Ruxolitinib in cytopenic myelofibrosis: Response, toxicity, drug discontinuation, and outcome

Patients with cytopenic myelofibrosis (MF) have more limited therapeutic options and poorer prognoses compared with patients with the myeloproliferative phenotype.


INTRODUCTION
Myelofibrosis (MF) is a rare, chronic, Philadelphia chromosomenegative myeloproliferative neoplasm (MPN) that may present as primary disease (PMF) or secondary to essential thrombocythemia or polycythemia vera (SMF). 1 Cytopenic MF includes patients with thrombocytopenia, leukopenia, and/or anemia. 2 Moderate (platelet counts, 50-100 � 10 9 /L) thrombocytopenia frequently pairs with anemia and is present in approximately 25% of patients at diagnosis. 3 The prevalence increases to 45% at 1 year after diagnosis and to more than 70% at any time during follow-up. 4,5 The prognostic significance of a platelet count <100 � 10 9 /L and hemoglobin <10 g/dL is incorporated into the Dynamic International Prognostic Scoring System (DIPSS) 6 and DIPSS-Plus 7

and in the Mutation and Karyotype-Enhanced International
Prognostic Scoring System for PMF. 8 Similarly, a platelet count <150 � 10 9 /L and hemoglobin <11 g/dL are poor prognostic markers in the Myelofibrosis Secondary to Polycythemia Vera and Essential Thrombocythemia Prognostic Model (MYSEC-PM). 9 The role of leukopenia in the prognosis of MF is less thoroughly validated. 10,11 A recent retrospective study showed that the cytopenic phenotype is associated with high-risk clinical and molecular features and correlates with inferior survival in patients with prefibrotic and overt PMF. 12 Also, treatment options are limited in patients with cytopenic MF. Ruxolitinib is a JAK1/JAK2 inhibitor that may significantly improve MF-related splenomegaly and symptoms. 13,14 However, patients with moderate thrombocytopenia are treated with low doses, whereas those with platelet count below 50 � 10 9 /L are excluded from treatment. 15 Ruxolitinib is also burdened by on-target hematological toxicity, with many dose reductions and treatment discontinuations caused by anemia and/or thrombocytopenia. 16,17 New JAK2 inhibitors, namely fedratinib, pacritinib, and momelotinib, are becoming available for the treatment of MF and may have a role in patients with cytopenia.
In the current study, we investigated the prognostic correlates of the cytopenic phenotype in a large cohort of patients with MF requiring ruxolitinib therapy, in terms of response and toxicity rates, drug discontinuations, and outcome.

Patients and study design
After institutional review board approval, the RUX-MF retrospective study collected 886 patients with chronic-phase MF who received ruxolitinib outside clinical trials in 26 hematology centers dedicated to treating MF. The list of the participating centers is available in the Appendix. All centers were asked to report, in an electronic case report form, their consecutive patients with MF who received ruxolitinib according to standard clinical practice. The total number of medical files was reported by each center by data input into an electronic database developed to record all study data after deidentifying patients with an alphanumeric code to protect personal privacy. Any treatment decision, including starting ruxolitinib doses and dose adjustments over time, was at the physician's discretion, based on patients' characteristics and independent from participation to this study. After the first data entry, the follow-up information was validated with revision of clinical data, and specific queries were addressed to the participating center in case of inconsistent data. All PALANDRI ET AL. patients were followed from 2013 until death or to data cutoff (June 28, 2022), with a median follow-up time of 4.4 years.

Definitions
Diagnoses of PMF and SMF were made according to 2016 World Health Organization criteria and International Working Group on Myelofibrosis Research and Treatment criteria, respectively. 18 Cytopenias at ruxolitinib start were defined as follows: white blood cell <4 � 10 9 /L, hemoglobin <11 g/dL for males and <10 g/dL for females, and platelets (PLTs) <100 � 10 9 /L. Cytopenic phenotype was defined by the presence of at least one cytopenia. Patients not included in the cytopenic group were considered as having a proliferative phenotype.
Risk category was assessed at the time patients started on ruxolitinib according to the DIPSS in PMF and to the DIPSS/MYSEC-PM in SMF. 6,9 Histologic examination was performed at local institutions; fibrosis was graded according to the European Consensus Grading System. 20 Unfavorable karyotype was categorized as previously described. 7 Diagnosis of leukemic transformation was made according to World Health Organization criteria. 18 (Figures 2A-C).

Baseline characteristics associated with cytopenic phenotype
This was also confirmed in PMF and SMF patients separately.
Notably, ruxolitinib starting dose was 5 or 10 mg twice daily in   Main reasons for discontinuation were hematological toxicity (17.9%), lack/loss of spleen response (23.3%), and leukemic transformation (13.8%). Among patients who discontinued ruxolitinib, 6.3% underwent ASCT and 6.7% were later enrolled in an investigational clinical trial. Reasons for discontinuation, including ASCT, were comparable among cytopenic and proliferative patients, except for hematological toxicity, which was higher in patients with cytopenia (21.8% vs. 12.5%, p = .005). After competing risk analysis, the cumulative incidence of ruxolitinib discontinuation at 5 years was 57% and 38% in cytopenic and proliferative patients (p < .001), with a median time to discontinuation of 1.8 versus 2.9 years, respectively ( Figure 3A). Incidence of ruxolitinib discontinuation was significantly higher in patients with ≥2 cytopenias compared with one cytopenia (median discontinuation time, 1.1 vs. 2.0 years, respectively; p < .001). Analyzing PMF and SMF separately, cytopenic phenotype remained significantly associated with higher incidence of ruxolitinib discontinuation in both settings (p = .03 in PMF and p < .001 in SMF) ( Figure S1A-C).

Impact of cytopenic phenotype on outcome
After competing risk analysis, the cumulative incidence of leukemic transformation was not different between cytopenic and proliferative phenotypes (19% vs. 14% at 5 years, respectively; p = .06) ( Figure 3B). This was also confirmed in the separate analysis of PMF (p = .37) and SMF (p = .16). Considering prefibrotic PMF only, the cumulative incidence of leukemic transformation was significantly higher in patients with a cytopenic phenotype (16% vs. 26% in proliferative patients; p = .05) ( Figure S1D). No differences were observed between cytopenic and proliferative patients with overt PMF (20% vs. 22%; p = .41).

DISCUSSION
The efficacy of ruxolitinib in cytopenic MF, and the prognostic impact of these hematological features in a homogeneously treated cohort, is unknown.
Here, we observed that most (45.9%) patients presented at least one (mainly, anemia) cytopenia and 20.6% more than one cytopenias at treatment start. A cytopenic phenotype was associated with prognostically detrimental genetic markers (HMR mutations and unfavorable karyotype) and with higher DIPSS/MYSEC-PM risk category. These results are in line with those observed in a cohort of patients with prefibrotic and overtly fibrotic PMF at diagnosis. 12 Notably, the percentage of patients who started ruxolitinib at intermediate 1 risk was high overall (55.2%) and increased over the years up to 70%. Early real-life use of ruxolitinib was likely related to F I G U R E 2 Ruxolitinib (RUX) starting (A) and median doses during the first 3 months (B) and overall (C) according to cytopenic/ proliferative phenotype and according to platelet (PLT) count at ruxolitinib start (D-F). *p < .001. **Patients who started with a ruxolitinib dose lower than expected based on platelet count.
the demonstration that early treatment could improve the likelihood of responses, without worsening the toxicity profile at least in the short to medium term, and possibly improving survival. [22][23][24][25][26] The presence of cytopenias resulted in using lower doses of ruxolitinib, both at the beginning of therapy and on average during the first 3 months and throughout the observation period. This was partially expected because the dose of ruxolitinib is determined by platelet count. However, a substantial number of patients (n = 365; 41.2% of the total cohort) started ruxolitinib at lower doses than expected based on platelet count. Of these, 48.5% had other cytopenia (mostly, anemia) that might warrant reduced initial dosing.
Indeed, the prospective Realise phase 2 study recently showed that ruxolitinib start at the dose of 10 mg twice daily may be beneficial in patients with baseline anemia. 27 In the remaining 188 patients (21.2% of the total cohort), ruxolitinib was started at low doses by clinical decision only.
A significantly lower rate of spleen and symptoms response at 6 months was observed in cytopenic MF. This adverse result may be primarily related to the use of lower ruxolitinib doses. Indeed, a correlation between dose and response has been observed in the prospective phase 1/2 trial and in real-world studies. [28][29][30] Because dose also correlates with hematological toxicity, we accordingly observed a lower rate of drug-induced anemia in patients with cytopenia.
The probability of ruxolitinib discontinuation was significantly higher in patients with cytopenic MF. Also, survival was worse in patients with cytopenic PMF and SMF and in those with more than one cytopenia. The substantial overlap between this outcome result and that observed in a retrospective cohort of patients with PMF undergoing heterogeneous therapeutic strategies 12 suggests that the cytopenic phenotype has a key prognostic value, likely because of its association with high-risk biological features, which ruxolitinib does not significantly alter. Additionally, both absence of spleen response and ruxolitinib discontinuation are associated with worse 23,31 outcome. Finally, after competing risk analysis, the cumulative incidence of leukemic transformation was not statistically different among cytopenic and proliferative patients. However, we confirmed a significant association between cytopenic phenotype and worse outcome in patients pre-PMF, as already showed by Coltro et al. 12 Overall, this study shows that cytopenic MF has a lower probability of therapeutic success with ruxolitinib as monotherapy and suggests that these patients should be considered for alternative therapeutic strategies. Unlike ruxolitinib, fedratinib seems effective and tolerable with standard dosing in patients with moderate thrombocytopenia without the need for titration during treatment course [32][33][34][35] Pacritinib, a JAK2, FLT3, and IRAK1 inhibitor, is characterized by less myelosuppression compared with ruxolitinib and fedratinib and seems to be most promising in patients with MF and severe thrombocytopenia. [36][37][38] Momelotinib is an oral JAK1/2, ACVR1 inhibitor that reduces expression of hepcidin, with increased iron availability for erythropoiesis and significant rates of anemia response. 39,40 The implementation of new drugs specifically tailored to this patient population represents an important focus of future clinical research and practice.