International Prognostic Scoring System Criteria Research Articles

Effect of New or Worsening Anemia on Clinical Outcomes in 2233 Patients with Myelofibrosis Treated with Ruxolitinib in the Expanded-Access Jump Study

Introduction: Transient dose-dependent anemia is a known consequence of ruxolitinib treatment and can influence decisions regarding initiation, dosing, and discontinuation of therapy. Whether new or worsening anemia following ruxolitinib initiation has an impact on efficacy is unknown. A recent analysis of pooled COMFORT-I/II data indicated that new or worsening anemia did not impact the clinical outcomes of spleen volume response or symptom control (Al-Ali et al., Abstract PB2185, Presented at EHA 2023). The analysis presented here sought to validate this result using data from JUMP, the largest trial of ruxolitinib in patients with myelofibrosis (MF) to date. Methods: JUMP was a large (N=2233) single-arm, phase 3b, expanded-access trial that enrolled and provided ruxolitinib treatment for patients with MF in a setting similar to routine clinical practice. The study evaluated the safety and efficacy of ruxolitinib in patients aged ≥18 years with diagnosed primary or secondary intermediate (Int)-1, Int-2, or high-risk MF (International Prognostic Scoring System criteria) with baseline platelets ≥50×10 9 /L. All patients received ruxolitinib twice daily at a starting dose of 5-20 mg based on baseline platelet count. In this post hoc analysis, patients were stratified at baseline based on anemia due to MF (anemia defined as hemoglobin [Hb] <100 g/L) and transfusion status among patients with anemia (transfusion-requiring anemia [TRA; received ≥2 units of red blood cells over 8 weeks before first ruxolitinib dose] or non-transfusion-requiring anemia [NTRA]). Outcomes were stratified by presence or absence of new or worsening anemia following ruxolitinib initiation (defined as a decrease in Hb of ≥15 g/L or new transfusion requirement at Week 4, 8, or 12). Outcomes evaluated included spleen length response (SLR; defined as ≥50% reduction at Week 24 or 48 from baseline assessed with manual palpation), ≥6.5-point increase in Functional Assessment of Cancer Therapy-Lymphoma total score (FACT-Lym TS response) from baseline at Weeks 24 and 48, and overall survival (OS) measured by Kaplan-Meier method. Results: 2233 patients were included (baseline status: nonanemic, n=1386 [62.1%]; NTRA, n=521 [23.3]; TRA, n=326 [14.6]). Median (range) age of all patients was 67.0 (18-89) years, and 54.5% were men. Baseline characteristics were comparable between patients with vs without new or worsening anemia. Rates of SLR at Week 24 among patients with vs without new or worsening anemia were 31.5% vs 31.2%, respectively, (nonanemic; P=0.93), 24.4% vs 27.9% (NTRA; P=0.49), and 25.0% vs 29.8% (TRA; P=0.48; Table). FACT-Lym TS response at Week 24 for patients with vs without new or worsening anemia was 34.5% vs 34.0% (nonanemic; P=0.86), 32.7% vs 29.6% (NTRA; P=0.52), and 41.7% vs 32.1% (TRA; P=0.13). Similar trends were observed at Week 48 among patients with vs without new or worsening anemia for both SLR (35.6% vs 26.1%; P=0.02 [nonanemic], 29.6% vs 27.2%; P=0.71 [NTRA], and 19.0% vs 33.3%; P=0.10 [TRA]) and FACT-Lym (30.4% vs 23.3%; P=0.02 [nonanemic], 26.4% vs 27.6%; P=0.84 [NTRA], and 34.2% vs 33.3%; P=0.91 [TRA]). For nonanemic patients at baseline, time to median OS was not reached in either cohort; however, better OS was seen in those without vs with new/worsening anemia (hazard ratio: 0.559, [95% CI: 0.357-0.876]; P=0.01; Figure). For patients with baseline anemia (NTRA and TRA), no difference in OS was observed in those with or without new/worsening anemia ( P=0.24) Conclusions: Analysis of 2233 patients in the JUMP trial indicates that onset of new or worsening anemia following ruxolitinib initiation did not diminish clinical benefit of treatment. Ruxolitinib was associated with improvements in spleen size and symptom burden irrespective of baseline anemia and transfusion status. These results are consistent with a recent analysis of pooled COMFORT-I/II data (n=277), which reported similar findings for spleen volume and symptom responses. In contrast to the controlled clinical trial setting of COMFORT-I/II, JUMP reflects a real-world setting and enrolled a broader MF population, including those with platelet count <100×10 9/L and lower-risk MF. Taken together, these results support real-world use of ruxolitinib in patients with MF, regardless of baseline anemia or development of treatment-related anemia.

Sabatolimab in Combination with Hypomethylating Agents (HMAs) Was Safe in Patients (Pts) with Intermediate-, High-, or Very-High-Risk Myelodysplastic Syndrome (MDS)

CONCLUSIONS Complete remission (CR) with standard-of-care HMAs in pts with intermediate-, high-, and very-high-risk MDS is usually infrequent and transient, and prognosis remains poor for these pts, who have limited second-line treatment options. Sabatolimab is a high-affinity, humanized anti-TIM3 IgG4 monoclonal antibody that blocks the TIM3 immune checkpoint receptor, which is preferentially expressed on leukemic stem cells and blasts and plays a key role in regulating adaptive and innate immune responses. In a phase Ib study, sabatolimab in combination with intravenous (IV) HMA was safe and well tolerated in pts with high-risk MDS with overall response rates of 61.1% and 57.9% with decitabine and azacitidine, respectively. We present an interim analysis of the STIMULUS-MDS US trial (NCT04878432) to assess the safety of sabatolimab in combination with not only parenteral but also oral HMAs in pts with intermediate-, high-, and very-high-risk MDS. This is a multicenter, phase II, open-label, single-arm study of sabatolimab in combination with HMAs. Adults aged ≥18 years with intermediate-, high-, or very-high-risk MDS per Revised International Prognostic Scoring System criteria who were not previously treated with HMAs were eligible. Pts received an HMA of investigator's choice (decitabine/cedazuridine 35 mg/100 mg oral days 1-5, decitabine 20 mg/m 2 IV days 1-5, or azacitidine 75 mg/m 2 IV or subcutaneous [SC] days 1-7 or days 1-5 plus days 8 and 9) with sabatolimab 800 mg IV every 4 weeks starting at day 8 or any day between days 5 to 8. The primary objective of this study was to assess the safety of sabatolimab in combination with oral, IV, and SC HMAs. Secondary objectives included assessing the efficacy of the combination. The study includes a core phase for up to 12 months, an extension phase for efficacy and survival status up to 12 months after the core phase, and a post-treatment safety follow-up for 30 days following the last dose of HMA or 150 days following the last dose of sabatolimab, whichever is later. This interim analysis included 33 pts with intermediate-, high-, and very-high-risk MDS at the data cutoff of 6 months after cycle 1 day 1 of treatment with sabatolimab and an HMA. The median age was 69 years (range, 39-86). At data cutoff, 8 pts were in ongoing treatment, and 25 pts had discontinued the core phase. Reasons for discontinuation included new therapy for study indication (n=6), physician decision (n=6), pt decision (n=5), progressive disease (n=4), unsatisfactory therapeutic effect (n=2), adverse event (AE) (n=1), and death (n=1). Of those who discontinued study treatment, 6 pts were in ongoing evaluation in the extension phase and 3 pts were in ongoing evaluation in the post-treatment follow-up phase. The median duration (range) of exposure was 3.9 (0.92-5.91) months for sabatolimab and 4.2 (1.05-6.08) months for HMAs. Among 33 pts evaluable for safety, most experienced all-grade and grade ≥3 AEs, AEs requiring additional therapy, and serious AEs (Figure). However, the most frequent (≥10%) grade ≥3 AEs were expected hematologic AEs, including febrile neutropenia (42.4%), anemia (39.4%), neutrophil count decrease (39.4%), and platelet count decrease (36.4%). Nonhematologic grades ≥3 AEs occurring in >1 pt included hypertension (18.2%), pneumonia (9.1%), hypoxia (6.1%), and fall (6.1%). Only 1 pt was reported with encephalopathy leading to treatment discontinuation, which was not attributed to study treatment. One pt had a fatal AE for which the cause was not identified but not thought to be related to study treatment by the investigator. The best overall response results in up to 6 months of treatment were available for 22 pts. Marrow CR (mCR) with and without hematologic improvement (HI) was reported in 18.2% and 9.1%, respectively. Partial remission (PR) and stable disease (SD) with HI was reported in 4.5%, each. CR + mCR + PR was 31.8% (95% CI, 13.9%-54.9%), CR + PR + HI was 27.3% (95% CI, 10.7%-50.2%), and CR + mCR + PR + HI was 36.4% (95% CI, 17.2%-59.3%). This interim analysis of the STIMULUS-MDS US study demonstrated that sabatolimab in combination with an oral, IV, or SC HMA was safe and well tolerated, with AEs consistent with previous reports for pts with MDS treated with HMAs. Response rates for the combination are preliminary, and more information will be provided with longer follow-ups.

A Phase Ib Dose-finding Study of Panobinostat and Ruxolitinib in Myelofibrosis.

A Phase Ib Dose-finding Study of Panobinostat and Ruxolitinib in Myelofibrosis.

Response To Ruxolitinib In Patients With Intermediate-1, Intermediate-2 and High-Risk Myelofibrosis: Interim Results Of The UK Robust Trial

BackgroundRuxolitinib is a selective small molecule inhibitor of Janus kinase 1 (JAK1) and 2 (JAK2). Ruxolitinib suppresses the activity of the JAK/STAT pathway, and thus targets the underlying pathogenic cause of myelofibrosis (MF). The efficacy and safety of ruxolitinib for the treatment of MF has been demonstrated in two pivotal phase III clinical trials, COMFORT-I and COMFORT-II. Ruxolitinib demonstrated a statistically significant reduction in splenomegaly compared with placebo (in COMFORT-I) and compared with best supportive care (in COMFORT-II) and has been approved for the treatment of patients with primary myelofibrosis (PMF), post polycythaemia myelofibrosis (PPV MF) or post-essential thrombocythaemia myelofibrosis (PET-MF) based on the results of these studies. Both pivotal studies involved patients with intermediate-2 or high-risk disease according to International Prognostic Scoring System criteria. However, a number of myelofibrosis patients with intermediate-1 risk disease have significant constitutional symptoms or pain relating to splenomegaly. The ROBUST trial, a UK open label, multicentre exploratory phase 2 study of ruxolitinib for patients with PMF, PPV MF or PET-MF further investigates the response to ruxolitinib in patients with MF and includes patients with intermediate-1 risk disease in addition to patients with intermediate-2 and high-risk disease. MethodsThis open-label multicentre UK study enrolled adult patients diagnosed with PMF, PPV MF or PET-MF (World Health Organization criteria) with or without prior therapy and who had intermediate-1, intermediate-2 or high-risk disease according to the International Working Group for Myelofibrosis Research & Treatment criteria. Patients received ruxolitinib at a dose of 15 or 20 mg twice daily (according to baseline platelet counts) and continued treatment until disease progression, unacceptable toxicity, death, or withdrawal from the study. Spleen size was assessed at baseline and at 4-week intervals by palpation, and symptoms were assessed by patients using the Myelofibrosis Symptom Assessment Form (MF-SAF) at baseline and weeks 4, 12 and 24. This interim analysis presents data at 24 weeks. ResultsA total of 48 patients (risk classification: intermediate-1, n = 20; intermediate-2, n = 11; high, n = 17) were included in the study. Mean ± SD age was 69.1 ± 10.4 years and 43.8% of patients were female. Most patients had an ECOG performance status at baseline of 0 (52.1%) or 1 (35.4%). Mean spleen length at baseline was 13.9 ± 6.9 cm and mean ± SD MF-SAF total symptom score (TSS) was 16.4 ± 11.5. A ≥50% decrease in spleen length from baseline at any time was achieved in 27/48 (56.3%) patients overall, and was similar across all risk groups. At week 24 a decrease in mean spleen length from baseline of 6.4 ± 5.2 was observed overall and was similar across the three risk groups (Table). A mean ± SD improvement in TSS at 24 weeks of 9.1 ± 11.3 was observed overall and improvements were similar in patients with intermediate-1 risk and with high-risk disease (Table). ConclusionsThese results indicate that in patients with MF, ruxolitinib provides marked and sustained reductions in splenomegaly and disease-related symptoms. Symptom and spleen responses were observed across risk categories, including intermediate-1 patients, providing further evidence of the clinical benefit of ruxolitinib in patients with MF. Missing data will be updated prior to the ASH2013 meeting, allowing more robust comparison across risk groups for the different endpoints. Disclosures:Harrison:S Bio: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Speakers Bureau; Celgene: Honoraria; YM Bioscience: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Clark:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Chacko:Amgen: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Knapper:Novartis: Funding for travel to overseas conference Other, Honoraria. Milojkovic:BMS: Honoraria; Pfizer: Honoraria; Ariad: Honoraria; Novartis: Honoraria. Farquharson:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ali:Novartis: Honoraria. Andrews:Novartis Pharmaceuticals UK Limited: Employment, Equity Ownership. Graham:Novartis Pharmaceuticals UK Limited: Employment. Mead:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abnormal mRNA Expression Levels of Telomere-Binding Proteins Represent Biomarkers in Myelodysplastic Syndromes: A case control study

Objective:As evidence was shown that abnormal shortening of telomeres begins to accumulate in myelodysplastic syndrome (MDS) patients, this study was conducted to determine the relationship between the mRNA expression levels of telomere-binding proteins (TRF1/TRF2/TIN2/TPP1/POT1/RAP1) and the risk level in MDS.Materials and Methods:There were 40 patients with MDS and 40 normal controls in this study. Methods including telomere content assays and quantitative reverse transcription-polymerase chain reaction were used to examine the mRNA levels of TRF1/TRF2/TIN2/TPP1/POT1/RAP1 in patients with MDS.Results:Compared to the normal group used as a control, the mRNA expression levels of RAP1/POT1/TPP1 of the patients with MDS were decreased, whereas their levels of TRF1/TRF2 and TIN2 were increased. A positive correlation was found between the TRF1, TRF2, and TIN2 mRNA expression levels and the risk level of the International Prognostic Scoring System (IPSS) and the World Health Organization Prognostic Scoring System (WPSS) criteria; however, a negative correlation was found between RAP1/POT1/TPP1 mRNA expression levels and the risk levels of IPSS and WPSS criteria.Conclusion:Because the reduction of TRF1/TRF2/TIN2 mRNA expression and the increase of RAP1/POT1/TPP1 mRNA expression are closely related to the risk levels of the IPSS and WPSS criteria in MDS, it is thought that these telomere-binding proteins could lead to abnormal telomere length and function, which cause chromosomal abnormalities in MDS. With this evidence, we suggest that those proteins’ mRNA expressions could be used as biomarkers for the assessment of the risk degree of MDS patients.

A Pooled Overall Survival (OS) Analysis of 5-Year Data from the COMFORT-I and COMFORT-II Trials of Ruxolitinib for the Treatment of Myelofibrosis (MF)

A Pooled Overall Survival (OS) Analysis of 5-Year Data from the COMFORT-I and COMFORT-II Trials of Ruxolitinib for the Treatment of Myelofibrosis (MF)

Rigosertib versus best supportive care for patients with high-risk myelodysplastic syndromes after failure of hypomethylating drugs (ONTIME): a randomised, controlled, phase 3 trial

Hypomethylating drugs are the standard treatment for patients with high-risk myelodysplastic syndromes. Survival is poor after failure of these drugs; there is no approved second-line therapy. We compared the overall survival of patients receiving rigosertib and best supportive care with that of patients receiving best supportive care only in patients with myelodysplastic syndromes with excess blasts after failure of azacitidine or decitabine treatment. We did this randomised controlled trial at 74 hospitals and university medical centres in the USA and Europe. We enrolled patients with diagnosis of refractory anaemia with excess blasts (RAEB)-1, RAEB-2, RAEB-t, or chronic myelomonocytic leukaemia based on local site assessment, and treatment failure with a hypomethylating drug in the past 2 years. Patients were randomly assigned (2:1) to receive rigosertib 1800 mg per 24 h via 72-h continuous intravenous infusion administered every other week or best supportive care with or without low-dose cytarabine. Randomisation was stratified by pretreatment bone marrow blast percentage. Neither patients nor investigators were masked to treatment assignment. The primary outcome was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT01241500. From Dec 13, 2010, to Aug 15, 2013, we enrolled 299 patients: 199 assigned to rigosertib, 100 assigned to best supportive care. Median follow-up was 19·5 months (IQR 11·9-27·3). As of Feb 1, 2014, median overall survival was 8·2 months (95% CI 6·1-10·1) in the rigosertib group and 5·9 months (4·1-9·3) in the best supportive care group (hazard ratio 0·87, 95% CI 0·67-1·14; p=0·33). The most common grade 3 or higher adverse events were anaemia (34 [18%] of 184 patients in the rigosertib group vs seven [8%] of 91 patients in the best supportive care group), thrombocytopenia (35 [19%] vs six [7%]), neutropenia (31 [17%] vs seven [8%]), febrile neutropenia (22 [12%] vs ten [11%]), and pneumonia (22 [12%] vs ten [11%]). 41 (22%) of 184 patients in the rigosertib group and 30 (33%) of 91 patients in the best supportive care group died due to adverse events and three deaths were attributed to rigosertib treatment. Rigosertib did not significantly improve overall survival compared with best supportive care. A randomised phase 3 trial of rigosertib (NCT 02562443) is underway in specific subgroups of patients deemed to be at high risk, including patients with very high risk per the Revised International Prognostic Scoring System criteria. Onconova Therapeutics, Leukemia & Lymphoma Society.

Efficacy, Safety, and Confirmation of the Recommended Phase 2 Starting Dose of the Combination of Ruxolitinib (RUX) and Panobinostat (PAN) in Patients (Pts) with Myelofibrosis (MF)

Efficacy, Safety, and Confirmation of the Recommended Phase 2 Starting Dose of the Combination of Ruxolitinib (RUX) and Panobinostat (PAN) in Patients (Pts) with Myelofibrosis (MF)

Serem Ferritin Was the Only Prognostic Factor for Disease Free Survival in MDS Patients after Allo-HSCT: A Single Centre Study

▪Introduction: Myelodysplastic syndrome (MDS) represents a heterogeneous group of hematopoietic stem cell disorders characterized by single-lineage or multi-lineage cytopenias and a risk of progression to acute myeloid leukemia (AML). Despite the development of new drugs, allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only potential curative therapy. We have a retrospective analysis of the efficacy and security of the allo-HSCT therapy for MDS in our singal centre.Method: Between June1999 and March 2012, 39 MDS patients with a median age of 32 years (range, 12-52) were transplanted with a matched related donor (n=10), unrelated donor (n=20) or haploidentical donor (n=9) in our centre. Of the patients, 62% were male; 44% had intermediate-1 risk, 13% intermediate-2 risk and 43% poor risk cytogenetics by the International Prognostic Scoring System criteria. The cell source was bone marrow (BM) in 36%, peripheral blood (PB) in 59% and BM+PB in 5%. 51% patients had received chemotherapy prior HSCT. Conditioning regimens were BUCY or BUCY plus ATG for matched related HSCT and unrelated transplants, AraC+BuCy+ATG+MeCCNU for haploidentical transplants. The median number of CD34+ cells/kg infusion was 5.52×106(range, 0.8×106-10.38×106).Graft-versus-host disease prophylaxis was employed by cyclosporine A (CsA), mycophenolate mofetil (MMF) and short-term methotrexate (MTX). 25 patients received serum ferritin measurement berore HSCT. The mediun level of serum ferritin was 1100ng/ml (range, 456-2318).Result: The median follow-up was 27 months(range,1.5-154). The 3-year disease free survival(DFS) was 60.8%. Transplant related mortality(TRM) was assessed at 37% on the whole cohort. 5% has no engraftment for a total of 2 patients. A neutrophil count of >0.5 × 109/L was achieved at a median of 12 days (range, 9–24 days) and a platelet count of >20 × 109/L within 14 days (9–49 days) post-transplant. Acute GVDH grade 1-2 was documented in 49%, grade 3-4 in 5% and no GVDH in 46%. Chronic GVHD could be identified in 27 patients (69%), 5 of whom had extensive disease, while the other 22 had limited disease. Overall 14 patients (36%) died. Causes of death were Infection 57%,GVDH 8%, haemorrhage 14%, engraft failure 14% and “other causes” 7%. Only one patients died because of relapse of the disease.DFS according to donor source (matched related donor 87.5%, unrelated donor 51.6% and haploidentical donor 55.6%) was not significant (p =0.22 ). Likewise no significant difference was found on DFS among BM 57%, PB 66.4% and BM+PB 50% (p =0.65). A similar DFS was seen in different risk categories (56.7% in intermediate, 66.7% in high-risk; p=0.51). No difference was seen in DFS according to the CD34+ cell number and whether received chemotherapy prior to HSCT. Only the elevated serum ferritin is associated with inferior DFS after HSCT(p =0.018 ). DisclosuresNo relevant conflicts of interest to declare.

Efficacy, Safety, and Confirmation of the Recommended Phase 2 Dose of Ruxolitinib Plus Panobinostat in Patients with Intermediate or High-Risk Myelofibrosis

Background: Myelofibrosis (MF) is a clonal neoplastic disease resulting in bone marrow fibrosis, splenomegaly, and debilitating constitutional symptoms. The Janus kinase (JAK) pathway is often dysregulated in MF, and agents targeting this pathway have demonstrated efficacy in this disease. Ruxolitinib (RUX), a potent JAK1/JAK2 inhibitor, demonstrated superiority in spleen volume reduction, symptom improvement, and survival compared with the control arm in the phase III COMFORT-I and COMFORT-II studies. Panobinostat (PAN), a potent pan-deacetylase inhibitor (pan-DACi), inhibits JAK signaling through disruption of the interaction of JAK2 with the protein chaperone heat shock protein 90. In phase I/II studies, PAN has shown splenomegaly reduction and improvement of bone marrow fibrosis. The combination of RUX and PAN demonstrated synergistic anti-MF activity in preclinical studies. These preliminary results led to the initiation of a phase Ib study evaluating the combination of RUX and PAN in patients (pts) with MF. The updated results from the expansion phase of this trial are presented here.Methods: Eligible pts had intermediate-1, -2, or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF by International Prognostic Scoring System criteria, with palpable splenomegaly (≥ 5 cm below the costal margin). The primary objective was determination of the maximum tolerated dose (MTD) and/or recommended phase II dose (RPIID). Secondary objectives included safety, efficacy, and pharmacokinetics. Exploratory endpoints included assessment of improvement in bone marrow fibrosis and reduction of JAK2 V617F allele burden. The treatment schedule was RUX (5-15 mg) twice daily (bid) every day and PAN (10-25 mg) once daily 3 times per week (tiw; days 2, 4, and 6) every other week (qow) in a 28-day cycle. Following dose escalation and identification of the potential RPIID, additional pts were enrolled into the expansion phase and treated at this dose.Results: As of March 14, 2014, a total of 61 pts were enrolled (38 escalation phase and 23 expansion phase). The median duration of exposure to PAN and to RUX was 24.6 weeks and 24.0 weeks, respectively, for pts treated in the expansion phase. Three DLTs were observed in the escalation phase (grade 4 thrombocytopenia [n = 2], grade 3 nausea [n = 1]). No MTD was reached. The RPIID was confirmed to be RUX 15 mg bid and PAN 25 mg tiw qow in May 2014. Among the 34 pts treated at the RPIID, grade 3/4 adverse events (AEs) regardless of causality included anemia (32%), thrombocytopenia (24%), diarrhea (12%), asthenia (9%), and fatigue (9%). AEs led to discontinuation in 6% of pts treated at the RPIID. Two pts treated at the RPIID died due to causes unrelated to study treatment (1 due to myocardial infarction and 1 due to progression of myelofibrosis). Among the pts treated at the RPIID, 79% showed a >50% decrease in palpable spleen length, with 100% decrease (non-palpable spleen) being observed in 53% of pts. Additionally, 48% of pts treated at the RPIID in the expansion phase achieved ≥35% reduction in spleen volume (Figure). These results are similar to those observed for spleen volume response at 24 weeks among pts who received single-agent RUX on the phase III COMFORT-I (41.9%) and COMFORT-II (32%) studies.Conclusions: The combination of the JAK1/JAK2 inhibitor RUX and the pan-DACi PAN was well tolerated and resulted in high rates of reductions in splenomegaly in pts with intermediate- and high-risk MF. Although a relatively larger proportion of patients experienced spleen volume reductions at week 24 as compared to the COMFORT studies, the smaller sample size, shorter follow up times and potential differences in the patient populations preclude definitive comparisons. Similar to COMFORT-I and II trials, hematological AEs, specifically anemia and thrombocytopenia, were the most common AEs observed in pts treated with the combination therapy. Pts continue to be treated in the expansion phase at the RPIID. Updated safety, efficacy, and exploratory analyses on bone marrow fibrosis, JAK V617F allele burden, and biomarkers, including cytokines, will be presented. [Display omitted] DisclosuresKiladjian:Novartis: Honoraria, Research Funding, Speakers Bureau; Shire: Membership on an entity’s Board of Directors or advisory committees; AOP Orphan: Honoraria, Research Funding. Heidel:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Vannucchi:Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ribrag:Celgene: Consultancy; Pharmamar: Consultancy; Epizyme: Research Funding; Bayer: Consultancy, Research Funding; Servier: Consultancy, Honoraria, Research Funding. Conneally:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Kindler:Novartis: Consultancy. Acharyya:Novartis: Employment. Gopalakrishna:Novartis: Employment. Ide:Novartis: Employment, Equity Ownership. Loechner:Novartis: Employment. Mu:Novartis: Employment. Harrison:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria; CTI: Consultancy, Honoraria; Gilead: Honoraria; SBio: Consultancy; Shire: Speakers Bureau.

A Phase 1b, Dose-Finding Study Of Ruxolitinib Plus Panobinostat In Patients With Primary Myelofibrosis (PMF), Post–Polycythemia Vera MF (PPV-MF), Or Post–Essential Thrombocythemia MF (PET-MF): Identification Of The Recommended Phase 2 Dose

A Phase 1b, Dose-Finding Study Of Ruxolitinib Plus Panobinostat In Patients With Primary Myelofibrosis (PMF), Post–Polycythemia Vera MF (PPV-MF), Or Post–Essential Thrombocythemia MF (PET-MF): Identification Of The Recommended Phase 2 Dose

Transplantation For Myelodysplastic Syndrome Evolving From Aplastic Anemia Treated With Immunosuppressive Therapy: From The Fred Hutchinson Cancer Research Center and Center For International Bone Marrow Transplantation Research

BackgroundImmunosuppressive therapy (IST) offers effective treatment for 40% - 70% of patients with aplastic anemia (AA). However, 15% - 40% of AA patients given IST will develop a clonal disorder of hematopoiesis clinically presenting as myelodysplastic syndrome (post-AA MDS) many of whom will proceed to allogeneic hematopoietic cell transplantation (HCT). Whether the success of HCT is comparable to or different from that in patients with de novo MDS is not known. Patients and MethodsWe identified 123 patients who underwent HCT for post-AA MDS (N = 89 with refractory anemia; N = 34 with more advanced MDS). Transplants occurred from 1977 through 2011 (75% since 2000). Patients with post-AA MDS were 2-68 (median 28) years old; 64% were male, 36% female. The interval from diagnosis of post-AA MDS to HCT was <1 – 152 (median 6) months; 25% had good risk, 25% intermediate risk, and 50% poor risk cytogenetics by the International Prognostic Scoring System criteria. Eighty percent of HCTs were from unrelated donors, and among these, 75% were HLA-matched. In a matched-pair analysis the 123 post-AA MDS patients (cases) were matched to patients with de novo MDS (N = 393; controls) for age, disease status, donor type and HLA-match, intensity of conditioning regimen and transplant period. Seventy-four cases were matched to 4 controls, 13 to 3 controls, 22 to 2 controls, and the remaining 14 cases to 1 control. Controls were more likely to have a longer interval from diagnosis of MDS to HCT (median 9 vs. 6 months; p<0.001) and less likely to have poor risk cytogenetics (39% vs. 53%; p=0.008) or to have received ATG (38% vs. 53%, p=0.003). The source of stem cells for controls and cases was bone marrow (42% vs. 53%), blood progenitor cells (44% vs. 35%) or cord blood (13% vs. 12%). Endpoints in the analysis were graft failure, GVHD, relapse, non-relapse mortality (NRM), relapse-free and overall survival. Relapse and NRM were treated as competing risks. ResultsTime to neutrophil engraftment (18 vs. 17 days) and engraftment rate (87% vs. 89%; p=0.44) were similar for cases and controls; there were 11 primary and 3 secondary graft failures among cases and 21 primary and 9 secondary graft failures among controls (p=0.17). The day-100 incidence of grades II-IV acute GVHD was 52% vs. 47% (p=0.30), and the 1-year incidence of chronic GVHD 49% vs. 41% (p=0.13) for cases and controls, respectively. With a median follow-up of 4 years for cases and controls, the 5-year probabilities of NRM, relapse, overall and relapse-free survival were 37%, 19%, 49% and 45% for cases, and 27%, 30%, 49% and 43%, respectively, for controls. In multivariate analysis the risk of overall mortality was similar for cases and controls (HR 1.03, p=0.83). The NRM risk was marginally higher for cases (HR 1.44, p=0.06) while relapse risk was lower (HR 0.60, p=0.02) than for controls, and there was no difference in relapse-free survival (HR 0.94, p=0.62). Cytogenetic risk was independently associated with mortality. Among cases, compared to good cytogenetic risk, intermediate risk (HR 2.13, p=0.03) but not poor risk (HR 0.79, p=0.41) was associated with higher mortality. Among controls, both intermediate risk (HR 1.55, p=0.02) and poor risk cytogenetics (HR 1.44, p=0.04) were associated with higher mortality. Summary and ConclusionTransplant success with related and unrelated donors in patients with post-AA MDS was similar to that in patients with de novo MDS, with a 5-year relapse-free survival of 41%. The slightly higher NRM risk in post-AA MDS patients, which deserves further investigation, was negated by lower relapse risk. The apparent higher risk of mortality with intermediate risk cytogenetics among patients with post-AA MDS was unexpected, but may be related to small numbers or is the expression of undetermined biologic features. Disclosures:No relevant conflicts of interest to declare.

MRNA expression of telomere protection protein TIN2 and POT1 in bone marrow of patients with myelodysplastic syndrome

This study was purposed to explore the relationship between the mRNA expression of telomere protection protein TIN2 and POT1 and the pathogenesis of myelodysplastic syndrome (MDS). The expression of TIN2 and POT1 genes at the mRNA levels were detected by real-time fluorescence quantitative PCR in 51 patients with MDS and 10 normal controls. The results showed that the mRNA expressions of TIN2 in RA/RARS/RCMD/MDS-U, RAEB-1 and RAEB-2 groups according to the World Health Organization criteria were significantly higher than that in the controls (P < 0.05); the mRNA expressions of POT1 in RA/RARS/RCMD/MDS-U, RAEB-1 and RAEB-2 groups were significantly lower than that in the controls (P < 0.05). The mRNA expressions of TIN2 in high-risk group, inter risk-2 group and inter risk-1 group according to the international prognostic scoring system criteria were significantly higher than that in controls (P < 0.05). There was no significant difference between low risk group and the control group. The mRNA expressions of POT1 in high risk group, inter-risk-2 group and inter-risk-1 group were significantly lower than the controls (P < 0.05). There was no significant difference between low risk group and the control group. The mRNA expression of TIN2 in normal chromosome group was significantly lower than that in abnormal chromosome group (P < 0.05). There was no significant difference between normal chromosome group and the control group. The mRNA expression of POT1 in normal chromosome group was significantly higher than that in abnormal chromosome group (P < 0.05). There was no significant difference between normal chromosome group and the control group. It is concluded that the abnormal mRNA expression of TIN2 and POT1 may be involved in the regulation of telomere dynamics of MDS patients, the regulatory mechanism may be related to the telomere length and the pathogenesis of MDS.

Conditioning with Treosulfan and Fludarabine followed by Allogeneic Hematopoietic Cell Transplantation for High-Risk Hematologic Malignancies

In this prospective study 60 patients of median age 46 (range: 5-60 years), with acute myelogenous leukemia (AML; n= 44), acute lymphoblastic leukemia (ALL; n = 3), or myelodysplastic syndrome (MDS; n = 13) were conditioned for allogeneic hematopoietic cell transplantation with a treosulfan/fludarabine (Flu) combination. Most patients were considered at high risk for relapse or nonrelapse mortality (NRM). Patients received intravenous treosulfan, 12 g/m(2)/day (n = 5) or 14 g/m(2)/day (n = 55) on days -6 to -4, and Flu (30 mg/m(2)/day) on days -6 to -2, followed by infusion of marrow (n = 7) or peripheral blood stem cells (n = 53) from HLA-identical siblings (n = 30) or unrelated donors (n = 30). All patients engrafted. NRM was 5% at day 100, and 8% at 2 years. With a median follow-up of 22 months, the 2-year relapse-free survival (RFS) for all patients was 58% and 88% for patients without high-risk cytogenetics. The 2-year cumulative incidence of relapse was 33% (15% for patients with MDS, 34% for AML in first remission, 50% for AML or ALL beyond first remission and 63% for AML in refractory relapse). Thus, a treosulfan/Flu regimen was well tolerated and yielded encouraging survival and disease control with minimal NRM. Further trials are warranted to compare treosulfan/Flu to other widely used regimens, and to study the impact of using this regimen in more narrowly defined groups of patients.

Red Blood Cell Transfusion Dependence and Outcome after Allogeneic Peripheral Blood Stem Cell Transplantation in Patients with de Novo Myelodysplastic Syndrome (MDS)

The prognosis of patients with de novo myelodysplastic syndrome (MDS) who are red blood cell transfusion-dependent (TD) and receive supportive care is inferior to that of patients who do not require transfusions. Whether TD also affects outcome after allogeneic transplantation is unknown. Consequently, in 172 de novo MDS patients (median age, 51 years), we analyzed the impact of TD on outcome after high-dose conditioning and allogeneic peripheral blood stem cell transplantation (PBSCT). With a median follow-up of 37 months, the probability of 3-year overall survival (OS) did not differ significantly between patients who were TD and those who were not TD before PBSCT (P=.1); however, transfusion burden, as reflected by ferritin levels, was correlated with a greater probability of severe acute graft-versus-host disease (aGVHD; P=.03) and a higher comorbidity index (P=.01), and OS was inferior in those patients with a ferritin level>1000 microg/L before PBSCT (P=.03). In multivariate analysis, only marrow myeloblast count (P=.01) and comorbidity index (P=.001) had a significant impact on OS. Our data do not identify TD as an independent negative prognostic factor for outcome after allogeneic PBSCT' however, iron overload (presumably transfusion-related) may contribute to poor transplantation success by adding to the overall comorbidities. Whether clinical intervention in the form of iron chelation can improve the outcome of allogeneic PBSCT in TD patients with MDS remains to be determined.

Validation of IPSS criteria in more than 1,600 MDS patients

7079 Myelodysplastic syndromes (MDS) are a diverse group of clonal stem cell disorders characterized by bone marrow failure, dysmyelopoiesis and peripheral cytopenias and affecting predominantly an elderly population. The International Prognostic Scoring System (IPSS) incorporates the number of peripheral cytopenias, percentage of bone marrow blasts and chromosomal abnormalities and assigns a score to predict survival and risk of disease progression to AML. Using the extensive MDS database at the University of Massachusetts we analyzed survival time in relation to IPSS scoring and also its various individual components, i.e. blast percentage, number of cell lines involved and the number of karyotype abnormalities in 1,200+ patients. The overall median survival time in 1,424 MDS patients as a group was 2.9 years. IPSS low group had the longest median survival time of 7.5 years with IPSS Int-1 3.6 years. There was minimal difference in the median survival time between IPSS Int-2 and IPSS high risk group 1.2 and 1.1 years respectively. These results were significant for a P value of &lt;0.0001. The median survival time for blasts &lt;5% was 5.3 years and blast 5–10% was 1.7 years. Interestingly, there was minimal survival difference between median survival time for blasts 11–20% and blasts &gt;20% showing 1.2 years and 1.3 years respectively. Again, these results were significant for a P value of &lt;0.0001. The median survival time for the number of cytopenias involved was also calculated with 0, 1, 2 and 3 numbers of cytopenias showing 6.4 years, 4.4 years, 2.6 years and 1.8 years respectively, with P value of &lt;0.0001. The median survival time for normal karyotype versus one or two karyotype abnormality was 4.9 years, 2.6 years and 2.4 years respectively. Three or more karyotype abnormalities showed a median survival time of 0.8 years. The P value was again significant (&lt;0.0001). Our results not only validate the prognostic value of IPSS scoring system as a whole but also its various individual prognostic indicators. No significant financial relationships to disclose.

Combined stratification of refractory anemia according to both WHO and IPSS criteria has a prognostic impact and improves identification of patients who may benefit from stem cell transplantation

A retrospective analysis of the relationship between the initial classification according to either FAB or WHO criteria, the presence of risk factors and the type of therapy including stem cell transplantation (SCT) on the survival was performed in a group of 106 patients with primary myelodysplastic syndrome (MDS) of FAB RA subtype. Allogeneic SCT early in the course of the disease did not significantly affect median survival in RA patients evaluated either according to FAB criteria (63.2 months in 17 SCT patients versus 64.4 months in 89 non-transplanted (non-SCT) patients) or in subgroups classified separately according to WHO (64.0 months in SCT versus 91.0 months in non-SCT RA patients and 66.2 months in SCT versus 43.0 months in non-SCT refractory cytopenia with multilineage dysplasia (RCMD) patients) or International Prognostic Scoring System (IPSS) criteria despite decreased incidence of leukemic transformation (5% in SCT versus 32% in non-SCT patients). Neither univariate or multivariate analysis of different clinical and laboratory parameters revealed a significant effect of SCT on 3 or 5 years survival in RA patients. The most probable explanation was a relatively high rate of transplantation related mortality (41%) on one hand together with a slow disease progression towards leukemia (24% at 5 years in non-SCT) on the other hand. A more refined stratification of patients based on the combined WHO morphology classification and IPSS cytogenetic criteria revealed subgroup of 11 non-SCT patients with RCMD and poor karyotype with median survival significantly different from that in five SCT patients (9.2 months in non-SCT versus 89.3 months in SCT, P=0.05). Thus, combined WHO morphology/IPSS cytogenetics criteria may be helpful for identification of the high risk patients with the RA group who may benefit from early SCT despite the relatively high incidence of SCT-related complications.

Hemopoietic stem cell transplantation for myelodysplastic syndrome.

The term myelodysplastic syndrome (MDS) describes a spectrum of disorders that are characterized by dysplastic marrow cell morphology, the development of peripheral blood cytopenias, and a tendency to evolve into acute myeloid leukemia. MDS has been recognized as a stem-cell disease, and hemopoietic stem-cell transplantation is currently the only potentially curative therapy. In patients with less advanced MDS (<5% blasts in the marrow), 3-year survival rates of 70% and 65% can be achieved with HLA-identical related and HLA-matched unrelated donors, respectively. The overall probability of disease recurrence in these patients is less than 5%. Of patients with advanced disease (5% marrow blasts or more), about 40% to 45% and 25% to 30% are surviving in remission after transplantation from a related or an unrelated donor, respectively. This inferior outcome is largely due to a higher incidence of post-transplantation relapse (20% to 30%). Inclusion of the International Prognostic Scoring System criteria into outcome analyses shows an inverse correlation between overall risk category and relapse-free survival after transplantation. Future trials should explore the usefulness of different transplantation regimens for different risk categories. Among patients with less advanced disease, use of a conditioning regimen that combines cyclophosphamide and busulfan, dose adjusted to reach target plasma levels, has been associated with improved survival in recipients of transplants from related and unrelated donors. It has also permitted successful hemopoietic stem-cell transplantation in patients as old as 66 years of age. Improved survival with transplants from unrelated volunteer donors has been achieved with selection of donors based on high-resolution HLA typing. Autologous stem-cell transplantation may provide excellent consolidation for selected patients who have obtained complete remission with conventional chemotherapy. High treatment-related morbidity and mortality rates, particularly after allogeneic transplantation, remain challenges that must be addressed with innovative approaches.