolic parameters in pts treated with FEDR 400 mg/day. METHODS: JAKARTA enrolled pts with INT-2 or high-risk primary or post-ET/post-PV MF, platelet counts ≥ 50 ×109/L, palpable splenomegaly (≥ 5 cm below LCM), and ECOG PS ≤ 2. Pts were randomized 1:1:1 to FEDR 400 mg, FEDR 500 mg, or PBO, administered once-daily for at least 6 continuous 28-day Tx cycles (ie, 24 weeks). This analysis focuses on pts randomized to FEDR 400 mg/day (approved starting dose) or PBO. We assessed changes from BL in weight, BMI, albumin, fasting glucose, and systolic and diastolic blood pressure (SBP and DBP) at the end of cycle 6 (EOC6; PBO pts could crossover to FEDR after EOC6). Reported changes from BL at EOC6 are for pts who completed 6 Tx cycles. As a supporting analysis, we assessed changes in these parameters for pts in JAKARTA2, who all received FEDR 400 mg/day (starting dose). RESULTS: In JAKARTA, 96 pts received FEDR 400 mg and 95 pts received PBO. Median age at BL was 63 years (range 39-86) in the FEDR arm and 66 (27-85) in the PBO arm, and mean [±SD] spleen volumes were 2755 [1353] mL and 2928 [1484] mL, respectively. In the FEDR arm, mean weight at BL was 69.4 kg, and remained relatively unchanged during FEDR Tx, increasing by 0.8 kg from BL to EOC6 (Figure). In the PBO arm, mean weight decreased by 0.1 kg from BL (68.6 kg) to EOC6. Mean BMI increased nominally by 0.3 in the FEDR arm (BL 24.0) and was unchanged from BL (24.3) in the PBO arm. In the FEDR arm, mean albumin level increased slightly by 0.24 g/dL from BL (4.14 g/dL) to EOC6, and fasting glucose was unchanged from BL (5.5 mmol/L). No clinically significant changes were observed in SBP or DBP during FEDR Tx, which were 124.5 and 70.6 mmHg at BL, respectively, and increased nominally at EOC6 by 1.7 and 0.1 mmHg. In the PBO arm, mean albumin level was 4.07 g/dL at BL and decreased by 0.09 g/dL at EOC6, fasting glucose was 5.6 mmol/L and decreased by 0.1 mmol/L, SBP was 124.3 mmHg and increased by 1.3 mmHg, and DBP was 70.6 mmHg and decreased by 1.3 mmHg. JAKARTA2 included 97 pts with advanced MF previously treated with RUX. Median age at study entry was 67 years (range 38-83) and mean [±SD] spleen volume was 3095 [1459] mL. At BL, mean weight was 73.5 kg and BMI was 25.5; these decreased by 0.6 kg and 0.2, respectively, by EOC6. From BL to EOC6, mean albumin, fasting glucose, SBP, and DBP changed by +0.39 g/dL (BL 3.94 g/dL), -0.6 mmol/L (BL 6.6 mmol/L), +3.8 mmHg (BL 124.1 mmHg), and +2.9 mmHg (BL 66.7 mmHg), respectively. Median spleen volume change from BL to EOC6 with FEDR 400 mg was -40% in JAKARTA and -34% in JAKARTA2. There was no apparent correlation between changes in weight and spleen volume in pts treated with FEDR 400 mg in either trial. CONCLUSIONS: Disproportionate weight gain not correlating with MF symptom resolution is a concern with long-term RUX Tx. In JAKARTA, FEDR did not meaningfully increase pts' weight or BMI after 6 Tx cycles. Modest increases in albumin compared with BL suggest improved nutritional status during FEDR Tx, and there were no clinically relevant changes in fasting glucose or BP after 6 FEDR Tx cycles. Changes in weight and metabolic parameters in JAKARTA2 support findings with FEDR 400 mg from JAKARTA. Unlike observations in pts treated with RUX (Mesa 2015), spleen volume reductions during FEDR Tx were not associated with weight increases. Disclosures Cavalli: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Banerjee:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Rose:Bristol-Myers Squibb Company: Current Employment, Current equity holder in publicly-traded company. Mascarenhas:Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution); Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy.

The telomerase inhibitor imetelstat in patients (pts) with intermediate-2 or high-risk myelofibrosis (MF) previously treated with Janus kinase (JAK) inhibitor: A phase 2, randomized study.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. TPS7079-TPS7079
Author(s):  
Ayalew Tefferi ◽  
Naseema Gangat ◽  
Dietger Niederwieser ◽  
Jan Van Droogenbroeck ◽  
Maria R. Baer ◽  
...  
Keyword(s):  
High Risk ◽  
Randomized Study ◽  
Janus Kinase ◽  
Jak Inhibitor ◽  
Phase 2 ◽  
Telomerase Inhibitor ◽  
Previously Treated

A phase 3, randomized, double-blind, placebo-controlled study of ruxolitinib plus parsaclisib in patients with JAK- and PI3K-inhibitor treatment-naïve myelofibrosis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS7058-TPS7058
Author(s):  
Abdulraheem Yacoub ◽  
Susan Erickson-Viitanen ◽  
Feng Zhou ◽  
Albert Assad
Keyword(s):  
Platelet Count ◽  
The United States ◽  
Janus Kinase ◽  
Pi3k Inhibitor ◽  
Controlled Study ◽  
Risk Category ◽  
Spleen Volume ◽  
Phase 3 ◽  
Double Blind ◽  
Patient Reported

TPS7058 Background: Ruxolitinib (JAK1/JAK2 inhibitor) significantly improves outcomes in patients with myelofibrosis (MF); however, a subset of patients may experience a suboptimal response. Recent phase 2 data showed that addition of PI3Kδ inhibitor parsaclisib to ruxolitinib monotherapy resulted in additional alleviation of MF symptoms and splenomegaly in patients with MF (Yacoub. EHA2020. S216). This phase 3, randomized, double-blind study (INCB 50465-313; NCT04551066), evaluates the combination of ruxolitinib and parsaclisib in patients with MF who are naïve to Janus kinase (JAK) and PI3K inhibitor therapies. Methods: Eligible patients are aged ≥18 years with a diagnosis of primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF, have a Dynamic International Prognostic Scoring System (DIPSS; Passamonti. Blood. 2010;115:1703-1708) risk category of at least Intermediate (INT)-1, palpable spleen ≥5 cm below left subcostal margin; total symptom score ≥10 at screening, ECOG PS 0–2, and life expectancy ≥24 weeks. Patients will be excluded if they previously received therapy with any JAK inhibitor, any PI3K inhibitor, any experimental or standard drug therapy for MF ≤3 months of first study dose and/or lack of recovery from all toxicities related to previous therapies to grade ≤1, have recent history of inadequate bone marrow reserve (eg, platelet count = 50×109/L) or have inadequate liver or renal function at screening. Approximately 440 patients will be randomized (1:1) to ruxolitinib plus parsaclisib 5 mg QD or ruxolitinib plus matching placebo, with stratification at randomization by DIPSS risk category (high vs INT-2 vs INT-1) and platelet count (≥100×109/L vs 50 to = 100×109/L inclusive). Treatment will begin on Day 1, with starting ruxolitinib dose level determined by baseline platelet count, and will continue as long as treatment is tolerated and discontinuation criteria are not met. When the last enrolled patient has completed 24 weeks of treatment, the study will be unblinded and patients randomized to ruxolitinib plus placebo who have adequate hematology parameters will be able to crossover to receive parsaclisib together with continued ruxolitinib. The primary objective is the evaluation and comparison of spleen volume at Week 24 for patients who received ruxolitinib plus parsaclisib versus ruxolitinib plus placebo. Secondary objectives include evaluation and comparison of patient-reported MF symptoms, overall survival, time to onset and duration of response in spleen volume, and safety and tolerability for ruxolitinib plus parsaclisib versus ruxolitinib plus placebo. Sites are opening across the United States, Europe, Asia, and New Zealand. Clinical trial information: NCT04551066.

Treatment of High Risk MDS and AML Post-MDS with Azacytidine (AZA): Preliminary Results of the French ATU Program.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2664-2664 ◽  
Author(s):  
Claire Fabre ◽  
Fatsiha Chermat ◽  
Laurence Legros ◽  
Sophie Park ◽  
François Dreyfus ◽  
...  
Keyword(s):  
High Risk ◽  
Response Duration ◽  
Response Rates ◽  
Phase Iii ◽  
Monosomy 7 ◽  
Phase Iii Trial ◽  
Early Evaluation ◽  
Fda Approval ◽  
Previously Treated ◽  
Patient Refusal

Abstract Background : Following FDA approval of AZA for MDS and activation of a phase III trial randomizing AZA to conventional treatment in higher risk MDS, a compassionate program for the use of AZA (ATU nominative) was started in France for MDS with exclusion criteria for this trial. Patients (pts) : IPSS int-2 and high-risk MDS (and some int-1) with contra-indication to the trial (ie therapy related (t-MDS) or already treated by cytoreductive agents or having progressed to AML or patient refusal), received AZA 75 mg/m/d (d 1–7) (SC) every 4 weeks. Results : From Sept 2004 to May 2006, 90 pts from 31 centres were included, of whom 77 had completed at least one course of AZA : M/F: 52/25, median age 71 y [42–88]. WHO at inclusion : 15 RAEB1, 30 RAEB2, 14 AML post-MDS, 7 CMML, 3 RA, 3 RAS, 2 RCMD, 3 unclassified MDS. 22 pts had previously received intensive Anth-AraC, 9 low dose AraC, 16 EPO and 13 other treatments (alkylators, Arsenic, androgens, Thal) and 1 had t-MDS. 32 (42%), 16 (21%) and 29 (37%) pts had fav, int and unfav karyotype, resp. 37 pts (48%) were IPSS high, 26 pts (34%) int-2 and 14 pts (18%) int-1. Pts received a median of 4 cycles [range 1–16]. Response was generally assessed after 4 cycles, unless pts progressed before. Thus, 16 pts were not yet evaluable for response. Of the remaining 61 pts, 10 (16%) achieved CR (IWG criteria), 15 (25%) achieved PR and 13 (21%) achieved HI (Overall response rate OR=62%). 23 pts (38%) were considered failure of whom 4 died before evaluation and 10 of them were considered failure because early evaluation after only 2 cycles showed stable disease only, and AZA was then stopped. OR was 73%, 57%, 67% and 36% for RAEB1, RAEB2, CMML and AML post-MDS resp (p<0.1); 75%, 56% and 59% for fav, int and unfav karyotype, resp (p=NS). 4/6 pts with monosomy 7 responded (1 CR+3 PR), 2/4 pts with + 8 (1 PR+1 HI) and 13/23 pts with complex karyotype (5 CR+6 PR+2 HI). OR was 56%, 77% and 56% for IPSS high, int-2 and int-1 pts, resp (p=NS) and 50%, 76% in pts previously treated or not by cytoreductive agents resp (p<0.05). Median survival from inclusion was 7 months [range 3–17]. AZA induced myelosuppression lead to dose reduction in 17% pts and hospitalization in 13% pts but was not responsible for any death. Other side effects included frequent local reactions (reversible with local NSAID) (32%), grade I-II gastro-intestinal disorders (39%), unexpected cardiac arythmias (3%). Conclusion : AZA, in this population with overall unfavorable features, gave response rates at least similar to those of CALGB studies, that may have been higher if treatment had not been stopped in some of the pts stable after 2 courses. Pts with unfavorable karyotype (− 7, complex) or + 8 had about 50% response rates. Accrual in this program is continuing. Data on response duration will be presented.

Fedratinib (FEDR) in myelofibrosis (MF) patients previously treated with ruxolitinib (RUX): A reanalysis of the JAKARTA-2 study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 7057-7057 ◽  
Author(s):  
Claire N. Harrison ◽  
Nicolaas Schaap ◽  
Alessandro M Vannucchi ◽  
Jean-Jacques Kiladjian ◽  
Eric Jourdan ◽  
...  
Keyword(s):  
Symptom Burden ◽  
Response Duration ◽  
Median Number ◽  
Spleen Volume ◽  
Jak2 Inhibitor ◽  
Volume Response ◽  
Life Threatening ◽  
Previously Treated ◽  
Definition Of ◽  
Ecog Ps

7057 Background: MF is a life-threatening MPN for which RUX is the only approved treatment (Tx) option. Patients (pts) who are relapsed/refractory (R/R) or intolerant to RUX have a particularly high unmet medical need. FEDR is an oral selective JAK2 inhibitor active against wt and mut JAK2. The JAKARTA-2 study demonstrated ≥35% spleen volume responses (SVR) in pts resistant or intolerant to RUX per investigator assessment. This JAKARTA-2 reanalysis employs a more stringent definition of RUX failure than used in the previous analysis. Methods: Adult pts previously treated with RUX with intermediate or high-risk primary, post-PV, or post-ET MF, palpable splenomegaly, ECOG PS ≤2, and platelet counts ≥50 × 109/L received FEDR 400 mg QD in continuous 28-day cycles. The primary endpoint was spleen volume response rate (SVRR): ≥35% SVR from baseline (BL) at cycle 6 end per blinded central review of MRI/CT scans. A key secondary endpoint was symptom RR (≥50% decrease in total symptom score from BL). Results: 79/97 enrolled pts (81%) met the more stringent criteria for RUX R/R (n=65, 82%) or intolerance (n=14, 18%). Median BL spleen volume was 2946 mL (~14× normal). Median prior RUX Tx duration was 11.5 mo (range 1.0–62.4). Median number of FEDR Tx cycles was 7 (1–20). SVRR with FEDR was 30% (95% CI 21, 42). KM estimated median spleen response duration was not estimable (95% CI 7.2 mo, NE). Symptom RR was 27%. Safety was consistent with prior reports. Conclusions: FEDR provided clinically meaningful reductions in splenomegaly and symptom burden in pts with MF who met more stringent criteria for R/R or intolerance to RUX. Clinical trial information: NCT01523171. [Table: see text]

scholarly journals A New Prognostic Index for Waldenström Macroglobulinemia Based on a Multicenter Retrospective Study of the Japanese Society of Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5320-5320
Author(s):  
Akio Saito ◽  
Atsushi Isoda ◽  
Takeshi Odajima ◽  
Mitsuhiro Itagaki ◽  
Go Yamamoto ◽  
...  
Keyword(s):  
Platelet Count ◽  
High Risk ◽  
Research Funding ◽  
Pharmaceutical Research ◽  
Prognostic Index ◽  
Risk Groups ◽  
Poor Risk ◽  
Ecog Ps ◽  
Pleural Involvement ◽  
Good Risk

Abstract Background: We recently reported that the International Prognostic Scoring System for Waldenström macroglobulinemia (ISSWM), which is widely used to predict the prognosis of WM patients, might not be applicable to Japanese patients, and evidence of pleural effusion might be a novel adverse prognostic factor for symptomatic WM in the rituximab era. Further studies with a large number of patients are deemed to be conducted. Methods: We retrospectively analyzed the clinical data of 498 patients with WM diagnosed between January 2001 and December 2015 from 44 institutes involved with the Japanese Society of Myeloma. The overall survival (OS) was analyzed using Kaplan-Meier methods and compared using log-rank test. Several clinical characteristics at the diagnosis were assessed by Cox regression for univariate and multivariate analyses of the OS. Results: We included 420 cases diagnosed with symptomatic (n=314) and asymptomatic WM (n=106) in accordance with the classification of the Second International Workshop on WM. The median age at the diagnosis was 69 (range, 32-91) years, with 75.5% male, and 16.0% had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 2-4. Oral alkylating agents, purine analogs, cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) or CHOP-like regimens ± rituximab, rituximab monotherapy, or dexamethasone, rituximab and cyclophosphamide (DRC) were mainly administered as initial treatment. Rituximab-containing therapy was administered in 76.8% of all patients. The median follow-up was 45 months. The 5-year OS rate for all patients was 77.9%, while the rates for those with symptomatic and asymptomatic WM were 72.9% and 92.2%, respectively. Significant differences in the survival were seen between risk groups of ISSWM in symptomatic WM patients (5-year OS: high, 55.4%; intermediate, 81.2%; low, 90.2%; p<0.0001) (Figure 1). A univariate analysis showed that age >65 years, platelet count ≤10×104/µL, serum β2-microglobulin (β2-MG) >3 mg/L, ECOG PS 2-4, abnormal karyotype, pleural involvement, WBC <4000/µL, amyloidosis, fluid retention, pleural effusion, ascites, serum albumin ≤3.5 g/dL, serum creatinine >1.5 mg/dL, CRP >2.0 mg/dL and sIL-2R >4000 U/mL were significant adverse prognostic factors for the OS. A multivariate analysis revealed that a platelet count ≤10×104/µL (hazard ratio [HR] 5.942; 95% confidence interval [CI] 2.265-14.761), serum β2-MG >3 mg/L (HR 2.748; 95% CI 1.091-7.655), ECOG PS 2-4 (HR 2.899; 95% CI 1.219-6.290), and pleural involvement (HR 11.066; 95% CI 3.672-29.829) were adverse independent risk factors for symptomatic WM. We constructed a prognostic model by combining these prognostic variables as follows: patients with good risk (n=219), no adverse factors or only serum β2-MG >3 mg/L or ECOG PS 2-4; patients with poor risk (n=81), ≥1 adverse factors with a platelet count ≤10×104/µL, pleural involvement, or both serum β2-MG >3 mg/L and ECOG PS 2-4. The 5-year OS rates were 82.3% for good risk and 44.4% for poor risk, and this prognostic model significantly stratified symptomatic WM patients separately by the survival (p<0.0001) (Figure 2). The survival of patients with both poor risk in our model and high risk in ISSWM were extremely poor (5-year OS: poor and high [n=57], 24.7%; poor and intermediate [n=14], 80.0%; poor and low [n=2], not available; p=0.0031). In contrast, no significant differences were observed for the survival for the ISSWM risk groups in patients with good risk in our model (5-year OS: good and high [n=69], 76.0%; good and intermediate [n=83], 81.6%; good and low [n=42], 89.5%; p=0.2045). Conclusion: Although ISSWM may be useful for survival risk stratification in Japanese patients, we found that intermediate- and high-risk patients seemed to have a better prognosis than those in Western studies in the rituximab era (Dimopoulos MA, et al. Haematologica. 2008; 93: 1420-22). Thrombocytopenia and pleural involvement were found to be strong adverse prognostic factors in symptomatic WM, and our new prognostic index including them was easy to use in daily clinical practice and superior to ISSWM for detecting high-risk patients. Further studies are warranted to validate our prognostic index, especially in the era of novel agents. Disclosures Yamamoto: Bristol-Myers Squibb: Honoraria. Hagiwara:Celgene: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Sunami:Celgene: Honoraria, Research Funding; Sanofi: Research Funding; Janssen: Research Funding; Daiichi-Sankyo: Research Funding; Ono: Honoraria, Research Funding; Bristol-Myers Squibb K.K.: Honoraria, Research Funding; AbbVie: Research Funding; Takeda: Research Funding; MSD: Research Funding; GlaxoSmithKline: Research Funding; Novartis: Research Funding. Kurokawa:Teijin Pharma: Research Funding; Eizai: Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Chugai Pharmaceutical: Research Funding; Sumitomo Dainippon Pharma: Research Funding; Pfizer: Research Funding; Takeda Pharmaceutical: Research Funding; MSD: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Nippon Sinyaku: Honoraria, Research Funding; Astellas Pharma: Research Funding; Otsuka Pharmaceutical: Research Funding. Takamatsu:Janssen: Honoraria; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Ono: Research Funding. Ito:Bristol-Myers Squibb, Celgene: Honoraria. Tamura:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria; Takeda Pharmaceutical: Honoraria.

scholarly journals A Phase 2a Study of the LSD1 Inhibitor Img-7289 (bomedemstat) for the Treatment of Myelofibrosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 556-556 ◽  
Author(s):  
Kristen Pettit ◽  
Aaron T. Gerds ◽  
Abdulraheem Yacoub ◽  
Justin M. Watts ◽  
Maciej Tartaczuch ◽  
...  
Keyword(s):  
Platelet Count ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Spleen Volume ◽  
Employment Equity ◽  
Advisory Committees ◽  
Once Daily ◽  
Equity Ownership

Ruxolitinib (Jakafi®) is the one approved therapy for myelofibrosis (MF) based on reduction of splenomegaly and symptoms but JAK inhibition has not proven to significantly modify disease progression. There remains the need for novel therapies with distinct modes of action that can improve the patient experience of MF and impact progression. Lysine-specific demethylase, LSD1, is an epigenetic enzyme critical for self-renewal of malignant myeloid cells and differentiation of myeloid progenitors. LSD1 bound to GFI1b permits maturation of progenitors to megakaryocytes and enables their normal function. IMG-7289 (bomedemstat) is an orally available LSD1 inhibitor. In mouse models of myeloproliferative neoplasms (MPN), IMG-7289 reduced elevated peripheral cell counts, spleen size, inflammatory cytokines, mutant allele frequencies, and marrow fibrosis (Jutzi et al. 2018) supporting its clinical development. IMG-7289-CTP-102 is an ongoing, multi-center, open-label study that recently transitioned from a Phase 1/2a dose-range finding study to a Phase 2b study of IMG-7289 administered orally once-daily in adult patients with intermediate-2 or high-risk MF resistant to or intolerant of ruxolitinib. The key objectives are safety, PD, changes in spleen volume (MRI/CT) and total symptoms scores (TSS) using the MPN-SAF instrument. Inclusion criteria included a platelet count ≥100K/μL. Bone marrow (BM) biopsies and imaging studies (both centrally-read) were conducted at baseline and during washout (post-Day 84). The MPN-SAF was self-administered weekly. Phase 1/2a patients were treated for 84 days followed by a washout of up to 28 days. Patients demonstrating clinical benefit could resume treatment for additional 12 week cycles. Dosing was individually tailored using platelet count as a biomarker of effective thrombopoiesis. Patients were started at a presumed sub-therapeutic dose of 0.25 mg/kg/d and up-titrated weekly until the platelet count rested between 50 and 100K/μL. This preliminary analysis includes 20 patients; 18 enrolled in the Phase 1/2a study, 2 in the Phase 2b portion. 50% had PMF, 35% Post-ET-MF, 15% Post-PV-MF. The median age was 65 (48-89) with 70% males. The median baseline platelet count was 197 k/μL (102-1309k/μL). 12 patients (56%) were transfusion-dependent at baseline. Sixty percent were IPSS-classified as high risk, the remainder, intermediate risk-2. 71% had more than 1 mutation of the 261 AML/MPN genes sequenced of which 63% were high molecular risk (ASXL1, U2AF1, SRSF2) mutations; 31% had abnormal karyotypes. Sixteen patients completed the first 12 weeks; 4 patients withdrew, one due to fatigue (Day 33), one for progressive disease (Day 39), one due to physician decision (Day 76), one for an unrelated SAE of cellulitis (Day 83). All patients were up-titrated from the starting dose 0.25 mg/kg to an average daily dose of 0.89 mg/kg ± 0.20 mg/kg, the dose needed to achieve the target platelet count range; 17 achieved the target platelet range in a mean time of 45 days. Of patients evaluable for response after cycle 1 in Phase1/2a (N=14), 50% had a reduction in spleen volume from baseline (median SVR: -14%; -2% to -30%). Further, 79% (N=11) recorded a reduction in TSS (mean change -28%; -13% to -69%); for 21% of patients (N=3), the change was &gt;-50%. Improved BM fibrosis scores at Day 84 were observed in 2/13 patients. Two patients had improvement in transfusion requirements. Plasma IL-8 levels were significantly elevated in 6/14 patients at baseline and dropped in a dose-dependent manner over 21 days in 5/6 patients. The mean duration of treatment is 166 days (14-539) at the census point in this ongoing study. Nineteen patients (95%) reported 358 AEs of which 22 were SAEs. Of the SAEs, 2 were deemed by investigators as possibly related: painful splenomegaly and heart failure. There have been no safety signals, DLTs, progression to AML, or deaths. This is the first clinical study of an LSD1 inhibitor in patients with MPNs. Once-daily IMG-7289 was well-tolerated in a heterogeneous population of patients with advanced MF and limited therapeutic options. Despite under-dosing and slow dose escalation, IMG-7289 improved symptom burdens in most patients and modestly reduced spleen volumes in a subset of patients. The Phase 2b 24-week expansion study with more aggressive dosing aimed at preserving safety and enhancing efficacy is open for enrollment in the US, UK and EU. Figure Disclosures Pettit: Samus Therapeutics: Research Funding. Gerds:Imago Biosciences: Research Funding; Celgene Corporation: Consultancy, Research Funding; CTI Biopharma: Consultancy, Research Funding; Roche: Research Funding; Sierra Oncology: Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy. Yacoub:Hylapharm: Equity Ownership; Agios: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Ardelyx: Equity Ownership; Cara: Equity Ownership; Dynavax: Equity Ownership. Watts:Pfizer: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bradley:AbbVie: Other: Advisory Board. Shortt:Celgene: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Astex: Research Funding; Amgen: Research Funding; Gilead: Speakers Bureau; Takeda: Speakers Bureau. Natsoulis:Imago BioSciences: Consultancy, Equity Ownership. Jones:Imago BioSciences: Employment, Equity Ownership. Talpaz:Samus Therapeutics: Research Funding; Novartis: Research Funding; Incyte: Research Funding; Constellation: Research Funding; Imago BioSciences: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; CTI BioPharma: Research Funding. Peppe:Imago BioSciences: Employment, Equity Ownership. Ross:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rienhoff:Imago Biosciences: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

scholarly journals Efficacy of Pomalidomide, Bortezomib and Dexamethasone in Relapsed or Refractory Multiple Myeloma Post-Lenalidomide: Results from a Systematic Literature Review and Indirect Treatment Comparison

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2201-2201
Author(s):  
Katja C. Weisel ◽  
Sujith Dhanasiri ◽  
Aline Gauthier ◽  
Amie Padhiar ◽  
Eva Casal ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Employment Equity ◽  
Phase 3 ◽  
Advisory Committees ◽  
Treatment Comparison ◽  
Significant Difference ◽  
Previously Treated ◽  
Indirect Treatment ◽  
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Background: The current standard of care in MM, lenalidomide (LEN), is frequently used as part of first-line (1L) treatment (tx) or as maintenance tx following autologous stem cell transplantation; therefore, there is a growing need for appropriate tx options in patients (pts) with relapsed/refractory MM (RRMM) previously treated with LEN. OPTIMISMM is the first and only phase 3 trial in early RRMM (median 1-2 prior lines) to specify prior LEN tx as an inclusion criterion. The trial showed a significant improvement in progression-free survival (PFS) with pomalidomide + bortezomib (BORT) + dexamethasone (DEX) (PVd) vs BORT + DEX (Vd) (median PFS 11.2 months (mo) [95% confidence interval (CI): 9.66-13.73] vs 7.1 mo [5.88-8.48]; hazard ratio [HR] = 0.61, 95% CI: 0.49-0.77; P < 0.0001). How the PVd results from the OPTIMISMM trial compare with results achieved with other tx options for LEN-exposed pts with RRMM has not been established. Aim: This analysis aimed to put the phase 3 OPTIMISMM (PVd) trial results into perspective by comparing with results achieved for other tx options post LEN. Methods: A systematic literature review (SLR) was conducted in May 2018 and updated in Dec 2018, in line with National Institute for Health and Care Excellence (NICE) and Cochrane guidelines, to identify randomized controlled trial (RCT) data on efficacy outcomes in LEN-exposed pts with early RRMM. Electronic database searches were performed in Embase®, MEDLINE, and the Cochrane Library, and study eligibility criteria were defined using the PICOS framework. Searches were restricted to Jan 2004 onward. Descriptive statistics were used to assess between-trial heterogeneity in study design, baseline demographics, and clinical characteristics. Where the evidence network and heterogeneity assessment suggested an indirect treatment comparison (ITC) was feasible, the analysis was conducted in the Bayesian framework, according to the NICE Decision Support Unit guidelines. Results: ENDEAVOR and CASTOR were the only relevant trials that reported PFS in pts with RRMM previously treated with LEN. Comparator txs included carfilzomib + DEX (Kd) (ENDEAVOR) and daratumumab + BORT + DEX (DVd) (CASTOR). OPTIMISMM was designed to prospectively evaluate pts who had prior LEN, whereas ENDEAVOR and CASTOR reported only pt subgroups with prior LEN; all studies reported the number of pts who were refractory to LEN, with values varying from 18% (DVd) in CASTOR to 71% (PVd) in OPTIMISMM (Table). Differences in prognostic baseline characteristics were noted between the overall study populations in OPTIMISMM and ENDEAVOR; as the corresponding data were not available for CASTOR, a full assessment of heterogeneity was not possible. Although Vd initially seemed to link the network of evidence, the comparator arm of the CASTOR trial had a fixed 8-cycle Vd tx duration, whereas pts randomized to the comparator arm in OPTIMISMM and ENDEAVOR received Vd continuously until disease progression. As the Vd arms could not be considered comparable, DVd was excluded from the ITC. Based on data from ENDEAVOR and OPTIMISMM, PVd could only be compared with Kd and Vd. Based on the ITC, Vd was associated with a statistically significant shorter PFS vs PVd (HR PVd vs Vd = 0.62, 95% credible interval [Crl]: 0.50-0.76) in the prior-LEN RRMM population. No statistically significant difference was observed in PFS for Kd vs PVd (HR PVd vs Kd = 0.90, 95% Crl: 0.62-1.28). It is important to note that pt characteristics vary between these trials, particularly regarding prior LEN. Discussion: Due to increasing use of LEN in the 1L setting and as maintenance tx, a growing population of pts with early RRMM are treated with LEN. This SLR found that OPTIMISMM is the only study to date to prospectively investigate the efficacy of regimens in this population. Only 2 other RCTs were identified that reported data for pts with prior LEN, and in both cases, these were subgroups of the overall trial population, thus limiting the robustness of the comparator data. HRs for PFS from the ITC aligned with those from OPTIMISMM, confirming the superiority of PVd over Vd. The ITC between PVd and Kd found no statistically significant difference between these regimens. Comparison with DVd was not possible given the differences in design between CASTOR and OPTIMISMM. Further studies in pts previously treated with LEN are warranted, given the impact of prior tx on outcomes for pts with early RRMM. Disclosures Weisel: Janssen: Consultancy, Honoraria, Research Funding; GSK: Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Juno: Consultancy. Dhanasiri:Celgene Corporation: Employment, Equity Ownership. Gauthier:Amaris Consulting: Employment, Equity Ownership; Celgene Corporation: Consultancy. Padhiar:Amaris Consulting: Employment. Casal:Celgene Corporation: Employment. Richardson:Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.

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