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Randomized Controlled Trial
. 2017 Sep 29;10(1):156.
doi: 10.1186/s13045-017-0527-7.

Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses

Srdan Verstovsek  1 , Jason Gotlib  2 , Ruben A Mesa  3 , Alessandro M Vannucchi  4 , Jean-Jacques Kiladjian  5 , Francisco Cervantes  6 , Claire N Harrison  7 , Ronald Paquette  8 , William Sun  9 , Ahmad Naim  9 , Peter Langmuir  9 , Tuochuan Dong  10 , Prashanth Gopalakrishna  11 , Vikas Gupta  12
Affiliations
Randomized Controlled Trial

Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses

Srdan Verstovsek et al. J Hematol Oncol. .

Abstract

Background: Myelofibrosis (MF) is associated with a variety of burdensome symptoms and reduced survival compared with age-/sex-matched controls. This analysis evaluated the long-term survival benefit with ruxolitinib, a Janus kinase (JAK)1/JAK2 inhibitor, in patients with intermediate-2 (int-2) or high-risk MF.

Methods: This was an exploratory analysis of 5-year data pooled from the phase 3 COMFORT-I and -II trials. In both trials, patients could cross over to ruxolitinib from the control group (COMFORT-I, placebo; COMFORT-II, best available therapy). All continuing patients in the control groups crossed over to ruxolitinib by the 3-year follow-up. Overall survival (OS; a secondary endpoint in both trials) was evaluated using pooled intent-to-treat data from patients randomized to ruxolitinib or the control groups. OS was also evaluated in subgroups stratified by baseline anemia and transfusion status at week 24.

Results: A total of 528 patients were included in this analysis; 301 were originally randomized to ruxolitinib (COMFORT-I, n = 155; COMFORT-II, n = 146) and 227 to control (n = 154 and n = 73, respectively). The risk of death was reduced by 30% among patients randomized to ruxolitinib compared with patients in the control group (median OS, 5.3 vs 3.8 years, respectively; hazard ratio [HR], 0.70 [95% CI, 0.54-0.91]; P = 0.0065). After correcting for crossover using a rank-preserving structural failure time (RPSFT) method, the OS advantage was more pronounced for patients who were originally randomized to ruxolitinib compared with patients who crossed over from control to ruxolitinib (median OS, 5.3 vs 2.3 years; HR [ruxolitinib vs RPSFT], 0.35 [95% CI, 0.23-0.59]). An analysis of OS censoring patients at the time of crossover also demonstrated that ruxolitinib prolonged OS compared with control (median OS, 5.3 vs 2.4 years; HR [ruxolitinib vs censored at crossover], 0.53 [95% CI, 0.36-0.78]; P = 0.0013). The survival benefit with ruxolitinib was observed irrespective of baseline anemia status or transfusion requirements at week 24.

Conclusions: These findings support ruxolitinib treatment for patients with int-2 or high-risk MF, regardless of anemia or transfusion status. Further analyses will be important for exploring ruxolitinib earlier in the disease course to assess the effect on the natural history of MF.

Trial registration: ClinicalTrials.gov identifiers, NCT00952289 and NCT00934544 .

Keywords: Anemia; Myelofibrosis; Overall survival; Ruxolitinib; Transfusion.

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Conflict of interest statement

Ethics approval and consent to participate

Both trials (COMFORT-I and -II) were approved by the institutional review boards at each participating site and conducted in accordance with the International Conference on Harmonization guidelines for Good Clinical Practice. All patients provided written informed consent.

Consent for publication

Not applicable.

Competing interests

SV has served on advisory boards for Incyte Corporation and received research funding for the conduct of clinical studies from Incyte Corporation, Roche, AstraZeneca, Lilly Oncology, Geron, NS Pharma, Bristol-Myers Squibb, Celgene, Gilead, Seattle Genetics, Promedior, CTI BioPharma Corp, Galena BioPharma, Pfizer, and Genentech. JG has received honoraria and research funding from Incyte Corporation and served on an advisory committee for Incyte Corporation. RAM has received research funding from Incyte Corporation, Gilead, CTI BioPharma Corp, Promedior, and Celgene; he has served as a consultant for Novartis, Ariad, and Galena. AMV has received research funding from and served on advisory committees and speakers bureaus for Novartis. J-JK has received research funding from Novartis and AOP Orphan. FC has served on advisory committees for Novartis, Baxalta, and AOP Orphan and on speakers bureaus for Novartis and Baxalta. CNH has received honoraria from and served on speakers bureaus for Novartis, Shire, CTI BioPharma Corp, Gilead, Baxalta, and Incyte Corporation; served as a consultant for Novartis, CTI BioPharma, and Baxalta; and received research funding and reimbursement for travel accommodations or expenses from Novartis. RP served on speakers bureaus for and received research funding from Ariad, Bristol-Myers Squibb, and Novartis. WS, AN, and PL are employees of and have equity ownership in Incyte Corporation. TD is an employee of and has equity ownership in Novartis Pharmaceutical Corporation. PG is an employee of and has equity ownership in Novartis Pharma AG. VG has served as a consultant for and received research funding from Incyte Corporation and Novartis and has received honoraria from Novartis.

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Figures

Fig. 1
Fig. 1
Overall survival: 5-year pooled data. OS analysis of 5-year pooled data from the COMFORT-I and -II trials. Data are presented a for the ITT population, b corrected for crossover with the RPSFT model, c censored at crossover, and d stratified by IPSS risk status. Originally presented at the American Society of Hematology 58th Annual Meeting [13]. HR, hazard ratio; int-2, intermediate-2; IPSS, International Prognostic Scoring System; ITT, intent-to-treat; NE, not evaluable; OS, overall survival; RPSFT, rank-preserving structural failure time
Fig. 2
Fig. 2
Overall survival: 5-year pooled data stratified by baseline anemia status and week 24 transfusion status. OS analysis of 5-year pooled data from the COMFORT-I and -II trials stratified by baseline anemia status and week 24 transfusion status. Patients in the ruxolitinib and control groups were stratified by anemia status at baseline and (a, b, e, f) transfusion independence status at week 24 or (c, d, g, h) transfusion dependence status at week 24. OS probability in the ruxolitinib group was not significantly affected by transfusion status at week 24 (transfusion independent vs not independent, P = 0.1322*; transfusion dependent vs not dependent, P = 0.4547*), but was significantly affected in the control group (transfusion independent vs not independent, P = 0.0004*; transfusion dependent vs not dependent, P = 0.0323*). Baseline anemia was defined as receiving any units of RBCs within 12 weeks before baseline measurement or having baseline hemoglobin < 10 g/dL; nonanemic was defined as not meeting criteria for anemia. Transfusion independence at week 24 was defined as the absence of RBC transfusions and hemoglobin levels ≥ 8 g/dL during weeks 13 to 24; not transfusion independent at week 24 was defined as requiring RBC transfusions or hemoglobin levels < 8 g/dL during weeks 13 to 24. Transfusion dependence at week 24 was defined as requiring ≥ 4 units of RBCs or hemoglobin levels < 8 g/dL during weeks 17 to 24; not transfusion dependent at week 24 was defined as requiring < 4 units of RBCs and hemoglobin levels ≥ 8 g/dL during weeks 17 to 24. Originally presented at the American Society of Hematology 58th Annual Meeting [13]. IPSS, International Prognostic Scoring System; OS, overall survival; RBC, red blood cell. *Stratified by study, IPSS risk, and baseline anemia status
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