Stem Cell Transplantation For Myelofibrosis Research Articles

Myeloablative and Reduced-Intensity Conditioned Allogeneic Hematopoietic Stem Cell Transplantation in Myelofibrosis: A Retrospective Study by the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation.

This retrospective study by the European Society for Blood and Marrow Transplantation analyzed the outcome of 2224 patients with myelofibrosis (MF) who underwent allogeneic stem cell transplantation (allo-SCT) between 2000 and 2014; 781 (35%) underwent myeloablative conditioning (MAC) and 1443 (65%) reduced-intensity conditioning (RIC). Median patient age was 52.9 years (range, 18 to 74 years) and 57.5 years (range, 21 to 76 years) in the MAC and RIC cohorts, respectively. Donor type was similar: matched sibling donors (MAC, 317 [41%]; RIC, 552 [38%]) and unrelated donors (MAC, 464 [59%]; RIC, 891 [62%]). Median time to both neutrophil and platelet (>20 × 109/L) engraftment did not differ between cohorts. Rates of grade II to IV acute GVHD were 28% (MAC) and 31% (RIC; P = NS). Cumulative chronic GVHD rates (limited/extensive) were 22%/27% (MAC) and 19%/31% (RIC; P = .10). Cumulative incidences of nonrelapse mortality (NRM) at 1, 3, and 5 years were 25.5%, 32.2%, and 34.6% (MAC) and 26.3%, 32.8%, and 34.4% (RIC), respectively. There was a trend toward a higher relapse rate with RIC regimens compared with MAC (P = .08); rates at 1, 3, and 5 years were 10.9%, 17.2%, and 20.1% (MAC) and 14%, 19.7%, and 23.2% (RIC), respectively. No significant difference in 5-year probabilities of overall survival (OS) was noted: MAC (53.0%; 95% confidence interval [CI], 49.1% to 56.9%) and RIC (51.0%; 95% CI, 48.3% to 53.7%); P = .78. Regarding the composite end point of GVHD-free/relapse-free survival (GRFS), the unadjusted Kaplan-Meier estimate of 5-year GRFS was 32.4% (95% CI, 29.0% to 36.1%) in the MAC group and 26.1% (95% CI, 23.9% to 28.2%) in the RIC group (P = .001). In the MAC cohort, multivariable analysis confirmed worse OS and NRM with older age (>50 years), using an unrelated donor and a Karnofsky Performance Status of 80 or less. For the RIC cohort, worse OS and NRM were associated with age 60 to 70 years compared with younger recipients, use of a mismatched donor, and poor performance status. In conclusion, although similar OS rates existed for both cohorts overall, this study suggests that MAC should still be used for younger individuals suitable for such an approach due to a trend toward less relapse and an overall suggested advantage of improved GRFS, albeit this should be examined in a more homogeneous cohort. RIC allo-SCT still offers significant survival advantage in the older, fitter MF allograft patient, and optimization to reduce significant relapse and NRM rates is required.

State-of-the-art review: allogeneic stem cell transplantation for myelofibrosis in 2019.

Advances in understanding the pathogenesis and molecular landscape of myelofibrosis have occurred over the last decade. Treating physicians now have access to an ever-evolving armamentarium of novel agents to treat patients, although allogeneic hematopoietic stem cell transplantation remains the only curative approach. Improvements in donor selection, conditioning regimens, disease monitoring and supportive care have led to augmented survival after transplantation. Nowadays, there are comprehensive guidelines concerning allogeneic hematopoietic stem cell transplantation for patients with myelofibrosis. However, it commonly remains difficult for both physicians and patients alike to weigh up the risk-benefit ratio of transplantation given the inherent heterogeneity regarding both clinical course and therapeutic response. In this timely review, we provide an up-to-date synopsis of current transplantation recommendations, discuss usage of JAK inhibitors before and after transplantation, examine donor selection and compare conditioning platforms. Moreover, we discuss emerging data concerning the impact of the myelofibrosis mutational landscape on transplantation outcome, peritransplant management of splenomegaly, poor graft function and prevention/management of relapse.

Assessment of Quality of Life Following Allogeneic Stem Cell Transplant for Myelofibrosis

Background:Myelofibrosis (MF) is a bone marrow disorder characterized by anemia, splenomegaly and constitutional symptoms. There has been substantial work documenting quality of life (QoL) in patients with MF, however, very little data about patients following allogeneic stem cell transplant (alloSCT) for MF. Many patients decline alloSCT due to concerns secondary to QoL.Methods:Medical facts and patient reported outcomes (PRO) measures were collected within a month prior to transplant, at day 30, 100 and 1 year post alloSCT. PRO measures include Brief Fatigue Inventory, Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT), global assessment of change and the Myeloproliferative Neoplasms Symptom Assessment Form (MPN-SAF). The group was measured as a whole, and the patients in the upper quartile of MPN-TSS (the aggregate score of the 10 core items of the MPN-SAF) were also considered.Results:Fifty patients were enrolled on this study, 47 who proceeded with transplant. The median age of the patients was 63, ranging from 35-74. The majority of the patients were male (29, 66%), and Caucasian (43 (96%)). Most patients had primary MF (26, 59%), 9 patients had post-PV MF, and 9 patients had post-ET MF. Twenty patients had DIPSS Intermediate 2 risk disease, and 16 had DIPSS high risk disease. Twenty-six (51%) had a matched unrelated donor, 12 (30%) had a matched related donor and 5 (12%) had a mismatched unrelated donor. The majority of the patients had RIC regimens (35, 88%). At baseline the mean MPN-TSS was 27.7 (out of possible 100), and at day 30, day 100 and 1 year it was 24.6, 32.0, and 25.0, which reflected no significant change between the time points. Interestingly, all the MPN specific symptoms (including fevers, night sweats, pruritis, abdominal pain) had a significant improvement at least one time point following alloSCT. Patients in the highest quartile based on baseline TSS score (12 patients with scores at baseline greater than or equal to 37), had significant improvement in TSS score at day 100, headache at day 30, insomnia at day 100, night sweats at day 100, itching at day 100 and overall QOL at day 100. With regards to the FACT BMT, as would be expected, there was a significant decline in the FACT BMT total score, as well as trial outcome index (TOI) at day 30, but a return to close to baseline by one year.In the global assessment of change, on day 30, 11 (27.5%) of patients reported feeling a little/moderately/very much better overall quality of life since their transplant and 27 (67.5%) felt a little/moderately/very much worse quality of life. At day 100, 11 (31.4%) reported better quality of life and 20 (57%) reported worsening since transplant. By one year, 17 (60.7%) reported feeling better and 7 (25%) reported worsening.These findings did not appear to have a correlation with presence or absence of graft versus host disease. We were unable to assess the impact of conditioning as the majority of the patients had RIC conditioning.Discussion/ Conclusions:Our study evaluated the quality of life in patients with myelofibrosis who have undergone bone marrow transplantation. We have shown that there is very little change in symptom burden over the first year following transplant in general; however, significant improvement was observed in MF specific symptoms, and in patients who had a high symptom burden at baseline. By one year 61% felt that their QoL was better than it was prior to transplant. Our findings suggest that many of the patients do not experience a significant decline in QoL at 1 year after alloSCT, and actually report that their QoL improves. Further investigation is required to validate these findings. DisclosuresPalmer:Novartis: Research Funding. Dueck:Phytogine: Employment; Pfizer: Honoraria; Bayer: Employment. Mesa:Novartis: Consultancy; NS Pharma: Research Funding; Incyte Corporation: Research Funding; UT Health San Antonio - Mays Cancer Center: Employment; Pfizer: Research Funding; CTI Biopharma: Research Funding; Celgene: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Genentech: Research Funding.

Family Mismatched Allogeneic Stem Cell Transplantation for Myelofibrosis: Report from the Chronic Malignancies Working Party of European Society for Blood and Marrow Transplantation

This analysis included 56 myelofibrosis (MF) patients transplanted from family mismatched donor between 2009 and 2015 enrolled in the European Society for Blood and Marrow Transplantation database. The median age was 57years (range, 38 to 72); 75% had primary MF and 25% had secondary MF. JAK2 V617F was mutated in 61%. Donors were HLA mismatched at 2 or more loci. Stem cells were sourced from bone marrow in 66% and peripheral blood in 34%. The median CD34+ cell dose was 4.8 × 106/kg (range, 1.7 to 22.9; n = 43). Conditioning was predominantly myeloablative in 70% and reduced intensity in the remainder. Regimens were heterogeneous with thiotepa, busulfan, fludarabine, and post-transplant cyclophosphamide used in 59%. The incidence of neutrophil engraftment by 28days was 82% (range, 70% to 93%), at a median of 21days (range, 19 to 23). At 2years the cumulative incidence of primary graft failure was 9% (95% CI 1% to 16%) and secondary graft failure was 13% (95% CI 4% to 22%). The cumulative incidence of acute graft-versus-host disease (GVHD) grades II to IV and III to IV was 28% (95% CI 16% to 40%) and 9% (95% CI 2% to 17%) at 100days. The cumulative incidence of chronic GVHD at 1 year was 45% (95% CI 32% to 58%), but the cumulative incidence of death without chronic GVHD by 1 year was 20% (95% CI 10% to 31%). With a median follow-up of 32 months, the 1- and 2-year overall survival was 61% (95% CI 48% to 74%) and 56% (95% CI 41% to 70%), respectively. The 1- and 2- year progression-free survival was 58% (95% CI 45% to 71%) and 43% (95% CI 28% to 58%), respectively, with a 2-year cumulative incidence of relapse of 19% (95% CI 7% to 31%). The 2-year nonrelapse mortality was 38% (95% CI 24% to 51%). This retrospective study of MF allo-SCT using family mismatched donors demonstrated feasibility of the approach, timely neutrophil engraftment in over 80% of cases, and acceptable overall and progression-free survival rates with relapse rates not dissimilar to the unrelated donor setting. However, strategies to minimize the risk of graft failure and the relatively high nonrelapse mortality need to be used, ideally in a multicenter prospective fashion.

Stem cell transplantation in myelofibrosis

Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg Germany This is an open access Abstract Book distributed under the Attribution-NonCommercial-NoDerivs (CCBY-NC-ND), which allows third parties to download the abstracts and share them with others as long as they credit the author and the abstract book, but they cannot change the content in any way or use them commercially. http://creativecommons.org/licenses/by-nc-nd/4.0

258 - Immunosuppression Withdrawal is an Effective Treatment of Relapse after Allogeneic Stem Cell Transplant for Myelofibrosis

258 - Immunosuppression Withdrawal is an Effective Treatment of Relapse after Allogeneic Stem Cell Transplant for Myelofibrosis

Is allogeneic stem cell transplantation for myelofibrosis still indicated at the time of molecular markers and JAK inhibitors era?

The role of allogenic stem cell transplantation (ASCT) is still debated in myelofibrosis (MF). A retrospective analyzed was performed to compare the outcome of 71 patients with intermediate-2 or high-risk Dynamic International Prognosis Scoring System+ (DIPSS+) primary (PMF) or secondary (SMF) myelofibrosis with an indication of ASCT as they ultimately underwent the procedure (n=34) or not (n=37). Five-year overall survival (OS) was not statistically different between both groups (allograft: 52% vs no allograft: 34%, P=.12). However, progression to myelodysplastic syndrome or acute myeloid leukemia at 5years was significantly lower in transplanted patients (14% vs 50%, P=.01). In univariate analysis, 5-year OS was significantly higher for transplanted vs non-transplanted patients with unfavorable karyotype (75% vs 0%, P=.001), SMF (71% vs 20%, P=.001) or high DIPSS+ score (46% vs 15%, P=.03). There was also a trend for better 5-year OS in allografted patients with high JAK2V617F burden (>65%) (75% vs 8%, P=.07). Interestingly, the survival of patients who did not proceed to ASCT was dramatically increased by the use of ruxolitinib. Not all intermediate-2/high-risk DIPSS+ MF patients benefit from ASCT, especially since the introduction of JAK2 inhibitors.

Impact of Molecular Genetics on Outcome in Myelofibrosis Patients after Allogeneic Stem Cell Transplantation

Molecular genetics may influence outcome for patients with myelofibrosis. To determine the impact of molecular genetics on outcome after allogeneic stem cell transplantation, we screened 169 patients with primary myelofibrosis (n = 110), post-essential thrombocythemia/polycythemia vera myelofibrosis (n = 46), and myelofibrosis in transformation (n = 13) for mutations in 16 frequently mutated genes. The most frequent mutation was JAK2V617F (n = 101), followed by ASXL1 (n = 49), calreticulin (n = 34), SRSF2 (n = 16), TET2 (n = 10), U2AF1 (n = 11), EZH2 (n = 7), MPL (n = 6), IDH2 (n = 5), IDH1 (n = 4), and CBL (n = 1). The cumulative incidence of nonrelapse mortality (NRM) at 1 year was 21% and of relapse at 5 years 25%. The 5-year rates progression-free (PFS) and overall survival (OS) were and 56%, respectively. In a multivariate analysis CALR mutation was an independent factor for lower NRM (HR, .415; P = .05), improved PFS (HR, .393; P = .01), and OS (HR, .448; P = .03). ASXL1 and IDH2 mutations were independent risk factors for lower PFS (HR, 1.53 [P = .008], and HR, 5.451 [P = .002], respectively), whereas no impact was observed for “triple negative” patients. Molecular genetics, especially CALR, IDH2, and ASXL1 mutations, may thus be useful to predict outcome independently from known clinical risk factors after allogeneic stem cell transplantation for myelofibrosis.

383 - Comparison of Reduced-Intensity Conditioning Regimens Used in Patients Undergoing Hematopoietic Stem Cell Transplantation for Myelofibrosis

383 - Comparison of Reduced-Intensity Conditioning Regimens Used in Patients Undergoing Hematopoietic Stem Cell Transplantation for Myelofibrosis

258 - Quality of Life Following Allogeneic Stem Cell Transplant for Myelofibrosis

258 - Quality of Life Following Allogeneic Stem Cell Transplant for Myelofibrosis

Quality of Life Following Allogeneic Stem Cell Transplant for MF

Background:Myelofibrosis (MF) is a myeloproliferative neoplasm that is characterized by significant scar tissue and fibrosis in the bone marrow, enlarged spleen and/or liver from extramedullary hematopoiesis, and may include significant constitutional symptoms such as bone pain, night sweats, pruritis, and cachexia. The only curative therapy is allogeneic stem cell transplant. Although the symptom burden has been explored in the literature, the impact of hematopoietic stem cell transplant (HCST) on QoL in patients with MF has not been evaluated. We sought to longitudinally describe QoL in patients undergoing HCST for MF.Methods:We prospectively followed patients undergoing HSCT for MF. We assessed symptoms, functioning, and QoL using the FACT-BMT and MPN-SAF total symptom score (TSS) pre-transplant and at day 30, day 100 and one year post-transplant. Scores at the post-transplant time points were compared with baseline scores by paired t-tests. Pearson correlations between FACT-BMT and MPN-SAF TSS questionnaires were also computed.Results:16 patients were enrolled [median age 64.0 (49-69) years; 13 (81%) male; 13 (81%) Caucasian], two did not have day 30 data as they died prior to then or did not go to transplant. Fourteen patients had day 30 information, 11 had day 100 information, and only 4 had one year information. Of the 14 who had day 30 information, 6 patients died within the first year, two from treatment related mortality and four from relapse. One patient had intermediate-1 risk, the remainder of the patients were intermediate-2 or high risk. All patients had RIC conditioning. Mean MPN-SAF TSS score was 28.1 (SD=14.2) and FACT-BMT total score was 99.8 (SD=17.4) at baseline. FACT-BMT and MPN-SAF TSS at baseline were inversely correlated; lower symptom score was associated with higher QoL (r=-0.62; p=0.01). FACT-BMT at day 30 was lower (mean change: -12.5, SD=16.7; p=0.03). Two MF-specific symptoms showed improvement that reached statistical significance compared to baseline: night sweats mean improvement day 30, 2.5 (SD=3.1; p=0.01) and mean improvement day 100, 1.7 (SD=2.6; p=0.05, Figure 1); headache mean improvement day 100, 1.5 (SD=1.9) p=0.02. In general, scores showed a worsening at day 30, improvement at day 100 and stability at one year. The MPN-SAF TSS worsened at day 30 (6 points) and improved by day 100 (4.5 points). Changes that showed improvement at day 100 include Brief Fatigue Inventory (BFI) with a mean improvement of 1.2 points and concentration (1 point). Of the four surveys that were collected at one year, a modest decline was noted in BFI (1.5 points), inactivity (1.5 points) and cough (3 points). However improvements were noted in night sweats (2.25 points), abdominal discomfort (1 point), insomnia (1.75 points), bone pain (1 point).Discussion:This is the first study to evaluate serially the QoL and symptom burden of patients who underwent a transplant for MF. A decline in QoL in the first 30 days was observed, with modest improvement at day 100. Few surveys have been completed at 1 year to date in this ongoing study. Collection of surveys past one year may be more informative regarding long-term impact of transplant on quality of life. [Display omitted] DisclosuresMesa:Gilead: Research Funding; Novartis: Consultancy; Ariad: Consultancy; CTI Biopharma: Research Funding; Galena: Consultancy; Celgene: Research Funding; Promedior: Research Funding; Incyte: Research Funding.

A Novel Somatic Mutation in IKZF1 Is Common in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplant for Myelofibrosis

Background:Myeloproliferative neoplasms (MPN) including polycythemia vera, essential thrombocytosis, and primary and secondary myelofibrosis (MF) are characterized by driver mutations in JAK2, CALR, and MPL. Additional somatic variants can be seen. Currently allogeneic hematopoietic stem cell transplant (HCT) is the only treatment with curative potential, but it is associated with a high risk of mortality, exceeding 50% in some patient subsets. The risk of disease progression usually outweighs the risk of transplant in patients with advanced MF. Here, we have evaluated the mutational profile using a targeted next-generation sequencing panel of 54 genes involved in myeloid neoplasms in patients with MF treated with HCT.Patients and Methods:48 patients with a diagnosis of primary (n=18) or secondary (n=30) MF who received a HCT at our center and from whom genomic DNA was available from pre-HCT marrow aspirates were evaluated. DNA was isolated from whole marrow aspirates obtained prior to HCT. Paired-end indexed libraries were sequenced at an average read depth of 1000x on Illumina MiSeq platform. Sequences were aligned to hg19 using the Burrows-Wheeler Aligner, and nucleotide variants were identified using the Genome Analysis Toolkit and Picard tools. Variants were annotated with ANNOVAR. Variants present at >5% variant allele frequency (VAF) with at a minimum of 25 variant reads were selected for further analysis. Variants were called "mutations" if they resulted in (1) non-synonymous changes in amino acid sequence, including nonsense and missense mutations, (2) the variant was known to be associated with hematologic malignancies in COSMIC database, or (3) the variant was present at < 0.5% in 1000 genomes and ExAC databases. Comparisons between clinical variables and mutations were analyzed with chi-square tests, adjusted for multiple testing.Results:The average age of the 48 patients was 55 years (range 23-72) and 52% of patients were female. Disease risk was estimated with DIPSS-Plus (High 33%, INT-2 53%, INT-1 7%, Low 7%). Unfavorable cytogenetics were present in 27% of patients. Donors included a matched sibling donor in 30% (n=14), a matched unrelated donor in 60% (n=29), and an alternative donor in 10% (n=5). At 3 years, overall survival was 52%, 17% of patients had relapsed disease, and 31% had non-relapse mortality.In our cohort, 38% had a mutation in CALR (n=15 type-I and n=3 type-II), 29% in JAK2 (n=14), 0% in MPL, and 33% were triple-negative (n=16; no evidence of CALR, JAK2, or MPL mutation). The average VAF of CALR mutations was 50% (range 20-82%) and JAK2 mutations was 58% (range 25-81%). In addition to driver mutations, 94% of patients had at least one other mutation in 26 of the 54 genes sequenced. On average, patients had 2.1 other mutations (range 0-5 mutations in addition to driver mutation). The most common other mutations were in ASXL1 (31%), IKZF1 (23%), ETV6 (17%), and U2AF1 (17%). The VAF of these other mutations spanned 9-76%.Patients with triple-negative MF were more likely to have primary MF (p=0.019) and platelets <100 (p<0.001), than patients with JAK2 and CALR mutations. Patients with ≥3 other mutations were more likely to have hemoglobin <10 (p=0.02) and a higher rate of relapse (p<0.01) than patients with <3 other mutations. Patients with ASXL1 mutations were more likely to have peripheral blood blasts (p<0.001).Mutations in ASXL1, ETV6, and U2AF1 have been previously reported in myeloid malignancies. Like other groups, we found ASXL1 mutations associated with worse prognosis. Here we report a novel, recurrent mutation in the gene IKZF1. All patients with IKZF1 mutation carried the same insertion of 11 nucleotides leading to an early frameshift and ultimate nonsense mutation (L92fs), which would lead to deletion of the zinc-finger domain. Such a mutation likely leads to loss of IKZF1 tumor suppressor function.Conclusions:Somatic mutations, in addition to driver mutations, are common in patients with MF treated with HCT. Mutation profiling in this patient subset may improve relapse risk prediction. Loss of heterozygosity on chromosome 7 mapping to the IKZF1 locus has been found by others to be associated with leukemic transformation in patients with MPN (Jaeger et al. 2010. Leukemia. 24: 1290). Given their frequency in this high risk MF population, further study of the role of IKZF1 mutations in MPN is warranted. DisclosuresRadich:Novartis: Consultancy, Other: laboratory contract; Bristol-MyersSquibb: Consultancy; TwinStrand: Consultancy; ARIAD: Consultancy; Pfizer: Consultancy.

Outcome Improvement After Allogeneic Stem-Cell Transplantation in Myelofibrosis.

Outcome Improvement After Allogeneic Stem-Cell Transplantation in Myelofibrosis.

Incidence and risk factors of poor graft function after allogeneic stem cell transplantation for myelofibrosis.

Allogeneic hematopoieteic stem cell transplantation (HSCT) is the only curative treatment for myelofibrosis (MF), but it is still associated with significant risks and complications. One of these complications is poor graft function, but incidence and risk factors have not been studied yet. We retrospectively studied a cohort of 100 patients with primary MF or post-ET/PV MF who received a reduced-intensity HSCT in our center. The cumulative incidence of primary leukocyte engraftment was 98%. The cumulative incidence of poor graft function was 17% and all of the cases occurred before day 100 after HSCT at a median of 49 days (range 24-99 days). In the univariate analysis, age as continuous parameter (P=0.05; hazard ratio 1042) and persistence of significant splenomegaly (defined as palpable splenomegaly of ⩾10 cm under costal margin) at d+30 after HSCT (33% vs 12%; P=0.05) showed an increased cumulative incidence of poor graft function. In conclusion, the incidence of poor graft function after HSCT for MF is rather high, but did not influence survival. Persistence of splenomegaly after transplantation is a significant factor for poor graft function in myelofibrosis patients. Whether therapeutic reduction of splenomegaly before HSCT would result in a lower incidence of poor graft function should be investigated in future studies.

Allogeneic Transplantation for Patients With Advanced Myelofibrosis: Splenomegaly and High Serum LDH are Adverse Risk Factors for Successful Engraftment

Thirty consecutive patients underwent hematopoietic stem cell transplantation for myelofibrosis (MF) at our institution. The median age at the time of transplant was 49 (range, 18-68) years, 74% of patients had advanced Dynamic International Prognostic Scoring System (DIPSS) scores, and 83% received reduced-intensity conditioning. With a long follow-up of our patients, we analyzed disease and transplant variables that contributed to engraftment and outcomes. Neutrophil engraftment was achieved in 27 patients (90%) at a median time of 15 (range, 10-44) days, and 19 patients (63%) achieved platelet recovery at a median time of 18 (range, 8-100) days. Splenomegaly was associated with poor neutrophil engraftment (subdistributional hazard ratio [SHR], 0.42; 95% confidence interval [CI], 0.21-0.83; P= .01) and platelet engraftment (SHR, 0.18; 95% CI, 0.07-0.48; P<.001). Increased levels of lactate dehydrogenase (LDH) was associated with poor platelet engraftment (SHR, 0.39; 95% CI, 0.16-0.94; P= .04). The median follow-up for surviving patients was 49 (range, 3-155) months. The 1-year cumulative incidence of nonrelapse mortality (NRM) and relapse were respectively, 57% (95% CI, 29%-76%) and 25% (95% CI, 7%-48%). Increased levels of LDH was associated with high NRM (SHR, 2.82; 95% CI, 1.08-7.35; P=.03). The 4-year overall survival (OS) and relapse-free survival (RFS) were 44% (95% CI, 29%-67%) and 37% (95% CI, 23%-61%), respectively. In the multivariable model, splenomegaly and Eastern Cooperative Oncology Group (ECOG) performance status (PS) > 1 were associated with worse OS (hazard ratio [HR], 5.40; 95% CI, 1.19-24.56); P= .03) and RFS (HR, 3.78; 95% CI, 1.01-14.06; P< .05), respectively. ECOG PS > 1 was also associated with worse RFS (HR, 5.00; 95% CI, 1.31-19.14; P= .02). In this patient group with advanced disease, DIPPS score, Lille score, Janus-Associated Kinase V617F (JAK2 V617F) mutation status, and donor type did not predict transplant outcome. We confirm curative potential, but high NRM of allogeneic transplant for advanced MF.

Current Challenges in Stem Cell Transplantation in Myelofibrosis.

Primary or post-ET/PV myelofibrosis is one of the Philadelphia-negative myeloproliferative neoplasms with worst survival. Allogeneic stem cell transplantation (ASCT) can cure a substantial number of patients but is still not universally applicable due to toxicity which leads to therapy-related morbidity and mortality. In the more recent years, outcome of ASCT has improved by less toxic conditioning regimens and optimization of relapse prevention strategies. The introduction of novel therapies such as JAK2 inhibitors may also be helpful in preparation of the transplant by reducing spleen size and constitutional symptoms. To reduce the risk of relapse, molecular monitoring and adoptive immunotherapy with donor lymphocytes have been introduced. Despite lacking prospective randomized trials, it is justified to offer ASCT to eligible patients with PMF whose median survival is expected to be less than 5 years. This includes patients with intermediate-2 and high risk according to IPSS or DIPSS, respectively. The benefit/risk ratio should be considered in each patient taking also transplant- and patient-specific factors into account.

Janus Kinase Inhibitors and Stem Cell Transplantation in Myelofibrosis.

Myelofibrosis (MF) is characterized by splenomegaly, blood count abnormalities, particularly cytopenias, and a propensity for transformation to acute leukemia. The current treatment approach is to ameliorate symptoms due to these abnormalities. Treatment with Janus kinase 2 inhibitors reduces spleen size and improves symptoms in patients with MF, but most of the patients eventually have disease progression and stop responding. Allogeneic stem cell transplantation remains the only curative option. However, its efficacy must be balanced against the risk of treatment-related death and long-term sequelae of transplant like chronic graft versus host disease. The challenge is to integrate treatment with Janus kinase inhibitors with allogeneic stem cell transplantation.

Safety and outcome of allogeneic stem cell transplantation in myelofibrosis.

We evaluated the safety and outcome of allo-HSCTs in myelofibrosis (MF). A total of 27 patients with primary (n = 20) or secondary (n = 7) MF, aged 51 (21-63) yr, transplanted from HLA-matched related (59%) or unrelated (41%) donors were analyzed. Conditioning was reduced in 26 and myeloablative in one patient; and ATG was used in 25. Sources of stem cells were as follows: peripheral blood (21), bone marrow (4) or both (2). Prognostic factors that adversely affected overall survival (OS) in the multivariate analysis were as follows: recipient age >45 yr (HR = 10.55, P = 0.025) and unrelated donor (HR=3.73, P = 0.026). Post-transplant transfusion dependence adversely affected OS in the univariate analysis: dependence from either both RBCs and platelets (HR = 33.26, P = 0.001) or from either of them (HR = 10.53, P = 0.043). Of 16 JAK2V617F-positive patients evaluated post-transplant, it was eradicated in 69% and decreased in 25%. Acute GVHD III-IV developed in 19% and extensive chronic GVHD in 26% of patients; the relapse in four patients was treated with second allo-HSCT. Spleen decreased in all evaluated patients (n = 24). Fibrotic changes improved or disappeared in 80% of evaluated patients (n = 10). Allo-HSCT may prolong survival, provide disease regression and improve quality of life in MF, especially in patients ≤ 45 yr transplanted from matched related donors. Achieving transfusion independence post-transplant indicates the favorable outcome.

Dynamic of Bone Marrow Fibrosis Regression Predicts Survival after Allogeneic Stem Cell Transplantation for Myelofibrosis

We correlate regression of bone marrow fibrosis (BMF) on day 30 and 100 after dose- reduced allogeneic stem cell transplantation (allo-SCT) in 57 patients with primary or post–essential thrombocythemia/polycythemia vera myelofibrosis with graft function and survival. The distribution of International Prognostic Scoring System (IPSS) risk score categories was 1 patient with low risk, 5 patients with intermediate-1 risk, 18 patients with intermediate-2 risk, and 33 patients with high risk. Before allo-SCT, 41 patients (72%) were classified as XXX [myclofibrosis (MF)]-3 and 16 (28%) were classified as MF-2 according to the World Health Organization criteria. At postengraftment day +30 (±10 days), 21% of the patients had near-complete or complete regression of BMF (MF-0/-1), and on day +100 (±20 days), 54% were MF-0/-1. The 5-year overall survival rate at day +100 was 96% in patients with MF-0/-1 and 57% for those with MF-2/-3 (P = .04). There was no difference in BMF regression at day +100 between IPSS high-risk and low/intermediate-risk patients. Complete donor cell chimerism at day +100 was seen in 81% of patients with MF-0/-1 and in 31% of those with MF-2/-3. Patients with MF-2/-3 at day +100 were more likely to be transfusion-dependent for either RBCs (P = .014) or platelets (P = .018). Rapid BMF regression after reduced-intensity conditioning allo-SCT resulted in a favorable survival independent of IPSS risk score at transplantation.

Graft Failure Following Allogeneic Stem Cell Transplantation for Primary Myelofibrosis: A Case Report

Myelofibrosis is a Philadelphia chromosome-negative myeloproliferative neoplasm characterized by marrow fibrosis, splenomegaly with cytopenias, constitutional symptoms and poor quality of life. Rates of graft failure following allogeneic stem cell transplantation range from 0 to 5%, being more frequent in non-HLA identical donors. Here we present an infrequent complication, a graft failure in a patient following identical sibling donor stem cell transplantation for myelofibrosis with objective indicators of disease remission. J Med Cases. 2014;5(2):76-79 doi: http://dx.doi.org/10.14740/jmc1639w