Incidence of Thrombotic Microangiopathies in Quebec: An 8-Year Overview from a Laboratory Centralizing Adamts-13 Testing

Abstract Primary and secondary thrombotic microangiopathies (TMA) constitute a group of life-threatening diseases of different aetiologies characterized by similar symptoms. The comprehensive compilation of data related to TMA is challenging due to their rare occurrence. The objective of this study was to provide an overview of the incidence of thrombotic thrombocytopenia (TTP) and non-TTP TMAs in the Province of Quebec (PQ) (8.485 Million inhabitants in 2019) by taking advantage of the centralized ADAMTS-13 activity and antibody testing for PQ since 2013 at the CHU Sainte-Justine (CHUSJ) All ADAMTS-13 activity and antibody titration were performed locally at CHUSJ. ADAMTS-13 results and patient demographic characteristics from April 2012 to December 2019 were extracted from the Laboratory Information System of CHUSJ and used in an anonymized database. Information on previous TMA episodes was obtained from a standardized clinical assessment form accompanying each plasma sample. Statistical analyses were performed with IBM SPSS version 26.0. The annual incidence rates were calculated based on the number of patients with a first-time recorded diagnosis of TMA using the Quebec mid-year (yr) estimated population of the years at stake. Patients with suspected TMA were further divided into two categories: individuals with TTP, defined by either an ADAMTS-13 activity ≤10% or a positive anti-ADAMTS-13 antibody titration, and patients with a suspected TMA other than TTP (non-TTP TMA) with a result of ADAMTS-13 activity >10%. The study was approved by the Research Ethics Committee of CHUSJ. A progressive increase in the annual requests for ADAMTS13 activity was observed over the study period. The number of new patients increased from 2012 to 2016 but plateaued after 2016 at an average number of 170 new patients per year. The number of confirmed TTP cases in Quebec was higher from 2014 to 2018 compared to in 2012, 2013 and 2019 (Figure 1). A total of 2081 requests for ADAMTS13 activity testing were received during the study period, representing 846 subjects with a suspected TMA. 147 subjects (17%) had a confirmed TTP and 699 (83%) had a suspected non-TTP TMA. TMAs were suspected more often in females (59%), both in confirmed TTP (62%) and non-TTP TMA (58%). The mean annual incidence rate (MAIR) of TTP was 1.91 case/million/yr (95%CI: 1.46-2.35). This was higher in females (2.36 cases/million/yr; 95%CI: 1.34-3.37) compared to males (1.42 case/million/yr; 95%CI: 0.57-1.44; p=0.001). The MAIR of non-TTP TMA was 9.97 cases/million/yr (95%CI:5.85-14.09), 11.52 for females (95%CI:6.71-16.33) versus 8.41 for males (95% CI: 4.81-12.02; p=0.001). In non-TPP TMA, the MAIR for males ranged from 3.9 to 7.2 cases per million prior to 60 year of age and increased after up to 24.5 at ages 80-89. For females, a first peak MAIR above 10 cases per million was observed during their thirties and a second peak was observed during their seventies (Figure 2). In TPP, peaks incidences in females were observed from ages 20 to 49. It dipped from ages 50 to 69 and then increased again. In males, a highest MAIR was observed between ages 40 to 79. In conclusion, the provincial centralization of ADAMTS-13 testing has enabled us to depict comprehensive picture of TTP and other suspected non-TPP TMA, thereby providing valuable information for caregivers and health authorities into these rare diseases. Sex and age related incidences observed in this study are comparable to those obtained through other registries and aggregated studies. Further analyses on clinical presentation of TMAs and patient follow up are now possible using the identification of this large cohort. Figure 1 Figure 1. Disclosures Lapeyraque: Alexion Pharmaceuticals Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Rivard: Bayer Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma Inc: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk Inc: Membership on an entity's Board of Directors or advisory committees; CSL Behring Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Bonnefoy: Sanofi Genzyme Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Interim FDG PET Imaging in CALGB 50203 Trial of Stage I/II Non-Bulky Hodgkin Lymphoma: Would Using Combined PET and CT Criteria Better Predict Response Than Each Test Alone?,

Blood ◽

10.1182/blood.v118.21.3644.3644 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3644-3644 ◽

Cited By ~ 2

Author(s):

Lale Kostakoglu ◽

Heiko Schoder ◽

Nathan Hall ◽

David J. Straus ◽

Jeffrey L Johnson ◽

...

Keyword(s):

Board Of Directors ◽

Hodgkin Lymphoma ◽

Fdg Pet ◽

Research Funding ◽

Roc Analysis ◽

Stage I ◽

Advisory Committees ◽

Interim Pet ◽

Number Of Patients ◽

Pet Ct

Abstract Abstract 3644 Use of interim PET in Hodgkin Lymphoma (HL) for risk-adapted treatment has been confounded by a lack of standardized criteria for interpretation. The International Harmonisation Project (IHP) criteria (JCO 2007;25:571) have been validated and are widely used for restaging following therapy. Our objective was to validate the IHP criteria for response evaluation based on PET after two cycles and correlate with the “London”criteria and diagnostic CT-based (dCT) lesion size changes. Methods: Pts were accrued prospectively to CALGB 50203, a trial of doxorubicin, vinblastine and gemcitabine (AVG) for initial treatment of stage I-II non-bulky Hodgkin lymphoma (HL). All had FDG PET or PET/CT and a separate high-resolution dCT scan at baseline, after two cycles of AVG (PET-2 and dCT-2) and at the end of therapy. No treatment change was made based on the PET-2 results. Of 99 assessable pts, 88 had both PET-2 and dCT-2. The primary PET-2 interpretation was based on IHP criteria (uptake > mediastinal blood pool/background is positive), a secondary interpretation was performed using the 5 point London criteria (uptake > liver is positive). The percent decrease in the sum of the products of the diameter (%SPPD) was determined between baseline dCT and dCT-2. A receiver operator curve (ROC) analysis was performed to determine the best cut-off for %SPPD to define a positive and negative CT result. The PET-2 and dCT-2 (%SPPD change) data were correlated with progression free survival (PFS). Results: Sixty-four pts (73%) achieved a complete remission (CR)/CR unconfirmed (CRu), 23.9% a partial response (PR), and 3% had stable disease. After a median follow-up of 3.3 years (1.8–5.0 years), 23.9% of patients relapsed/progressed with an estimated 3-year PFS of 0.77 [CI 68,84]. Eleven of 24 (45.8%) PET-2 positive patients relapsed vs. 10 of 64 (15.6%) PET-2 negative patients (p=0.0004). The best cut-off determined from ROC analysis for %SPPD change was 65%. The comparative results for individual evaluation criteria are displayed in the Table. In the PET-2 positive group, a negative dCT-2 increased PFS by 27–35%, suggesting an influence from dCT-2 results. However, in the combinatorial analysis, some of the confidence intervals are large due to small number of patients in each individual group, particularly, when both PET-2 and dCT-2 were positive as well as when PET-2 was positive and dCT-2 was negative. Conclusions: Interim PET/CT after two cycles of chemotherapy using either IHP or London criteria has a high NPV in early stage non-bulky HL. However, the PPV of interim PET needs to be improved to guide clinical management. Combining PET-2 with %SPPD decrease after 2 cycles improves prediction of PFS compared to each test alone. These data provide a proof of concept for risk-adapted clinical trials and further studies are underway to confirm these findings in a larger population. Disclosures: Bartlett: seattle genetics: Research Funding. Cheson:Celphalon: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celegen: Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Research Funding.

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The Influence Of KIR Haplotype In ITP Incidence, Treatment Response and Bleeding Symptoms

Blood ◽

10.1182/blood.v122.21.2316.2316 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2316-2316

Author(s):

Bethan Psaila ◽

Nayla Boulad ◽

Emily Leven ◽

Naznin Haq ◽

Christina Soo Lee ◽

...

Keyword(s):

Platelet Count ◽

B Cells ◽

Nk Cells ◽

Board Of Directors ◽

Research Funding ◽

Nk Cell ◽

Advisory Committees ◽

Kir Genes ◽

Number Of Patients

Abstract The pathogenesis of immune thrombocytopenia (ITP) is multifactorial, with both cellular and humoural immune dysfunction. The role of NK cells has not been well defined in ITP but in other diseases NK cells have a role in rejecting “foreign” eg transplanted organ or tumor, and also acting against self as occurs in autoimmunity. NK cell activity is orchestrated by the balance of activating vs. inhibitory signalling, in particular via the killer cell immunoglobulin-like receptor (KIR) family of receptors. Significant variation exists in KIR allelic subtype and copy number for the KIR between individuals, and associations have been made with certain haplotypes and a number of autoimmune disorders including rheumatoid arthritis, scleroderma and diabetes. Previous reports have demonstrated a reduction in natural killer (NK) cell number and function in ITP and expression of inhibitory KIR genes is increased in patients in remission vs. active ITP. Methods To explore whether a particular KIR haplotype might predispose to ITP, and also affect response to ITP treatment, we performed KIR genotyping using the Invitrogen SSP kit on 92 patients attending a haematology centre in New York and compared the results to data from 213 controls taken from the USA Eastern Database. Genomic DNA was typed for the inhibitory KIR genes KIR2DL1, KIR2DL2, KIR2DL5A (alleles 001 and 002), KIR2DL5B (alleles 002-004, 06, and 007), KIR3DL1, KIR3DL3; the activating KIR genes KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, KIR2DS5, KIR3DS1; the framework genes KIR2DL3, KIR2DL4, KIR3DL2, KIR3DP1; and the pseudogene KIR2DP1. The patients with ITP had been or were receiving treatment with IVIG (n=64), corticosteroids (72) and rituximab (37). Bleeding symptoms were recorded. Response to treatment was defined as complete - platelet count increase to > 100 x 109/mL; partial - platelet count increase to > 50 x 109/mL; or no response. For the purpose of analysis, PRs and CRs were combined. A comprehensive database allowed a logistic regression, assessing both responses to treatments, platelet counts, neutrophil counts, CRP, lymphocyte subsets and bleeding symptoms. Results The expression of two inhibitory KIR genes, 2DL1 and 3DL1, was significantly lower in the patients with ITP as compared to controls (87% 2DL1 and 87% 3DL1 compared to 99% in controls - P < 0.02). Response to rituximab was strongly related to KIR haplotype expression. 2DL1 expression was higher among nonresponders to Rituximab (100% of non responders compared to 82% of responders), whereas 2DL3 expression was significantly lower (79% compared to 90%) (P < 0.05, Figure 1B). Separately, patients with the 2DS3 allele, an activatory KIR, were 5.5 times more likely to have experienced significant bleeding. Conclusions Although these findings are preliminary and require further investigation, these data suggest that increased cytotoxic autoimmunity due to reduced KIR inhibition may be associated with the development of ITP and possibly contribute importantly to the pathogenesis. Anti-CD20 targeting therapy directed at B cells was strongly influenced by 2 different KIRs (1 upregulated and one down-regulated) emphasizing the potential role of NK cells in elimination of tissue-based (nodal) B cells. Finally a more pronounced clinical phenotype with a markedly higher incidence of severe bleeding associated with an increased activatory KIR expression demonstrates the role of NK cells in bleeding presumably via their effects on either endothelial cells or platelet function. These exciting findings will be pursued for confirmation in a larger number of patients. Disclosures: Bussel: Amgen: Family owns stock Other, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Genzyme: Research Funding; GlaxoSmithKline: Family owns stock, Family owns stock Other, Membership on an entity’s Board of Directors or advisory committees, Research Funding; IgG of America: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Symphogen: Membership on an entity’s Board of Directors or advisory committees.

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Off-Label Prescription of Hydroxycarbamide (Hydroxyurea, HU) for Severe Anemia: Preliminary Results from European Non-Interventional, Multicentric, Prospective Escort-HU Study

Blood ◽

10.1182/blood.v130.suppl_1.758.758 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 758-758

Author(s):

Mariane De Montalembert ◽

Gylna Loko ◽

Jerome Clouzeau ◽

Valentine Brousse ◽

Frederic Galacteros ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Expert Panel ◽

Safety Data ◽

Incidence Rates ◽

Cell Disease ◽

Advisory Committees ◽

Off Label ◽

Preliminary Results ◽

The Mean

Abstract HU is licensed in Europe in the prevention of recurrent painful vaso-occlusive crises (VOC) including acute chest syndromes in adults, adolescents and children older than 2 years with sickle-cell disease (SCD). However, based on US and European expert panel recommendations (Yawn 2014, Habibi 2015) and results from placebo-controlled clinical trials, HU could be useful in SCD patients with severe anemia without VOC since it has been demonstrated to increase total Hb level (Wang 2011) and to decrease the need for blood transfusion. We hereby present preliminary results on effectiveness and safety data related to the prescription of HU for anemia from ESCORT-HU (European Sickle Cell Disease COhoRT - HydroxyUrea), a multicentric, prospective, non-interventional European study designed to collect long-term safety data on HU in SCD population. Between January 2009 and June 2017, 1841 patients were enrolled from 63 centers in France, Germany, Greece and Italy, amongst which 126 patients (6.8%) were started on HU for anemia from 34 centers. Of these 126, 96 were HU-naive. These HU-naive patients treated for anemia ('anemic' subpopulation) were selected for analysis to evaluate effectiveness and safety of HU in this indication and compared with data in HU-naive patients treated for other SCD indications. Demographic data and Hb genotypes are displayed in Table 1. The mean age, distribution of gender, Hb genotype and the mean HU dose at initiation were comparable in the 'anemic' subpopulation and the 'non-anemic' HU-naive cohort. Not surprisingly, mean Hb level at initiation was markedly lower in the 'anemic' subpopulation (7.07 ± 0.88 g/dl) than in the 'non-anemic' HU-naive cohort (8.71 ± 1.51 g/dl), with a lower proportion of patients with history of VOC and SCD-related hospitalization prior to HU initiation. The mean HU dose after 6 months was comparable in both groups (15.6 ± 3.83 mg/kg/day and 15.4 ± 4.11 mg/kg/day, respectively). Variation of blood parameters are displayed in Table 2. Similarly to what has been observed previously, a dramatic rise in Hb concentration (> 2 g/dl) was observed. This increase was comparable in absolute value to the increase observed in non-anemic patients. An increase in HbF was observed in the "anemic" subpopulation, with a near 2-fold increase in %HbF, markedly in children. Changes in reticulocyte counts were inconclusive due to small number of patients in the dataset. Safety of HU in the population of patients treated for anemia was evaluated by comparing incidence rates of non-SCD related adverse events (AEs) in HU-naive patients treated for anemia with the 'non-anemic' HU-naive ESCORT-HU subpopulation (Table 3). With mean follow-up periods of 18.3 months in 'anemic' subpopulation and 34.2 months in 'non-anemic' HU-naive cohort, preliminary results showed no striking difference in the incidence rate of reported AEs (total and serious) between the two populations (112.5% vs 139.8%, respectively for incidence rate of total AEs), and in the distribution of AEs by System Organ Class (SOC), at least in SOC where the number of adverse events was large enough to allow for comparison between the groups. Similarly, when focusing on AE causally related to HU (as judged by the investigators), the most frequently reported toxicity in the 'anemic' population was myelosuppression (anemia, neutropenia thrombocytopenia, pancytopenia reported in 4 children, one event each), as in the 'non-anemic' HU-naive cohort, with comparable incidence rates. In conclusion, even though HU is not licensed in Europe in severe chronic anemia, European and US expert panel guidelines recommend treatment with HU in this indication. Data from ESCORT-HU observational study on a subset of SCD patients treated off label in this indication confirmed total Hb level increase while the safety profile of HU in this subpopulation did not differ significantly from the 'non-anemic' HU-naive population. Disclosures De Montalembert: Novartis: Consultancy, Honoraria, Research Funding; Addmedica: Consultancy, Honoraria, Research Funding. Brousse: Add Medica: Membership on an entity's Board of Directors or advisory committees. Galacteros: Addmedica: Membership on an entity's Board of Directors or advisory committees.

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Racial and Age-Related Differences in Impacts of High-Risk Cytogenetic Abnormalities on Survival in Multiple Myeloma in a Nationwide Electronic Health Record-Derived Database

Blood ◽

10.1182/blood-2021-152774 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4121-4121

Author(s):

Gregory S Calip ◽

Mustafa S Ascha ◽

Xiaoliang Wang ◽

Amy E Pierre ◽

Kathleen Maignan ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Publicly Traded ◽

Advisory Committees ◽

Cytogenetic Abnormalities ◽

Age Related ◽

Black Patients ◽

Double Hit ◽

White Patients

Abstract Background: The incidence of multiple myeloma (MM) and enrichment of cytogenetic abnormalities differ significantly between racial/ethnic groups in the US, and their significance in determining myeloma progression and survival is not well understood. Whole genome sequencing has identified unique mutational signatures in MM, including an age-related process common in hyperdiploid myeloma. Our purpose was to describe racial and age-related differences in the impact of high-risk cytogenetic abnormalities (HRCAs) on survival in MM. Methods: We conducted a retrospective cohort study of adult MM patients starting first-line therapy between January 2011 and May 2021 using the nationwide Flatiron Health electronic health record-derived de-identified database. Patient-level demographic and clinical characteristics were ascertained using structured and unstructured data, curated via technology-enabled abstraction. Patients who had documented fluorescence in situ hybridization testing within 30 days prior to or 90 days following the start of first-line treatment were included. HRCAs, including gain or amplification 1q21, deletion 17p, t(4;14), t(14;16) and t(14;20), were identified and categorized as 0, 1, or 2+ HRCAs. Our outcomes of interest were real world progression free survival (rwPFS) and overall survival (rwOS). Cox proportional hazards models were used to calculate adjusted hazard ratios (HR) and 95% confidence intervals (CI), adjusted for demographic and clinical characteristics and treatment including time-dependent receipt of autologous stem cell transplantation. Results: From a cohort of 4889 MM patients, there were 790 (16%) Black and 2995 (61%) White patients with median ages at diagnosis of 68 and 70 years, respectively. Compared to White patients, a higher proportion of Black patients had IgG M-protein (61% vs 55%) and a lower proportion had 1+ HRCAs identified (31% vs 34%). Among all racial groups, compared to patients aged <65 years (N=1771), a higher proportion of patients aged 65+ years (N=3118) had IgA M-protein (21% vs 17%) and 1+ HRCAs identified (35% vs 33%). Multivariable models showed evidence of significant statistical interaction between age and prevalence of HRCA for rwPFS (P-int: 0.02). Among White patients, having 2+ HRCAs ("double-hit MM") compared to no HRCAs was associated with worse rwPFS in both younger and older patients (<65 years: HR 2.88, 95% CI 1.93-4.32, P<0.01; 65+ years: HR 1.51, 95% CI 1.18-1.94, P<0.01). Among Black patients, associations between double-hit MM and rwPFS were attenuated and not statistically significant regardless of age (<65 years: HR 1.81, 95% CI 0.69-4.74, P=0.23; 65+ years: HR 1.61, 95% CI 0.92-2.81, P=0.09). Similarly, we also found evidence of statistical interaction between age and prevalence of HRCA for rwOS (P-int: 0.02). Among White patients, double-hit MM was significantly associated with worse rwOS but the magnitude of increased risk differed for younger (HR 3.39, 95% CI 2.24-5.14, P<0.01) and older (HR 1.61, 95% CI 1.27-2.05, P<0.01) patients. Double-hit MM was significantly associated with worse rwOS among older Black patients (HR 1.78, 95% CI 1.03-3.06, P=0.04), but not younger Black patients (HR 1.60, 95% CI 0.58-4.40, P=0.36). Conclusions: In this cohort of newly diagnosed MM patients treated in routine practice, having double-hit MM was differentially predictive of poor survival across age groups. Double-hit MM was associated with worse rwPFS and rwOS among White patients, but these trends were less consistent among Black patients. Our current understanding of cytogenetic risk stratification of MM requires further study and additional data for identifying low- and high-risk subsets of patients across different ages and racial groups. Figure. Kaplan-Meier survivor functions for rwPFS in White (Panel A) and Black (Panel B) patients by age group and number of HRCAs Figure 1 Figure 1. Disclosures Calip: Flatiron Health: Current Employment; Roche: Current equity holder in publicly-traded company; Pfizer: Research Funding. Ascha: Flatiron Health: Current Employment; Roche: Current equity holder in publicly-traded company. Wang: Roche: Current equity holder in publicly-traded company; Flatiron Health: Current Employment. Pierre: Flatiron Health, Inc: Current Employment; Roche: Current holder of stock options in a privately-held company. Maignan: Flatiron Health: Current Employment; Roche: Current equity holder in publicly-traded company. Wadé: Roche: Current equity holder in publicly-traded company; Flatiron Health: Current Employment. Leng: Roche: Current equity holder in publicly-traded company; Flatiron Health: Current Employment. Seymour: Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Current equity holder in publicly-traded company; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Flatiron Health Inc: Current Employment. Patel: Janssen: Consultancy; Amgen: Consultancy; Celgene: Consultancy. Neparidze: Eidos Therapeutics: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Research Funding; Janssen: Research Funding.

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Mutational Profiling Predicts Clinical Outcomes to Azacytidine and Low Dose Cytarabine Plus Fludarabine (FLUGA) in Elderly Acute Myeloid Leukemia Patients Enrolled in the Pethema Phase III Flugaza Trial

Blood ◽

10.1182/blood-2019-127187 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3891-3891

Author(s):

Rosa M. Ayala ◽

Inmaculada Rapado ◽

David Martínez-Cuadron ◽

Esther Onecha ◽

Laura Rufian ◽

...

Keyword(s):

Board Of Directors ◽

Older Patients ◽

Research Funding ◽

Low Dose ◽

Gene Mutations ◽

Early Death ◽

Advisory Committees ◽

Tp53 Mutations ◽

Number Of Patients ◽

Low Dose Cytarabine

BACKGROUND: Older patients with acute myeloid leukaemia (AML) who are unsuitable for standard induction therapy have limited treatment options. While DNMT3A, TET2, IDH1/2 and TP53 mutations have been previously associated to better response to hypomethylating agents, there are no molecular biomarkers for low-dose cytarabine (LDAC)-based regimens. AIMS: To predict outcome in AML older patients at diagnosis based on mutation status in the context of FLUGAZA trial. FLUGAZA trial was focus on >65 years AML de novo patients comparing azacytidine vs. fludarabine and LDAC (FLUGA Scheme). METHODS: We analyzed bone marrow (BM) samples at diagnosis from 209 out of 285 AML patients treated according Flugaza trial (NCT02319135), azacytidine-arm (n=97) and FLUGA-arm (n=112). In this trial, patients were randomized to receive 3 induction cycles with fludarabine and cytarabine (FLUGA) followed by 6 consolidation cycles with reduced intensity FLUGA, vs 3 induction cycles with 5-azacytidine (AZA) followed by 6 consolidation cycles with AZA. Median age at diagnosis was 75 years (65-90). Both treatment groups were balanced for age, leucocytes count, baseline BM blasts, karyotype risk (ELN), and FLT3-internal tandem duplication and NPM1 gene mutations. Mutational profile analysis was carried out by NGS targeted gene sequencing (Ion Torrent S5XL System-Thermo Fisher Scientific) using a 43 genes custom panel implicated in leukemia prognosis. RESULTS: We detected 893 variants, 247 Indels and 646 SNVs. 206 (23.1%) of them were included as pathogenic or like-pathogenic by clinvar database. Ninety-five percent of patients (n=203) had at least one detectable mutation, and the median number of mutations was 4 (range = 0-8 mutations). The most common gene mutations were TET2 (N=55), FLT3 (n=52), SRSF2 (n=49), TP53 (n=45), DNMT3A (n=45), ASXL1 (n=45), RUNX1 (n=43), IDH2 (n=36), IDH1 (n=34), NPM1, (n=33) and NRAS (n=23). This mutational landscape is different to previous published in younger patients (Grimwade, Blood 2016), with higher number of patients with mutations in TP53 (21.5 vs 8%), SRSF2 (23.9 vs 2%), IDH1 (16.3 vs 7%) and IDH2 (17.2 vs 9%) and lower number of patients with mutation in NMP1 (15.8 vs 33%). The median OS of global series was 6 months (range 0-40). Multivariate Cox regression in the global series showed that NRAS and TP53 mutations predict reduced OS (Table 1). Distribution of mutations between both arms was not homogeneous (Figure 1) and NRAS (p=0.012) was more frequent among patients randomized to the FLUGA-arm. However, TP53 mutation frequency distribution was homogeneous: 23.7% in AZA-arm and 19.6% in FLUGA-arm (p=NS). In the AZA-arm, patient´s age was the only variable associated with not achieving composite complete remission (CR plus CR with incomplete recovery) and TET2 and EZH2 mutations were predictors to achieve composite CR. In the FLUGA-arm, TP53 and NRAS mutations were associated with not reaching composite CR (table 2). In the AZA-arm, cytogenetic was the only variable associated with risk of early death. In the FLUGA-arm, leucocyte count, TP53 and NRAS mutations were associated with risk of early death (table 3). In the AZA-arm, BCORL1 mutations (4.1%) were the only variable associated with high risk of relapse. In the FLUGA-arm, BCOR (7.1%) and TP53 (19.6%) mutations were associated with high risk of relapse (table 4). CONCLUSION The mutational profile of AML in elderly patients is different from the previously published in young patients. We have confirmed that a molecular pattern can identify patients with poor prognosis in elderly AML patients. NRAS and TP53 mutations confer a poor prognosis in LDAC (FLUGA-arm) patients, but this effect disappeared in the AZA-arm. BCOR and BCORL1 mutations were associated to a reduced DFS. These results confirm that azacytidine could be more efficacious than LDAC treatment for older patients with AML and mutations in TP53, NRAS, TET2 and EZH2. The percentage of patients who presented mutations in these genes amounted to 77% in this AML series. The study is registered at www.ClinicalTrials.gov as NCT02319135. This study was supported by the Subdirección General de Investigación Sanitaria (ISCIII, Spain) grants PI13/02387 and PI16/01530. Disclosures Salamero: Celgene: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Daichii Sankyo: Honoraria. Paiva:Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche, and Sanofi; unrestricted grants from Celgene, EngMab, Sanofi, and Takeda; and consultancy for Celgene, Janssen, and Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau. Fernandez:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Single-Cell Transcriptomics Study of Human Hematopoietic Progenitors Reveals Alterations Associated with Aging and Myeloid Malignancies

Blood ◽

10.1182/blood-2021-153550 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1082-1082

Author(s):

Marina Ainciburu ◽

Teresa Ezponda ◽

Nerea Berastegui ◽

Ana Alfonso Pierola ◽

Amaia Vilas-Zornoza ◽

...

Keyword(s):

Single Cell ◽

Board Of Directors ◽

Research Funding ◽

Healthy Aging ◽

The Elderly ◽

Advisory Committees ◽

Myeloid Malignancies ◽

Age Related ◽

Healthy Donors ◽

Transcriptional Alterations

Abstract Hematopoietic stem and progenitor cells (HSPCs) comprise a continuum of cells with varying differentiation potential and priming toward specific lineages. During both healthy aging and myeloid malignancies, changes occur in the composition and regulation of HSPCs. In this study, we evaluated human HSPCs obtained from young and elderly healthy donors using single-cell RNA sequencing to identify the transcriptional and regulatory alterations associated with aging at single cell resolution. We then applied this knowledge to the study of specific perturbations associated with the development of myeloid pathologies. We isolated >90,000 bone marrow CD34+ cells from 5 young (18-20 y/o), 3 elderly (>65 y/o) healthy donors, 1 patient with myelodysplastic syndrome (MDS) and 1 patient with acute myeloid leukemia (AML), using fluorescence-activated cell sorting. scRNA libraries were prepared with the 10X chromium platform and sequenced. Finally, bioinformatic analysis was performed using available R and Python algorithms such as Seurat, Palantir and Scenic. First, we characterized HSPC subpopulations in young donors by unsupervised clustering and manual annotation. Taking the previous findings as reference, we then classified the elderly and pathological HSPC using elastic-net regularization prediction models (Figure 1A). Comparison of subpopulations in young and elderly donors confirmed the age-related increase in HSC, as well as reduction of lymphoid progenitors and myelomonocytic compartments. Next, we performed differential expression and pathways analysis to uncover age-associated alterations in the transcriptional profile of cells with the same identity. We found a generalized enrichment in elderly HSPC of pathways activated upon stress and inflammation, such as p53, hypoxia and TNF alpha response. This suggests an age-related increased response to the more inflammatory microenvironment of elderly individuals. On the other hand, young HSPC were enriched for cell cycle activation and proliferation pathways, as well as metabolic processes (Figure 1B). Using trajectory analysis, we recovered 6 differentiation paths present in our young donor's data. When compared to the elderly, the greatest changes occurred along the monocytic trajectory. For some genes, expression differed through the whole trajectory, indicating the existence of original transcriptional alterations already at the HSC compartment. On the other hand, expression of myelomonocytic differentiation markers, such as MPO and CD74, reached lower levels in our elderly HSPC data, pointing towards a loss of capacity for monocytic differentiation in progenitors from elderly individuals. Finally, to identify key transcription factors regulating the progression of differentiation routes, we built gene regulatory networks. Overall, we found lower activation levels for transcriptional programs in the early progenitors from elderly donors. In addition, gene ontology enrichment analysis showed that the active networks in the young were enriched for differentiation-related terms, while networks from the elderly were not. These results also indicate an age-associated loss of differentiation capability. We then applied the same computational tools to analyze aberrant hematopoiesis in samples from 2 patients suffering from myeloid malignancies (MDS and AML). On one hand, we subjected the MDS sample to trajectory analysis, focusing on the erythroid lineage. We observed perturbations in the expression dynamics of genes playing a role in erythropoiesis. In the AML sample, we encountered a significant expansion of the most immature cell compartments (HSC, LMPP and MEP). In addition, GRN reconstruction showed up the specific activity of transcription programs activated by factors deregulated during leukemia, such as ZSCAN18 and GFI1. In conclusion, our work described the transcriptional alterations that occur in early hematopoiesis, both during healthy aging and myeloid pathology. We used multiple approaches, such as the study cellular proportions, differentiation trajectories and GRNs. The inclusion of samples from patients with myeloid pathology provided insights into the potential role of single-cell technologies for understanding and treating hematological malignancies. Figure 1 Figure 1. Disclosures Sanchez-Guijo: Gilead: Consultancy, Honoraria; Celgene/Bristol-Myers-Squibb,: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Takeda: Honoraria, Research Funding; Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Diez-Campelo: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Valcarcel: BMS: Consultancy, Honoraria, Speakers Bureau; CELGENE: Consultancy, Honoraria, Speakers Bureau; ASTELLAS: Consultancy, Honoraria, Speakers Bureau; AMGEN: Consultancy, Honoraria, Speakers Bureau; NOVARTIS: Consultancy, Honoraria, Speakers Bureau; TAKEDA: Consultancy, Honoraria, Speakers Bureau; JAZZ: Consultancy, Honoraria, Speakers Bureau; SOBI: Consultancy, Honoraria, Speakers Bureau; SANOFI: Consultancy, Honoraria, Speakers Bureau. Romero: 10X Genomics: Current Employment. Prosper: Janssen: Honoraria; Oryzon: Honoraria; BMS-Celgene: Honoraria, Research Funding.

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Cytomegalovirus Reactivation Does Not Increase Subsequent Risk for Acute Graft-Versus-Host Disease, Malignant Disease Relapse, or Infection Following Allogeneic Hematopoietic Cell Transplantation

Blood ◽

10.1182/blood.v128.22.3409.3409 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3409-3409

Author(s):

Jeffery J Auletta ◽

Monica I Ardura ◽

Sumithira Vasu ◽

Ying Huang ◽

Qiuhong Zhao ◽

...

Keyword(s):

Board Of Directors ◽

Cumulative Incidence ◽

Research Funding ◽

Malignant Disease ◽

Hematopoietic Cell Transplantation ◽

Incidence Rates ◽

Disease Relapse ◽

Advisory Committees ◽

Increased Risk ◽

Subsequent Risk

Abstract Background: Identifying factors that influence donor-derived immune response may ultimately enable its therapeutic redirection, lessening risk for complications following allogeneic hematopoietic cell transplantation (alloHCT) like acute graft-versus-host disease (aGvHD) and promoting protection against infection and malignant disease relapse. Viral reactivation seems poised to influence donor-derived immune response, potentially disrupting the balance between immune surveillance in eradicating malignancy and infection and immune tolerance in preventing aGvHD. Cytomegalovirus (CMV) is a clinically-significant virus with immunomodulatory capabilities. However, studies interrogating such effects are limited in the modern transplant era. The primary study aim was to estimate the cumulative incidence of initial CMV reactivation (RA) and aGvHD in alloHCT patients and to assess reciprocal influence between CMV RA and aGvHD. The secondary study aim was to define whether CMV RA predisposed alloHCT patients to infection or increased relapse risk. Methods: Consecutive adult patients (n=324) with acute lymphoblastic leukemia, acute myelogenous leukemia or myelodysplasia whom received initial matched sibling or unrelated donor (MUD) bone marrow (n=33), peripheral blood stem cell (PBSC, n=253) or umbilical cord blood (n=38) grafts from January 2010 through December 2014 at The Ohio State University Comprehensive Cancer Center comprised the study cohort. Patient-, transplant-, and infection-related data were retrospectively analyzed (Table 1). Initial CMV RA was defined as plasma quantitative CMV PCR≥1000 viral copies/ml for which CMV-directed antiviral therapy was started. Microbiologically-documented infections were recorded for the first year after alloHCT and categorized as bacterial blood stream infection, invasive fungal infection, human herpes virus 6 viremia, and respiratory viral infection. Cumulative incidences of CMV RA and aGvHD were estimated accounting for competing risks (death from any cause). Association between CMV RA and incidence of aGvHD was evaluated in a proportional sub-distribution hazards model, where CMV RA was treated as a time-dependent covariate with competing risk as death from any cause. Similarly, influence of aGvHD on incidence of CMV RA was evaluated where development of aGvHD was treated as the time-dependent covariate and CMVR RA as the end point of interest. Associations between CMV RA and subsequent infection or disease relapse were similarly analyzed. To evaluate impact of CMV and aGvHD on long-term outcomes, landmark analysis (LMA) at D100 and D365 were compared among four distinct patient groups: (1) No CMV RA, no aGvHD; (2) CMV RA, no aGvHD; (3) No CMV RA, aGvHD; and (4) CMV RA and aGvHD. Results: Most transplant patients had AML in CR1, received MUD PBSC grafts following myeloablative conditioning, and were given methotrexate and calcineurin-based GvHD prophylaxis. Patients who developed aGvHD grades 2 (HR=1.93, 95% CI 1.15-3.23, p=0.013) or grades 3 and 4 (HR=3.36, 95% CI 1.76-6.45, p<0.001) had higher risk for developing subsequent CMV RA. In contrast, patients with initial CMV RA did not have increased risk for developing future aGvHD. Similarly, CMV RA did not have a significant impact on future infection, regardless of infection type, nor impact subsequent risk of malignant disease relapse. Overall survival (OS) at 1, 2, and 3 years post-transplant were 63%, 53%, and 45%, respectively. Cumulative incidence rates for non-relapse mortality (NRM) at 1, 2, and 3 years were 16%, 19%, and 23%, respectively; for infection-related mortality (IRM), cumulative incidence rates were 10%, 13%, and 16%, respectively. OS, NRM and IRM were stratified by initial CMV RA and aGvHD status at D100 and D365 (Table 2). Among patients who were alive, patients whom had initial CMV RA and aGvHD by D100 were at higher risk for NRM (HR=2.85, 95% CI 1.24-6.56, p=0.014) and IRM (HR=3.65, 95% CI 1.39-9.57, p=0.008) than patients who experienced neither CMV RA nor aGvHD. D365 LMA did not reveal any statistically significant differences in OS, NRM, and IRM between groups. Conclusion: aGvHD associated with increased risk for CMV RA, but initial CMV RA did not associate with subsequent aGvHD risk. Furthermore, initial CMV RA did not associate with increased risk for disease relapse or infection, but did increase NRM and IRM, particularly in combination with aGvHD. Disclosures Auletta: Shire Pharmaceuticals: Consultancy. Lozanski:Genentech: Research Funding; Stemline Therapeutics Inc.: Research Funding; Boehringer Ingelheim: Research Funding; Beckman Coulter: Research Funding. Hofmeister:Janssen: Pharmaceutical Companies of Johnson & Johnson: Research Funding; Karyopharm Therapeutics: Research Funding; Signal Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees; Incyte, Corp: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Arno Therapeutics, Inc.: Research Funding; Takeda Pharmaceutical Company: Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees. Andritsos:Hairy Cell Leukemia Foundation: Research Funding.

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Impact of Genomic Alterations on Outcomes in Myelofibrosis Patients Undergoing JAK1/2 Inhibitor Therapy

Blood ◽

10.1182/blood.v128.22.4263.4263 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4263-4263

Author(s):

Jay Spiegel ◽

Caroline Jane McNamara ◽

Andrea Arruda ◽

Tony Panzarella ◽

James A. Kennedy ◽

...

Keyword(s):

Treatment Failure ◽

Board Of Directors ◽

Research Funding ◽

Univariate Analysis ◽

Inhibitor Therapy ◽

Jak Inhibitor ◽

Jak Inhibitors ◽

Advisory Committees ◽

Number Of Patients

Abstract Introduction: The advent of next generation sequencing (NGS) has brought intense interest to the complex genetic landscape of myeloproliferative neoplasms (MPN). However, data regarding clinical outcomes in the context of novel MPN therapies such as JAK inhibitors are scarce. Limited data indicate that high molecular risk signature (HMR, presence of at least one mutation in ASXL1, EZH2, IDH1/2, SRSF2) or multiple mutations may be associated with decreased spleen response and a shorter time to discontinuation of Ruxolitinib in myelofibrosis (Patel et al, Blood 2015). Methods: All myelofibrosis patients seen in the MPN program at Princess Margaret Hospital between November 2009 and May 2016 and treated with JAK1/2 inhibitor therapy were identified. NGS molecular profiling of 54 genes (39 hotspot region; 15 complete coding region coverage) was performed on peripheral blood or bone marrow samples using the TruSight Myeloid Sequencing Panel. Reporting was restricted to well-covered, exonic nonsynonymous, intronic splice site, and known pathogenic synonymous variants. Variants with global mean allele frequency >1% were identified using multiple population databases (1000 genomes, ESP, ExAC) and excluded. The primary endpoint was time from start of JAK1/2 inhibitor therapy to treatment failure (TTF) defined as treatment discontinuation, progression to accelerated phase or leukemic transformation, spleen progression or death. Secondary endpoints included best spleen, anemia and IWG response achieved by 48 weeks of treatment and overall survival. Response was assessed according to the 2013 revised IWG-MRT criteria. Transfusion dependency was assessed as any transfusion in 12 weeks prior to treatment or being identified as transfusion dependent in medical history. Results: Of 159 patients treated with JAK1/2 inhibitors at our institution, 102 met the inclusion criteria (see Table 1). Patients were excluded if; no sample was available for analysis (19), short use of JAK inhibitor prior to transplant (9), active clinical trial (5), in accelerated phase/acute leukemia (4) and others (20). First JAK inhibitor used was ruxolitinib in 77 patients and momelotinib in 25. At least one mutation was identified in every patient. Twenty (20%) patients had one mutation, 32 (31%) had 2 mutations and 50 (49%) patients had ≥ 3 mutations. Eighty (82%) patients had the JAK2V617F mutation, 15 (15%) had mutations in CALR, 4 (4%) had MPL mutations and one patient was triple negative. One patient had mutations in both CALR and JAK2 while another had mutations in MPL and CALR. Forty-eight (47%) patients had mutations consistent with HMR profile. Mutation profile is summarized in Table 2. With median follow-up of 2.5 years, 51 (50%) patients experienced treatment failure. On univariate analysis, TTF was associated with DIPSS, pre-treatment transfusion status and Hb <100 prior to initiating JAK inhibitor therapy. However, TTF was not associated with specific driver mutations, the number of mutations or HMR profile. Exploratory analysis of genes mutated in ≥5% of the population showed EZH2 (p=0.004) and CBL (p=0.005) mutated patients had shorter TTF. Multi-variable analysis employing anemia <100 and DIPSS with either of the number of mutations or HMR profile did not show any association with TTF. There was a trend towards TTF in patients with Hb<100 (HR 2.21, 95%CI: 0.99-4.95, p=0.05). Of 102 patients, 91 were evaluable for spleen response with 43 (47%) achieving a spleen response by 48 weeks of treatment. Twelve (23%) of the 53 patients evaluated met criteria for anemia response. Neither spleen nor anemia response was associated with the use of a particular JAK inhibitor. Of the 95 patients with at least 48-week follow-up, best response while on treatment was clinical improvement and spleen response in 29 (31%) and 19 (20%) patients respectively. Conclusions: In this study of myelofibrosis patients treated with JAK inhibitors, EZH2 and CBL mutated patients had shorter TTF. We did not find any association between TTF and number of mutations or other high risk mutations such as ASXL1/SRSF2. Anemia was the only significant independent predictor of shorter TTF. Our findings highlight the need for multicenter collaborative studies on a large number of patients and cautious use of mutation profiling results in routine clinical decision making with current treatment approaches. Spiegel and McNamara are co-primary authors. Disclosures Panzarella: Cellgene: Consultancy. Schimmer:Novartis: Honoraria. Schuh:Amgen: Membership on an entity's Board of Directors or advisory committees. Yee:Novartis Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kamel-Reid:BMS: Research Funding. Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Research Funding.

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Hospitalization Patterns and Medicare Spending for Non-Malignant Morbidity Among Older Survivors of Non-Hodgkin Lymphoma (NHL)

Blood ◽

10.1182/blood-2020-135931 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 1-2

Author(s):

Kelly Kenzik ◽

Gaurav Goyal ◽

Amitkumar Mehta ◽

Smita Bhatia

Keyword(s):

Cardiovascular Disease ◽

Board Of Directors ◽

Research Funding ◽

B Cell Lymphoma ◽

Advisory Committees ◽

Stratified Care ◽

Hospitalization Rates ◽

Age Related ◽

Race Ethnicity ◽

Medicare Spending

Introduction: Growth in the number of older cancer survivors in the face of projected healthcare workforce shortages is challenging the US health-care system in delivering appropriate care. A risk-stratified approach based on burden of morbidity and healthcare expertise is urgently needed to provide efficient and cost-effective care. We examined the cumulative, non-malignant, condition-specific hospitalization rates and associated spending in older NHL survivors compared to non-cancer controls, using a population-based approach, to develop evidence for risk-stratified care. Methods: Using SEER-Medicare data, we identified 14,533 patients diagnosed with NHL at age >65y (2008-2015). An age, race, sex, and follow-up time comparable non-cancer cohort (n=14,533) was also identified. Hospitalizations for 10 health conditions were used to examine cumulative utilization burden of non-malignant morbidity by time from diagnosis to 5y or date of bone marrow transplant (whichever came first), censoring at 6 mo prior to death or end-of-study (12/31/2016). We estimated the average number of hospitalizations per 100 individuals, up to 1y and 5y, accounting for the competing risk of leaving the cohort (BMT or 6 months prior to death). We calculated incident rate ratios [IRR] per person-time comparing NHL patients to controls controlling for pre-cancer comorbidity, Dual Medicaid-Medicare coverage, race/ethnicity, and pre-NHL hospitalization. We calculated Medicare spending per hospitalization and per person-year (adjusted to 2016 pricing), defining high hospitalization or high spending using the 90th percentile cutpoint for predicted hospitalization or spending. Results: Hospitalization: In Fig 1, we summarize the average number of condition-specific hospitalizations/100 individuals by 1y and by 5y. Adjusting for demographics and pre-existing comorbidity, NHL patients were significantly more likely to be hospitalized when compared with controls (IRR1y=3.08, IRR5y=1.54, all p<0.001). Compared with controls, NHL patients were at higher risk for hospitalizations related to cardiovascular disease (IRR1y=3.08, IRR5y=1.54, all p<0.001), age-related conditions (IRR1y=7.14, IRR5y=2.53, all p<0.001), gastrointestinal (GI) disease (IRR1y=5.84, IRR5y=2.30, all p<0.001), and pulmonary conditions (IRR1y=3.06, IRR5y=1.36, p<0.001). Factors associated with high hospitalization rates included a diagnosis of diffuse large B cell lymphoma (RR=6.36, p<0.001) and ≥2 pre-existing comorbidities (RR=10.1, p<0.001), non-white race/ethnicity (Black: RR=1.74, p<0.001; Hispanic (RR=1.97, p<0.001), residence in low-education area (RR=1.49, p<0.001) or low-income area (RR=37, p<0.001), or rural residence (RR=1.38, p<0.001). The high-hospitalization subgroup (n=1,435) had 3.24 times the hospitalization rate when compared with the lowest-hospitalization subgroup (p<0.001). Spending: Average hospitalization spending per person-year was higher in the NHL cohort (Y1: $8,178 vs. $1,621; 5y: $3,805 vs. $1,543) when compared with non-cancer controls (Fig 2). The average spending per hospitalization over 5y was also higher for the NHL cohort ($16,950 vs. $13,474, Fig 3). Pulmonary conditions were associated with the largest per hospitalization spending differential between NHL and controls ($18k vs. $9k). Other per hospitalization spending disparities between NHL patients and controls included GI disease ($17.8k vs. $10.2k) and age-related conditions ($12.6k vs. $7.9k). The NHL high-spending group was similar to the high-hospitalization group (71% overlap). The highest spending group had 2.5 times the spending compared with the lowest spending (10th percentile) group (p<0.001). Conclusions: Medicare beneficiaries diagnosed with NHL experience significantly greater rates of non-malignant hospitalizations and spending compared to their non-cancer counterparts. These hospitalizations are related to cardiovascular disease, gastrointestinal disease, pulmonary complications and aging-related conditions. Non-white DLBCL patients from lower SES with ≥2 comorbidities and living in rural areas were at greatest risk of high hospitalization and spending, providing evidence for a targeted risk-stratified care. Disclosures Mehta: Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche-Genentech: Research Funding; Merck: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Affimed: Research Funding; Takeda: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Innate Pharmaceuticals: Research Funding; fortyseven Inc/Gilead: Research Funding; Juno Parmaceuticals/BMS: Research Funding; Gelgene/BMS: Research Funding; Oncotartis: Research Funding; Kite/Gilead: Research Funding.

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Outcome of Patients with Myelofibrosis Relapsing after Allogeneic Stem Cell Transplant: A Retrospective Study By the Chronic Malignancies Working Party of EBMT

Blood ◽

10.1182/blood.v126.23.1958.1958 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1958-1958

Author(s):

Donal McLornan ◽

Richard Szydlo ◽

Anja van Biezen ◽

Linda Koster ◽

Evgeny Klyuchnikov ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Median Survival ◽

Research Funding ◽

Working Party ◽

Active Management ◽

Cell Transplant ◽

Advisory Committees ◽

Number Of Patients ◽

Significant Difference

Abstract Background: Over the last decade, there has been a significant increase in the number of patients with Myelofibrosis (MF) undergoing allogeneic stem cell transplantation (SCT). However, scarce information exists on the outcome and management of those patients who relapse following SCT. Moreover, the management of relapse occurring post-SCT is often heterogeneous and ranges from palliation to intensive salvage approaches. We therefore conducted a retrospective EBMT registry analysis of adult MF patients who relapsed following first SCT episode. Results: A total of 1216 adult patients (997 (82%) with Primary MF (PMF) and 219 (18%) with secondary MF (sMF)) underwent 1st allogeneic SCT between 2000 and 2010. A total of 251 patients from this cohort (206 with PMF and 45 with sMF) had conformed relapse ≥ day 30 after HSCT and were included in the analysis. Within this relapse cohort, there were 163 males and 88 females; median age was 55 years old (range 21.5-70 years). A total of 84 patients (33%) had received Myeloablative Conditioning (MAC) and 167 patients (67%) Reduced Intensity Conditioning (RIC). Regarding donor type, there were 123 matched siblings (49%) and 128 unrelated donors (51%). Acute GVHD (aGVHD) status was available for 243/251 (97%) patients; no aGVHD was evident in 143 patients, Grade I-II aGVHD 76 patients, Grade III-IV aGVHD 22 patients and 2 patients with aGVHD ungraded. The median time to relapse after SCT was 7.1 months (range 1-111 months). The median Overall Survival (OS) from the time of relapse was 17.7 months (95% Confidence Intervals 11-24). Collectively, there was a significant difference in survival outcome for those relapsing > 7.1 months post-SCT (median survival 30.3 months post relapse) compared to those relapsing within 7.1 months following the initial SCT episode (median survival 7.9 months post relapse; p<0.001). Absence of aGVHD or grade I aGVHD only was associated with a trend towards improved survival following relapse compared to those with Grade II-IV aGVHD (p=0.12). For PMF, disease duration prior to SCT did not significantly affect outcome post relapse. Heterogeneous practice existed as regards management of the relapse episode, with considerable variation in median survival (MS) estimates. 47 patients received Donor Lymphocyte Infusions (DLI) alone (MS 76 months); 21 had chemotherapy alone (MS 23 months) whereas 14 patients had DLI combined with chemotherapy (MS 13.6 months). As regards 2nd allografts: 53 patients underwent 2nd allograft alone (MS 23.6 months) and 26 underwent DLI and 2nd SCT (MS 53.9). In 90 patients active management -if any- was not documented (most likely many were palliative) but represented a very poor risk group with a MS of only 4.8 months. Overall, there was a significant improvement in OS post relapse for those undergoing 2nd SCT (n=79) versus those who did not have a 2nd SCT (n=172; p=0.019). Conclusions : This analysis represents the first study to define the outcome of MF patients who undergo relapse following allogeneic SCT. Treatment of relapse presents huge challenges and the heterogeneous management strategies highlighted above reflects current practice where approaches range from palliation through to intensive chemotherapy and 2nd SCT. It is clear from this analysis that early relapse has a much worse prognosis than those who relapse later than 7.1 months post-SCT. There is a definite survival advantage for those who undergo DLI and/or a 2nd SCT procedure, although we acknowledge that those patients undergoing a 2nd SCT represent a highly selected group who are fit enough to undergo such intervention. Moreover, how relapse management practice will change in the era of novel therapies such as JAK inhibitors to bridge towards 2nd SCT is currently unclear and requires evaluation in prospective studies. Disclosures McLornan: Novartis: Research Funding, Speakers Bureau. Finke:Riemser: Research Funding, Speakers Bureau; Neovii, Novartis: Consultancy, Research Funding, Speakers Bureau; Medac: Research Funding. Craddock:Celgene: Consultancy, Honoraria, Research Funding; Pfizer: Speakers Bureau; Sunesis: Honoraria; Johnson and Johnson: Consultancy. Apperley:BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ARIAD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Niederwieser:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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