Page 38 - 2019_04-Haematologica-web

D.P. McLornan et al.
a large retrospective study.61 A targeted 16-gene panel was used to analyze a total of 169 patients (110 with primary myelofibrosis, 46 with secondary myelofibrosis and 13 in transformation). Multivariate analysis revealed that the presence of a CALR mutation was associated with favor- able overall survival (HR: 0.448; P=0.03) and progression- free survival (HR: 0.393; P=0.01), and reduced NRM (HR, 0.415; P=0.05). Additionally, both IDH2 and ASXL1 muta- tions were independent prognostic risk factors for reduced progression-free survival (HR: 5.451; P=0.002 and HR: 1.53; P=0.008, respectively). Interestingly, ‘triple negativi- ty’ did not appear to have a significant effect on post- transplant outcomes in this cohort although the numbers analyzed were small. Overall, where possible and depend- ent on local facilities, we recommend that a targeted gene panel is used to determine the mutational risk profile.
Poor graft function
Despite initial engraftment, it is well established that poor graft function can be problematic and patients may remain transfusion dependent and/or require growth fac- tor support for a considerable period. Alchalby et al. reported that the cumulative incidence of poor graft func- tion was 17% in a cohort of 100 RIC allogeneic SCT patients and that the median onset of this complication was day +49 (range, 24-99 days).62 Poor graft function was defined by either two or three cytopenias (hemoglobin <100 g/L, neutrophil count <1.0×109/L, platelet count <30×109/L) at day +30 after allogeneic SCT, with transfu- sion requirements in the presence of complete donor chimerism and an absence of severe GvHD/disease relapse. Persistence of significant splenomegaly at day +30 remained a significant risk factor for poor graft function and univariate analysis revealed an association with older recipient age, perhaps reflecting age-related changes in a hostile bone marrow niche. Poor graft function did not appear to influence survival. Of relevance, Hart et al. recently compared engraftment kinetics in a small cohort of acute myeloid leukemia and myelofibrosis allogeneic SCT recipients.63 Compared to the group with acute myeloid leukemia, the myelofibrosis patients had marked early clearance of hematopoietic stem cells due to early splenic pooling accompanied by a significant reduction in VCAM1 expression in the bone marrow niche which may well explain, in part, the observed early poor graft func- tion. Whether JAK inhibitor-mediated reductions in splenomegaly will result in lower incidences of poor graft function remains undetermined. Judicious monitoring of chimerism and appropriate growth factor and transfusion support are necessitated by the recognition that some patients may require stem cell top up or consideration given to splenectomy if bulky splenomegaly persists.
Measurable residual disease monitoring and donor lymphocyte infusion strategies
Measurable residual disease (MRD) monitoring to guide weaning of immunosuppression with or without utiliza- tion of immunotherapeutic strategies has become well established in the setting of allogeneic SCT for myelofibro- sis. Alchalby et al. demonstrated that clearance of detectable JAK2V617F after allogeneic SCT was associated with a significantly reduced risk of relapse.59 Both MPL and CALR mutations can be used as markers of MRD.64-65 More recently, the significance of MRD was evaluated in a large, single-center cohort (n=136), in which pre-transplant
molecular profiling revealed JAK2V617F (n=101), MPL (n=4) and CALR (n=31) mutations.66 Individuals with a detectable mutation at either day +100 or day +180 had a significantly higher risk of clinical relapse at 5 years compared to those in whom molecular studies were negative (62% versus 10%, P<0.001 and 70% versus 10%, P<0.001, respectively). Multivariate modeling revealed that detectable MRD at day +180 and high-risk disease status were significant fac- tors associated with higher relapse rates. MRD status and chimerism studies should be used in tandem to determine whether donor lymphocyte infusions are required. Kroger et al. described the use of both pre-emptive (n=8) and sal- vage donor lymphocyte infusion (n=9) regimens in 17 myelofibrosis patients undergoing allogeneic SCT, high- lighting the utility of MRD monitoring for guiding donor lymphocyte infusions and that pre-emptive strategies take precedence over salvage approaches.67
Relapse following allogeneic stem cell transplantation: is this still a significant clinical problem?
Relapse remains a significant issue following allogeneic SCT for myelofibrosis. Longer term follow-up of the EBMT prospective study described above suggested relapse rates of up to 25% at 5 years.32 A more recent EBMT retrospective study by McLornan et al. investigated the management and outcomes of 202 relapsed patients.68 The overall median time to relapse was relatively short at 7 months (range, 1.4-111). Patients who relapsed early had significantly worse outcomes than those of patients who relapsed later. Management approaches to the relapse episode were heterogeneous and direct comparisons were not possible; however, there was a suggested benefit from adoptive immunotherapeutic approaches with donor lym- phocyte infusions and/or a second allograft. There is some experience on the use of using JAK inhibitors following relapse to bridge to a second transplant and for symptom control but no improvements in donor chimerism or reductions in JAK2 allelic burden, where applicable, were seen.69 Pre-emptive use of JAK inhibitors in the post-trans- plant setting to reduce relapse incidence is of interest and requires prospective studies.
Conclusions
Rapid advances in the availability of novel therapeutic agents for myelofibrosis has made it increasingly complex to gauge the timing and sequencing of allogeneic SCT in the patient’s care process. Nonetheless, allogeneic SCT remains the only curative approach for transplant-eligible patients. All available prognostic information and recent scoring systems should be utilized, including comprehen- sive mutational profiling where available, to stratify real- istic patient-specific prognostic outcomes and assess the risk-benefit ratio. Changes in practice are required so that potential candidates are assessed by transplant physicians at an earlier stage, even if this is only to discuss and pro- vide information about the procedure, assess fitness and identify potential donors. JAK inhibitors have become an integral part of the pre-allogeneic SCT pathway for many patients and increasing data on outcome analysis are now available. Overall, the use of these drugs prior to allogene- ic SCT appears to be safe, with no adverse effects on engraftment; tapering is appropriate leading up to condi- tioning therapy and there is emerging data concerning
666
haematologica | 2019; 104(4)