scholarly journals Changing Patterns of Symptomatic Myeloma after the Implementation of the 2014 IMWG Diagnostic Criteria and Reduced Early Mortality

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1636-1636
Author(s):  
Efstathios Kastritis ◽  
Maria Gavriatopoulou ◽  
Maria Roussou ◽  
Evangelos Eleutherakis-Papaiakovou ◽  
Magdalini Migkou ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Diagnostic Criteria ◽  
Research Funding ◽  
Clinical Presentation ◽  
Statistical Significance ◽  
Early Mortality ◽  
Bone Marrow Infiltration ◽  
Focal Lesion ◽  
Smoldering Myeloma ◽  
The Impact

Abstract In 2014, the IMWG updated the diagnostic criteria for symptomatic myeloma and in addition to classical "CRAB", implemented "biomarkers of malignancy" (BoM) (FLC ratio>100, more than 1 focal lesion in MRI and bone marrow infiltration of at least 60%). As a result, a subset of patients previously considered as having "smoldering myeloma" were characterized as symptomatic and were eligible to start therapy; these criteria are also adopted in clinical trials. However, the impact of the 2014 IMWG criteria in the overall clinical presentation of symptomatic myeloma patients who start therapy or in the outcomes of patients who present only with biomarkers of malignancy, has not been fully appreciated. We evaluated the characteristics and outcomes of patients who started therapy in the past 5 years, when the 2014 IMWG criteria were implement in our clinical practice and compare their characteristics and outcomes with those of patients that started in an earlier period. To adjust for advances in diagnosis and especially imaging, the analysis included 1007 consecutive patients who started therapy in the Department of Clinical Therapeutics between 1/1/2010 and 31/12/2020. Our prospectively maintained database includes all consecutive patients who start therapy for myeloma. The patients were divided in two cohorts: those that started therapy after 1/1/2015 (after 2014 IMWG criteria implementation) and those that started therapy between 1/1/2010 and 31/12/2014. In these two chronological periods, methods for the assessment of disease were similar except for wider use of ldWBCT after 2013 and more frequent use of conventional CT before 2013. In the 2010-2014 period, 393 patients started therapy vs 614 that started between 2015-2020. Patients in the two groups had similar age (mean 67 vs 66.3, p=0.399) and similar b2-microglobulin levels (7.39 vs 7.33 mg/L, p=0.907) but hemoglobin (mean 10.2 vs 10.6 gr/dl, p=0.016), platelet counts (mean 230 vs 246 x10 9/L, p=0.021), serum albumin (3.6 vs 3.8 gr/dl, p=0.003) were higher in the 2015-2020 era. Although it did not reach statistical significance, mean bone marrow infiltration in trephine biopsy (60.5% vs 57.3%, p=0.056) and eGFR (mean 66.6 vs 62.3 ml/min/ 1.73 m2, p=0.057) were higher and mean serum calcium levels lower (9.9 vs 10.2 mg/dl, p=0.073) in 2015-2020 group, while, serum LDH >ULN (19.6% vs 21.4%, p=0.513) and high risk cytogenetics (20.4% vs 20.8%) were found in similar rates. Accordingly, ISS and R-ISS stage distribution was similar (p=0.496). Per CRAB criteria, hemoglobin < 10 gr/dl was present in 48.9% of patients in the 2010-14 period vs 43.6% in the 2015-2020 (p=0.1), hypercalcemia in 18.2% vs 15% (p=0.185), serum creatinine ≥2 mg/dl in 22% vs 18% (p=0.124) and lytic bone disease in 76.9% vs 76.8%, p=0.973). At least one CRAB was present in 96.4% vs 94% of patients in the two periods (p=0.603). Even in the era before the publication of the 2014 IMWG criteria, 3.6% of patients that started therapy did not fulfill the CRAB criteria of that time; in retrospect, most had at least one BoM present. In the 2015-2020 period, 6% of new patients were considered as symptomatic based on the presence of BoM only. The median follow-up of the 2010-2014 cohort is 63 months and is 25 months for the 2015-2020 group; the 1- and 2-year OS is 83% vs 90% and 75% vs 79% respectively (p=0.057) for the two groups; early mortality (within 3 months from start of therapy) was 7.4% vs 3.9% (p=0.016) respectively. The OS of patients starting therapy based on the presence of BoM only is not reached (3-year OS 87%) vs 59 months (3 year OS: 65%) for patients presenting with CRAB (p=0.051). Because there may be a lead time bias, we also compare the OS of patients with biomarkers of malignancy only vs those with CRAB and ISS-1 disease: OS was similar although with a trend towards better OS for those with BoM. In conclusion, the implementation of the 2014 IMWG diagnostic criteria has resulted in about 6% of newly diagnosed patients starting therapy based only on the presence of BoM. Although the implementation of the criteria has resulted in slightly better clinical presentation (less severe CRAB) and reduced early mortality, most patients still present with disease complications. These data point to the need to develop tools that can identify myeloma patients earlier during their disease course, before they develop devastating complications, in order to further improve their outcomes and quality of life. Disclosures Kastritis: Janssen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Genesis Pharma: Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Gavriatopoulou: Karyopharm: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Genesis: Honoraria; GSK: Honoraria; Amgen: Honoraria. Terpos: Novartis: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding. Dimopoulos: Takeda: Honoraria; BMS: Honoraria; Amgen: Honoraria; Beigene: Honoraria; Janssen: Honoraria.

DNA Flow Cytometry and Metaphase Cytogenetics Can Predict Progression of Asymptomatic Monoclonal Gammopathies (AMG) to Symptomatic Multiple Myeloma (MM).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2915-2915
Author(s):  
Xenofon Papanikolaou ◽  
Sarah Waheed ◽  
Madhav V. Dhodapkar ◽  
Saad Z Usmani ◽  
Christoph Heuck ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Flow Cytometry ◽  
Dna Content ◽  
Research Funding ◽  
Statistical Significance ◽  
S Phase ◽  
M Protein ◽  
Clinical Staging ◽  
The Impact

Abstract Abstract 2915 Background: AMG is the most common plasma cell dyscrasia, currently classified as either monoclonal gammopathy of undetermined significance (MGUS) or asymptomatic multiple myeloma (AMM), based on the level of monoclonal immunoglobulin (M-protein), bone marrow plasmacytosis and other criteria defined by the International Myeloma Working Group. While information is available on the impact of clinical variables such as bone marrow plasmacytosis, free light chains, isotype and M-protein on the hazard of progression to symptomatic MM (MM), little is known about the value of the karyotype and DNA content, as determined by DNA/cIg flow cytometry, on the risk of progression from AMG to MM. Methods: Patients from the Myeloma Institute for Research and Therapy (MIRT) with AMG that were enrolled in a prospective observational clinical trial were evaluated. All patients underwent detailed clinical staging at entry and were followed at pre-specified intervals per protocol. Cox proportional hazards regression was used to model univariate and multivariate associations of baseline features with progression to MM. The number of distinct DNA stem lines in the flow cytometry assay, their percentages, respective DNA Indices (DI), cytoplasmic Immunoglobulin Indices (cIgI), and percent of cells in S phase were evaluated alone and in relation to the karyotype report at baseline. A DI between 0.99 and 1.01 referred to diploidy, lesser than 0.99 to hypodiploidy and more than 1.01 hyperdiploidy. Results: Data from 267 eligible MIRT patients with AMG were analyzed. Of these patients 99% (265/267) had performed DNA/cIg flow cytometry and had a karyotype report at diagnosis. Cytogenetic abnormalities were detected in 20 of the 265 patients from whom data were available. From the 265 patients from whom DNA/cIg flow cytometry data were available, no abnormal clones were identified in 14% (37/265), one clone was identified in 95 patients (36%), two clones in 122 patients (46%), three clones in 10 (4%), and in 1 patient 4 clones were identified. Most patients with abnormal DNA content had hyperdiploid clones (132/243 patients). The second most frequent finding was diploid DI, in 39% (104/243) of patients; 3% (7/243) had a hypodiploid DI. The median DI was 1.01 (0.9–2.02) and median cIg was 7 (1–50). Interestingly, the median cIgI value in AMG was more than twice that of its value (3.4, 1–22) in Total Therapy 3 MM patients (p=0.001). In univariate analysis of the parameters in this study, the presence of an abnormal karyotype (p=0.032, HR=2.62), the number of DNA/cIg clones (p=0.016, HR=1.69) and the percentage of the dominant clone (p=0.003, HR=1.03) were significantly related to progression to MM. Ploidy by DNA/cIg analysis, the S-phase fraction, and cIg did not reach statistical significance (p=0.863, p=0.132 and p=0.240, respectively). In multivariate analysis, only the number of abnormal clones (p=0.013, HR=1.78) retained statistical significance, while the percentage of the dominant clone neared significance (p=0.070, HR=1.02). Using running log rank tests we were able to identify optimal cut-points for the percentage of the dominant clone and the number of clones (12% and 2 clones respectively). From these, a risk score was obtained which identifies three distinct groups with 3-yr MM progression probabilities of 12%, 30% and 67% (p<0.001) (Figure 1). Conclusions: Abnormal metaphase cytogenetics and DNA/cIg flow cytometry have a prognostic value in the prediction of progression of AMG to MM. Hyperdiploidy is the dominant finding in AMG, however, its presence or absence does not predict progression. Clonal heterogeneity, as portrayed through DNA/cIg flow cytometry analysis, with the number of abnormal clones and the percentage of the dominant clone were major prognostic factors for progression to MM. Taken together they identify three distinct subgroups with a low (12%), moderate (30%) and high (67%) probability of 3-year time to progression to MM. Disclosures: Dhodapkar: Celgene: Research Funding; KHK: Research Funding.

scholarly journals Increased Early Mortality after Fludarabine and Melphalan Conditioning with Peripheral Blood Grafts in Haploidentical SCT with Post-Transplant Cyclophosphamide

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4496-4496 ◽  
Author(s):  
Luke Eastburg ◽  
David A. Russler-Germain ◽  
Ramzi Abboud ◽  
Peter Westervelt ◽  
John F. DiPersio ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Early Mortality ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Post Transplant ◽  
Equity Ownership

The use of post-transplant cyclophosphamide (PTCy) in the context of haploidentical stem cell transplant (haplo-SCT) has led to drastically reduced rates of Graft-vs-Host (GvH) disease through selective depletion of highly allo-reactive donor T-cells. Early trials utilized a reduced-intensity Flu/Cy/TBI preparative regimen and bone marrow grafts; however, relapse rates remained relatively high (Luznik et al. BBMT. 2008). This led to the increased use of myeloablative (MA) regimens for haplo-SCT, which have been associated with decreased relapse rates (Bashey et al. J Clin Oncol. 2013). Most studies have used a MA total body irradiation (TBI) based regimen for haplo-SCT. Preparative regimens using fludarabine and melphalan (FluMel), with or without thiotepa, ATG, and/or low dose TBI have also been reported using bone marrow grafts. Reports on the safety and toxicity of FluMel in the haplo-SCT setting with PTCy and peripheral blood stem cell (PBSC) grafts are lacking. In this two-center retrospective analysis, the safety/toxicity of FluMel as conditioning for haplo-SCT was evaluated. We report increased early mortality and toxicity using standard FluMel conditioning and PBSC grafts for patients undergoing haplo-SCT with PTCy. 38 patients at the University of Rochester Medical Center and the Washington University School of Medicine underwent haplo-SCT with FluMel conditioning and PBSC grafts between 2015-2019. Outcomes were measured by retrospective chart review through July 2019. 34 patients (89.5%) received FluMel(140 mg/m2). Two patients received FluMel(100 mg/m2) and two patients received FluMel(140 mg/m2) + ATG. The median age at time of haplo-SCT was 60 years (range 21-73). 20 patients were transplanted for AML, eight for MDS, two for PMF, two for NHL, and five for other malignancies. The median Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) score was 4 (≥3 indicates high risk). 11 patients had a history of prior stem cell transplant, and 16 patients had active disease prior to their haplo-SCT. Seven patients had sex mismatch with their stem cell donor. Median donor age was 42 (range 21-71). 20 patient deaths occurred by July 2019 with a median follow up of 244 days for surviving patients. Nine patients died before day +100 (D100, "early mortality"), with a D100 non-relapse mortality (NRM) rate of 24%. Median overall and relapse free survival (OS and RFS, respectively) were 197 days (95% CI 142-not reached) and 180 days (95% CI 141-not reached), respectively, for the entire cohort. The 1 year OS and NRM were 29% and 50%. The incidence of grades 2-4cytokine release syndrome (CRS) was 66%, and 52% of these patients were treated with tocilizumab. CRS was strongly associated with early mortality, with D100 NRM of 36% in patients with grade 2-4 CRS compared to 0% in those with grade 0-1. The incidence of acute kidney injury (AKI) was 64% in patients with grade 2-4 CRS, and 8% in those without (p < 0.001). 28% of patients with AKI required dialysis. Grade 2-4 CRS was seen in 54% of patients in remission prior to haplo-SCT and in 92% of those with active disease (p = 0.02). Of the 9 patients with early mortality, 89% had AKI, 44% needed dialysis, and 100% had grade 2-4 CRS, compared to 31%, 10%, and 55% in those without early mortality (p = 0.002, p = 0.02, p = 0.01). Early mortality was not significantly associated with age, HCT-CI score, second transplant, disease status at transplant, total dose of melphalan, volume overload/diuretic use, or post-transplant infection. In conclusion, we observed a very high rate of NRM with FluMel conditioning and PBSC grafts for haplo-SCT with PTCy. The pattern of toxicity was strongly associated with grade 2-4 CRS, AKI, and need for dialysis. These complications may be mediated by excessive inflammation in the context of allo-reactive donor T-cell over-activation. Consistent with this, multiple groups have shown that FluMel conditioning in haplo-SCT is safe when using bone marrow or T-cell depleted grafts. Based on our institutional experiences, we would discourage the use of FluMel as conditioning for haplo-SCT with PTCy with T-cell replete PBSC grafts. Alternative regimens or variations on melphalan-based regimens, such as fractionated melphalan dosing or inclusion of TBI may improve outcomes but further study and randomized controlled trials are needed. This study is limited in its retrospective design and sample size. Figure Disclosures DiPersio: WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Karyopharm Therapeutics: Consultancy; Magenta Therapeutics: Equity Ownership; Celgene: Consultancy; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; NeoImmune Tech: Research Funding; Amphivena Therapeutics: Consultancy, Research Funding; Bioline Rx: Research Funding, Speakers Bureau; Macrogenics: Research Funding, Speakers Bureau; Incyte: Consultancy, Research Funding; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees. Liesveld:Onconova: Other: Data safety monitoring board; Abbvie: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Clinical Characteristics, Immunophenotype and Outcomes of Blastic Plasmacytoid Dendritic Cell Neoplasms in a Peruvian Cohort

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 42-43
Author(s):  
Daniela Dueñas ◽  
Elizabeth Cervantes ◽  
Daniel J Enriquez ◽  
Claudio Flores ◽  
Carlos Barrionuevo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cell ◽  
Clinical Characteristics ◽  
Conflicts Of Interest ◽  
Plasmacytoid Dendritic Cell ◽  
Age At Diagnosis ◽  
Bone Marrow Infiltration ◽  
Maturation Stage ◽  
Female Predominance ◽  
The Impact

Background:Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and fatal myeloid malignancy characterized by clonal proliferation of immature plasmacytoid dendritic cells. BDCN has been frequently described in men and age above 60 years, and usually involves the skin and bone marrow. Immunophenotyping is based on CD123+, CD4+ and CD56+ expression and is necessary rule out other myeloid malignancies. Objective: We aimed to describe the clinical characteristics and immunophenotype of BPDCN cases diagnosed at two tertiary Peruvian cancer institutions between 2018-2019. Methods: We retrospectively reviewed medical records of patients diagnosed of BPDCN at two tertiary Peruvian cancer centers (Instituto Nacional de Enfermedades Neoplasicas and Oncosalud-AUNA, Lima-Peru) between 2008 and 2019. Clinical characteristics, treatments, outcomes and immunophenotype by pathology or flow cytometry review, were collected. Patients were classified according to their maturation stage using CD34 and CD117 expression into three subgroups: Immature-Intermediate blastic (IIB-BPDCN; partial expression of CD117 and absence or minimal expression of CD34), mature (M-BPDCN; absence of CD34 and CD117) and unknown(U-BPDCN). Overall survival (OS) and event-free survival (EFS) curves were estimated using the Kaplan-Meier method and compared with the Log-rank test to determine the impact of immunophenotype. Results: Thirty-eight cases were included during the study period. The median age at diagnosis was 38 years (7-82), only six (16%) were older than 65 years, and a notorious female predominance (F/M ratio: 1.7:1) was observed. Twenty-four cases had CD34/117 expression available and were classified according to the maturation stage in IIB-BPDCN (13) and M-BPDCN(11), additionally 14 cases had unknown stage (U-BPDCN). Table 1 summarizes clinical characteristics, treatment and outcomes according to their immunophenotype. Bone marrow infiltration was more frequent in immature phenotypes (92% IIB-BPDCN vs 73% M-BPDCN, p=0.001), as well as skin infiltration was more common in mature phenotype (72% vs 31%, p=0.008). CNS infiltration at diagnosis was 15% and 55% in IIB-BPDCN and M-BPDCN, respectively. Sixteen patients received treatment based on ALL-like protocols, 8 AML-like, 5 CHOP-like and 9 patients only palliative care. At 5 years median follow-up, median EFS and OS was 12 and 16 months, respectively. IIB-BPDCN had the lowest survival (4 months EFS and 6 months OS). Conclusions: We describe a Peruvian cohort of BPDCN patients with younger age at diagnosis and female predominance than reported previously by other series, however further studies in Latino population are required to confirm these results. Immature phenotypes based on CD34 and CD117 expression were associated with high rate of bone marrow infiltration and fatal outcomes. New successful target therapies must be warranted for this rare and fatal condition. Disclosures No relevant conflicts of interest to declare.

Meta Analysis of Grade 3 and/or 4 Toxicities in Low-Grade Non-Hodgkin Lymphoma (LG-NHL) Patients Receiving Maintenance Rituximab (MR) Therapy: Impact of Schedule on Toxicity

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2704-2704
Author(s):  
Chadi Nabhan ◽  
Dana Villines ◽  
Tina V. Valdez ◽  
Michele Ghielmini ◽  
Shu-Fang Hsu Schmitz ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Research Funding ◽  
Meta Analysis ◽  
Statistical Significance ◽  
Comparative Trial ◽  
Progression Free Survival ◽  
Low Grade ◽  
Front Line ◽  
Grade 3 ◽  
The Impact

Abstract Abstract 2704 Background: MR has improved the outcome and progression-free survival (PFS) in patients with follicular lymphoma (FL) in front-line and relapsed settings. However, maintenance schedules have been empirically designed based on either B-cell depletion kinetics or rituximab levels, with no consensus on the optimal regimen. Overall, toxicities have been predictable and tolerable but the impact of MR schedule on toxicities has not been previously reported and could influence selection of maintenance regimens. Methods: Using PubMed, prospective clinical trials employing MR were identified. Data presented in abstract form or at meetings were deemed incomplete and thus excluded. Data were analyzed from published manuscripts as percentages of subjects experiencing an adverse event (AE). Percentages were considered as the unit of analysis as this adjusted for the uneven sample sizes. Data were collected for overall Grade 3 and/or Grade 4 toxicity (AE reported at any phase of treatment) and was further categorized as AE occurring during initial treatment or during MR. Grade 1 and 2 toxicities were excluded from meta-analysis, given lack of consistent reporting. No grade 5 toxicities were reported. The incidence, severity, and type of toxicity was analyzed by type of induction (Rituximab (R) vs. R plus chemotherapy), histology (FL vs. FL plus other LG-NHL), setting (front-line vs. relapsed), and MR schedule (one dose every 2 months vs. one dose every 3 months vs. 4 doses every 6 months). Results: Nine clinical trials involving 1,928 patients were included in this Meta analysis (4 of which were randomized controlled in the MR phase). Of those, 1,004 patients received MR. The mean percentage of Grade 3/4 toxicities during any phase of treatment was 26% (95% CI = 0.12–51.88) but when restricted to the MR phase; it was 12.88% (95% CI = 6.50–19.26). Toxicities were numerically higher in patients receiving R induction plus chemotherapy versus R induction alone and in patients receiving MR for relapsed disease versus newly diagnosed patients, but did not reach statistical significance (P = 0.661 and 0.517, respectively). However, patients receiving MR every 2 months were significantly more likely to develop grade 3 and 4 toxicities compared to patients receiving MR every 6 months (P = 0.005). No statistical differences were demonstrated between the 2 vs. 3 months schedules or when comparing the 3 vs. 6 months schedules (P = 0.342 and 0.267, respectively) (Table 1). Statistically significant differences were also found in studies restricted to FL versus others allowing non-FL histologies (P = 0.025) with the FL patients experiencing more toxicity than others. The most frequently reported toxicities were neutropenia and infections. There were no treatment-related deaths in any of the arms. Conclusions: Approximately 13% of patients receiving MR experience grade 3 and/or 4 toxicities, mainly consisting of neutropenia and infections. MR given every 6 months appears to provide the least grade 3 and 4 toxicities. There is a suggestion of increased toxicity in FL histologies. It is important to note that this meta-analysis did not address efficacy and only a true comparative trial can definitively establish the relative risk/benefit ratios amongst MR schedules. Disclosures: Nabhan: Genentech: Research Funding, Speakers Bureau. Ghielmini:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Smith:Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

A Phase I Study of Ruxolitinib Plus Nilotinib in Chronic Phase CML Patients with Molecular Evidence of Disease

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1892-1892 ◽  
Author(s):  
Kendra L. Sweet ◽  
Lori Hazlehurst ◽  
Eva Sahakian ◽  
John J. Powers ◽  
Lisa Nodzon ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Adverse Events ◽  
Phase I ◽  
Research Funding ◽  
Rt Pcr ◽  
Transcript Levels ◽  
Future Studies ◽  
Fatigue Severity ◽  
Grade 3 ◽  
The Impact

Abstract Background: BCR-ABL tyrosine kinase inhibitors (TKI) are the standard treatment for CP-CML. A subset of patients have profound molecular responses with BCR-ABL transcripts no longer detectable using RT-PCR (MR4.5). The ENESTnd trial compared nilotinib versus imatinib as frontline therapy in CML, and reported an increase in the cumulative incidence of MR4.5 of approximately 11% per year for the first five years in nilotinib treated patients. Discontinuation of TKIs is successful in 40-50% of patients who have a durable MR4.5. The phosphorylation of STAT3-Y705 via the JAK-STAT signaling pathway provides a protective microenvironment for the leukemic stem cells (LSC) and is a well described mechanism of resistance to TKIs. The residual LSCs likely contribute to relapse after TKI discontinuation. Data suggests that by simultaneously blocking JAK2 and TYK2, pSTAT3 is inhibited, thereby eliminating the protective environment in the bone marrow, and sensitizing the LSCs to TKIs. Ruxolitinib is a JAK2 and TYK2 inhibitor. Here we used ruxolitinib in combination with nilotinib in CP-CML patients to establish the maximal tolerated dose (MTD) of ruxolitinib, and obtain preliminary data about the impact of this combination on BCR-ABL transcript levels. Methods: This phase I, dose-escalation study used ruxolitinib plus nilotinib in CP-CML. All subjects were taking nilotinib prior to enrollment. Eligible subjects had a complete cytogenetic response (CCyR), yet had detectable BCR-ABL transcripts by RT-PCR at enrollment. We used a 3+3 design with 3 cohorts. The nilotinib dose remained unchanged, and the three doses of ruxolitinib were 5mg BID, 10mg BID and 15mg BID. Two additional subjects were treated at the MTD. Subjects remained on combination therapy for six months, at which point ruxolitinib was discontinued. RT-PCR was used to measure BCR-ABL transcript levels in the peripheral blood and/or bone marrow at baseline and every 3 months. The primary endpoint was the MTD of ruxolitinib. Secondary endpoints included toxicity assessment, incidence of MR4.5 at six months, change in fatigue severity scores and impact of ruxolitinib on pSTAT3/5 inhibition assessed with a plasma inhibitory assay (PIA) Descriptive statistics were used for baseline demographics, toxicity, MR4.5 and pSTAT3 levels. Subjects completed the fatigue severity index (FSI) questionnaire at baseline and every 3 months. A paired samples t-test was used to measure the difference in fatigue severity over time. Results: A total of 11 patients were enrolled between April 2013 and March 2016. Median age was 41 (25-63). 73% (n=8) were male. 36% (n=4) had received one TKI prior to nilotinib. The nilotinib dose was 300mg (n=8) or 400mg BID (n=3). Median time from diagnosis to enrollment was 11 months (6-135). Each cohort enrolled 3 subjects, and two additional subjects were treated at the MTD. There were no dose limiting toxicities; therefore the MTD/RP2D of ruxolitinib was 15mg PO BID. There were no grade 3/4 adverse events in any cohort, and no clinically significant cytopenias. Grade 1/2 transaminitis occurred in 1 subject in cohorts 1 and 2. No dose reductions were needed. At data cutoff, 9 subjects have completed six months on trial, and 2 remain active. Of those nine, 3 (33%) had ≥1-log reduction in BCR-ABL transcripts from baseline and 4 (44%) achieved MR4.5. One subject in cohort 1 progressed after three months and a kinase domain mutation analysis found a T315I mutation. FSI data available on seven subjects showed a non-significant decline in average fatigue severity from baseline (mean 2.78, SD 1.79) to follow-up (mean 1.86, SD 1.21), p=0.29. Results from the plasma inhibitory assay and updated results of all 11 subjects will be presented at the meeting after all subjects will have completed the trial. Conclusion: Our data suggest that ruxolitinib is safe and tolerable at 15mg PO BID when combined with nilotinib in CP-CML, and with no grade 3/4 adverse events reported, this should be considered the RP2D for future studies. The incidence of MR4.5 after six months was 44% which surpasses that of historical controls, although the sample size is small and a larger study is needed to confirm these results. The combination leads to an improvement in fatigue severity that did not reach statistical significance. This data serves as justification for future studies using ruxolitinib in combination with TKIs to determine the true impact on eradication of MRD in CP-CML. Disclosures Sweet: Karyopharm: Honoraria, Research Funding; Pfizer: Speakers Bureau; Incyte Corporation: Research Funding; Ariad: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Nodzon:Novartis: Speakers Bureau. Pinilla-Ibarz:Janssen: Consultancy, Honoraria; Pharmacyclics: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Novartis: Consultancy; Abbvie: Consultancy, Speakers Bureau.

scholarly journals Targeting the Inflammatory Niche in MDS By Tasquinimod Restores Hematopoietic Support and Suppresses Immune-Checkpoint Expression in Vitro

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2596-2596
Author(s):  
Manja Wobus ◽  
Ekaterina Balaian ◽  
Uta Oelschlaegel ◽  
Russell Towers ◽  
Kristin Möbus ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mrna Expression ◽  
Immunohistochemical Staining ◽  
Research Funding ◽  
Fold Increase ◽  
Low Risk ◽  
Hematopoietic Stem ◽  
Healthy Donors ◽  
The Impact

Abstract Introduction Myelodysplastic syndromes (MDS) belong to the most common hematological neoplasms in the elderly population, characterized by ineffective hematopoiesis, peripheral cytopenia and the risk of transformation into acute myeloid leukemia. There is increasing evidence that an aberrant innate immune response and a proinflammatory bone marrow (BM) microenvironment play a critical role in the pathogenesis of MDS. The alarmin S100A9, a key player for regulation of inflammatory responses, has been shown to be elevated in MDS patients. It directs an inflammatory cell death (pyroptosis) by increased NF-kB mediated transcription and secretion of proinflammatory, hematopoiesis-inhibitory cytokines and production of reactive oxygen species. Tasquinimod (TASQ, Active Biotech) is a novel, oral small molecular drug with S100A9 inhibitory activity and it is currently investigated in a phase Ib/IIa trial in relapsed/refractory multiple myeloma (NCT04405167). TASQ has demonstrated anti-angiogenic, antitumor and immunomodulatory properties in a broad range of preclinical solid tumor models; however, little is known about its effects in myeloid malignancies. Aim We investigated the role of S100A9 in cellular models of MDS and the potential of TASQ to target S100A9 within the MDS stroma in vitro. Methods Immunohistochemical staining of S100A9, CD271+ mesenchymal stromal cells (MSCs), CD68+ macrophages and CD66b+ neutrophils in BM tissues from MDS patients and healthy donors was performed with multiplex immunohistochemistry and analyzed with the VECTRA imaging system. MSCs from patients with either low-risk MDS, CMML or age-adjusted healthy donors were exposed to S100A9 (1.5µg/ml) in the presence or absence of TASQ (10µM). Subsequently, TLR4 downstreaming molecules such as IRAK1, gasdermin and NF-kB-p65 were analyzed by Western blot. Moreover, the mRNA expression of further proinflammatory molecules (IL-1b, IL-18, caspase1) and PD-L1 was quantified by real-time PCR. To study the impact on the hematopoietic support, MSCs were pre-treated for one week with S100A9 ± TASQ before CD34+ hematopoietic stem and progenitor cells (HSPCs) were seeded on the stromal layer. The colony formation (CAF-C) was analyzed weekly followed by a CFU-GEMM assay in methylcellulose medium. Additionally, PD-1 mRNA expression was quantified in cocultured HSPCs. Results Immunohistochemical staining of BM tissue demonstrated S100A9 expression mainly by CD66b+ neutrophils and with less extent by CD68+ macrophages. In line with this, we could not detect relevant S100A9 mRNA expression in cultured MDS or healthy MSCs in vitro. Exposure of MDS and healthy MSCs with S100A9 induced TLR4 downstream signalling as demonstrated by increased expression of IRAK1 and NF-kB-p65. We further detected a higher expression of gasdermin, an inductor of pyroptosis, in S100A9 exposed MSCs. Addition of TASQ abolished these effects and inhibited the expression of the mentioned proteins, indicating an alleviation of inflammation. Furthermore, we detected a 2-fold increase of mRNA expression of the proinflammatory cytokines IL-1b and IL-18 as well as a 5-fold increase of their activator caspase 1 in MSCs after treatment with S100A9, which could be prevented by TASQ. Interestingly, PD-L1 as a potential downstream target was induced by S100A9 by 2.5-fold and could be suppressed by TASQ to about 50%. To evaluate the impact on the hematopoietic support of MSCs, we analysed MSC/HSPC cocultures after treatment with S100A9. We observed a decreased number of cobblestone area forming cells (CAF-C) as well as reduced numbers of colonies (CFU) in a subsequent clonogenic assay, indicating a disturbed hematopoietic support by S100A9 treated MSCs. Interestingly, both the number of CAF-C and CFU could be increased by TASQ pre-treatment. Finally, the PD-1 expression in co-cultured HSPCs was regulated in the same way as its ligand in treated MSCs, nominating this interaction as a potential target of S100A9/TASQ in the MDS BM. Conclusion In summary, we provide evidence that the pathological inflammasome activation in the myelodysplastic bone marrow can be rescued by TASQ at least in part by inhibition of the S100A9 mediated TLR4 downstream signalling including NF-kB-p65 transcription and PD-L1 expression. These effects result in an improved hematopoietic support by MSCs, suggesting a potential efficacy to improve cytopenia in low-risk MDS patients. Disclosures Balaian: Novartis: Honoraria. Törngren: Active Biotech: Current Employment. Eriksson: Active Biotech: Current Employment. Platzbecker: AbbVie: Honoraria; Takeda: Honoraria; Celgene/BMS: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Geron: Honoraria. Röllig: Novartis: Honoraria, Research Funding; Jazz: Honoraria; Janssen: Honoraria; Bristol-Meyer-Squibb: Honoraria, Research Funding; Amgen: Honoraria; AbbVie: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Roche: Honoraria, Research Funding.

scholarly journals Bone Marrow Hematopoietic Dysfunction in Untreated Chronic Lymphocytic Leukemia Is Partially Mediated By Exposure to Constituents of the Leukemic Microenvironment

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3132-3132
Author(s):  
Bryce Manso ◽  
Kimberly Gwin ◽  
Charla R Secreto ◽  
Henan Zhang ◽  
Wei Ding ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Healthy Controls ◽  
Advisory Committees ◽  
The Impact

Abstract Peripheral immune dysfunction in B-Chronic Lymphocytic Leukemia (CLL) is well-studied and likely relates to the incidence of serious recurrent infections and second malignancies that plague CLL patients. However, the current paradigms of known immune abnormalities are not able to consistently explain these complications and it is not easy to correct CLL patient immune status. Here, we expand on our preliminary reports that demonstrate bone marrow (BM) hematopoietic dysfunction in early and late stage untreated CLL patients. We found reduced short-term functional capacity of hematopoietic progenitors in BM using colony forming unit assays (Figure 1A-C) and flow cytometry revealed significant reductions in frequencies of hematopoietic stem and progenitor cell (HSPC) populations (exemplified by Lin-CD34+ HSPCs, Figure 1D). We further report that protein levels of the transcriptional regulators HIF-1α, GATA-1, PU.1, and GATA-2 are overexpressed in distinct HSPC subsets from CLL patient BM, providing molecular insight into the basis of HSPC dysfunction. Interestingly, sustained myelopoiesis, evaluated by limiting dilution analysis in long-term culture-initiating cell (LTC-IC) assays maintained for five weeks, revealed no difference between healthy controls and CLL patients. These new data indicate that when HSPCs are removed from the leukemic microenvironment for ample in vitro culture time, they recover the ability to sustain myelopoiesis. To further assess the impact of the CLL microenvironment on HSPC biology, isolated HSPCs (CD34+ BM cells) from healthy controls were exposed in vitro to known leukemic microenvironment constituents. Exposure to TNFα, a cytokine constitutively produced by CLL B cells, resulted in rapid increases in PU.1 and GATA-2 proteins (Figure 2A-D). Similarly, addition of TNFα to the LTC-IC assay resulted in a striking ablation of myelopoiesis, even at the highest input cell concentration. Further, overexpression of PU.1 and GATA-2 were observed in HSPCs following co-culture with CLL B cells, a result that was not recapitulated when cells were exposed to IL-10, another cytokine constitutively produced by CLL B cells. These findings indicate specific components of the leukemic microenvironment are involved in HSPC modulation. Together, these findings expand on our previous observations of BM hematopoietic dysfunction in untreated CLL patients and offer new molecular insights into the contribution of the leukemic microenvironment on immunodeficiency in CLL. Disclosures Ding: Merck: Research Funding. Parikh:Pharmacyclics: Honoraria, Research Funding; MorphoSys: Research Funding; Janssen: Research Funding; Abbvie: Honoraria, Research Funding; Gilead: Honoraria; AstraZeneca: Honoraria, Research Funding. Kay:Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding; Infinity Pharm: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cytomx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Uninvolved Immunoglobulin Suppression Determined By "Hevylite" ASSAY. Strongly Predicts Evolution of Smoldering Myeloma (SMM) to Symptomatic Multiple Myeloma (MM)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5584-5584
Author(s):  
Paraskevi Papaioannou ◽  
Annita Ioanna Gkioka ◽  
Kallirroi Tsalimalma ◽  
Aspasia Koudouna ◽  
Anastasia Kopsaftopoulou ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Plasma Cell ◽  
Light Chain ◽  
Conflicts Of Interest ◽  
Statistical Significance ◽  
Rapid Evolution ◽  
Great Majority ◽  
Bone Marrow Infiltration ◽  
Prognostic Information ◽  
Increased Risk

Abstract SMM may have an indolent course and remain stable for years; however, some patients evolve to MM requiring treatment within two years or less. To timely recognize these patients, three biomarkers (FLCR>100, ≥1 osteolysis and ≥60% plasma cell bone marrow infiltration) were recently established to discriminate asymptomatic MM patients at increased risk of rapid evolution and therefore, patients displaying the aforementioned biomarkers are considered symptomatic and receive immediate treatment. Despite the usage of the new IMWG definition criteria, there are still patients evolving rapidly and the notion of High risk SMM remains subjective among scientific groups. We herein studied wherever immunoglobulin (Ig) Heavy/Light Chain (HLC) measurements with the "Hevylite" assay that measures separately HLC-IgA, -G, -M-kappa or lambda, could add prognostic information on SMM evolution, with special attention to the significance of polyclonal Ig suppression. This method allows exact quantification of the amount of pure monoclonal fraction but also the degree of suppression of uninvolved polyclonal Igs. Patients and Methods: We studied 79 SMM patients of whom 30 were men and 49 women, with median age 65 (31-84) Ig type was IgG in 64 patients (81%) and IgA in the rest (19%). None of the patients had a free light chain ratio (FLCR) of more than 100, bone disease or more than 60% plasma cell bone marrow infiltration, in accordance to the last IMWG definition criteria. Patients were regularly followed (each 3 months) since SMM diagnosis and for a long period of time (median 98 months) during which 15 patients evolved to MM. "HevyLite" assay measurements were performed by nephelometry according to the manufacturer's instructions in frozen sera sample drawn at the time of diagnosis. We then calculated in all patients the ratio of involved/uninvolved Ig (HLCR); we also scored on a 5 points scale the eventuality of uninvolved Ig kappa or lambda below normal limits, that are, according to the manufacturer's testing on healthy individuals, 3608, 2023, 300, 312, 267, and 185 mg/L for IgG-kappa, IgG-lambda, IgA-kappa, IgA-lambda, IgM-kappa and IgM-lambda respectively. Results' relationship with SMM evolution were analyzed by standard methods using the SPSS v22.0. software and p values below 0,05 were considered statistically significant. Survival curved were drawn according to Kaplan-Mayer method. Results: Monoclonal Ig type was IgG-kappa, IgG-lambda, IgA-kappa, IgA-lambda in 61%, 19%, 11% and 9% of SMM patients respectively. Uninvolved IgG-kappa, IgG-lambda, IgA-kappa, IgA-lambda, IgM-kappa, IgM-lambda ranged from 625 to 14300 mg/L, 495 to 12700 mg/L , 214 to 2930 mg/L, 38 to 2580 mg/L, 19 to 1300 mg/L, 51 to 950 mg/L respectively. Median HLCR was 7 (range 0,24-707). Patients with HLCR above median tended to evolve faster than the others (p=0,1-not reaching statistical significance). Thirty-five patients had no one uninvolved Ig class depressed (score 0), 28 had 1, 9 had 2, 5 had 3 and 2 had 4; No score 5 was observed. Time to evolution strongly correlated to high score uninvolved Ig suppression (p< 0,00001). A simplified score separating 3 groups, the first with 0 Ig suppression, the 2nd with 1 or 2 and the 3rd with 3 or 4 proved to be equally potent in separating 3 risk-groups of SMM patients at risk of evolution to myeloma (p< 0,00001) and the great majority of the patients in the 3rd group evolved within two years (figure). In conclusion, the presence of decreased uninvolved Ig levels as determined by "Hevylite" constitutes a powerful prognostic marker of SMM evolution to MM. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

scholarly journals Bone Marrow Involvement in Patients with Type 1 Gaucher Disease Receiving Low-Dose Long Term Enzyme Replacement Therapy (median 18 years)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4862-4862
Author(s):  
Shoshana Revel-Vilk ◽  
Jeffrey Szer ◽  
Michal Becker Cohen ◽  
Ari Zimran
Keyword(s):  
Bone Marrow ◽  
Gaucher Disease ◽  
Research Funding ◽  
Low Dose ◽  
Bone Marrow Involvement ◽  
Bone Marrow Infiltration ◽  
Enzyme Replacement ◽  
Fat Fraction ◽  
Type 1 Gaucher Disease

Bone complications are the most dramatic and life-impairing outcomes of type 1 Gaucher disease (GD1), a common lysosomal storage disorder. Bone marrow infiltration by Gaucher cells substantially decreases the bone marrow fat fraction (FF), and the extent of this reduction correlates with the overall severity of skeletal manifestations in this disorder. Previous studies have demonstrated that the degree of infiltration can best be estimated by magnetic imaging resonance (MRI)-based quantitative chemical shift imaging (QCSI) and that the fat fraction (FF) score so derived can predict the risk of clinically important bone events. The aim of this study was to evaluate bone marrow involvement in GD1 patients who had received enzyme replacement therapy (ERT) for at least 5 years. Methods: Patients from SZMC Gaucher unit, ≥ 18 years, who were treated with ERT for ≥ 5 years, with a stable dose in the previous 6 months, were recruited. Patients taking another experimental drug, with past exposure to taliglucerase-alfa, presence of any medical, emotional, behavioral or psychological condition were excluded. Energy x-ray absorptiometry (DEXA) was performed at SZMC and the QSCI was performed at the Academic Medical Center in Amsterdam, Netherlands as previously described [Mass et al, Am J Radiol 2002:179:961-965]. A QCSI score of <0.30 was indicative of bone at risk. This investigator initiated clinical trial was approved IRB at SZMC and AMC and sponsored by Pfizer. Study number registration- MOH-2017-04-000351. Results: Thirty patients (13 females) at a median (range) age of 46 (19-71) years consented to participate in this study and to perform the QCSI test. GBA mutations of study patients included N370S homozygote (n=12), N370S compound heterozygote (n=17), and T431 homozygote (n=1). The median (range) duration of ERT was 18 (5-26) years. Thirteen patients were receiving imiglucerase as the primary ERT [median (range) duration, 19 (9-26) years], five patients were receiving velaglucerase alfa [median (range) duration, 11 ( 5-12) years], and 12 patients converted from imiglucerase to velaglucerase alfa [median (range) duration, 7 (6-10) years]. The majority of patients received low-dose regimen, i.e. 15 Units/kg/2 weeks (Table 1). The median (range) T score for lumbar spine from DEXA scans, available for 26 of 30 patients, was −1.3 (−2.8-0.0). The median (range) QCSI score was 0.42 (0.24-0.66). Seven patients, 23% (95% confidence interval 10%-42%), had abnormal QCSI FF scores (<0.30). Abnormal QSCI score was more common in female compared to male (Table 1) (p=0.025). Only one of these was menopausal. No differences were found in age, gender, genotype, history of splenectomy, duration and type of ERT and GD-related parameters between those with QSCI score of bone at risk to those with normal score (Table 1). In summary, these findings demonstrate that, despite prolonged treatment with imiglucerase and/or velalgucerase alfa, 23% of patients still had QCSI scores indicative of an inadequate response in bones. Nevertheless, most patients with prolonged low-dose ERT maintain a normal QCSI, indicative of a positive bone status. The higher prevalence of women in the cohort with low FF is not related to menopausal phase and remains unexplained. As no other patient-related nor GD-related parameter predicted abnormal bone marrow infiltration, a more widely available, quantitative measure of bone marrow infiltration is required for the assessment of response in bones to ERT for patients with GD1. The second phase of this study will evaluate the impact of a switch to a third ERT in those patients from this study with QCSI scores of <0.30. These patients will be offered treatment with taliglucerase alfa at equivalent doses and subsequent reassessment of any impact on clinical symptoms and QCSI scores evaluated. Disclosures Revel-Vilk: Takeda: Honoraria, Other: Travel, Research Funding; Prevail therapeutics: Honoraria, Other: Travel, Research Funding; Pfizer: Honoraria, Other: Travel, Research Funding; Sanofi: Honoraria, Other: Travel, Research Funding. Szer:Alexion: Honoraria, Other: Travel, Research Funding; Amgen: Honoraria, Other: Travel, Research Funding; Celgene: Honoraria, Other: Travel, Research Funding; MSD: Honoraria, Other: Travel, Research Funding; Novartis: Honoraria, Other: Travel, Research Funding; Pfizer: Honoraria, Other: Travel, Research Funding; Takeda: Honoraria, Other: Travel, Research Funding; Sanofi: Honoraria, Other: Travel, Research Funding; Prevail Therapeutics: Honoraria, Other: Travel, Research Funding. Zimran:Centogene: Other: research grant; Shire: Consultancy, Honoraria, Research Funding; TAKEDA: Honoraria; Pfize: Honoraria, Research Funding; Bio-events: Honoraria; Targeted Cell Therapies: Consultancy; Prevail Therapeutics: Consultancy.

scholarly journals Impact of Genomic Alterations on Outcomes in Myelofibrosis Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2301-2301 ◽  
Author(s):  
Raajit K. Rampal ◽  
Roni Tamari ◽  
Nan Zhang ◽  
Caroline Jane McNamara ◽  
Franck Rapaport ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Research Funding ◽  
Triple Negative ◽  
Unrelated Donor ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Disease Characteristics ◽  
Donor Type ◽  
The Impact ◽  
Reduced Intensity

Abstract Introduction: The impact of genomic alterations, such as mutations in ASXL1, on the risk of disease progression and leukemic transformation in patients with myelofibrosis (MF) is well established. Further, emerging data suggests that the number and type of mutations may impact response to therapies such as ruxolitinib or imetelstat. Allogeneic hematopoietic stem cell transplant (allo-HSCT) remains the only potentially curative treatment for MF patients. However, the impact of somatic mutations on overall survival (OS) and relapse-free survival (RFS) is poorly understood. Using next-generation sequencing of pre-transplant blood and bone marrow samples from a well clinically-annotated cohort of MF patients who underwent allo-HSCT, we sought to determine the impact of mutational burden on outcomes. Methods: A multicenter retrospective analysis of a cohort of 84 patients was carried out. This included 52 patients treated on the MPD-RC 101 prospective study (NCT00572897), 18 patients treated at Prince Margaret Hospital, and 14 patients treated at Memorial Sloan Kettering Cancer Center. Patient and transplant characteristics are displayed in Table 1. DNA was extracted from pre-transplant bone marrow aspirate samples or peripheral blood samples. High-throughput sequencing of a panel of genes was performed. Average coverage of 829x (standard deviation of ±130) was obtained. Mutect was utilized to call single point variants (comparing our samples to a pool of normal samples) and PINDEL was used to call short insertions and deletions. We excluded all mutations present in at least one database of known non-somatic variants (DBSNP and 1000 genomes) and absent from COSMIC. Univariate Cox regression and Kaplan-Meier graphics were used to investigate the association of patient, transplant, and disease characteristics with OS and RFS. Results: JAK2V617F was the most frequent mutation detected in 41(48.8%) patients (Table 2). Eighteen patients (21.4%) had triple negative disease (negative for JAK2, MPL, and CALR mutations). Univariate analysis included the following: patient characteristics (age, gender), transplant characteristics (related vs. unrelated donor, matched vs. mismatched donor and myeloablative vs. reduced intensity conditioning) and disease characteristics (DIPSS and presence of mutations). Decreased OS was associated with unrelated donor status (HR 2.09, 95% CI: 1.03-4.23, p=0.04), reduced intensity conditioning (HR 4.21, 95% CI: 1.01-17.59, p=0.049), triple negative disease (HR 2.09, 95% CI: 1.02-4.30, p=0.04), and presence of U2AF1 (HR 2.53, 95% CI: 1.10-5.81, p=0.03) or SUZ12 mutations (HR 3.92, 95% CI: 1.19-12.21, p=0.02). Decreased RFS was associated with unrelated donor status (HR 2.27, 95% CI: 1.16-4.45, p=0.02), and the presence of SUZ12 mutation (HR 6.97, 95% CI: 2.37-20.49, p<0.001). A descriptive decrease in RFS in patients with U2AF1 (HR 2.15, 95% CI: 0.94-4.88, p=0.07) was observed but did not reach statistical significance. Importantly, mutations previously reported to be associated with reduced OS and RFS in the non-transplant setting, such as ASXL1, EZH2, IDH1/2, and SRSF2, were not associated with poorer outcomes in this analysis in transplanted patients. In an exploratory multivariate analysis including donor type (related vs. unrelated) and presence of U2AF1 and SUZ12 mutations, there was a significantly reduced OS and RFS in patients who harbor these mutations regardless of donor type (OS: HR 5.30, 95% CI: 2.08-13.47, p<0.001; RFS: HR 5.49, 95% CI: 2.27-13.30, p<0.001). In patients without the above mutations, having an unrelated donor was associated with worse OS (HR 2.55, 95% CI: 1.09-5.96, p=0.03) and RFS (HR 2.61, 95% CI: 1.17-5.83, p=0.02, Figure 1). Conclusions: Our analysis demonstrates that mutations previously associated with poor prognosis in MF, such as ASXL1, do not appear to confer a worsened prognosis in patients undergoing allo-HSCT, suggesting transplant may be able to overcome the impact of these mutations. However, mutations in SUZ12 and U2AF1 are associated with reduced OS in univariate and multivariate analysis (together with donor type). Further studies with larger cohorts of patients are indicated to validate these findings, and to elucidate the impact of these mutations on disease biology. Disclosures Rampal: Incye and CTI: Consultancy. Mascarenhas:Janssen: Research Funding; CTi Biopharma: Research Funding; Promedior: Research Funding; Merk: Research Funding; Incyte: Research Funding. Mesa:Galena: Consultancy; Gilead: Research Funding; Promedior: Research Funding; Incyte: Research Funding; CTI Biopharma: Research Funding; Celgene: Research Funding; Ariad: Consultancy; Novartis: Consultancy. Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Research Funding.

Sign in / Sign up

Export Citation Format

Share Document