Hematopoietic Cell Transplantation For Myelofibrosis Research Articles

Association between the choice of the conditioning regimen and outcomes of allogeneic hematopoietic cell transplantation for myelofibrosis.

Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative treatment for myelofibrosis. However, the optimal conditioning regimen either with reduced-intensity conditioning (RIC) or myeloablative conditioning (MAC) is not well known. Using the Center for International Blood and Marrow Transplant Research database, we identified adults aged ≥18 years with myelofibrosis undergoing allo-HCT between 2008-2019 and analyzed the outcomes separately in the RIC and MAC cohorts based on the conditioning regimens used. Among 872 eligible patients, 493 underwent allo-HCT using RIC (fludarabine/ busulfan n=166, fludarabine/melphalan n=327) and 379 using MAC (fludarabine/busulfan n=247, busulfan/cyclophosphamide n=132). In multivariable analysis with RIC, fludarabine/melphalan was associated with inferior overall survival (hazard ratio [HR]=1.80; 95% confidenec interval [CI]: 1.15-2.81; P=0.009), higher early non-relapse mortality (HR=1.81; 95% CI: 1.12-2.91; P=0.01) and higher acute graft-versus-host disease (GvHD) (grade 2-4 HR=1.45; 95% CI: 1.03-2.03; P=0.03; grade 3-4 HR=2.21; 95%CI: 1.28-3.83; P=0.004) compared to fludarabine/busulfan. In the MAC setting, busulfan/cyclophosphamide was associated with a higher acute GvHD (grade 2-4 HR=2.33; 95% CI: 1.67-3.25; P<0.001; grade 3-4 HR=2.31; 95% CI: 1.52-3.52; P<0.001) and inferior GvHD-free relapse-free survival (GRFS) (HR=1.94; 95% CI: 1.49-2.53; P<0.001) as compared to fludarabine/busulfan. Hence, our study suggests that fludarabine/busulfan is associated with better outcomes in RIC (better overall survival, lower early non-relapse mortality, lower acute GvHD) and MAC (lower acute GvHD and better GRFS) in myelofibrosis.

Pulmonary Engraftment Syndrome: A Unique Complication of Allogeneic Hematopoietic Cell Transplantation for Myelofibrosis

Background: In myelofibrosis patients undergoing alloHCT, we have observed a pulmonary infiltrate predominant engraftment syndrome with or without hypoxemia. Therefore, we sought to characterize this unique syndrome further and determine its association with pre-HCT patient and disease characteristics and determine its impact on HCT outcome. Methods: From our HCT database, we identified 83 patients with primary/secondary myelofibrosis who underwent alloHCT at our institution from 2015 to 2020 at City of Hope. Data on patient demographics, disease characteristics, disease status at HCT, mutations, HCT-related variables and outcome measures were collected from patient medical records. Pulmonary ES (PES) was defined as the combination of new onset of pulmonary opacities in the absence of infection, fluid overload, and cardiac dysfunction with or without hypoxemia occurring between ten to twenty days after stem cell infusion. All statistical analysis was performed using SAS statistical software. Results: Among the 83 patients included in this study, 49% had PMF, and 51% had secondary MF. Their median age was 62 years (range 55-68) and the majority of the patients were male (n=53,64%). The JAK2 V617F mutation was detected in 65% (n=54) of patients. Prior to an alloHCT, 61% (n= 51) had received treatment with ruxolitinib. The median spleen size was 20 cm (range 16-23 cm). Graft source for allo-HCT was matched unrelated donor (MUD) in 54%, followed by matched related donor (MRD) in 23%, mis-matched unrelated (MMUD) in 12%, and Haplo-identical donor in 11%. Mobilized peripheral blood stem cells were used as a graft source in 97.6% of donors. Most patients (94%) received a non-myeloablative/reduced-intensity conditioning regimen. Tacrolimus/sirolimus was used in more than half of the patients (57.8%, n=48). The median CD34+ and CD3 cells were infused at a median 6x10^6 cells/kg (range: 2.49 - 12.96) and 2.21x10^8 cells/kg (range: 0.25 - 4.90) respectively. The median time for neutrophil engraftment was 20.0 days. 25 patients (30%) had new pulmonary infiltrates between days 10 and 20 of HCT. 22% (n=18) met the criteria for PES. Nine of those patients (50%) required an ICU admission. A majority (n=12) of patients with PES required systemic steroid therapy. Demographic factors and transplant characteristics did not reveal any risk factors for PES. Pre-HCT CT scan chest was reported as normal in 87% of patients. There was no association between abnormal CT chest before HCT and occurrence of pulmonary ES (OR 0.29, 95% CI 0.01 - 2.52, p 0.42). Pulmonary artery hypertension (defined as PASP ≥35 mmHg) was observed in 61 patients (77%) in this cohort. PAH was associated with increased risk of PES with an odds ratio 3.68 (95% CI 1.13,12; P=0.04). An abnormal pulmonary function test (PFT), defined as FEV1<80%, FEV1/FVC<70%, and DLCO< 80 were found in 19%, 23% and 72% patients during pre-HCT testing, respectively. No association was seen between PFT abnormalities and the occurrence of PES (FEV1 p=0.25 95% CI 2.60 0.50-13.32, FEV1/FVC p=1.00, 95% CI 0.84 0.08-5.40, DLCO p=0.74 95% CI 0.18-4.10). 12-month OS and 2-yr OS was 65% and 63%, respectively. Patients who experienced PES had no difference in overall survival (OS) and Non-Relapse Mortality (NRM) in comparison to those who did not have PES (HR;1.93, 95% CI 0.94-3.97, P 0.074 and HR 1.63; 95% CI 0.70- 3.83, P 0.26, respectively). There was a significant difference in ICU stay by PES (50% vs 17%, p=0.01). But length of ICU stays were not significantly different by PES (median 18 days vs 5 days, p = 0.13). Patients with median PASP>35 and pre-HCT spleen size >20 cm had worse OS in multivariate analysis (HR 2.58, 95% CI 1.24-5.40, P<0.001, and HR 4.14, 95% CI 1.83-9.36, p<0.001), while pre-HCT median PASP of greater or equal with 35 mmHg was associate with worse NRM (HR 2.42, 95% CI 1.04-5.62, p 0.040) Conclusion: In this study, we describe a novel variation of engraftment syndrome consisting of predominantly pulmonary infiltrates, occurring around the time of neutrophil engraftment in patients undergoing alloHCT for MF. Although this syndrome was not associated with decreased overall survival or increased non-relapse mortality, it was associated with significant morbidity and requires early recognition to initiate corticosteroid therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Novel therapies vs hematopoietic cell transplantation in myelofibrosis: who, when, how?

Abstract Myelofibrosis is one of the classical Philadelphia chromosome–negative myeloproliferative neoplasms characterized by progressive marrow failure and chronic inflammation. Discovery of the JAK2 mutation paved the way for development of small molecular inhibitors and further facilitated the research in understanding of molecular biology of the disease. Development of novel medications and synergistic combinations with standard JAK inhibitor (JAKi) therapy may have the potential to improve depth and duration of disease control and symptomatic benefit, whereas advancements in allogeneic hematopoietic stem cell transplantation (HCT) have improved tolerability and donor availability, allowing for more patients to pursue this potentially curative therapy. The increase in options for medical therapy and changing risk profile of HCT is leading to increased complexity in counseling patients on choice of management strategy. In this case-based review, we summarize our approach to symptom-directed medical therapy, including the use of novel drugs and combination therapies currently under study in advanced clinical trials. We outline our recommendations for optimal timing of HCT, including risk-adapted selection for early HCT as opposed to delayed HCT after upfront JAKi therapy, as well as the use of pretransplant JAKi and alternative donor sources.

Ruxolitinib Therapy during Hematopoietic Cell Transplantation for Myelofibrosis

Background :The beneficial effects of JAK 1/2 inhibitors (JAKi) ruxolitinib in MF patients have led to control of disease related symptoms,but ruxolitinib has been limited by their inability to deplete the malignant stem cell clones. Allogeneic hematopoietic cell transplantation (HCT) is currently the only treatment with proven curative potential for myelofibrosis (MF). Previous research suggested pre-HCT ruxolitinib may improve post-HCT outcome because of ruxolitinib accelerate engraftment, improve graft function, decrease the risk and severity of graft-versus-host disease (GVHD). However,HCT in PMF with higher non-relapse mortality (NRM),In the present study, we aimed to prospectively assess the effects of Rux therapy during HCT period(NCT04526223).Objective Preliminarily investigate the safety and efficacy of ruxolitinib in myelofibrosis patients during the peri-transplantation period.Method: To prospectively analyze the clinical data of 26 patients with myelofibrosis who were used DAC bridge BF as conditioning treatment and treated with ruxolitinib(5mg bid +6d to +60d) during the peri-transplantation period.Results: 26 patients were eligible if they had primary myelofibrosis (PMF) as defined by the 2008 World Health Organization classification or secondary MF as defined by the IWG for Myeloproliferative Neoplasms Research and Treatment criteria and met the criteria for Intermediate-1 (Int-1), Int-2, or high-risk disease by the DIPSS scoring system at the time of enrollment. Patients consenting to treatment with Rux for at least 8 weeks prior to HCT and could receive Rux (5mg bid +6d to +60d) during the peri-transplantation period. DAC bridge BF as Myeloablative regiment, There have been no episodes of cytokine release syndrome and all patients achieved sustained engraftment. Neutrophil reconstitution was obtained in 26 patients with a median time of 15 (10 to 31) d; platelet reconstitution was obtained in 26 patients with a median time of 26(12 to 68) d. Acute GVHD occurred in 26 patients (46.15%) , of which 1(3.8%) were ш°; chronic GVHD occurred in 9 patients (34.6%), 1 patients with extensive chronic GVHD. There patients relapsed and two patients died because of resistance to alvage treatment . With a median follow-up 336 (70-993) days，no patient died of non-relapse mortality (NRM)., overall survival is 92.3% (95% CI: 0.73, 0.97) and DFS is 88.5% (95% CI: 0.63, 0.96) at1 year post-HCT.Conclusion: This study demonstrates that Ruxolitinib therapy during HCT is well tolerated and suggests that during-HCT Rux may improve post-HCT outcome.Keywords: Ruxolitinib;Hematopoietic Cell Transplantation;Myelofibrosis DisclosuresNo relevant conflicts of interest to declare.

Superior Outcomes with Fludarabine-Busulfan (Flu/Bu) Based Conditioning for Allogeneic Hematopoietic Cell Transplantation in Myelofibrosis - a Comparative Analysis By CIBMTR

Background:Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative therapeutic modality for patients with myelofibrosis (MF). However, the optimal conditioning regimen for allo-HCT either in the myeloablative conditioning (MAC) or in the reduced intensity conditioning (RIC) setting is not well known.Methods:Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we identified adults aged ≥18 years with MF who underwent allo-HCT between the years 2008-2018. Donor types included matched sibling donor (MSD), 8/8 matched unrelated donor (MUD), and 7/8 MUD. Outcomes were compared separately in the MAC and RIC cohorts based on the most common conditioning regimens used in each setting - MAC [(Fludarabine/Busulfan (Flu/Bu) vs. Busulfan/cyclophosphamide (Bu/Cy)] or RIC [(Flu/Bu vs. Fludarabine/melphalan (Flu/Mel)]. Overall survival (OS), disease free survival (DFS), non-relapse mortality (NRM), relapse, acute and chronic graft versus host disease (GVHD) and GVHD-free relapse-free survival (GRFS) were evaluated. Survival analysis was done using Kaplan-Meier method and significant predictors were evaluated using Cox-proportional hazard regression method. Multivariable regression model included main effect (conditioning regimen) and covariates (patient age, gender, race, CMV match, disease subtype, DIPSS at HCT, comorbidities score (HCT-CI), Karnofsky performance status, prior therapy (ruxolitinib use/splenic radiation therapy/splenectomy), interval between diagnosis and transplant, conditioning intensity, stem cell source, donor-recipient HLA-match, GVHD prophylaxis, ATG/alemtuzumab use, transplant year, and center affect). All analyses were performed at a two-sided significance level of 0.05.Results:Of 872 patients who met the study criteria, 379 patients underwent allo-HCT using MAC (Flu/Bu=247, Bu/Cy=132) and 493 patients using RIC (Flu/Bu=166, Flu/Mel=327). Key baseline characteristics of the patients are summarized in Table 1. In multivariable analysis, significant differences in outcomes were observed in the MAC and RIC setting based on the choice of conditioning regimen (Table 2). In the MAC setting, Bu/Cy was associated with a higher risk of acute GVHD (grade 2-4 HR 2.33, 95% CI 1.67-3.25, p<0.01; grade 3-4 HR 2.31, 95% CI 1.52-3.52, p<0.01) and inferior GRFS (HR 1.94, 95% CI 1.49-2.53, p<0.01) as compared to Flu/Bu. In the RIC setting, Flu/Mel was associated with inferior OS (HR 1.80, 95% CI 1.15-2.81, p<0.01), higher risk of NRM (HR 1.81, 95% CI 1.12-2.91, p=0.01) and acute GVHD (grade 2-4- HR 1.45, 95% CI 1.03-2.03, p=0.03; grade 3-4 HR 2.21, 95%CI 1.28-3.83, p<0.01) as compared to Flu/Bu. These higher risks associated with Flu/Mel were primarily observed early post-transplant. The results were consistent when the outcomes were evaluated based on the two common melphalan doses employed in the RIC setting (100mg/m 2 vs 140mg/m 2).Conclusions:Our study demonstrates that the choice of conditioning regimen significantly influences the outcomes of allo-HCT in MF. The results favor Flu/Bu based conditioning in the MAC (lesser acute GVHD and better GRFS) and RIC (better OS, lower NRM, lower acute GVHD) setting. Hence, this aspect should be explored in future studies as the modification of conditioning strategies could lead to improved outcomes. [Display omitted] DisclosuresGuru Murthy: TG therapeutics: Other: Advisory board; Cardinal Health Inc.: Honoraria; Qessential: Consultancy; Guidepoint: Consultancy; Techspert: Consultancy; Cancerexpertnow: Honoraria. Sobecks: CareDX: Membership on an entity's Board of Directors or advisory committees. Scott: Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Saber: Govt. COI: Other.

Thiotepa-busulfan-fludarabine (TBF) conditioning regimen in patients undergoing allogeneic hematopoietic cell transplantation for myelofibrosis: an outcome analysis from the Chronic Malignancies Working Party of the EBMT.

Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative option in MF. There is no consensus on the optimal conditioning regimen. We report outcomes of 187 patients with MF transplanted between 2010 and 2017 conditioned with TBF. Median age was 58 years. Median interval from diagnosis to allo-HCT was 44 months. Donors were haploidentical (41%), unrelated (36%) or HLA-identical siblings (23%). Stem cell source was PB in 60%. Conditioning was myeloablative in 48% of cases. Antithymocyte globulin (ATG) was used in 41% of patients. At 100 days, neutrophil and platelet engraftment were 91% and 63% after a median of 21 and 34 days, respectively. Grade II-IV and III-IV acute GVHD occurred in 24% and 12%, while at 3 years, all grade chronic GVHD and chronic extensive GVHD had been diagnosed in 38% and 11%. At 3 years, OS, RFS and GRFS were 55%, 49% and 43%, respectively. RI and NRM were 17% and 33%. On multivariate analysis, poor KPS and the use of unrelated donors were associated with worse GRFS and a higher grade II-IV acute GVHD, respectively. Neither donor type nor intensity of the conditioning regimen influenced survival outcomes. TBF is a feasible conditioning regimen in allo-HCT for MF in all donor settings although longer term outcomes are required.

Pre- Transplant Ferritin Predicts Overall Survival and Non-Relapse Mortality in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation for Myelofibrosis

Background: Elevated serum ferritin (SF) is common in patients with myelofibrosis (MF) given the frequent red-cell transfusion requirements and impaired iron metabolism. The dysregulation of iron metabolism is associated with increased hepcidin levels which predict for inferior survival in patients with MF (Pardanani et al AJH 2013). High pre-transplant SF negatively impacts overall survival and non-relapse mortality in patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) for hematological malignancies (Chee et al BMT 2017 &amp; Yan et al 2018). However, the impact of elevated pre-transplant SF specifically on post-alloHCT outcomes has not been described in MF. Methods: We conducted a retrospective study of patients with MF undergoing allo-HCT at Mayo clinic Rochester, Arizona, and Florida from January 1st 2012 - December 31st 2019. We abstracted demographic and outcome variables to evaluate the impact of pre-transplant ferritin levels on post-transplant outcomes. We used a Receiver Operand Characteristic Curve to identify a pre-transplant serum ferritin (SF) of ≥ 1,123 ng/mL as the cutoff which best correlated with poor survival. Results: We identified 67 patients with MF who underwent allo-HCT during the study period with readily available data. Patients with a pre-transplant ferritin ≥ 1,123 ng/mL (n=18) had a median age of 59.4 years and were predominantly male (n=9, 50%) with primary myelofibrosis (n=12, 67%), had a DIPSS-plus int-2 (n=10, 56%) and high (n=6, 33%) risk categories and received a reduced-intensity conditioning (n=14, 78%) from a matched-unrelated donor (n=7, 50%) Table1. Patients with SF ≥ 1,123 ng/mL had a worse overall survival (OS) (median OS= 12.64 months [95%CI=6.08-19.20 months] vs. not-reached (NR) p=0.001). Patients with elevated SF had an increased non-relapse mortality (NRM) rate at 6 months (16.7%, [95%CI=0.4-37.2%]) vs 8.2%,[95%CI= 2.6-18.1%] p=0.021) and 12 months (33.3% [95%CI=13.0-55.4%] vs 10.4% [95%CI=3.8-21.0%] p=0.021) Patients with ≥ 1,123 ng/mL SF had a non-statistically significant higher rate of acute graft-vs-host disease grades 3-4 (28% vs 12.2% p=0.13) but similar rates of moderate to severe chronic graft-vs-host disease (31% vs 28% p=0.78). In the univariate analysis, SF ≥1,123 ng/mL and a Hematopoietic stem cell transplant comorbidity index (HCT-CI) ≥3 were associated with an increased risk of mortality (Hazard ratio [HR]=4.18 [95%CI=1.64-10.62] p=0.003] and HR=4.42 [95%CI=1.70-11.46] p=0.003, respectively). Both retained significance in multivariate analysis SF ≥1,123 ng/mL (HR= 2.80 [95%CI= 1.0-7.6], p=0.04)] and HCT-CI score ≥ 3 (HR 3.10 [95%CI= 1.12-8.62, p=0.03]) after adjusting for age, DIPSS-plus score, conditioning regimen intensity, donor type, CMV risk, prior use of ruxolitinib, and ABO mismatch. We grouped the patients into low, intermediate and high risk categories using SF level and HCT-CI scores as detailed in Figure 1. The risk category based on SF and HCT-CI was statistically significant in impacting OS and NRM in this cohort. The 12 month OS rate was lower in the high risk category (44.4% [95%CI= 13.6%-71.9%]) when compared to the intermediate (64.6%, [95%CI=39.7%-81.3%]) and low risk (91.9%, [95%CI= 76.9%-97.3%], p=0.0002) categories. Similarly, the 12 month NRM rate was higher in the high risk category (44.4%, [95%CI=11.0%-74.2%]) when compared to the intermediate (25%, [95%CI=8.7%-45.5%]) and low risk (5.3% [95%CI=0.9%-15.9%], p=0.0046) categories. Conclusion: In patients undergoing allogeneic SCT for myelofibrosis, serum ferritin ≥ 1,123 ng/mL is a predictor of high NRM and inferior OS. Combining ferritin serum levels with HCT-CI may help in better patient selection for allo-HCT in MF population. Larger patient cohort is warranted to confirm our findings. Disclosures Kharfan-Dabaja: Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy. Shah:Dren Bio: Consultancy.

Role of Allogeneic Hematopoietic Cell Transplant in Patients with Myelofibrosis in the JAK Inhibitor Era

Role of Allogeneic Hematopoietic Cell Transplant in Patients with Myelofibrosis in the JAK Inhibitor Era

Predicting Survival after Allogeneic Hematopoietic Cell Transplantation in Myelofibrosis: Performance of the Myelofibrosis Transplant Scoring System (MTSS) and Development of a New Prognostic Model.

Accurate prognostic tools are crucial to assess the risk/benefit ratio of allogeneic hematopoietic cell transplantation (allo-HCT) in patients with myelofibrosis (MF). We aimed to evaluate the performance of the Myelofibrosis Transplant Scoring System (MTSS) and identify risk factors for survival in a multicenter series of 197 patients with MF undergoing allo-HCT. After a median follow-up of 3.1 years, 47% of patients had died, and the estimated 5-year survival rate was 51%. Projected 5-year risk of nonrelapse mortality and relapse incidence was 30% and 20%, respectively. Factors independently associated with increased mortality were a hematopoietic cell transplantation-specific comorbidity index (HCT-CI) ≥3 and receiving a graft from an HLA-mismatched unrelated donor or cord blood, whereas post-transplant cyclophosphamide (PT-Cy) was associated with improved survival. Donor type was the only parameter included in the MTSS model with independent prognostic value for survival. According to the MTSS, 3-year survival was 62%, 66%, 37%, and 17% for low-, intermediate-, high-, and very high-risk groups, respectively. By pooling together the low- and intermediate-risk groups, as well as the high- and very high-risk groups, we pinpointed 2 categories: standard risk and high risk (25% of the series). Three-year survival was 62% in standard-risk and 25% in high-risk categories (P < .001). We derived a risk score based on the 3 independent risk factors for survival in our series (donor type, HCT-CI, and PT-Cy). The corresponding 5-year survival for the low-, intermediate-, and high-risk categories was 79%, 55%, and 32%, respectively (P < .001). In conclusion, the MTSS model failed to clearly delineate 4 prognostic groups in our series but may still be useful to identify a subset of patients with poor outcome. We provide a simple prognostic scoring system for risk/benefit considerations before transplantation in patients with MF.

Early post-transplantation factors predict survival outcomes in patients undergoing allogeneic hematopoietic cell transplantation for myelofibrosis

Factors predicting allogeneic hematopoietic cell transplantation (HCT) outcomes in myelofibrosis in the early post-HCT period have not been defined thus far. We attempt to study such factors that can help identify patients at a higher risk of relapse or death. This retrospective study included 79 patients who underwent first HCT for myelofibrosis at three centers between 2005 and 2016. Univariate analysis showed that red blood cell (RBC) transfusion dependence (HR 9.02, 95% CI 4.0–20.35), platelet transfusion dependence (HR 8.17, 95%CI 3.83–17.37), 100% donor chimerism in CD33 + cells (HR 0.21, 95%CI 0.07–0.62), unfavorable molecular status (HR 4.41, 95%CI 1.87–10.39), normal spleen size (HR 0.42, 95%CI 0.19–0.94), grade ≥ 2 bone marrow fibrosis (vs. grade ≤ 1; HR 2.7, 95%CI 1.1–6.93) and poor graft function (HR 2.6, 95%CI 1.22–5.53) at day +100 were statistically significantly associated with relapse-free survival (RFS). RBC transfusion dependence and unfavorable molecular status were also statistically significant in the multivariate analysis. Patients in whom both of these factors were present had a significantly worse RFS when compared to those with one or none. While limited by a small sample size, we demonstrate the significance of transfusion dependence and molecular status at day +100 in predicting outcomes.

Pulmonary hypertension is associated with increased nonrelapse mortality after allogeneic hematopoietic cell transplantation for myelofibrosis.

Allogeneic hematopoietic cell transplantation (alloHCT) is the only curative therapy for primary myelofibrosis (MF) as well as myelofibrosis secondary to other myeloproliferative neoplasms (MPN). Pulmonary hypertension (PH) is a known complication of MF and may occur in up to 50% of such patients. PH (defined as a mean pulmonary artery pressure ≥25 mmHg at rest) can eventually lead to right heart failure and may be associated with complications after alloHCT. We examined the association of PH with alloHCT outcome in patients with MF associated with MPN. Pre- and post-HCT echocardiograms were reviewed to estimate the peak pulmonary artery systolic pressure (PASP). Median PASP was 37.0 mmHg (range: 16.0-57.9) prior to HCT with 37 of 65 patients (57%) studied. With median follow-up of 35.0 months (range: 3.3-119.4) PH was significantly associated with inferior OS (58.9% vs. 88.8%, P = 0.025), primarily due to increased NRM (21.6% vs. 7.1%, P = 0.007). The majority of the deaths (8 of 14) in patients with PH occurred within 100 days after HCT. In patients with an available post-HCT echocardiogram (n = 33), the median PASP was 30 mmHg (range: 5.0-56.2); eight patients (24%) had persistent PH. Compared with pre-HCT values, PASP was significantly reduced after HCT (p < 0.001). We conclude that PH is associated with inferior survival due to the increased NRM in patients with MF undergoing alloHCT. PH appears at least partially reversible after successful alloHCT. PH should be considered a risk factor for early mortality after alloHCT and surveillance of pulmonary artery pressure in MF patients being considered for alloHCT may be useful.

Long-term outcome after allogeneic hematopoietic cell transplantation for myelofibrosis.

Allogeneic hematopoietic stem cell transplant remains the only curative treatment for myelofibrosis. Most post-transplantation events occur during the first two years and hence we aimed to analyze the outcome of 2-year disease-free survivors. A total of 1055 patients with myelofibrosis transplanted between 1995 and 2014 and registered in the registry of the European Society for Blood and Marrow Transplantation were included. Survival was compared to the matched general population to determine excess mortality and the risk factors that are associated. In the 2-year survivors, disease-free survival was 64% (60-68%) and overall survival was 74% (71-78%) at ten years; results were better in younger individuals and in women. Excess mortality was 14% (8-21%) in patients aged <45 years and 33% (13-53%) in patients aged ≥65 years. The main cause of death was relapse of the primary disease. Graft-versus-host disease (GvHD) before two years decreased the risk of relapse. Multivariable analysis of excess mortality showed that age, male sex recipient, secondary myelofibrosis and no GvHD disease prior to the 2-year landmark increased the risk of excess mortality. This is the largest study to date analyzing long-term outcome in patients with myelofibrosis undergoing transplant. Overall it shows a good survival in patients alive and in remission at two years. However, the occurrence of late complications, including late relapses, infectious complications and secondary malignancies, highlights the importance of screening and monitoring of long-term survivors.

Ruxolitinib Therapy Followed by Reduced-Intensity Conditioning for Hematopoietic Cell Transplantation for Myelofibrosis: Myeloproliferative Disorders Research Consortium 114 Study

We evaluated the feasibility of ruxolitinib therapy followed by a reduced-intensity conditioning (RIC) regimen for patients with myelofibrosis (MF) undergoing transplantation in a 2-stage Simon phase II trial. The aims were to decrease the incidence of graft failure (GF) and nonrelapse mortality (NRM) compared with data from the previous Myeloproliferative Disorders Research Consortium 101 Study. The plan was to enroll 11 patients each in related donor (RD) and unrelated donor (URD) arms, with trial termination if ≥3 failures (GF or death by day +100 post-transplant) occurred in the RD arm or ≥6 failures occurred in the URD. A total of 21 patients were enrolled, including 7 in the RD arm and 14 in the URD arm. The RD arm did not meet the predetermined criteria for proceeding to stage II. Although the URD arm met the criteria for stage II, the study was terminated owing to poor accrual and a significant number of failures. In all 19 transplant recipients, ruxolitinib was tapered successfully without significant side effects, and 9 patients (47%) had a significant decrease in symptom burden. The cumulative incidences of GF, NRM, acute graft-versus-host disease (GVHD), and chronic GVHD at 24 months were 16%, 28%, 64%, and 76%, respectively. On an intention-to-treat basis, the 2-year overall survival was 61% for the RD arm and 70% for the URD arm. Ruxolitinib can be integrated as pretransplantation treatment for patients with MF, and a tapering strategy before transplantation is safe, allowing patients to commence conditioning therapy with a reduced symptom burden. However, GF and NRM remain significant.

Allogeneic hematopoietic cell transplantation for myelofibrosis (MF) in high risk patients.

7062 Background: Although allogeneic transplantation(alloHCT) is the only curative treatment modality for MF, given the median age of MF, most patients are not candidates for alloHCT due to concerns for treatment-related mortality(TRM), age and comorbidities. Methods: We reviewed the outcomes of 24 recipients of matched related/unrelated donor alloHCT for MF at the Medical College of Wisconsin. All patients with JAK2 mutation(62%) and/or constitutional symptoms recieved Roxulitinib atleast 4 months prior to alloHCT with discontinuation of Ruxolitinib 48 hrs prior to the start of conditioning. Majority(91%) received conditioning with Fludarabine and Busulfan(Flu/Bu4, Flu/Bu3,Flu/Bu4). Only 2 patients received TBI based regimen; Flu/TBI(2-4Gy). Those with splenomegaly &gt; 22cm received pre-transplant splenic radiation(n = 11;49%). Survival outcomes were analyzed using Kaplan-Meier curves and compared between groups using log-rank test. Results: Median age was 57 years(range,40-67) with 29% &gt; 60 years. A 46% had primary ET or PV that evolved to MF and 17% had MDS cytogenetics. Majority(74%) patients MF-3 grade. More than 80% recieved Ruxolitinib and 25% were treated with hypomethylating/cytotoxic chemotherapy. HCT-CI score was≥3 in 62%. Four patients had cirrhosis and portal hypertension(PHTN), and another 3 had PHTN without Cirrhosis.At median follow up of 36months, 3-year overall survival(OS) and relapse-free survival were(RFS) 70%. Marrow fibrosis improved post HCT with only 15% grade 3. One patient relapsed and died from AML 15 months post-HCT. TRM was 25% at 3 years; causes of death were sepsis(n = 3), alveolar hemorrhage(n = 1) and myocardial infarction(n = 1). Variables such as type of donor, DIPSS scoring, MF grade and age of the patient were not significantly associated with OS/RFS on univariate analysis. Conclusions: Despite advanced age and 62% with HCT CI≥3, we report excellent survival outcomes compared to other prior data. Careful patient selection, use of Ruxolitinib pre-HCT, splenic irradiation pre-HCT and Flu/Bu based conditioning regimen all contributed to the remarkable results in this series.

The Impact of Allogeneic Hematopoietic Cell Transplantation (HCT) and Treatment with Ruxolitinib on Survival in Patients with Myelofibrosis

Allogeneic HCT is curative in myelofibrosis (MF) with a survival (OS) advantage compared to non-JAK-inhibitor treatments in patients (pts) with Int-2/high-risk DIPSS (Kroeger et al, Blood 2015). On the other hand, data demonstrate a OS benefit of the JAK1/JAK2 inhibitor ruxolitinib (RUX) in intermediate (Int)-2/high-risk IPSS (Cervantes et al, Blood 2013; Verstovsek et al, Haematologica 2015). Yet, comparative data to the impact of RUX and HCT on OS are lacking. This was pursued retrospectively at the University of Leipzig in light of clinical-, cytogenetic-, phenotype-driver-, and somatic mutations-based prognostic variables.Patient and Methods: RUX became available in November, 2009. MF pts (n=137; median age 58y) seen afterwards were included with the exception of MPL + pts (small number). Characteristics are shown in table 1. RUX was given for spleenomegaly and/or constitutional symptoms [n=76 (55%)]. Irrespective of RUX, a donor search was initiated in int-2 and high-risk IPSS pts < 70 y and HCT performed if a suitable donor identified. Based on this biologic randomization, 50 (37%) received HCT, 58 (42%) continued with RUX (median exposure 19 months), and 29 (21%) pts had other options. The RUX- and HCT-groups were balanced in terms of IPSS, platelets, cytogenetic-, and epigenetic molecular-risks. Treatment was initiated within the first year (median 10 months), thus probability of OS 5 years after diagnosis was calculated (SPSS20 software). Cytogenetic-risk was conducted according to Caramazza et al. Leukemia 2011. Somatic mutations detected by NGS were used to calculate molecular-risk (Vannucchi et al. Leukemia 2013).Results: Median OS time was 6.8 y. The RUX-group was older (median age 64 y) with profound spleenomegaly and a higher JAK2 V617F allele burden compared to the HCT group (median age 55 y) (p<0.0005). The 56% OS at 5 years in the RUX group was comparable to that after HCT (60%; p=0.5). In the transplant setting, prior RUX-treatment (n=21; OS 65%) had no negative impact compared to up-front HCT (n=29; OS 55%) (p=0.9). Whilst IPSS low-/int-1-risk retained its survival impact (p=0.04), OS at 5 years was comparable for int-2 and high-risk. OS in the HCT and RUX groups for int-2 was 59% and 62% respectively (p=0.4) and for high-risk IPSS 54% and 50% respectively (p=0.2). Advanced age was associated with an inferior OS (p=0.002) and correlated with higher IPSS, transfusion-dependency and thrombocytopenia. In the HCT group, OS in pts <50 y was 91% vs. 49% in pts >50 y (p=0.001). In the RUX group, age <60 and not <50 y was OS-relevant [79% in pts <60y vs. 43% in those >60 y (p=0.02)]. No prognostic implication of anemia, WBC, peripheral blasts, and constitutional symptoms could be detected with both treatments. OS in JAK2 + pts was similar to CALR + pts in both therapy cohorts (p=0.3). Triple negativity retained its detrimental influence (p<0.0001) even after HCT, with frequent AML-typical mutations (transcription and/or signaling genes) and a leukemic transformation (LT) rate of 35%. Although spliceosome mutations were associated with anemia (p=0.004)/transfusion-dependency (p=0.006) and mutations in chromatin modifiers (ASXL1, EZH2) with splenomegaly(p=0.02),high-molecular epigenetic risk had no impact on OS or LT in the treatment groups. Unfavourable cytogenetics were associated with LT (p=0.04) but not OS in the two groups. Of the 24 pts with a LT, 15 (62%) received no RUX and no HCT.Conclusions: Our data imply that, besides allogeneic HCT, a prolonged JAK1/JAK2 inhibition could, at least partly, attenuate most of the prognostic detrimental parameters. Pre-treatment with ruxolitinib prior to HCT does not seem to have a negative impact on survival. It is the first time where outcome with a non-transplant procedure is shown to be comparable to that after HCT in MF, even in high-risk disease. This needs to be verified in prospective randomized trials to define the role of allogeneic HCT in the era of JAK1/JAK2 inhibition.Table 1Patients characteristics ( n = 137 )VariableImpact on OSImpact on LTMedian age (years)580.0020.6JAK2+/CALR+/Double negative (%)63 / 20 / 17<0.00050.04Median number of MF-related mutations (range)1 (0-5)0.40.07High-molecular risk profile (%)(ASXL1, EZH2, SRSF2, IDH1/2)33.60.80.7Mutations in transcription/signaling genes (%)280.30.008Unfavorable cytogenetics (%)300.10.04IPSS (Int-2 / high-risk) (%)34 / 410.040.2 DisclosuresRoskos:Novartis: Honoraria. Al-Ali:Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding.

Allogeneic hematopoietic cell transplantation for myelofibrosis in patients pretreated with the JAK1 and JAK2 inhibitor ruxolitinib

The Janus-activated kinase 1 (JAK1) and JAK2 inhibitor ruxolitinib is effective in decreasing symptomatic splenomegaly and myelofibrosis (MF)-related symptoms. However, allogeneic hematopoietic cell transplantation (HCT) remains the only curative option. We evaluated the impact of ruxolitinib on the outcome after HCT. A cohort of 14 patients (median age 58 years) received a subsequent graft from related (n=3) and unrelated (n=11) donors after a median exposure of 6.5 months to ruxolitinib. At HCT, MF risk for survival according to the International Prognostic Scoring System was intermediate-2 or high risk in 86% of patients. Under ruxolitinib, MF-related symptoms were ameliorated in 10 (71.4%) patients and the palpable spleen reduced by a median of 41% in 7 (64%) of 11 patients with splenomegaly. Engraftment occurred in 13 (93%) patients. Acute GvHD grade-III occurred in 2 (14%) patients. Median follow-up was 9 months. Survival, EFS and treatment-related mortality were 78.6, 64 and 7%, respectively. Through the anti-JAK-mediated reduction in both cytokines and splenomegaly as well as improvement in performance status, ruxolitinib might improve outcome after allogeneic HCT in patients with MF. The downregulation of inflammatory cytokines might have a beneficial impact on graft failure and acute GvHD.

Allogeneic hematopoietic cell transplantation for myelofibrosis in the era of JAK inhibitors

AbstractThe discovery of JAK2617F mutation paved the way for the development of small molecule inhibitors of JAK1/2 resulting in first approved JAK1/2 inhibitor, ruxolitinib, for the treatment of patients with myelofibrosis (MF). Although JAK1/2 inhibitor therapy is effective in decreasing the burden of symptoms associated with splenomegaly and MF-related constitutional symptoms, it is neither curative nor effective in reducing the risk of leukemic transformation. Presently, allogeneic hematopoietic cell transplantation (HCT) is the only curative therapy for MF. A significant risk of regimen-related toxicities, graft failure, and GVHD are major barriers to the success of HCT in MF. Because of significant HCT-associated morbidity and mortality, divergent opinions regarding its appropriate role in this clinical situation have emerged. In this review, the risk-benefit ratios of modern drug therapy compared with HCT in MF patients are analyzed. A risk-adapted approach individualized to each patient's biologic characteristics and comorbidities is described, which is currently warranted in determining optimal treatment strategies for patients with MF. Inclusion of JAK1/2 inhibitor therapy in future transplant conditioning regimens may provide an opportunity to overcome some of these barriers, resulting in greater success with HCT for MF patients.

Allogeneic hematopoietic cell transplantation for myelofibrosis: A 10‐year experience at single institution

Allogeneic hematopoietic cell transplantation (HCT) remains the only curative approach for patients with myelofibrosis [1,2]; however, it can result in substantial transplant related mortality. We retrospectively examined the outcomes of 18 myelofibrosis patients who underwent allogeneic HCT between 2000 and 2008. Eleven (61%) had high-risk prognostic scores. Fourteen (78%) received a reduced-toxicity regimen of pharmacokinetically-targeted (a median AUC of 5,300 μm min ―1 ; range, 3,500-6,000) intravenous busulfan plus fludarabine (t-IV Bu/Flu). Source of hematopoietic cells were from HLA matched-related (50%), matched-unrelated (44%), or mismatched-unrelated (6%) donors. Fourteen (78%) received G-CSF-mobilized peripheral blood stem cells. Median time to neutrophil and platelet engraftment were 17 (range, 15-28) and 18 (range, 8-213) days, respectively. There were two cases of secondary graft failure after myeloablative conditioning and one case following t-IV Bu/Flu. Overall survival was 50.2% at 54 months (95% confidence interval [C: 24.1-71.6%) with a median follow-up of 15 (range, 3-63) months. Nonrelapsed mortality (NRM) at 100 days and at 1-year were 0 and 22.6% (95% CI: 9.1-49.7%), respectively. The causes of NRM comprised of infections (56%) and graft-versus-host-disease (44%). t-IV Bu/Flu is a feasible conditioning regimen for allogeneic HCT in myelofibrosis showing encouraging engraftment with 7% graft failure rate.

A retrospective comparison of conventional intensity conditioning and reduced-intensity conditioning for allogeneic hematopoietic cell transplantation in myelofibrosis

A retrospective comparison of conventional intensity conditioning and reduced-intensity conditioning for allogeneic hematopoietic cell transplantation in myelofibrosis

Allogeneic hematopoietic cell transplantation in myelofibrosis with myeloid metaplasia

Myelofibrosis with myeloid metaplasia is a clonal disorder resulting from proliferation of aberrant hematopoietic progenitors. It can occur either de novo or secondary to an antecedent chronic myeloid disorder such as essential thrombocythemia or polycythemia vera. The only curative option is allogeneic hematopoietic cell trans-plantation, which can result in durable donor engraftment and regression of myelofibrosis in approximately 50% of eligible patients. Unfortunately the median age at presentation is 65 years and many patients have serious comorbidities, so the vast majority of patients are excluded from such an approach. Reduced-intensity conditioning regimens have been shown to result in successful engraftment and resolution of myelofibrosis with less toxicity, although follow-up remains relatively short. Complications such as graft-versus-host disease remain the major barrier to greater success. At present this modality is generally restricted to younger patients with intermediate-to high-risk disease. We provide a current algorithm for incorporating allogeneic transplantation into the management of patients with myelofibrosis. We are hopeful that recent advances in allogeneic transplantation, combined with progress in understanding the molecular pathobiology of chronic myeloproliferative disorders, will lead in the near future to a further refinement of prognostic determinants, new molecular targets to exploit, and therefore a dynamic evolution of the indications for allogeneic transplantation.