Abstract
Introduction
CMML is an MDS/MPN overlap syndrome associated with poor overall survival. Like myelofibrosis, CMML patients (pts) suffer from profound disease related symptoms and splenomegaly with no optimal treatment options to improve OS or quality of life (QOL). Notably, the JAK2 inhibitor ruxolitinib was approved in myelofibrosis based partially on symptom score improvements, which have subsequently been strongly correlated with improvement in OS. Unlike myelofibrosis, no QOL tool exists specifically for CMML pts to evaluate symptom response after treatment. While response criteria for clinical benefit including the MPN-SAF TSS have been proposed, these have not yet had been validated or correlated with clinical outcomes. To study the impact of QOL improvements in CMML pts, we leveraged our phase II clinical trial with ruxolitinib for CMML because all pts on study reported daily MPN-SAF TSS and ruxolitinib improves QOL as measured by MPN-SAF TSS in pts with myelofibrosis. We test the hypothesis that changes in MPN-SAF and clinical benefit are associated with improved outcomes in pts with CMML.
Methods
Key eligibility criteria for this study included confirmed diagnosis of CMML and having either symptomatic splenomegaly or MPN-SAF TSS >17, ANC ≥ 250/μL, plts ≥35,000/ μL, serum creatinine <2.0 mg/dL, and serum bilirubin < 1.5 x ULN. Ruxolitinib was administered at 20 mg PO BID at the previously identified RP2D. Response was assessed using the proposed International Working Group (IWG) response criteria for MDS/MPNs and symptom change assessed using MPN-SAF TSS. Primary endpoint was defined as the proportion of patients achieving clinical benefit or better response. Serial blood counts, chemistry and bone marrow assessment were conducted to assure safety and assess efficacy. Spleen volume was measured by CT imaging and percentage of spleen volume reduction (SVR) was captured.
Results
Among 29 pts enrolled at 4 centers between 9/2019 and 6/2022, the median age was 74 years (63-87); 93% were white and 62% male. Most pts had CMML-0 (62%) and proliferative CMML (69%), and 59% were high risk by Mayo Clinic CMML risk model. Two pts had prior hypomethylating agents and 2 had received hydroxyurea. The most common mutations at baseline were TET2, SRSF2, and ASXL1. Among 18 pts with known mutation profile at baseline, 12 pts (67%) had proliferative mutations detected (RAS, CBL, and JAK2). The median duration of follow up was 42 months (mo) with 2 pts remaining on treatment. The median duration of treatment was 7.5 mo (0.5-46).
The median OS was 21 mo (95% CI 7.5-34.8) from enrollment on study. Clinical benefit per MDS/MPN IWG criteria was achieved in 82% of pts (23/28). The median OS was 23.4 mo (95% CI 14.5-32.2) for pts with clinical benefit versus 4.9 mo (95%CI 3.9-5.9, p=.04). Among 20 pts evaluable for spleen response, 30% (6/20) achieved ≥ 35% SVR measured by CT scan. The mean baseline MPN-SAF TSS was 31.3 (8-58). There was no difference in baseline TSS score based on mutation profile or subtype. The mean change from baseline was Δ -26 (-79 to 100) at day 30, Δ -40.5 (-87 to 55) at day 60, Δ -41.25 (-91 to 82) day 90, and Δ -29.65 (-92 to 82) at day 120. 57% (16/28) of patients achieved MPN-SAF TSS >50% reduction, the proposed cut-off for response. There was no difference in clinical benefit, SVR35, and TSS>50% reduction based on baseline clinical data or mutation profile (proliferative vs non-proliferative mutations).
The median OS for pts with MPN-SAF TSS >50% reduction at any time point was 23.4 mo (95%CI 19.4-27.4) versus 7.7 mo (95%CI 1.9-13.4, p=.39). The median duration on treatment was 9.2 mo (95%CI 7.9-10.4) versus 4 mo (95% CI .8-7.3-9.6,p=0.06) for those with TSS<50% reduction. The median OS for pts who achieved MPN-SAF TSS >25% reduction was 24.3 mo (95%CI 22.3-26.4) versus 6.3 mo (95%CI 2.7-9.9, p=0.008). The median duration on treatment was 9.2 mo (95%CI 8.6-9.8) versus 5.6 mo (95% CI 1.58-9.6) (p=0.01) in favor of those with TSS > 25%.
Conclusions
Ruxolitinib was associated with clinical benefit in the majority of patients with CMML and symptom improvement was associated with improved OS. The baseline symptom burden by MPN-SAF TSS of CMML patients is comparable between dysplastic and proliferative subtypes. MPN-SAF TSS improvement of >25% is a clinical marker of overall survival and duration on treatment. Future studies should explore reduction in MPN-SAF TSS>25% as a surrogate marker of clinical outcomes in CMML.
DeZern:Keros: Membership on an entity's Board of Directors or advisory committees; geron: Other: dsmb; servier: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibbs: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Appellis: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees. Carraway:Abbvie: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Stemline: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Luskin:Pfizer: Honoraria; KITE: Honoraria; Jazz: Honoraria; AbbVie: Research Funding; Novartis: Honoraria, Research Funding. Roboz:AbbVie, Amgen, Astrazeneca, Caribou Biosciences, Celgene, Daiichi Sankyo, Ellipses pharma, Geron, GSK, Glycomimetics, Janssen, Jasper Pharmaceuticals, Jazz Pharmaceuticals, Molecular Partners, Oncoverity: Consultancy; Janssen: Research Funding; OncoPrecision: Current holder of stock options in a privately-held company, Honoraria; Novartis, Pfizer, Roche, GlaxoSmithKline, BMS, Syndax, Rigel: Consultancy. Chan:Jazz: Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Aptitude Health: Honoraria. Gerds:Agios: Consultancy; Disc Medicine: Consultancy; PharmaEssentia: Consultancy; Rain Oncology: Consultancy; GSK: Consultancy; AbbVie: Consultancy; BMS: Consultancy. Kuykendall:Protagonist Therapeutics: Honoraria, Research Funding; Novartis: Research Funding; PharmaEssentia: Honoraria; Incyte: Honoraria. Steensma:Ajax Therapeutics: Current Employment; Novartis Pharmaceuticals: Ended employment in the past 24 months; Bluebird Bio: Current equity holder in publicly-traded company; Arrowhead: Current equity holder in publicly-traded company; Gamida Cell: Divested equity in a private or publicly-traded company in the past 24 months. Lancet:Prelude Therapeutics: Consultancy, Other: Bristol Myers Squibb; Bristol Myers Squibb: Consultancy, Other: Consultant/Advisory Board; Tradewell Therapeutics: Consultancy, Other: Consultant/Advisory Board. Sekeres:Schroedinger: 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, Research Funding; Kurome: Membership on an entity's Board of Directors or advisory committees. Sallman:Abbvie: Consultancy; Agios: Consultancy; Axiom: Consultancy; Gilead: Consultancy; Celyad: Consultancy; Froghorn: Consultancy; Incyte: Consultancy; Intellisphere, LLC: Consultancy; Johnson & Johnson: Consultancy; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; NextTech: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; AvenCell: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; BlueBird Bio: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Dark Blue Therapeutics: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Jasper Therapeutics: Membership on an entity's Board of Directors or advisory committees; NKARTA: Membership on an entity's Board of Directors or advisory committees; Orbital Therapeutics: Membership on an entity's Board of Directors or advisory committees; Rigel Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Apera: Research Funding; Jazz: Research Funding. Komrokji:Keros: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; DSI: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy; Sobi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sumitomo Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gero