Russo, Domenico

Abstract “Nonclassical” myeloproliferative neoplasms (MPNs) and myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) represent a heterogeneous group of malignancies characterized by a wide range of clinical manifestations. Unlike classical MPNs, there is no standardized management approach for these conditions, particularly concerning the indications for and management of allogeneic hematopoietic cell transplantation. To address this gap, the European Society for Blood and Marrow Transplantation (EBMT) Practice Harmonization and Guidelines (PH&G) Committee and the Chronic Malignancies Working Party (CMWP) have collaborated to develop shared guidelines aimed at optimizing the selection and management of patients with these rare forms of neoplasms. A comprehensive review of the literature from the publication of the revised fourth edition of the (2016) World Health Organization classification onward was conducted. A multidisciplinary group of experts in the field convened to produce this document, which was developed through multiple rounds of draft circulation. Key recommendations include the early identification of potential transplant candidates, particularly in cases of chronic neutrophilic leukemia, chronic eosinophilic leukemia (CEL)/CEL, not otherwise specified (CEL-NOS), myeloid/lymphoid neoplasm with eosinophilia and tyrosine kinase gene fusions with FGFR1, JAK2, ABL1, and FLT3 rearrangements, MDS/MPN with neutrophilia/atypical chronic myeloid leukemia, and MDS/MPN, NOS. For patients with MPN, NOS/MPN unclassifiable, standard recommendations for myelofibrosis should be applied. Similarly, in MDS/MPN with thrombocytosis, transplantation is recommended on the basis of established MDS guidelines. Given the current lack of robust evidence, this document will serve as a valuable resource to guide future research activities, providing a framework for addressing critical unanswered questions and advancing the field.

Introduction: Corticosteroids (CS) are the standard first-line treatment for patients (pts) with chronic graft-versus-host disease (cGvHD), but pts can be unresponsive or become refractory to or dependent on CS (SR/D).Ruxolitinib (RUX), a JAK1/2 inhibitor, is approved for the treatment of pts ≥12 years of age with SR/D-cGVHD, based on the primary outcomes from the randomized, phase III REACH3 (NCT03112603) study, which demonstrated the superior efficacy of RUX vs best available treatment (BAT) in pts with SR/D-cGVHD. Here, we present the final, long-term efficacy and safety outcomes from REACH3. Methods: Pts ≥12 years of age with moderate or severe SR/D-cGVHD were randomized 1:1 to receive either RUX 10 mg twice daily (BID) or investigator-selected BAT and followed for 3 years, till discontinuation or death. The primary analysis was conducted at week 24 (Cycle 7 Day 1 [C7D1]) in randomized pts, then pts entered the extension period (C7-39) in which they continued treatment, switched from BAT to RUX (crossover cohort), or discontinued treatment and entered long-term survival follow-up (FU). Failure-free survival (FFS; key secondary endpoint), duration of response (DOR), overall survival (OS), non-relapse mortality (NRM), malignancy relapse (MR), and safety were analyzed at 3 years (week 156; final data cut off 15 Dec 2022). Overall response rate (ORR) and best overall response (BOR) during the crossover treatment period were analyzed for pts who switched from BAT to RUX on or after C7D1. Results: Of 329 pts randomized, 53 completed the treatment period and 276 discontinued, 115 entered survival FU (RUX: 73/165; BAT:42/164); 70 pts crossed over from BAT to RUX of which 16 completed the crossover treatment period and 24 entered survival FU. Median FFS was longer in the RUX vs BAT arms (38.4 vs 5.7 months; hazard ratio [HR]=0.361, 95% confidence interval [CI]: 0.268, 0.485) with 12-month FFS probabilities of 64.0% (95% CI: 56.1, 70.8) and 28.8% (95% CI: 21.8, 36.1), respectively. Median OS was not reached and there was no difference in risk of death between the arms (HR=0.851, 95% CI: 0.544, 1.331) [Table 1]. Median DOR was 6.4 months (95% CI: 4.9, 11.4) in the BAT arm but was not reached for the RUX arm; notably, the probability of maintaining DOR at 3 years was higher in RUX (59.6%; 95% CI: 50.4, 67.6) vs BAT (26.7%; 95% CI: 18.5, 35.5). NRM event rates were similar between the arms (RUX: 29/165; BAT 34/164), and MR events were similar and low in both arms (13/156 and 11/160, RUX and BAT respectively) up to 3 years. The ORR at week 24 after crossover from BAT to RUX was 50.0% (95% CI: 37.8, 62.2), including complete response (CR) in 4 (5.7%) pts and partial response (PR) in 31 (44.3%) pts. The BOR during crossover was 81.4% (95% CI: 70.3, 89.7), including CR of 7.1% and PR of 74.3%; disease progression only occurred in 1 pt. Almost all pts treated during the main treatment period (RUX: 100%; BAT: 93.7%) experienced ≥1 adverse event (AE) and, in general, AE rates were higher in the RUX vs BAT arms [Table 2], likely due to prolonged FU and exposure to RUX (median exposure to treatment of 52.9 weeks vs. 24.1 weeks for RUX and BAT, respectively).Anemia was the most common AE (RUX: 33.9%; BAT: 15.8%) and grade ≥3 AE for RUX (17.6% vs BAT 9.5%, respectively); grade ≥3 neutropenia, thrombocytopenia, alanine aminotransferase increase, and gamma-glutamyltransferase increase were also ≥5% higher for RUX than BAT. Anemia (24.2%; grade ≥3, 10.3%) and thrombocytopenia (3.8%) were the most common RUX and BAT treatment-related AEs, respectively. Infections, excluding tuberculosis, were the most common AE of special interest (77.6% vs. 68.4%; grade ≥3, 31.5% and 26.6%, for RUX and BAT, respectively). On-treatment deaths were mainly due to cGvHD (n/N, RUX: 10/18; BAT 6/12). Conclusions: After 3 years of treatment in REACH3, the longer FFS and higher DOR with RUX vs BAT indicated that cGVHD was more in control with RUX treatment. Notably, efficacy was demonstrated in pts who switched from BAT to RUX with an ORR similar to that in pts randomized to RUX. RUX was well tolerated with no unexpected toxicities and safety that was consistent with earlier studies. Overall, the long-term control of cGVHD and tolerability of RUX was demonstrated for pts ≥12 years of age with SR/D-cGvHD.