Dynamic International Prognostic Scoring System Score Research Articles

Predictors of survival in the Egyptian patients with primary myelofibrosis: a single-center prospective cohort study

Abstract Background Primary myelofibrosis (PMF) is a clonal hematological myeloproliferative neoplasm distinguished by poor prognosis and reduced life expectancy. This study aimed to detect the overall survival (OS) in patients with PMF and assess the factors affecting clinical outcomes. Aim To assess factors affecting OS in patients with PMF. Design and Methods A prospective cohort study included 73 patients with PMF. The dynamic international prognostic scoring system (DIPSS) score was calculated for risk stratification. Age, DIPSS score, excess circulating blast, JAK2 V617F mutation, bleeding, and thrombosis complications were correlated with OS. Results The median age of our participants at diagnosis was 55 years. The JAK2 V617F mutation was positive in 26 (35%) patients. Our patients were classified according to the DIPSS score into intermediate-1, with 21 (28.77%); intermediate-2, with 43 (58.9%) patients; and high, with nine (12.33%) patients. The Kaplan–Meier curve was used to calculate time-to-death curves, which were compared by the log-rank tests. The Cox regression test was done to recognize risk factors for the OS. Age and excess peripheral blast cells were negative predictors of survival outcome (P=0.012 and 0.005, respectively). Conclusion Advanced age and excess peripheral blast cells are predictors of inferior survival outcomes in patients with PMF.

Allogeneic stem cell transplant for myelofibrosis- A retrospective single-center study.

Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment option for myelofibrosis (MF). Despite the benefits of long-term relapse-free survival, HSCT can be associated with substantial treatment-related morbidity and mortality. This is an observational retrospective study of 15 consecutive patients with MF who underwent allogeneic HSCT at a tertiary care center in Northern India between June 2012 and January 2020. The pre-transplant Dynamic International Prognostic Scoring System (DIPSS) and hematopoietic cell transplantation-specific co-morbidity index (HCT-CI) scores were used. The primary endpoints were overall survival (OS) and disease-free survival (DFS), and the secondary endpoints were post-transplant complications (acute and chronic graft-versus-host-disease [GvHD], graft failure [GF], and cytomegalovirus reactivation [CMV]). The OS and DFS in our study were 60% with no relapse at a median follow-up of 364 days (range 7-2,815 days). Twenty-seven percent of patients developed acute GvHD and 27% of patients developed chronic (limited) GvHD. The non-relapse mortality (NRM) was 40%, with the main cause of death being sepsis, followed by acute GvHD. MF remains a challenging condition to treat, with a poor prognosis. Our study showed that reduced toxicity conditioning provided good DFS and OS. Thus, it should be offered to patients with high DIPSS scores. Sepsis was the predominant cause of mortality in this cohort.

The Relationship between Cause of Death in Myelofibrosis and the Dynamic International Prognostic Scoring System

Background:The Dynamic International Prognostic Scoring System (DIPSS) and DIPSS Plus are well established systems for providing prognoses to patients with primary myelofibrosis. Five risk factors are included in the DIPSS: age > 65, hemoglobin < 10 g/dL, leukocyte count > 25 x 109/L, circulating blasts ≥ 1%, and presence of constitutional symptoms. The DIPSS plus score also factors in three additional variables: presence of an unfavorable karyotype, transfusion dependency, and platelet count < 100 x 109/L. The bulk of current research focuses on overall survival. The goal of this study was to examine if the presence of these risk factors were associated with cause of death (COD) in patients with myelofibrosis (MF).Methods:Follow-up information on 139 patients referred to Michigan Medicine with an initial diagnosis of myelofibrosis, who subsequently died between April 2007 and February 2017, was collected through retrospective chart review. Nine patients who had an unknown cause of death (COD), and 17 who died from complications due to BMT were excluded, leaving 113 evaluable patients (61 male, 52 female). DIPSS plus risk factors were collected at time of referral, though there was insufficient data available to include an analysis of transfusion-dependency or karyotype. P-values were obtained from a chi-squared test for independence between each variable and COD.PatientsThe median age at diagnosis was 70.7 years (IQR 63.0, 74.9), the median age at death was 73.1 years (IQR 65.8, 77.9), and the median time from diagnosis to death was 2.3 years (IQR 0.9, 4.0). 61.9% of patients had primary MF (n = 86), 23.0% had post-essential thrombocythemia MF (n = 32), and 14.4% had post-polycythemia vera MF (n = 20); one patient's history was unknown. 48.2% had a positive JAK2 mutation (n = 67), 24.5% were tested and negative (n = 34); 12 patient's JAK2 mutation status were unknown.Results:Seven causes of death were predefined, namely death from acute myeloid leukemia (n = 26), bone marrow failure (n = 21), congestive heart failure or pulmonary hypertension (n = 20), spleen or liver complications (n = 17), infection not related to cytopenias (n = 7), failure to thrive (n = 7), or any other COD (n = 15). Among the seven characteristics, a significant association was observed among patients with a platelet count < 100 x 109/L; disproportionately more died due to bone marrow failure and less died due to cardiac or pulmonary causes (p = 0.012). This should be interpreted in the context of no statistically significant associations between COD and the other five clinical risk factors. Overall DIPSS score ≥ intermediate-2 also did not lead to significant associations. Of the 113 patients, sixteen had missing DIPSS scores and/or unknown JAK2 status. Among the remaining 97, a larger-than-expected number of patients with a JAK2 mutation had an Intermediate-1 DIPSS risk; conversely, more patients without a JAK2 mutation had an Intermediate-2 risk. A statistical test for independence yielded a p = 0.009, suggesting that patients with JAK2 mutations have lower DIPSS-calculated risk.Conclusions:DIPSS Plus variables are often collected at referral to provide prognostic information to patients. It appears that the presence of thrombocytopenia is more likely to predict bone marrow failure as a patient's ultimate COD compared to the presence of anemia. Additionally, patients with JAK2 mutations seem to have lower DIPSS-calculated risk. Knowledge of this clinical information can aid management of myelofibrosis. DisclosuresTalpaz:ARIAD: Other: Travel, Research Funding; Pfizer Inc: Consultancy, Other: Travel, Research Funding.

Long-Term Survival in Myelofibrosis after Allogeneic Hematopoietic Cell Transplantation Using Fludarabine/Melphalan Conditioning Regimen

Allogeneic hematopoietic cell transplantation (AlloHCT) is the only curative approach for myelofibrosis (MF). However the significant risk of morbidity and mortality associated with this treatment necessitate careful patient selection and intense peri-transplant management. Here we report on the clinical outcome of a large cohort of MF patients who underwent alloHCT with fludarabine/melphalan (FluMel) condition regimen at City of Hope (COH).A total of 110 consecutive patients with MF (primary MF: n=58, secondary MF: n=52) without prior acute leukemic transformation, underwent allo-HCT between 2004 and 2017 at COH. Median age at the time of transplant was 58.5 years (range: 38-72 years) with median interval from diagnosis of primary or secondary MF to HCT of 15.2 months (range: 1.6-332.5 months). A majority of patients (n=107) received peripheral blood stem cells and 3 were transplanted with bone marrow as stem cell source. AlloHCT donors were matched related (MRD: n=49), matched unrelated (MUD: n=32), mismatched unrelated (MMUD: n=27), mismatched relative (n=1), or haploidentical family (n=1). Dynamic international prognostic scoring system (DIPSS) score at the time of alloHCT was Intermediate-2 or high risk in 83 patients (76%). All patients received FluMel conditioning. Graft-versus-host disease (GVHD) prophylaxis was predominantly sirolimus/tacrolimus-based regimen, n=100 (91%). Of the 110 patients, 16 had splenectomy prior to alloHCT. Cytogenetics information was available for 104 out of 110 patients; among which, 60 patients had abnormal cytogenetics including but not limited to deletion 20q, trisomy 8 and trisomy 9.All but 2 patients were engrafted. After median follow-up of 56.8 months (range: 1.3-158.5 months) in surviving patients, 2- and 5-years overall survival (OS) were 74% (95% CI: 65-82%) and 65% (95% CI:54-73%), respectively (figure 1a.); 100 days, 2- and 5-years non-relapse mortality (NRM) were 12% (95%CI: 0.06-0.18), 18% (95% CI: 11-26%) and 24% (95% CI: 16-33%) (figure 1b.); 2- and 5-years. cumulative incidence of relapse (CIR) were 17% at both time-points (95% CI: 11-25%). In univariate analysis MMD and MUD were significantly associated with worse OS compared with MRD (HR: 2.60 [95% CI6: 1.15-5.88] and HR: 1.99 [95% CI: 0.94-4.18], P value= 0.045, respectively) (figure 1c.), in consistency with increased in NRM in these groups (HR: 3.24 [95% CI: 1.31- 8.03), for MMD and 2.48 [95% CI: 1.02-6.04], for MUD, P value=0.029). Lower DIPSS score at the time of transplant was associated with better OS, compared to intermediate-2/high risk (HR: 0.39, 95%CI: 0.16-0.94, p=0.029). Interestingly splenectomy prior the transplant was associated with higher relapse risk (RR), RR= 3.21 (95% CI: 1.24-8.33) (P value=0.018). Cytogenetics abnormalities were not associated with transplant relapse or other outcomes in our cohort. Mutational changes are being tested in pre-transplant samples and will be reported later.Incidence of grade II-IV and III-IV acute GVHD at 100 days were 45% (95% CI: 36-54%) and 17% (95% CI: 11-25%), respectively. At 36 months, cumulative incidence of all chronic GVHD was 66% (95% CI: 55-74%) and extensive chronic GVHD was 59% (95% CI: 49-68%). In this cohort, 32 patients that were treated with ruxolitinib prior to allo-HCT had higher risk of grade III-IV acute GVHD (p=0.011, RR 3.15 [95% CI: 1.31-7.58]) (figure 1d.). Furthermore, ABO incompatibility was associated with higher risk of acute GVHD grade III-IV (p=0.004, RR 4.09 [1.50-11.12]).In summary, we are presenting one of the largest single center experiences of FluMel-based allo-HCT for patients with MF. We showed that this patients have an excellent OS (64% at 5 years) with low risk of relapse (17% at 5 yrs). The risk of NRM was acceptable considering the relatively older age of a large subset of patients (43 aged >60yrs at alloHCT). Interestingly, prior use of ruxolitinib increased the risk of grade III-IV acute GVHD, possibly due to known inflammatory cytokine rebound. Extended use of ruxolitinib until day +30 is currently being evaluated in a prospective trial (NCT02917096). [Display omitted] DisclosuresPillai:Trillium Therapeutics: Research Funding. Salhotra:Kadmon: Consultancy. Stein:Stemline: Consultancy; Amgen: Consultancy, Speakers Bureau.

Chromosomal Aberrations in Pre-HCT Blood Samples and Outcomes after Transplantation in Patients with Myelofibrosis

Introduction: Allogeneic hematopoietic cell transplantation (HCT) is curative for myelofibrosis (MF). However, prognosis post HCT is variable. Identifying subsets of patients who can greatly benefit from HCT is important for clinical decision-making and patient counseling. The Dynamic International Prognostic Scoring System (DIPSS) score includes cytogenetic abnormalities provides important prognostic information. Here, we used high-resolution single nucleotide polymorphism (SNP) arrays to characterize chromosomal aberrations in pre-HCT blood samples from patients with MF and evaluated their added value in patient risk stratification for post HCT survival. Methods: We used the Illumina Global Screening Array to detect somatic copy number alterations (SCNAs) sized ≥2Mb (by calculating the log2 R ratio and B allele frequency and leveraging haplotype information) in pre-HCT blood samples (collected 2-4 weeks prior to HCT conditioning regimen administration) from 923 MF patients who underwent HCT between 2000-2016. Clinical data and blood samples were obtained from the Center for International Blood and Marrow Transplant Research. We used Kaplan-Meier survival analysis and multivariable Cox regression to evaluate the prognostic significance of observed SCNAs on survival after HCT. Results: Median age at HCT was 58 years (range=0.7-76). About 58% were males (N=536), 85% received unrelated donor HCT (N=787), 90% received peripheral blood stem cell grafts (N=826), 47% (N=429) received myeloablative conditioning (MAC), 34% (N=312) received HCT within 1 year from diagnosis, and 537 patients (58%) had known DIPSS score at HCT (47% of them were intermediate II or high). A high frequency of SCNAs were noted in MF (N=623; 67.5%), most commonly on chromosome (chr) 9p (N=224, 24%), chr13q (N=104, 11%), and chr20q (N=102, 11%) (Figure 1). Aberrations noted on chromosomal regions harboring the known MF genes (MPL, DNMT3A, TET2, EZH2, JAK2, SRSF2, CALR, ASXL1, U2AF1) accounted for 28% of all detected (40% of the patients), including JAK2 (9p24.1, N=253, 27%), MPL (1p34.2, N=30, 3.3%) and CALR (19p13.13, N=23, 2.5%). Multivariable models including all MF genes (adjusted for DIPSS score, KPS, year of HCT, hemoglobin count, splenectomy, age, sex, time from diagnosis to HCT, and stratified on CMV match, graft type and conditioning regimen) showed an association between SCNAs on TET2 or SRSF2 regions and poor survival (HR for TET2 =2.40, 95% CI=1.33-4.32, p=0.004; and HR for SRSF2= 2.22, 95% CI=1.26-3.89, p=0.006). TET2 region aberrations were associated with an increased risk of transplant-related mortality (TRM) (HR=2.97, 95% CI=1.53-5.78, p=0.001), worse disease-free survival (DFS; HR=2.22, 95% CI=1.33-3.69, p=0.002), but not the risk of relapse (p=0.12). SRSF2 region aberrations were associated with DFS (HR=1.94, 95% CI=1.11-3.37, p=0.02); no statistically significant association was noted with the risk of relapse (p=0.07) or TRM (p=0.44). These associations were predominant in patients receiving reduced intensity (RIC) or non-myeloablative regimens (Figure 2). Further univariate analyses focusing on all frequently affected chromosomes (affecting ≥10 patients) showed poor OS with SCNAs on chr17p (log-rank p&amp;lt;0.0001), 12p (p&amp;lt;0.0001), 5q (p&amp;lt;0.0001), 13q (&amp;lt;0.001), 8q (p=0.004), 18q (p=0.02) and 4q (p=0.03). In multivariable models stratified on conditioning regimens, chr17p aberrations showed a significant association with excess risk of relapse independent of regimen intensity (HR=5.31, p=0.01 in MAC, and HR=2.70, p=0.02 in RIC). The HR for OS was 2.55, p=0.09, and 2.86, p=0.002, respectively. Other chromosomal aberrations that showed significant associations with inferior OS in patients receiving RIC were SCNAs on chr8q (HR=5.55, p&amp;lt;0.001) (Figure 3), with excess risk of TRM (HR=5.09, p=0.002) but not relapse (p=0.34). In patients that received MAC, elevated risk of mortality was noted with chr5q SCNAs (HR=2.83, p=0.02) with a suggestive association with relapse (HR=2.72, p=0.08) but not with TRM (p=0.59). Conclusion: This study highlights the prognostic ability of pre-HCT detected SCNAs in patients with myelofibrosis, independent on DIPSS score. Relapse risk in patients with aberrations affecting TP53 region was not eliminated by MAC. Follow-up studies to confirm the poor prognosis of those chromosomal changes are warranted. Disclosures Lee: Incyte: Consultancy, Research Funding; Syndax: Research Funding; Kadmon: Research Funding; AstraZeneca: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Research Funding; Takeda: Research Funding; Novartis: Research Funding.

Survival following allogeneic transplant in patients with myelofibrosis

AbstractAllogeneic hematopoietic cell transplantation (HCT) is the only curative therapy for myelofibrosis (MF). In this large multicenter retrospective study, overall survival (OS) in MF patients treated with allogeneic HCT (551 patients) and without HCT (non-HCT) (1377 patients) was analyzed with Cox proportional hazards model. Survival analysis stratified by the Dynamic International Prognostic Scoring System (DIPSS) revealed that the first year of treatment arm assignment, due to upfront risk of transplant-related mortality (TRM), HCT was associated with inferior OS compared with non-HCT (non-HCT vs HCT: DIPSS intermediate 1 [Int-1]: hazard ratio [HR] = 0.26, P < .0001; DIPSS-Int-2 and higher: HR, 0.39, P < .0001). Similarly, in the DIPSS low-risk MF group, due to upfront TRM risk, OS was superior with non-HCT therapies compared with HCT in the first-year post treatment arm assignment (HR, 0.16, P = .006). However, after 1 year, OS was not significantly different (HR, 1.38, P = .451). Beyond 1 year of treatment arm assignment, an OS advantage with HCT therapy in Int-1 and higher DIPSS score patients was observed (non-HCT vs HCT: DIPSS-Int-1: HR, 2.64, P < .0001; DIPSS-Int-2 and higher: HR, 2.55, P < .0001). In conclusion, long-term OS advantage with HCT was observed for patients with Int-1 or higher risk MF, but at the cost of early TRM. The magnitude of OS benefit with HCT increased as DIPSS risk score increased and became apparent with longer follow-up.

Next Generation Myelofibrosis Risk Analysis in the Electronic Health Record

Background: Myelofibrosis (MF) is a devastating myeloproliferative neoplasm that is hallmarked by marrow fibrosis, symptomatic extramedullary hematopoiesis, and risk of leukemic transformation, most commonly driven by janus kinase 2 (JAK2) pathway mutations. MF risk classification systems guide prognosis, decisions regarding allogeneic stem cell transplantation, and disease modifying agents. Key systems include the Dynamic International Prognostic Scoring System (DIPSS) 2009, DIPSS plus 2010, Genetics-Based Prognostic Scoring System (GPSS) 2014, and Mutation-Enhanced International Prognostic Scoring System (MIPSS) 2014. System contributions include dynamic scoring (DIPSS), cytogenetics (DIPSS Plus), and high risk molecular mutations (GPSS and MIPSS). To power the next generation of MF risk prognostication, and ascertain new prognostic factors, large scale electronic health record (EHR) and genomic data will need integration. As a proof of concept, we leveraged our de-identified research EHR (2.9 million records) and linked genomic biobank (288,000 patients) to develop an all-inclusive phenotype-genotype-prognostic system for MF and recapitulate DIPSS, DIPSS Plus, GPSS and MIPSS.Methods: Our previously described methods (Bejan et al. AACR 2018) utilized natural language processing to algorithmically identify 306 MF patients. A subset (N=125) had available DNA for genotyping. We automatically extracted: age greater than 65, leukocyte count (WBC) greater than 25x109/L, hemoglobin (Hgb) less than 10g/dL, platelets (PLT) less than 100 x 109/L, circulating myeloid blasts ≥ 1%, and 10% weight loss compared to baseline as a proxy for constitutional symptoms. Transfusion data was not included. Karyotype data was manually reviewed. Next generation sequencing (NGS) was performed on biobanked peripheral blood DNA with the Trusight Myeloid Panel (Illumina®). Genotyped samples were restricted to dates after MF diagnosis. Multivariate Cox proportional hazard analysis was performed on all clinical and genomic variables. DIPSS plus was calculated without adjustment but lacked transfusion data. DIPSS, GPSS and MIPSS scores were calculated by published methods.Results: Multivariate Cox proportional hazard regression identified Hgb (HR=6.4; P=0.006), myeloid blasts (HR=3.8; P=0.03), and ASXL1 (HR=5.2; P=0.02) as significant in our cohort with regard to overall survival (OS). We noted a strong trend for high risk karyotype (HR=5.6; P=0.07). Our DIPSS model median survival (N=120) for each subgroup; low risk (median survival not met), intermediate-1 (108 months), intermediate-2 (47 months) and high risk (6 months) P=0.0002 (Figure 1a). DIPSS Plus (N=122) integrated karyotype data and PLT count with similar survival with the exception of high risk (4 months) P=0.00003 (Figure 1b). The percentage of patients with driver mutations in JAK2V617F (57%), CALR (3%) and MPLW515 (7.2%); JAK2WT, CALRWT and MPLWT triple negative (34%); high molecular risk ASXL1 (15%), EZH2 (6%), IDH1/2 (7%), SRFS2 (17%); other variants of interest TET2 (9.6%), TP53 (29%) and DNMT3A (16.8%). MIPSS (N=125; 48 months follow up) noted low risk, intermediate-1, and intermediate-2 (median survival not met) and high risk (32 months) P=0.0001 (Figure 1c). GPSS (N=125; 48 months follow up) did not demonstrate statistical separation among groups (Figure 1d).Discussion: This proof of concept transformed raw EHR records into clinical risk scores for MF. The addition of retrospective DNA analysis via NGS opens the possibility of multi-institutional EHR-biobank studies to most accurately create a system to define MF risk. Our sample size limited the significance of age, PLTs, poor risk mutations and other variables previously shown to impact OS. Likewise, we lacked the capacity to track transfusion dependence, previously shown to have prognostic relevance. Still, prognostication via the EHR mimics common scoring systems in MF and supports correct MF case selection, accurate laboratory extraction and reproducible genotyping of biobanked samples. Similar to the original GPSS report, our low risk cohort was small (N=2) and will benefit from expansion of genotyping underway. Finally, this phenotype-genotype-prognostic paradigm represents a technical advance and a unique opportunity to deploy patient specific comorbidities from lifetime EHR records to further refine risk across all myeloid disease. [Display omitted] DisclosuresSavona:Boehringer Ingelheim: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Survival Advantage to Allogeneic Transplant in Patients with Myelofibrosis with Intermediate-1 or Higher DIPSS Score

Introduction: Allogeneic hematopoietic stem cell transplantation (HCT) is the only curative therapy for myelofibrosis (MF). Consideration of HCT is recommended by international working groups and national guidelines for MF patients (pts) age <70 with intermediate-1 with adverse indicators, intermediate-2 or high-risk disease by the Dynamic International Prognostic Scoring System (DIPSS) for MF- a recommendation made in the absence of clear data indicating the optimal timing of HCT for MF. In this large multicenter retrospective study, we analyze overall survival in MF pts treated with and without HCT.Methods: Disease characteristics, treatments, and outcome data from MF pts receiving non-transplant therapy at 14 US academic medical centers between 2000-2014 were retrospectively collected. MF pts who underwent HCT were identified from the Center for International Blood and Marrow Transplant Research (CIBMTR). The Cox proportional hazards model was used. The reference time point (time zero) was time of referral for the non-transplant (non-HCT) arm and the time of transplant for the HCT arm. The main effect variable (HCT vs. non-HCT) violated the proportionality assumption where comparing to non-HCT, mortality was higher with HCT in early time period from time zero but then was lower in late time period; therefore, the comparison is presented as early time period and late time period. The Cox model identified 14 months from time zero as the ideal cut point to define early and late time periods. The proportionality assumption is satisfied within each of these two periods.Results: A total of 1377 and 551 pts were included in the non-HCT and HCT arms, respectively (Table 1). In the overall cohort, survival was higher with non-HCT vs. HCT in early time period (relative risk [RR]: 0.34, P< .0001, Figure 1D), but in late time period survival was lower with non-HCT vs. HCT (RR: 2.37, P< 0.001) (Table 2). In the DIPSS low-risk MF group, while survival was higher with non-HCT vs. HCT in the early time period (RR: 0.19, P=0.007, Figure 1A), survival was lower with non-HCT in the late time period, but the latter did not reach statistical significance (RR: 1.45, P=0.39). In the DIPSS intermediate-1 risk group, a survival advantage was present with non-HCT treatments vs. HCT in the early time period (RR: 0.27, P < .0001, Figure 1B), however survival was lower with non-HCT in the late time period (RR: 3.13, P < .0001). Similarly, in those with DIPSS intermediate-2 and high-risk MF, survival advantage was observed with non-HCT in the early time period (RR: 0.41, P< .0001, Figure IC), but survival was lower with non-HCT in the late time period (RR: 2.82, P < .0001).Conclusion: A long-term survival advantage with transplant was observed for pts with intermediate-1 or higher risk MF, but at the cost of potential early mortality. The magnitude of benefit increased as DIPSS risk score increased. Although this retrospective study has limitations, the results have an impact on clinical practice by suggesting that transplantation could be considered earlier in the disease course and supports the recommendation for consideration of HCT in the setting of intermediate-1 risk MF. [Display omitted] DisclosuresGowin:Incyte: Consultancy, Other: Scientific Advisory Board, Speakers Bureau. Verstovsek:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy; Italfarmaco: Membership on an entity's Board of Directors or advisory committees. Ali:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte: Research Funding. Gerds:Celgene: Consultancy; Apexx Oncology: Consultancy; CTI Biopharma: Consultancy; Incyte: Consultancy.

Treatment-Related Infections and Risk Factors in Patients with Myeloproliferative Neoplasms Treated with Ruxolitinib

▪Ruxolitinib is an orally available JAK1/2 inhibitor FDA approved for the treatment of myelofibrosis and polycythemia vera. Evidence suggest the effect of ruxolitinib on IL-1, IL-6, and TNF-α, among other immune mediators, may predispose patients to both opportunistic and non-opportunistic infections. Identification of patients at risk for infection while on a JAK inhibitor may impact clinical management. Authors sought to determine the cumulative incidence of ruxolitinib-related infections in the clinical practice setting and evaluated patient factors in order to characterize the types, onset, and severity of infections.This IRB approved, single-center, retrospective study at Memorial Sloan Kettering Cancer Center included myeloproliferative neoplasm (MPN) patients treated with ruxolitinib who were ≥18 years of age between 12/1/11 and 12/31/15. Patients on ruxolitinib for less than seven days, receiving ruxolitinib therapy for a non-MPN diagnosis, or had a manifestation of acute leukemia were excluded. Patients who met inclusion criteria were censored at time of splenectomy and hematopoietic stem cell transplant. Patients were identified through electronic medical records and an internal pharmacy database. Cumulative incidence of treatment-related infection was estimated and association with factors was assessed using competing risk regression analysis. Death without an infection was considered a competing risk event.A total of 44 patients were included in this analysis. The median age of this cohort was 66.5 years, with a slightly predominant male population (57%). There were 19 (43%) primary and 19 (43%) secondary myelofibrosis patients, 4 (9%) with polycythemia vera, and 2 (5%) patients with an unclassifiable MPN. For myelofibrosis patients, according to the Dynamic International Prognostic Scoring System (DIPSS), 2 (5%) were low risk, 3 (7%) were intermediate-1, 16 (36%) were intermediate-2, and 7 (16%) were high; remaining patients did not have available DIPSS scores at the time of evaluation. The median number of prior lines of therapy was 1.5 (range 0-4); median total daily dose of ruxolitinib was 10 mg. A majority of patients (70%) were not on concomitant immunosuppressive therapy during ruxolitinib treatment or strong CYP3A4 inhibitors (95%) that may have increased exposure to ruxolitinib.A total of 20 documented infections were identified throughout the evaluation period; median follow-up among survivors was 16 months (range 3-51). Cumulative incidences of treatment related infection were 33% by year 1 and 56% by year 2 of ruxolitinib treatment. Of these infections, four were CTCAEv4.0 grade 1 (one asymptomatic upper respiratory tract infection (URI) occurred after discontinuation was censored), seven were grade 2, and eight were grade 3. One grade 5 infection, septic shock of unknown origin occurred. Only one opportunistic pulmonary tuberculosis infection occurred 13 months post ruxolitinib treatment. The remainder of infections varied, including URIs(n=9), pneumonia, diverticulitis, osteomyelitis, clostridium difficile, proctitis, catheter-associated UTI, dental abscess, herpes zoster activation of the skin, and oral herpes simplex reactivation (all n=1)). One patient required viral prophylaxis for recurrent herpes simplex infections.With the limited number of events, no factors were found to be significantly associated with increased risk of infection but a trend toward increased risk of ruxolitinib-related infection was observed with baseline renal impairment. (Table 1).Conclusion: This data suggests a higher incidence of ruxolitinib associated infections observed in clinical practice compared to rates described in trials of ruxolitinib therapy. This may be attributable to differences between populations in the COMFORT and RESPONSE trials and patients in the clinical practice setting. Generally, infections were non-life threatening and managed with appropriate supportive care. Plasma values of ruxolitinib metabolites increase as renal function declines, correlation of infection risk via increased metabolites exposure warrants further exploration. Routine antimicrobial prophylaxis for all patients receiving ruxolitinib therapy is likely not warranted. However larger studies are needed to confirm these observations. [Display omitted] [Display omitted] DisclosuresMauro:Pfizer: Consultancy; Ariad: Consultancy; BMS: Consultancy; Novartis: Consultancy.

Relationship of JAK2V617F Allelic Burden (AB) to Demographics, Disease Characteristics, and Response to Therapy in Persist-1, a Randomized Phase III Study of Pacritinib (PAC) Versus Best Available Therapy (BAT) in Patients (pts) with Primary and Secondary Myelofibrosis (MF)

Background: The majority of pts with MF present with a mutation in exon 14 of the JAK2 gene (JAK2V617F). Studies have suggested that in pts with MF and this mutation, a lower AB is associated with a myelodepletive phenotype and shortened survival (Tefferi, Leukemia 2008; Guglielmelli Blood 2009; reviewed in Vannucchi, Ther Adv Hematol 2011). For example, in a Cox proportional hazard model for factors predictive of overall survival (OS) in pts with primary MF, a JAK2V617F AB of <25% was associated with a shortened OS (p=0.002; Guglielmelli, Blood 2009). In the phase III trials of ruxolitinib (RUX) therapy in JAK inhibitor-naïve MF, RUX-treated pts had a median decrease in AB of 16% (maximal) in COMFORT-I followed up to 216 weeks and 7% in COMFORT-II at 48 weeks. The median AB at the start of therapy was not reported for COMFORT-I and in COMFORT-II was 84.5% (Cervantes, Blood 2013; Deininger, Blood2015).Methods: In this communication, we report on clinical correlates of quantitative baseline JAK2 mutational status and the effect of treatment on JAK2V617Fmutational burden in the PERSIST-1 trial. This trial enrolled JAK inhibitor-naïve pts with primary or secondary MF without restrictions on baseline platelet counts, randomized 2:1 between PAC and BAT (excluding JAK2 inhibitors) arms. Stratifications included Dynamic International Prognostic Scoring System (DIPSS) risk category, and baseline platelet counts (<50,000/μL, 50,000-100,000/μL, >100,000/μL). Following the 24-week primary analysis, crossover was allowed by physician/pt choice and 90/107 BAT-treated pts (84%) crossed over to receive PAC. Baseline characteristics have been previously reported (Mesa, ASCO 2016) and included 203/327 (62%) pts with Primary MF, 42 (13%) with post-essential thrombocythemia MF and 81 (25%) with post-polycythemia vera MF. 320 of 327 pts had informative PCR testing for JAK2V617F. We report the baseline characteristics of pts with high (≥50%) AB of JAK2V617F, low (<50%) AB of JAK2V617Fand those without a detectable mutation at baseline (<0.1%), as well as the effect of PAC and BAT on AB and correlation with outcome measures.Results: 131 (40.9%) had AB >50% (high AB), 115 (35.9%) had an AB ≥0.1% and ≤50% (low AB), and 74 (23.1%) had AB <0.1% (wild-type JAK2). Median AB values were 80.3% for the high AB group and 30.3% for the low AB group. Baseline characteristics that were significantly different between high and low AB pts are shown in the Table. No differences were noted in the DIPSS risk category or baseline percentage of blasts between pts with low or high AB. There were a higher percentage of pts with a lower AB in the PAC arm (64% vs. 48%; p=0.01). PAC therapy resulted in a median decrement in AB at Week 24 of −15.8% vs −7.9% for pts in the BAT arm (Figure). The median greatest reduction from baseline in AB in PAC-treated pts was −31.6%. Decrease in AB was strongly correlated with spleen volume reduction (p=0.003) and trended towards correlation with improvement in total symptom score (p=0.07) in PAC-treated, but not in BAT-treated pts. Overall survival was shorter in PAC-treated pts with a minimal AB reduction vs pts with greater decreases in AB.Conclusions: In the PERSIST-1 trial, pts with a JAK2V617FAB of <50% had substantially different disease and demographic characteristics when compared with those pts with a >50% AB despite similar distribution of DIPSS scores. In this trial, reduction in AB associated with PAC, but not BAT correlated with clinical benefit. [Display omitted] [Display omitted] DisclosuresVannucchi:Novartis: Consultancy, Research Funding, Speakers Bureau; Baxalta: Speakers Bureau; Shire: Speakers Bureau. Mead:Baxalta: Consultancy, Honoraria. Perkins:Novartis Oncology: Consultancy, Honoraria; Bristol-Myers Squibb: Other: Travel, Accommodations, Expenses. Mayer:CTI BioPharma Corp.: Other: Travel, Accommodations, Expenses, Research Funding. Schouten:Sanofi: Consultancy; Novartis: Consultancy. Farber:Alexion: Equity Ownership; Celgene: Honoraria, Research Funding, Speakers Bureau; Genentech: Research Funding, Speakers Bureau; Acerta: Research Funding; Gilead: Research Funding, Speakers Bureau; TG Therapeutics: Research Funding; Seattle Genetics: Speakers Bureau; Pharmacyclics: Speakers Bureau. Kiladjian:Novartis: Honoraria, Research Funding; AOP Orphan: Consultancy, Research Funding. Nangalia:Novartis: Consultancy, Other: Travel, Accommodations, Expenses. Dean:CTI BioPharma Corp.: Employment, Equity Ownership. Zhou:CTI BioPharma Corp.: Employment, Equity Ownership. Singer:CTI BioPharma Corp.: Employment, Equity Ownership, Other: Leadership . Mesa:Novartis: Consultancy, Honoraria; Incyte: Research Funding; Gilead: Research Funding; CTI BioPharma: Research Funding; Celgene: Research Funding; Genetech: Research Funding; Promedior: Research Funding. Harrison:Novartis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; CTI BioPharma: Consultancy, Honoraria, Speakers Bureau; Baxter: Consultancy, Honoraria; Shire: Speakers Bureau; Gilead: Speakers Bureau; Incyte: Speakers Bureau.

Poor Correlation Between DIPSS and Passamonti Prognostic Risk Scores for Post Polycythemia Vera and Essential Thrombocythemia Myelofibrosis

Background: Post polycythemia vera (PV) and essential thrombocytosis (ET) myelofibrosis (MF), like primary MF (PMF), are heralded by splenomegaly, cytopenias, heavy symptom burden, and decreased overall survival. Risk prognostication tools, including the dynamic international prognostic scoring system (DIPSS) and the Passamonti risk score for post-PV MF (Passamonti et al. Blood 2010, 2008), are helpful to estimate survival and guide therapeutic decision-making. For Post-PV/ET MF, it is unknown if DIPSS correlates with the Passamonti risk score. Here we evaluate the correlation between the two available risk prognostication tools in post-PV/ET MF.Methods:Retrospective chart review conducted for patients with post-PV/ET MF seen between 2000-2012. Descriptive statistics were used to describe patient demographic and clinical variables in post PV/ET patients.DIPSS Score: calculated at time of last follow up: 1 point for age >65, 2 points for hemoglobin <10g/dL, 1 point for leukocytes >25 x 109, 1 point for circulating blasts 1% and 1 point for constitutional symptoms. Risk group was assigned: low-risk (0 adverse points), intermediate-1 risk (1 adverse point), intermediate-2 risk (2-3 adverse points) and high-risk (4-6 adverse points).Passamonti Risk Scores: calculated at time of last follow up: with 1 point assigned for hemoglobin level less than 100 g/L (10 g/dL), platelet count less than 100 x10 (9)/L, and/or leukocyte count more than 30x10(9)/L.Cross-tabulation of DIPSS score versus Passamonti risk score at time of last follow-up was conducted and the percent agreement was described. Spearman correlation coefficient between DIPSS score at follow-up with Passamonti score was conducted.Results:Patients:Sixty-one (58%) post-ET and 44 (42%) post-PV patients were identified, total N=105. Male to Female ratio was 1:1. Median age was 65 (range 25-87). JAK2 V617Fpresent in 68 (65.4%). Median hemoglobin was 10.9 g/dL (range 5.3-17.0), median platelet count 287 x 109 (range 20-1864), and median WBC was 11.1x 109 (range 1.1-165).Risk prognostication:When DIPSS risk scores were applied 11 patients were low, 48 patients were Intermediate-1, 31 patients were Intermediate-2, and 10 patients were high. When Passamonti risk scores were applied 57 patients received score of 0, 31 patients scored 1, 9 patients scored 2, and 3 patients scored 3.DIPSS and Passamonti risk score agreement:The overall agreement between DIPSS and Passamonti risk scores was low, with 24% of cases in agreement. Spearman correlation: Rho=0.451; p<0.001. See Table #1 with agreement seen in highlighted cells.Table 1DIPSS and Passamonti AgreementPassamonti Risk ScoreDIPSS0123TotalLow9 (75%)3 (25%)0012Int-131 (77.5%)8 (20%)1 (2.5%)040Int-217 (43.6%)14 (35.9%)6 (15.4%)2 (5.1%)39High06 (75%)1 (12.5%)1 (12.5%)8Total57 (57.6%)31 (31.3%)8 (8%)3 (3%)100Conclusion:Post PV/ET MF represents a unique clinical entity and risk prognostication schemes developed for PMF, such as DIPSS, may not represent accurate prognosis estimation in this subgroup of MF. When DIPSS and Passamonti risk scores were applied to same post PV/ET group, agreement was poor at 24%. Additionally, DIPSS was more likely to assign patients to high-risk category than Passamonti. Further studies are needed to evaluate the DIPSS and Passamonti prognostic risk score application to the post PV/ET MF population. DisclosuresMesa:Incyte Corporation: Research Funding; Pfizer: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; Incyte Corporation: Research Funding; Gilead: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Genentech: Research Funding; Promedior: Research Funding; CTI Biopharma: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; CTI Biopharma: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Pfizer: Research Funding; NS Pharma: Research Funding.

Recombinant interferon-α in myelofibrosis reduces bone marrow fibrosis, improves its morphology and is associated with clinical response

Recombinant interferon-α represents a well-established therapeutic option for the treatment of polycythemia vera and essential thrombocythemia. Recent studies also suggest a role for recombinant interferon-α in the treatment of ‘early stage’ primary myelofibrosis, but few studies have reported the bone marrow changes after clinically successful interferon therapy. The aim of the present study is to detail the histological responses to recombinant interferon-α in primary myelofibrosis and post–polycythemia vera/post–essential thrombocythemia myelofibrosis and to correlate these with clinical findings. We retrospectively studied 12 patients with primary myelofibrosis or post–polycythemia vera/post–essential thrombocythemia myelofibrosis, who had been treated with recombinant interferon-α. Six patients had received other prior cytoreductive therapies. Bone marrow biopsy was assessed for the following histological parameters: (i) cellularity; (ii) myeloid-to-erythroid ratio; (iii) megakaryocyte tight clusters; (iv) megakaryocyte and naked nuclei density; (v) megakaryocytic atypia; (vi) fibrosis; and (vii) the percentage of blasts. Clinical and laboratory data were included: (i) constitutional symptoms; (ii) splenomegaly, if present; and (iii) complete cell blood count. The clinical response to therapy was evaluated using the International Working Group for Myelofibrosis Research and Treatment/European LeukemiaNet response criteria. The Dynamic International Prognostic Scoring System (DIPSS) score was calculated before and after recombinant interferon-α administration. Successful interferon therapy for myelofibrosis was associated with a significant reduction of marrow fibrosis, cellularity, megakaryocyte density and naked nuclei density. The presence of JAK2V617F mutation correlated with improved DIPSS score. JAK2V617F-negative cases showed worsening of such score or evolution to acute myeloid leukemia. Cytogenetic analysis documented a normal karyotype in all cases. In conclusion, successful clinical response to interferon-α correlates well with an improvement of bone marrow morphology. The prognostic effect of such therapy may be influenced by the JAK2 mutational status. Additional studies are needed to confirm these preliminary data.

Prognostic Impact of Splenomegaly on Survival of Chinese with Primary Myelofibrosis

Median survival of persons with primary myelofibrosis (PMF) is about 7 years but ranges from <2 to >10 years. Different scoring systems were developed to predict survival of persons with PMF including the International Prognostic Scoring System (IPSS), the Dynamic IPSS (DIPSS), and the DIPSS-Plus. These scoring systems were developed predominately in persons of European descent and include few Asians. Recently, we analyzed a large dataset of Chinese with PMF to test validity of these scoring systems and determine if additional clinical or laboratory variables improved the prognostic accuracy of these scoring systems in Chinese with PMF who constitute a substantial proportion of people with PMF worldwide. We found frequencies of splenomegaly and anemia were significantly different between Chinese and persons of European descent with PMF and that splenomegaly, not included in the European-derived scoring systems, was an important independent predictor of survival in Chinese. Based on these data we developed a modified prognostic scoring system for Chinese subjects which included splenomegaly.The aim of our current study is to validate the prognostic value of this modified DIPSS for Chinese with PMF in a larger cohort of 874 subjects diagnosed August, 1984 to October, 2013 at the Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and evaluate the prognostic impact of splenomegaly on survival. All cases were blind re-reviewed by the pathologist and diagnosis based on the 2008 World Health Organization criteria.495 subjects (57%) had splenomegaly below the left costal margin. Splenomegaly subjects were younger (P=0.006) and had significantly higher hemoglobin concentrations (P<0.001) and levels of WBCs (P<0.001), platelets (P<0.001) and blood blasts (P=0.012). 217 subjects (62%) in the splenomegaly cohort had JAK2V617Fvs. 115 subjects (50%; P=0.003) in the no splenomegaly cohort. Distributions of RBC-transfusion-dependence (P<0.001) and DIPSS risk-cohorts (P=0.024) were also significantly different. Frequencies of constitutional symptoms and cytogenetic abnormalities were not significantly-different.Median follow-up is 22 months (range, 1-288 months); 215 subjects (25%) died during follow-up. We calculated DIPSS scores at diagnosis. Risk distribution according to the DIPSS for PMF was low risk in 182 subjects (21%), intermediate-1 risk in 398 subjects (46%), intermediate-2 risk in 281 subjects (32%) and high-risk in 13 subjects (2%). Corresponding median survivals are not reached, 110, 37 and 21 months. Using the DIPSS model survival curves of intermediate-2 and high-risk subjects are not significantly different (P=0.054). In our cohort, only 2% subjects were classified as high-risk in the DIPSS scoring system. The modified DIPSS for Chinese used three independent risk factors for briefer survival: DIPSS scores (low-risk, 0; intermediate-1 risk, 1; intermediate-2 risk, 2; and high-risk, 3), platelet levels <100´10E9/L and no palpable splenomegaly. The revised risk categorization was low-risk (score 0-1), intermediate-risk (score 2-3) and high-risk (score 4-5). Using the modified DIPSS median survivals are 288, 61 and 28 months.In univariate analyses, variables significantly correlated with survival were male gender (P=0.001), age >65 years (P<0.001), hemoglobin concentration < 100g/L (P<0.001), platelets <100×10E9/L (P<0.001), blood blasts ≥1% (P<0.001), no splenomegaly (P<0.001), RBC-transfusion-dependence (P<0.001) and DIPSS (P<0.001). Median survival in subjects with splenomegaly is 110 months compared with 64 months in subjects without splenomegaly.In multivariate analyses variables significantly correlated with survival were male gender (hazard ratio [HR]=1.63; 95% CI, 1.23-2.15; P=0.001), platelets >100×10E9/L (HR=1.58; 95% CI, 1.19-2.11; P=0.002), no splenomegaly (HR=1.45; 95% CI, 1.10-1.90; P=0.008), RBC-transfusion-dependence (HR =1.51; 95% CI, 1.11-2.06; P=0.009) and DIPSS (HR=1.90; 95% CI, 1.55-2.31; P<0.001).Our study confirms the predictive value of the modified DIPSS with splenomegaly as a variable in a large cohort of Chinese with PMF. Moreover, we found splenomegaly was strongly associated with several laboratory abnormalities. In contrast to persons of predominately European descent, splenomegaly is an important independent favorable prognostic variable in Chinese with PMF. DisclosuresNo relevant conflicts of interest to declare.

Survival of Allogeneic Stem Cell Transplantation Vs Conventional Therapies per DIPSS Stratification in Patients with Primary Myelofibrosis Younger Than 65 Years: A Retrospective Analysis on 673 Patients

IntroductionPrimary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm with a high risk of clonal evolution and mortality. Allogeneic stem cell transplantation (ASCT) is currently the only curative treatment approach for myelofibrosis. Due to the inherent complications, careful patient selection is mandatory.Patients and MethodsWith the goal of refining patient selection for ASCT we compared results of ASCT with non-transplant approaches in 673 patients with PMF stratified according the Dynamic International Prognostic Scoring System (DIPSS), which assigns a time-dependent risk on a scale of low, intermediate (int)-1, int-2, and high. Considering a commonly used age-threshold for indication of ASCT, we restricted the analysis to patients aged 65 years or younger. This included 190 PMF patients (median 50 years at diagnosis) who received ASCT (HLA-matched related, n= 88 [46%] HLA-matched unrelated and mismatched related, n= 102 [54%] donors) after reduced intensity (n=93), or high intensity conditioning (n=97), and 248 patients, median age 55 years, from the DIPSS database (PMF patients not receiving any experimental drug at data cut-off and censored at the time of ASCT). DIPSS scores at ASCT, or, for non-transplanted patients, at diagnosis, were low in 22 (11%) and 125 (49%), int-1 in 38 (20%) and 75 (29%), int-2 in 85 (45%) and 52 (20%), and high in 45 (24%) and 3 (1%) patients, respectively. The median time from diagnosis to ASCT was 1.2 years.In line with the dynamic nature of the DIPSS, risk scores in the non-transplanted cohort change with time and, accordingly, were accounted for as time-dependent covariates. The date of diagnosis was considered as origin of the time scale, and patients entered the analysis when receiving ASCT (ASCT cohort) or at the time of acquisition of a specific DIPSS category of a non-transplant cohort. Therefore, left truncated, right censored data were used for both cohorts. Left truncation (begin of observation) for the ASCT cohort was the time to ASCT after diagnosis, while for the non-transplant cohort it was the time of achieving the respective DIPSS risk category.Cox proportional hazard models were built separately for the four DIPSS stages, considering the cohort as a discrete covariate; the corresponding relative risks (RR) between the two cohorts were computed under the proportional-hazards approximation, and Wald tests were used to report significance. Age at diagnosis was not significant in any model and, therefore, was not included in the regressions. The present study could not address the potentially confounding factor of selection bias regarding ASCT.ResultsThe relative risk (RR) of dying among patients receiving ASCT relative to those receiving conventional therapies was 5.6 (95% CI: 1.7-19, p=0.0051) for low risk DIPSS, 1.6 (95% CI: 0.79-3.2, p=0.19) for int-1 risk DIPSS, 0.55 (95%CI: 0.36-0.83, p=0.005) for int-2 , and 0.37 (95%CI: 0.21-0.66, p=0.0007) for high risk DIPSS patients. The proportions of patients with low risk DPSS surviving at 1, 5 and 10 years were 100%, 69%, and 60%, respectively, for the ASCT cohort, and 98%, 95%, and 92% for the non-transplant cohort. The corresponding figures for patients with int-1 risk were 78%, 52%, and 41%, respectively, after ASCT, and 97%, 77%, and 63% for non-transplanted patients. Among patients with int-2 risk survival after ASCT was 82%, 50%, and 32%, respectively, and 77%, 41% and 11% among non-transplanted patients. The corresponding figures for high risk patients were 65%, 37% and 27% for the ASCT cohort, and 67%, 11% and 1%, respectively, for the non-transplant cohort. It should be noted that hazard ratios are not constant over time, and summarizing the risk in a single “average” RR ignores the specifics of the survival trends. Survival differences became pronounced beyond 5 years following diagnosis for int-2 and high risk patients.ConclusionPatients with PMF who, at any age≤ 65 years, have int-2 or high risk disease by DIPSS have superior survival if receiving ASCT during their disease history. Conversely, conventional therapy appears to result in superior outcome in low risk patients, while intermediate-1 risk patients represent a group in whom individual counseling may be particularly important. DisclosuresVannucchi:Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding.

Comparison of the Impact of Two Different Definitions of Red-Cell Transfusion Dependence on the Natural History of Myeloproliferative Neoplasm (MPN)-Associated Myelofibrosis (MF)

The current definitions of red-cell transfusion dependence (TD) for MPN-associated MF are based on expert opinion. The optimal definition of TD, and its impact on the natural history of MF is not well studied. We evaluated the impact of two definitions of red-cell TD on the natural history of 306 patients (pts.) with WHO/IWG-MRT-defined primary MF (PMF, n=202, 66%), post-polycythemia vera MF (PPV-MF, n=45, 15%) or post-essential thrombocythemia MF (PET-MF, n=59, 19%).Red-cell TD was defined according to IWG-MRT 2006 criteria (Tefferi et al, Blood, 2006), and on the results of the expert consensus RAND-Delphi panel (Gale et al, Leukemia Research, 2011). The IWG-MRT criteria require patients to have received ≥2 Units (U) packed red blood cells (PRBC) in the preceding 28 days for hemoglobin (Hb) <85 g/l. On the other hand, the more stringent Gale definition requires patients to receive ≥2 U of PRBC per month over 3 months without any specification for the Hb level. Patients were evaluated for disease risk stratification according to dynamic international prognostic scoring system (DIPSS), co-morbidities according to ACE-27, and red-cell TD at their first presentation to Princess Margaret Cancer Center or diagnosis.The study cohort was divided in 4 groups (gp.): Non-transfusion dependent (NTD) pts. with Hb ≥100 g/dl (gp1, n=156, 51%); patients with Hb <100 g/dl, but no transfusion in preceding 12 weeks (gp2, n=65, 21%); pts. qualifying IWG-MRT 2006 criteria of TD, but not qualifying Gale definition (gp3, n=41, 13%); and pts. qualifying the Gale definition of TD (gp4, n=44, 14%). There was no significant difference among the 4 groups with relation to age, disease distribution (primary vs. secondary), cytogenetics, blasts%, and ACE-27 co-morbidity scores. There was significant difference in the gp1, gp2, gp 3, and gp4 in relation to constitutional symptoms (35% vs. 45% vs. 46% vs.64%, p=0.006), median WBC count (x109/L) (11.5 vs. 8.3 vs. 6.8 vs. 6.5, p<0.0001), platelets (x109/l) (317 vs. 154 vs. 124 vs. 127, p<0.0001), and Int-2/high DIPSS (24% vs. 82% vs. 90% vs. 82%, p<0.0001).In a univariate analysis, probability of survival among the 4 groups at 3-years was 80%, 55%, 68%, 30%, respectively (Fig 1, p=0.0016). No difference in leukemic transformation was observed among the 4 groups (p=0.68). In a multivariate analysis, after adjusting for DIPSS and co-morbidity scores, hazard ratios among the gp2, gp3, and gp 4 were 1.58 (95% CI 0.78-3.19, p=0.21), 2.17 (95% CI 0.88-5.34, p=0.09), 2.82 (95% CI 1.29-6.16, p=0.009) in comparison to gp 1 (ref. group). There was no significant difference between NTD patients with Hb <100 vs. TD patients according to IWG-MRT 2006 criteria, but not meeting Gale Criteria (p=0.47). DIPSS was the only other independent prognostic factor for survival.Our study shows the independent prognostic impact of TD on survival defined according to Gale criteria, but not according to previous IWG-MRT 2006 definition, which does not meet Gale criteria. No impact of anemia or TD was observed on leukemic transformation. [Display omitted] DisclosuresSchuh:Celgene: Membership on an entity’s Board of Directors or advisory committees.

Impact Of Conditioning Regimen, Donor Source, and DIPSS Score On Outcome Of Allogeneic Hematopoietic Stem Cell Transplantation For Myelofibrosis

To investigate impact of conditioning regimen, donor source, and Dynamic International Prognostic Scoring System (DIPSS) on outcome of allogeneic hematopoietic stem cell transplantation for myelofibrosis, we analyzed results in 388 patients transplanted between 1990 and 2011 in three major transplant centers (Essen, Germany: n = 63; Hamburg, Germany; n = 156; Seattle, USA: n = 169), including 216 male and 171 female patients, 18 – 79 (median 54) years old, with either primary (n = 283) or post ET/PV (n = 150) myelofibrosis who received myeloablative (n = 190), reduced intensity (n = 182), or non-myeloablative (n = 16) conditioning and were given stem cells from related (n = 156, including 152 HLA-identical siblings, 1 haplo-identical relative, and 3 identical twins ) or unrelated donors (n = 232; 175 were HLA-matched and 57 were HLA-mismatched). Stem cell source was bone marrow (n = 51) or peripheral blood (n = 337). According to DIPSS at time of transplantation patients were classified as low (n = 35), intermediate-1 (n = 106), intermediate-2 (n = 161), or high (n = 84) risk. The conditioning regimen consisted of busulfan 16 mg/kg and cyclophosphamide (n = 136), busulfan 10 mg//kg and fludarabine (n = 154), treosulfan-based (n = 26), TBI 12 Gy-based (n = 52), or low dose TB 2 Gy and fludarabine (n = 16), and melphalan 140 mg/m2 and fludarabine (n = 4).After a follow-up of 3.5 – 7.7 (median 5) years the 1-year non-relapse mortality (NRM) of the entire study cohort was 24% (95% CI: 20 – 28). In multivariate analysis significant factors for NRM were age as continuous variable (HR: 1.029; 95% CI: 1.011 – 1.048, p = 0.002), HLA mismatch (HR: 2.026; 95% CI: 1.318 – 3.113, p = 0.001), and TBI containing conditioning (HR 1.872; 95% CI: 1.198 – 2.926, p = 0.006). The cumulative incidence of relapse was 17% (95% CI: 13 – 21) at 5 years, negatively impacted by age as continuous variable (HR: 1.030; 95% CI: 1.003 – 1.057, p = 0.028), unrelated donors (HR: 0.560; 95% CI: 0.339 – 0.926, p = 0.024), and the use of ATG (HR: 2.425; 95% CI: 1.342 – 4.381, p = 0.003) or campath (HR: 3.257; 95% CI: 2.129 – 6.985, p < 0.0001 The estimated 3 and 5 year overall survival for the study group was 62% (95% CI: 56 – 68%) and 59% (95% CI: 53 – 65%), respectively. Significant factors for 5-year survival in the univariate analysis were HLA-matched vs. mismatched donor (61% vs. 47%, p = 0.05), related vs. unrelated donors (65% vs. 54%, p = 0.03), high dose conditioning vs. RIC vs. NMA (58% vs. 61% vs. 32%, p = 0.04), non TBI vs. TBI containing conditioning regimens (62% vs. 42%; p = 0.001), and DIPSS score at transplantation (low 83% vs. intermediate-1 64% vs. intermediate-2 58% vs. high risk 45%; p < 0.001). In the multivariate analysis for survival significant factors were age as continuous variable (HR: 1.027; 95% CI: 1.009 – 1.045; p = 0.004), DIPSS score: intermediate-1 (HR: 1.662, p = 0.3), intermediate-2 (HR: 2.069, p = 0.09), high (HR: 2.924, p = 0.02), and TBI-containing conditioning regimen (HR: 1.973; p < 0.001). ConclusionThis analysis of results in a large cohort of patients confirms a high success rate of allogeneic hematopoietic stem cell transplantation for myelofibrosis significantly impacted by DIPSS classification at the time of transplantation. In addition the analysis confirms the risk factors of patient age and donor HLA-mismatch. Furthermore, the data show similar results between RIC and MAC, but less favorable outcome with TBI containing conditioning, regardless of the dose of TBI. Novel approaches need to be developed, particularly for patients with more advanced disease. ContributionThe authors NK and MD contributed equally. Disclosures:No relevant conflicts of interest to declare.

Splenectomy in Patients with Myeloproliferative Neoplasms (MPNs): Efficacy, Complications and Impact On Survival and Transformation.

AbstractAbstract 2853 Introduction:Splenectomy may be an effective therapeutic option for treating massive splenomegaly in patients with MPNs. There is still limited data on its short- and long-term benefits and risks. Objective: To describe short-term outcomes, complications and impact on survival and transformation to acute myeloid leukemia (AML) in patients with MPNs who underwent splenectomy. Methods:First, efficacy and short-term complications were analyzed in 94 patients with different MPNs who underwent splenectomy at MD Anderson between 1981–2009. Second, medical records of 696 patients with myelofibrosis (MF) seen at MD Anderson between 1966–2009 were reviewed (among which 91 underwent splenectomy either at or outside MD Anderson) to evaluate the long-term impact of splenectomy on overall survival (OS) and transformation-free survival (TFS). Improvement in anemia and thrombocytopenia were defined by the International Working Group on Myelofibrosis Research and Treatment response criteria. Survival was estimated by Kaplan-Meier method, and hazard ratios (HR) were determined by Cox multivariate analysis. Splenectomy was analyzed as a time-dependent covariate. Risk in patients with MF was determined by the Dynamic International Prognostic Scoring System (DIPSS). Accelerated phase (AP) criteria in MF were determined as thrombocytopenia <50×109/L, chromosome 17 abnormalities and blasts >10% in peripheral blood (PB) or bone marrow (BM). Results:Splenectomy improved spleen pain, anemia and thrombocytopenia in 84%, 47% and 66% of patients, respectively. Among patients with MF, improvement in anemia and thrombocytopenia was seen in 44% and 75% of patients, respectively. Hematological complications included post-operative leukocytosis (76%) and thrombocytosis (43%), developing within a median time of 1 day and 5 days post-surgery, respectively. Early (<7 days) intervention for control of elevated white blood cell and/or platelet count was needed in 37% of patients. Forty-six percent of patients developed non-hematological clinical complications, and the most common was venous thromboembolism (VTE; 16%). VTE sites included portal vein (N=11), supra-hepatic vein (N=3) and superior vena cava, pulmonary embolism and splenic vein (N=1 each). Post-operative mortality was 5%. Median survival post-splenectomy was 19.2 months, and 5-year survival 16.1%. In the second cohort of patients with MF, requirement for splenectomy was associated with decreased OS (HR=2.84, p<0.0001) and TFS (HR=2.79, p<0.0001). In the multivariable model, the time dependent covariate splenectomyremained an independent risk factor for inferior OS and TFS in patients with MF, alongside male sex, transfusion dependency, DIPSS score and AP criteria (Table). Conclusions:Splenectomyis a possible therapeutic option for patients with MF and other MPNs, and its greatest benefits are related to improvement in spleen pain and discomfort, anemia and thrombocytopenia. However, in patients with MF it appears to be associated with increased mortality and risk of transformation to AML.Table:Cox multivariable analysis for TFS and OSCovariateHR (95% CI)PTFSSplenectomy (yes vs. no)2.53 (1.86–3.44)<0.0001Male sex (yes vs. no)2.10 (1.62–2.73)<0.0001Transfusion dependency (yes vs. no)1.48 (1.14–1.92)0.003DIPSS risk category• Intermediate-1 (vs. Low)1.92 (1.07–3.45)0.02• Intermediate-2 (vs. Low)1.94 (1.07–3.52)0.02• High (vs. Low)2.53 (1.35–4.73)0.004AP Criteria• Present (vs. Absent)2.39 (1.80–3.17)<0.0001• Unclassifiable (vs. Absent)0.84 (0.52–1.34)0.46OSSplenectomy (yes vs. no)2.54 (1.86–3.48)<0.0001Male sex (yes vs. no)2.17 (1.65–2.85)<0.0001Transfusion dependency (yes vs. no)1.51 (1.16–1.97)0.002DIPSS risk category• Intermediate-1 (vs. Low)2.06 (1.09–3.88)0.02• Intermediate-2 (vs. Low)2.09 (1.10–3.98)0.02• High (vs. Low)2.93 (1.50–5.72)0.002AP Criteria• Present (vs. Absent)2.53 (1.89–3.38)<0.0001• Unclassifiable (vs. Absent)0.97 (0.59–1.57)0.91 Disclosures:No relevant conflicts of interest to declare.

Prediction of Overall Survival in 520 Patients with Primary Myelofibrosis: Outcome Update of the Dynamic International Prognostic Scoring System (DIPSS) Patient Cohort

AbstractAbstract 1729 Background:Primary myelofibrosis (PMF) is a myeloproliferative neoplasm whose survival at diagnosis is predicted by the International Prognostic Scoring System (IPSS), which is based on the presence of the following five risk factors: age greater than 65 years, presence of constitutional symptoms, hemoglobin level below 10 g/dL, leukocyte count greater than 25 ×109/L, and circulating blast cells 1% or greater (Cervantes et al, Blood 2009). To allow dynamic prognostication at any time during follow up, we further developed the Dynamic International Prognostic Scoring System (DIPSS), based on the same IPSS-factors, but with different score values (one point for each risk factor, two points for acquisition of anemia) and with a distinct score model (low risk, LR, 0 points; intermediate-1 risk, Int-1R, 1–2 points; intermediate-2 risk, Int-2R, 3–4 points; high risk, HR, 5–6 points) (Passamonti et al, Blood 2010). The DIPSS model was also efficient in the prediction of acute myeloid leukemia (AML) evolution (Passamonti et al, Blood 2010) and in the assessment of survival and non-relapse mortality after allogeneic hematopoietic stem cell transplantation (Scott et al, Blood 2012). Aim:The aim of the present study is to update outcome data of PMF patients included in the original series used to generate the DIPSS model and to assess the DIPSS prediction of survival in PMF patients with a longer follow up. The Institutional Review Board approved the study, and the procedures followed were in accordance with the Declaration of Helsinki. Patients and methods:This study was performed on 520 of 525 regularly followed DIPSS-PMF patients, as five patients have been lost to follow up after the original publication. Results:Updated median follow up was of 4.1 years (range, 0.1–30.1). At the time of analysis 326 (63%) patients died, of whom 194 due to known causes: 69 AML, 16 non-AML disease progression, 21 bleeding, 17 thrombosis, 33 infections, 38 other. Median survival was 6 years (95% CI: 5.1–6.7). DIPSS stratification allowed different survivals in PMF patients even with a longer follow-up (Figure 1). Hence, to assess the time to DIPSS-category progression, we evaluated the median time spent within each risk group. This estimate revealed that the median time spent in each risk category was: 4.9 years in LR (range, 0–26.7), 2.1 years in Int-1R (range, 0–18.7), 1.7 years in Int-2R (range, 0–13.4), and 0.74 years in HR (range, 0–13.7). To investigate the prognostic role of the DIPSS score on survival, we analyzed the score as a categorical time-dependent covariate in a Cox survival regression model: the hazard ratio of shifting category from LR to Int-1R was 5.0 (95% CI: 2.4–10.6; P <0.001), it was 3.6 when shifting from Int-1R to Int-2R (95% CI: 2.6–4.9; P <0.001), and 2.7 (95% CI: 2.0–3.6; P <0.001) from Int-2R to HR. Conclusion:The updated analysis shows that the DIPSS model continues to predict survival in patients with PMF. [Display omitted] Disclosures:No relevant conflicts of interest to declare.