Type 1/like Calr Mutation in Momelotinib-Treated Patients with Myelofibrosis Is the Most Prominent Predictor of Drug Survival and Longevity without Transplant
Authors: Tefferi Ayalew , Pardanani Animesh D. , Begna Kebede , Al-Kali Aref , Hogan William J. , Litzow Mark R. , Gangat Naseema 
Published: December 2023

Background:

Non-transplant treatment options in myelofibrosis MF are palliative in scope and include Janus kinase 2 (JAK2) inhibitors (JAKi). FDA-approved JAKi for the treatment of MF include ruxolitinib, fedratinib, and pacritinib. A fourth JAKi, momelotinib, is currently under review. We have previously reported long-term survival data on momelotinib and drug survival that was significantly longer, retrospectively compared to ruxolitinib ( AJH. 2022;97:E433). In the current study, we focused on molecular predictors of drug survival (i.e., drug retention) and longevity without allogeneic hematopoietic stem cell transplant AHSCT (transplant-censored survival).

Methods :

The current study included data from Mayo Clinic patients who participated in a phase-1/2 core study of momelotinib (NCT00935987). Study design, drug doses and schedule, and additional details on treatment effect and side effects have previously been published. Drug survival was calculated from time of initiation of momelotinib to time of treatment discontinuation. Survival analysis required censoring of patients at time of AHSCT. Conventional statistical methods were applied using JMP Pro 16.0.0 software (SAS Institute, Cary, NC, USA).

Results :

79 JAKi-naïve patients with MF were considered: median age 67 years; males 54%; PMF 65%, post-PV MF 20%, post-ET MF 15%; JAK2 71%, type 1/like CALR ( CALR-1) 14%, CALR-2 3%, MPL 8%, triple-negative 5%. Risk category according to DIPSS was high/intermediate in 80% of the patients and unfavorable karyotype in 29%. Non-driver mutation information was available in a subset of patients and included ASXL1 22% and SRSF2 18%. Median time from diagnosis to study entry was 25.2 months; patients were enrolled between November 2009 and March 2011 with follow-up information updated through July 2023; during this period, 68 (86%) deaths, 13 (16%) leukemic transformations, and 7 (9%) AHSCTs were recorded. Median follow-up for alive patients was 12.5 years (range 11.3-13.1). Anemia response rate was 48% and spleen 47%.

Median treatment duration was 25 months (range 0.1-157); the proportion of patients remaining on active therapy was 68% at 1 year, 30% at 3 years, 16% at 5 years, and 7% at 10 years (Figure 1a). At the time of this writing, 5 (6.3%) patients were still receiving momelotinib therapy with treatment durations of 152 to 157 months. In univariate analysis, molecular predictors of drug survival included CALR-1 (p=0.006) but not ASXL1 (p=0.6) or SRSF2 (p=0.3) mutation, or unfavorable karyotype (p=0.08). The 3-, 5-, and 10-year drug survival rates for CALR-1-mutated patients were 64%, 40%, and 18%, respectively, and for CALR-1 wild-type 25%, 11%, and 4% (p=0.01, Figure 1b). CALR-1 independent association with longer drug survival was also appreciated for younger age (p&lt;0.01) and absence of baseline transfusion dependency at time of study entry (p=0.02); all three risk factors remained significant during multivariable analysis with HR (95% CI) rates of 0.4 (0.2-0.87) for CALR-1, 0.5 (0.3-0.89) for age &lt;63 years, and 0.6 (0.3-0.9) for absence of transfusion-dependency. Spleen response (p&lt;0.01) but not anemia response (p=0.23) was also associated with longer drug survival; in multivariable analysis all 4 risk factors retained significance.

Multivariable analysis of genetic variables for transplant-censored survival identified absence of CALR-1 (HR 3.5, 95% CI 1.2-10.5; p=0.03) and presence of high molecular risk (HMR; ASXL1/ SRSF2) mutations (HR 2.3, 95% CI 1.1-4.6; p=02) to independently predict inferior survival. Among 11 patients with CALR-1 mutation, median transplant-censored survival was 125 months with 10-year survival rate of 60% (Figure 1c); by contrast, the corresponding figures were 37 months and 12%, in the 68 patients not harboring CALR-1 mutation (Figure 1c). In multivariable analysis, absence of CALR-1 (HR 2.9, 95% CI 1.02-8.1), age ≥63 years (HR 3.0, 95% CI 1.5-6.0), and absence of spleen response (HR 2.6, 95% CI 1.5-4.5) were identified as being most significant in predicting inferior transplant-censored survival.

Conclusions :

CALR-1 mutation is the most important risk factor for both drug survival and longevity without AHSCT, in momelotinib-treated patients with MF. Such information might help identify MF patients who might benefit from treatment with momelotinib and in whom AHSCT might be deferred or not.