PPM1D and DNMT3A Mutations in Myelodysplasia and Clonal Hematopoiesis

Introduction: Age-related clonal hematopoiesis (CH) has been implicated in an increased risk of myeloid neoplasms. While common driver genes mutated in CH largely overlap to those in myeloid neoplasms, a notable exception is protein phosphatase Mg2+/Mn2+dependent 1D gene (PPM1D), encoding a p53-targeting phosphatase. Although it is known to be involved in DNA damage response pathways and more frequently mutated in therapy-related myeloid neoplasms than in primary ones, its role in CH and myeloid neoplasms has not been fully understood. Aim: To identify genetic features associated with PPM1D mutations, we examined genetic profiles in the large cohorts of healthy elderly individuals and patients with myelodysplasia. Methods: We enrolled 10,826 healthy individuals (>60y) and 1,213 cases with myelodysplasia, including myelodysplastic syndromes (MDSs), myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) (n=1,080), and secondary acute myeloid leukemia (sAML) (n=133), of which 567 cases were treated by hematopoietic stem cell transplantation (HSCT) through the Japan Marrow Donor Program just after sampling, and 332 of them underwent any therapy before sampling. Samples from healthy individuals were subjected to multiplex-amplicon sequencing for 22 genes, including PPM1D and other genes, related to CH or myeloid neoplasms. Myelodysplasia samples had previously been sequenced for major myeloid drivers, except for PPM1D, which was newly sequenced in this study. Results: Frequency of PPM1D mutations in myelodysplasia and healthy individuals was 3.1% and 0.42%, with a median variant allele frequency (VAF) of 0.043 and 0.056, respectively. PPM1D mutations were more frequent in cases with previous treatment (4.8%) than in those without known history of therapy (2.3%) (P=0.038). In MDS and MDS/MPN cases, 59.5% of PPM1D mutations had accompanying mutations, in which DNMT3A mutations were the most frequently identified (16.2%, n=6). These 6 cases were diagnosed with RCUD (n=1), RCMD (n=2), RAEB-2 (n=2), or CMML (n=1). The association between PPM1D and DNMT3A mutations was also seen in 7 of 45 healthy individuals with PPM1D mutations, of which one had a DNMT3A-R882 mutation. In the HSCT cohort, 192 cases harbored ≥2 mutations of the 22 CH-related genes, and the relative temporal order of these mutations was investigated using Bradley-Terry model relying on their tumor cell fractions. The estimate of PPM1D mutations tended to be smaller than that of DNMT3A mutations. To further confirm chronological order of these mutations, VAF values were compared between them in the individuals with concurrent PPM1D and DNMT3A mutations (n=13; 6 myeloid neoplasms and 7 healthy donors). In the combined cohort, the VAFs of PPM1D and DNMT3A mutations were correlated (Spearman; correlation coefficient=0.87, P=1.2x10e-5). In both neoplastic and healthy cohort, the VAFs of DNMT3A-R882 mutations were larger than those of accompanying PPM1D mutations. These findings suggest that these mutations should be acquired in the same cell populations and that DNMT3A mutations might occur prior to PPM1D mutations. With regard to copy number alterations associated with PPM1D-mutated myelodysplasia, del(5q) (16.7%) and complex(-like) karyotypes (13.9%) were among the most frequent chromosomal abnormalities. Approximately 65% of PPM1D-mutated tumor samples had normal karyotype, which was similar to PPM1D-unmutated cases. PPM1D mutations did not significantly influence overall survival, although PPM1D mutations tended to negatively affect clinical outcome among patients who were treated with HSCT (Hazard ratio, 1.61; 95% confidence interval, 0.95 to 2.70). Conclusion: PPM1D mutations were more enriched in myelodysplasia than in CH, and the median value of VAF in PPM1D mutations in CH was not significantly different from that in myelodysplasia. The size of PPM1D-mutated clones tended to be relatively smaller compared with that of clones with other mutations in myelodysplasia. PPM1D and DNMT3A mutations might be cooperatively associated in the pathogenesis of myelodysplasia and CH. Disclosures Baer: MLL Munich Leukemia Laboratory: Employment. Nadarajah:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Atsuta:CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria; Kyowa Kirin Co., Ltd: Honoraria. Miyazaki:Chugai: Research Funding; Otsuka: Honoraria; Novartis: Honoraria; Nippon-Shinyaku: Honoraria; Dainippon-Sumitomo: Honoraria; Kyowa-Kirin: Honoraria. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Ogawa:Dainippon-Sumitomo Pharmaceutical, Inc.: Research Funding; Qiagen Corporation: Patents & Royalties; Asahi Genomics: Equity Ownership; RegCell Corporation: Equity Ownership; Kan Research Laboratory, Inc.: Consultancy; ChordiaTherapeutics, Inc.: Consultancy, Equity Ownership.

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Analysis of Second Primary Malignancies in Lenalidomide-Treated Patients with IPSS Low- or Int-1-Risk Myelodysplastic Syndromes

Blood ◽

10.1182/blood.v118.21.1704.1704 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1704-1704 ◽

Cited By ~ 2

Author(s):

Aristoteles Giagounidis ◽

Azra Raza ◽

Alan F. List ◽

Pierre Fenaux ◽

Bouchra Benettaib ◽

...

Keyword(s):

Research Funding ◽

Prior History ◽

Second Primary ◽

Employment Equity ◽

Phase 3 ◽

Advisory Committees ◽

Increased Risk ◽

History Of ◽

Equity Ownership ◽

Rbc Transfusion

Abstract Abstract 1704 Background: Lenalidomide (LEN) is approved in the US for the treatment of RBC transfusion-dependent patients with IPSS Low- or Int-1-risk myelodysplastic syndromes (MDS) with del(5q), with or without other cytogenetic abnormalities. In a phase 3 trial, treatment with LEN 5 mg and 10 mg resulted in RBC transfusion independence (TI) for ≥ 26 weeks in 43% and 56% of such patients, cytogenetic response in 25% and 50%, and a significant improvement of health-related quality of life (p <.05 for both 5 mg and 10 mg). Achievement of RBC-TI ≥ 8 weeks was associated with a significantly reduced risk of AML progression and death (p <.05 for both) (Fenaux P et al. Blood 2011;doi: 10.1182/blood-2011-01-330126). In newly diagnosed multiple myeloma patients, results of phase 3 trials showed a numerical imbalance in the occurrence of second primary malignancies (SPMs) between patients treated with LEN (in combination with melphalan or immediately after high-dose melphalan therapy and stem cell transplantation) and control cohorts. SPMs were analyzed in clinical trials of LEN across indications, including MDS. Methods: This was a single arm analysis of SPM data retrieved from RBC transfusion-dependent patients with IPSS Low- or Int-1-risk MDS with or without del(5q) who received LEN as monotherapy in 5 studies (MDS-001, -002, -003, -004, and -007). The cutoff date was February 28, 2011. SPMs were defined using MedDRA (Medical Dictionary for Regulatory Activities) categories of invasive SPMs (hematologic malignancies and solid tumors) and non-melanoma skin cancers (NMSC). Acute myeloid leukemia (AML) is considered part of the natural history of disease progression in MDS. Although further follow-up is needed, results of a phase 3 study showed no obvious evidence for an increased risk of AML progression in LEN-treated RBC transfusion-dependent patients with IPSS Low- or Int-1-risk MDS and del(5q) (Fenaux P et al. Blood 2011;doi: 10.1182/blood-2011-01-330126). AML was not included in the present analysis. The overall number of SPMs (invasive malignancies and NMSC), and the number and incidence rate (IR) of all invasive SPMs were evaluated, with IR defined as the number of new events per 100 person-years (pys). The IR of invasive SPMs was compared with the IR of new events of invasive cancer as reported from the SEER (Surveillance, Epidemiology, and End Results) cancer registry (2.1/100 pys for persons aged ≥ 65 years) (Howalder N et al. National Cancer Institute, 2011). Results: The combined population of all 5 studies comprised 557 LEN-treated patients. The median age was 71 years (range 27–95 years) and 72% of patients were aged ≥ 65 years. 88 patients (15.8%) had a prior history of cancer including malignant melanoma, meningioma, breast cancer, lung cancer, squamous cell carcinoma, and basal cell carcinoma. A total of 28 patients (5.0%) developed ≥ 1 SPM, including 17 (3.1%) with an invasive SPM and 12 (2.2%) with NMSC; 1 patient had both an invasive malignancy and a NMSC. Two of the 17 patients with invasive SPMs had a B-cell malignancy and 15 had solid tumors of heterogeneous type. Of the 28 patients with SPMs in total, 5 patients had a prior history of cancer. The IR of invasive SPMs was 2.60/100 pys (95% confidence interval 1.56–4.07), which is consistent with the IR reported in the SEER database among patients in this age group (2.1/100 pys for persons aged ≥ 65 years). The median time to onset of SPMs was 13.5 months (range 0.3–48.6 months). Conclusion: There was no clear evidence to associate LEN treatment with an increased risk of developing SPMs in patients with Low- or Int-1-risk MDS with or without del(5q). The IR of invasive SPMs among these LEN-treated patients is what would be expected from population-based estimates of invasive cancer incidence among persons in this age group. The collection of data on SPMs in LEN-treated patients including post-marketing information is ongoing. Disclosures: Giagounidis: Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. List:Celgene Corporation: Consultancy, Honoraria, Research Funding. Fenaux:Merck: Honoraria; Johnson & Johnson: Honoraria; Amgen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Cephalon: Honoraria; Novartis: Honoraria. Benettaib:Celgene Corporation: Employment, Equity Ownership. Brown:Celgene Corporation: Employment, Equity Ownership. Zhong:Celgene Corporation: Employment, Equity Ownership. Brandenburg:Celgene Corporation: Employment, Equity Ownership. Mufti:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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CC-486 (Oral Azacitidine) Following Allogeneic Hematopoietic Stem Cell Transplantation (AlloHSCT) in Patients with Myelodysplastic Syndromes (MDS) or Acute Myeloid Leukemia (AML)

Blood ◽

10.1182/blood.v124.21.990.990 ◽

2014 ◽

Vol 124 (21) ◽

pp. 990-990 ◽

Cited By ~ 2

Author(s):

Basem M. William ◽

Marcos de Lima ◽

Betul Oran ◽

Richard Champlin ◽

Esperanza B Papadopoulos ◽

...

Keyword(s):

Stem Cell ◽

Plasma Concentration ◽

Febrile Neutropenia ◽

Research Funding ◽

Concentration Profiles ◽

Employment Equity ◽

Hematopoietic Stem ◽

Post Transplant ◽

Equity Ownership ◽

Concomitant Medications

Abstract Background: Disease relapse and graft vs host disease (GvHD) following alloHSCT are major causes of treatment (Tx) failure in patients (pts) with MDS and AML (Paietta, 2012). Studies of parenteral azacitidine, an epigenetic modifier, have shown efficacy in preventing post-transplant relapse in MDS and AML pts, and possibly reducing GvHD severity (Platzbecker, 2012; de Lima, 2010). Azacitidine maintenance after alloHSCT may enhance graft vs leukemia (GvL) effects and reduce GvHD by expansion of regulatory T cells (Goodyear, 2010, 2012). CC-486 is a novel oral formulation of azacitidine which, as well as potentially allowing easier administration over extended schedules, could increase the duration of drug exposure to residual malignant cells. We now report preliminary results from a prospective phase I/II dose-finding study of CC-486 as maintenance Tx after alloHSCT in pts with MDS or AML. Objective: To evaluate the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics (PK), and safety outcomes of CC-486 following alloHSCT in pts with MDS or AML. Methods: Pts with WHO-defined MDS or AML who have undergone alloHSCT with myeloablative (MAC) or reduced-intensity conditioning (RIC) regimens and who had sibling or unrelated donors with ≤1 antigen mismatch at the HLA-A, -B, -C, -DRB1 or -DQB1 locus, are enrolled. CC-486 Tx is initiated between days (d) 42 and 84 after alloHSCT. Pts receive prophylactic Tx for GvHD and infections per institutional standard. A standard 3x3 MTD design is being used to evaluate 4 dosing schedules: CC-486 200 mg or 300 mg QD, administered for 7 d (Cohorts 1 and 2) or 14 d (Cohorts 3 and 4) of repeated 28d Tx cycles. MTD determination is based on DLT that occur during the first 2 Tx cycles (pts are not evaluable if unable to complete 2 Tx cycles for reasons other than a DLT). Adverse events (AEs) are graded using NCI-CTCAE v4.0. Pts are followed for safety, incidence of acute and chronic GvHD, and relapse. PK of azacitidine after CC-486 administration, alone or with standard concomitant medications, are evaluated on d 1 of CC-486 Tx cycles 1 and 2. Results: At data cut-off (7/17/2014), outcome data were available for 7 pts enrolled in the first 2 cohorts (Table): 1 pt had IPSS Int-2 MDS and 6 had AML with high-risk features. Stem cell source was from bone marrow (n=2) or peripheral blood (n=5) from unrelated (n=5) or sibling (n=2) donors. Two pts had 1 antigen mismatch and 5 had a full match.Conditioning included MAC (n=3) and RIC (n=4) regimens. One pt in Cohort 2 was not evaluable for DLT or PK assessments due to early discontinuation (AML relapse) during the first CC-486 Tx cycle. Of the 6 evaluable pts, 4 completed ≥6 CC-486 Tx cycles and 2 ongoing pts had not reached 6 cycles on-study at data cut-off (Table). One pt who had GvHD before CC-486 Tx subsequently withdrew from the study after developing febrile neutropenia and diarrhea related to GvHD of the bowel; 1 pt withdrew for personal reasons; and 1 pt discontinued after 6 Tx cycles due to relapse. At data cut-off, 3 pts remained on-study, all with continued CR (Table). No pt in Cohort 2 developed GvHD. For all pts, most AEs were grade 1-2. Grade 3-4 AEs were reported for 2 pts: both had nausea and vomiting, which were controlled with antiemetic agents upon onset; 1 also had device-related infection and dyspnea, and 1 also had febrile neutropenia and rash. No DLT emerged with these CC-486 regimens and no pt experienced secondary graft failure. Overall azacitidine plasma concentration profiles (Figure) and PK parameters were similar following CC-486 given alone or with concomitant medications, and were within range of values observed following similar CC-486 doses in pts with MDS, CMML, and AML (Garcia-Manero, 2011). The AUC range for oral CC-486 is ~10% of that seen with subcutaneous azacitidine administered at 75 mg/m2 (Garcia-Manero, 2011). Conclusion: Preliminary data from this analysis suggest that CC-486 administered at doses of 200 or 300 mg QD for 7 days every 4 weeks is safe and well tolerated in the post-transplant setting. Overall, azacitidine plasma concentration profiles and PK parameters were not affected by use of concomitant medications. No DLT and a low rate of GvHD support the ongoing evaluation of 14d extended CC-486 dosing regimens in this ongoing study, as a preliminary to a prospective, randomized trial of this new agent post-transplant. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures de Lima: Celgene: Consultancy. Champlin:Celgene: Consultancy. Giralt:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Scott:Celgene: Consultancy, Honoraria, Research Funding. Hetzer:Celgene: Employment, Equity Ownership. Wang:Celgene: Employment, Equity Ownership. Laille:Celgene: Employment, Equity Ownership. Skikne:Celgene: Employment, Equity Ownership. Craddock:Celgene: Honoraria, Research Funding.

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Prevalence and Impact on Outcomes of Additional Karyotypic Abnormalities in Patients (Pts) with Myelodysplastic Syndromes (MDS) and Del(5q) from the MDS-003 and MDS-004 Studies

Blood ◽

10.1182/blood.v126.23.1680.1680 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1680-1680

Author(s):

Aristoteles Giagounidis ◽

Alan F. List ◽

Eva Hellström-Lindberg ◽

Ghulam J. Mufti ◽

Brigitte Schlegelberger ◽

...

Keyword(s):

Research Funding ◽

Employment Equity ◽

Multicenter Studies ◽

Free Survival ◽

Cytogenetic Abnormalities ◽

Poor Risk ◽

Increased Risk ◽

Equity Ownership ◽

Good Risk ◽

Rbc Transfusion

Abstract Introduction: Approximately 50% of pts with de novoMDS present with cytogenetic abnormalities at diagnosis (Haase D, et al. Ann Hematol. 1995;70:171); deletion (del)5q occurs in ~15% of pts (Haase D, et al. Blood. 2007;110:4385). Cytogenetic abnormalities in addition to del(5q) may be associated with shorter overall survival (OS) and increased risk of progression to acute myeloid leukemia (AML) versus del(5q) alone (Mallo M, et al. Leukemia. 2011;25:110). In 2 large multicenter studies (MDS-003 and MDS-004), lenalidomide (LEN) was evaluated in red blood cell (RBC) transfusion-dependent pts with IPSS Low- or Intermediate-1-risk MDS and del(5q) (List A, et al. N Engl J Med. 2006;355:1456; Fenaux P, et al. Blood. 2011;118:3765). Here, we examine specific cytogenetic abnormalities and outcomes in pts with MDS and del(5q) plus ≥ 2 additional cytogenetic abnormalities from MDS-003 and MDS-004. Methods: Of 353 pts enrolled, 281 had available cytogenetic data with ≥ 12 evaluable metaphases, and were included. Pts received either LEN 10 mg on days 1-21 of each 28-day cycle, LEN 5 mg or 10 mg continuously, or placebo (PBO). In MDS-004, at week (wk) 16, PBO pts could cross over to LEN 5 mg. Centrally reviewed cytogenetic studies were performed at baseline, and wks 24 and 48 (MDS-003); and at baseline, wks 12 and 24, and every 24 wks thereafter (MDS-004). RBC transfusion independence (TI) ≥ 26 wks, cytogenetic response (CyR), AML progression, OS, and AML-free survival were assessed by baseline cytogenetic complexity in LEN-treated pts with del(5q) plus ≥ 2 additional abnormalities. These patients did not fulfill IPSS lower-risk classification after central pathologic/cytogenetic evaluation. Results: Of 281 pts, 25 (8.9%) had del(5q) plus ≥ 2 additional abnormalities at baseline. In these pts, the most common additional abnormalities at baseline were -7 (20.0%), del(13q) (20.0%), +21 (16.0%), and del(11q) (16.0%). Baseline characteristics were comparable across the 24 LEN-treated pts with 2 (n = 9), 3 (n = 8), or ≥ 4 (n = 7) additional abnormalities. Rates of RBC-TI ≥ 26 wks were 44.4%, 50.0%, and 28.6% in pts with 2, 3, or ≥ 4 additional abnormalities (P = 0.77), respectively. In pts evaluable for CyR (n = 21), rates of CyR were 33.3%, 28.6%, and 20.0% (P = 1.00), respectively; all cytogenetic responders achieved RBC-TI ≥ 26 wks. The other pts who achieved RBC-TI ≥ 26 wks but did not meet the criteria for CyR showed reductions in the del(5q) clone. No PBO pts achieved CyR; however, 1 pt had a partial response (PR) after crossover to LEN 5 mg. Of the pts randomized to LEN, 4 achieved a complete response (CR) (5 mg, n = 1; 10 mg, n = 3) and 2 achieved a PR (5 mg and 10 mg). Median duration of CyR was 282 days (range 168-957). The median number of additional cytogenetic abnormalities in the subset of pts with poor-risk abnormalities (i.e. 17p, 3q, and monosomal abnormalities; n = 7) was 3 versus 2 in pts with good-risk abnormalities (i.e. all other abnormalities; n = 14). Rates of RBC-TI ≥ 26 wks were 28.6% versus 57.1% for the poor-risk versus good-risk groups, respectively. Rates of CyR were 14.3% versus 35.7%, respectively (all CR). In pts with 2, 3, or ≥ 4 additional abnormalities, the 2-year AML progression rates were 56.3% (95% confidence interval [CI] 25.8-89.9), 40.0% (95% CI 14.8-80.5), and 33.3% (95% CI 5.5-94.6), respectively. Median time to AML was 1.8 years (95% CI 0.6-not reached [NR]), 3.1 years (95% CI 0.4-4.8), and NR (95% CI 1.6-NR) (P = 0.75), respectively (Figure 1A). Of 10 pts who developed AML, 6 had involvement of chromosome 7 [del(7q) or -7] at baseline, but presence of -7 did not necessarily portend a poor response in all. Median OS was 1.8 years (95% CI 0.6-3.7), 3.6 years (95% CI 0.5-NR), and 1.6 years (95% CI 0.2-3.3) (P = 0.17) in pts with 2, 3, or ≥ 4 additional abnormalities (Figure 1B). Median AML-free survival was 1.5 years (95% CI 0.6-3.7), 2.5 years (95% CI 0.4-4.8), and 1.6 years (95% CI 0.2-3.3) (P = 0.36), respectively (Figure 1C). Conclusions: Although RBC-TI and CyR with LEN do occur in pts with del(5q) plus ≥ 2 additional abnormalities, the prognosis is generally dismal and less favorable versus isolated del(5q) and del(5q) plus 1 additional abnormality (Giagounidis A, et al. Blood. 2014;124:abstract 3270). Pts with del(5q) and complex karyotypes are generally associated with IPSS Intermediate-2- or High-risk MDS, which require more intensive treatment approaches, including azacitidine and stem cell transplantation, if feasible. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures Giagounidis: Celgene Corporation: Honoraria. List:Celgene Corporation: Honoraria, Research Funding. Hellström-Lindberg:Celgene Corporation: Research Funding. Mufti:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Morrill:Celgene Corporation: Employment, Equity Ownership. Wu:Celgene Corporation: Employment, Equity Ownership. Skikne:Celgene Corporation: Employment, Equity Ownership. Fenaux:Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding.

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Treatment with Anti-CD19 BiTE® Blinatumomab in Adult Patients with Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (r/r ALL) Post-Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood.v126.23.861.861 ◽

2015 ◽

Vol 126 (23) ◽

pp. 861-861 ◽

Cited By ~ 4

Author(s):

Anthony Selwyn Stein ◽

Max S. Topp ◽

Hagop M Kantarjian ◽

Nicola Goekbuget ◽

Ralf C Bargou ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Complete Remission ◽

Stem Cell Transplantation ◽

Salvage Therapy ◽

Research Funding ◽

Employment Equity ◽

Hematopoietic Stem ◽

Equity Ownership ◽

Grade 3

Abstract Introduction: Current therapies for patients with r/r ALL who have had prior allogeneic hematopoietic stem cell transplantation (alloHSCT) have very poor outcomes. Improvements in the therapeutic options available for adult r/r ALL are required. Blinatumomab is a bispecific T-cell engager (BiTE®) antibody construct that redirects cytotoxic T cells to lyse CD19-positive B cells. The aim of the present analysis was to characterize a subset of patients with r/r ALL and prior alloHSCT before treatment with blinatumomab from a large confirmatory open-label, single-arm, multicenter phase 2 study (Topp MS et al Lancet Oncol 2015;16(1):57-66). Methods: Eligible patients (≥18 years) had Philadelphia chromosome-negative r/r ALL with 1 of the following negative prognostic factors: primary refractory, first relapse within 12 months of first remission, relapse within 12 months of alloHSCT, or second or greater salvage. Patients with active acute or chronic graft-versus-host disease (GvHD) were excluded. Patients were required to stop all immunosuppressive GvHD therapy within 2 weeks before starting blinatumomab. A total of 189 patients were enrolled and received blinatumomab by continuous intravenous infusion (4 weeks on/2 weeks off) for up to 5 cycles. The primary endpoint was complete remission or complete remission with partial hematologic recovery (CR/CRh) within the first 2 cycles. Secondary endpoints included overall survival (OS), relapse-free survival (RFS), and adverse events (AEs). Results: 64 (34%) patients had received alloHSCT before study enrollment; 10 patients had 2 prior alloHSCTs. Donor types primarily included 29 (45%) matched sibling and 31 (48%) unrelated, with 34 (59%) patients receiving myeloablative conditioning regimens (donor chimerism data were unavailable). Among those with prior alloHSCT, median age (range) was 32 (19-74) years. At baseline, 23 (36%) patients had 1 prior relapse, 24 (38%) had 2 prior relapses, and 17 (27%) had ≥3 prior relapses; 28 (44%) patients had relapsed post-alloHSCT. Of the 55 patients who had received previous salvage therapy, 38 (69%) had received salvage therapy after last alloHSCT and prior to blinatumomab. Median time (range) between the last alloHSCT and subsequent relapse was 6 (1-33) months. Median time from last prior alloHSCT to first dose of blinatumomab was 10 (3-40) months. Nineteen (30%) patients had a history of GvHD, and 42 (66%) had ≥50% bone marrow blasts at start of treatment as assessed by a central laboratory. Patients received blinatumomab for a median of 2 (1-5) cycles. Efficacy data are presented in Table 1. Overall, 45% (29/64; 95% confidence interval [CI], 33-58) of patients achieved CR/CRh within the first 2 cycles, with similar rates of remission also observed in the alloHSCT-naïve (42%; 52/125) group. With a median follow-up of 8.8 months, median (95% CI) OS was 8.4 (4.2-9.4) months for the 64 patients with prior alloHSCT treated with blinatumomab. Of the 29 responders (CR, n=18 and CRh, n=11), 22 (76%) had a minimal residual disease (MRD) response and 19 (66%) achieved a complete MRD response. Median RFS (95% CI) was 6.1 (5.0-7.7) months. 9/29 (31%) responders subsequently underwent another alloHSCT. In total, 56 (88%) patients had grade ≥3 treatment-emergent AEs, with the most frequent including neutropenia (22%), febrile neutropenia (20%), anemia (17%), and thrombocytopenia (14%). Six patients reported treatment-emergent GvHD (two grade ≥ 3) during blinatumomab treatment, 3 of whom had GvHD in skin. Eight patients had fatal treatment-emergent AEs, which included 1 due to gastrointestinal hemorrhage, 1 due to respiratory failure, and 6 due to infection/infestation; 1 of these (candida infection) was considered to be possibly related to treatment by the investigator. Of the subjects who had treatment-emergent fatal AEs, none were in remission at the time of death. Summary: In this heavily pretreated group of patients with r/r ALL and prior alloHSCT, single-agent blinatumomab was able to induce a CR/CRh rate of 45%, with an AE profile consistent with that previously reported. Post-alloHSCT patients who had relapsed performed equally as well as those without prior alloHSCT. To prolong remission in this poor outcome patient group, the addition of other immunotherapies to the treatment regimen may be considered for future investigations. Disclosures Stein: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Research Funding. Topp:Astra: Consultancy; Regeneron: Consultancy; Affimed: Consultancy, Research Funding; Roche: Consultancy, Other: Travel Support; Jazz: Consultancy; Pfizer: Consultancy; Amgen: Consultancy, Honoraria, Other: Travel Support. Goekbuget:Erytech: Consultancy; Gilead Sciences: Consultancy; Kite: Consultancy; Mundipharma: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Bayer: Equity Ownership; Sanofi: Equity Ownership; GlaxoSmithKline: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Eusapharma/Jazz: Consultancy, Honoraria, Research Funding; Medac: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; SigmaTau: Consultancy, Honoraria, Research Funding. Bargou:Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Patents & Royalties: Patent for blinatumomab; University of Wuerzburg, Germany: Employment; GEMoaB GmbH: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Rambaldi:Roche: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Celgene: Research Funding; Pierre Fabre: Honoraria. Zhang:Amgen: Employment, Equity Ownership. Zimmerman:Amgen: Employment, Equity Ownership. Forman:Mustang: Research Funding; Amgen: Consultancy.

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Age-Related Clonal Hematopoiesis Is a Precursor for Adult Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood-2021-152807 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3477-3477

Author(s):

Caner Saygin ◽

Todd C. Knepper ◽

Alexandra E Rojek ◽

Peng Wang ◽

Jeremy Segal ◽

...

Keyword(s):

Older Adults ◽

Acute Lymphoblastic Leukemia ◽

Clinical Outcomes ◽

Research Funding ◽

Lymphoblastic Leukemia ◽

Hematopoietic Stem ◽

Tp53 Mutations ◽

Clonal Hematopoiesis ◽

Age Related ◽

Gene 32

Abstract Acute lymphoblastic leukemia (ALL) represents 20% of adult leukemias. Recent technologic advances have enabled detailed characterization of the genetic basis of leukemogenesis in ALL, including somatic structural DNA rearrangements and sequence mutations that disrupt lymphoid development, signaling, tumor suppression, and epigenetic modification. These studies also showed differences in the molecular profiles of pediatric vs adult ALL. However, adults with ALL, especially older adults (≥40 years), were underrepresented in these large series. Clinical outcomes of older adults with ALL are inferior to younger patients (<40 years) and the molecular basis for these differences is not completely understood. Hematopoietic stem cells accumulate DNA mutations with aging, and age-related clonal hematopoiesis (ARCH) has been linked to increased incidence of myeloid malignancies. The prevalence of ARCH increases logarithmically as the population ages, but its role in lymphoid leukemogenesis has not been fully established. We hypothesize that ARCH is a common precursor lesion for the development of ALL in older adults, and patients with ARCH-associated ALL have different clinical outcomes compared to patients whose disease do not harbor these mutations. We retrospectively studied adults with ALL treated at the University of Chicago and Moffitt Cancer Center between July 2014 and April 2021. Genetic profiling of tumor samples was performed by using Miseq Illumina next-generation sequencing (NGS) platform with a comprehensive sequencing panel covering commonly mutated myeloid and lymphoid genes. We classified pathogenicity using American College of Medical Genetics and Genomics guidelines. In total, 345 patients were studied: 286 (83%) had B-ALL, 49 (14%) had T-ALL and 10 (3%) had early T-precursor (ETP)-ALL. Overall, median age at diagnosis was 47 years (range, 18-88 years), and 211 (61%) were ≥40 years at diagnosis; 154 (45%) were women. Cytogenetic groups were as follows: 24% had Ph+ ALL, 13% had Ph-like ALL, and 3% had ALL with KMT2A rearrangement. The most frequent mutation in our adult ALL cohort was the loss of CDKN2A gene (32%), followed by mutations in TP53 (17%), IKZF1 (16%), NOTCH1 (9%), NRAS (9%), and JAK2 (6%) genes. Mutations involving the recurrently mutated genes in ARCH were seen in 110 of 345 patients (32%) with the following order of frequency: TP53 (17%), DNMT3A (5%), TET2 (4%), RUNX1 (3.5%), ASXL1 (3%), IDH1/2 (2%), BCORL1 (2%), EZH2 (1%), CUX1 (1%), and U2AF1 (1%) (Figure 1A). ARCH-associated mutations were more common in older adults (≥40 years) compared to young adults (41% vs 17%, p< 0.0001). Variant allelic frequencies (VAFs) for the ARCH-associated mutations were higher than the mutations involving signaling pathways, which suggests the ancestral nature of the former and secondary nature of the latter (Figure 1B). We further observed clonal dynamics in patients with serial diagnosis, remission and relapse samples available for sequencing. Founder ARCH clones re-emerged at the time of relapse (patient 92 and 100), and were also detectable at the time of complete remission with persistent measurable residual disease (patient 100) (Figure 1C). The overall survival (OS) for patients with ARCH-associated ALL was shorter than patients without ARCH, but the difference did not reach statistical significance (median OS, 39 months vs 84 months, p= 0.16) (Figure 1D). Our results indicate that ARCH is commonly identified as an ancestral event in older adults with ALL, with TP53 mutations being the most prevalent. Unlike patients with AML and TP53 mutations, patients with ALL and ARCH-associated mutations had comparable clinical outcomes to patients without ARCH. This may reflect the frequent use of antibody-based therapies (i.e. blinatumomab and inotuzumab) at diagnosis (on a clinical trial basis) or relapse in the two centers where these patients were treated. Collectively, these data suggest that ARCH may constitute a fertile soil for acute lymphoblastic leukemogenesis and further studies are warranted to interrogate the dynamic interplay between myeloid and lymphoid compartments of these patients. Figure 1 Figure 1. Disclosures Stock: Pfizer: Consultancy, Honoraria, Research Funding; amgen: Honoraria; agios: Honoraria; jazz: Honoraria; kura: Honoraria; kite: Honoraria; morphosys: Honoraria; servier: Honoraria; syndax: Consultancy, Honoraria; Pluristeem: Consultancy, Honoraria. Shah: BeiGene: Consultancy, Honoraria; Incyte: Research Funding; Acrotech/Spectrum: Honoraria; Novartis: Consultancy, Other: Expenses; Pfizer: Consultancy, Other: Expenses; Amgen: Consultancy; Servier Genetics: Other; Jazz Pharmaceuticals: Research Funding; Precision Biosciences: Consultancy; Pharmacyclics/Janssen: Honoraria, Other: Expenses; Kite, a Gilead Company: Consultancy, Honoraria, Other: Expenses, Research Funding; Adaptive Biotechnologies: Consultancy; Bristol-Myers Squibb/Celgene: Consultancy, Other: Expenses.

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Assessment of Romiplostim Immunogenicity in Adult Patients in Clinical Trials and in a Global Registry

Blood ◽

10.1182/blood-2018-99-113484 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2427-2427 ◽

Cited By ~ 1

Author(s):

Troy E. Barger ◽

Andy Boshier ◽

Vibha Jawa ◽

June Kim ◽

Daniel T. Mytych ◽

...

Keyword(s):

Clinical Trials ◽

Platelet Count ◽

Research Funding ◽

Phase 1 ◽

Adult Patients ◽

Employment Equity ◽

Lower Baseline ◽

Increased Risk ◽

Equity Ownership ◽

Global Registry

Abstract Background: Romiplostim (Nplate®) is a thrombopoietin (TPO) receptor agonist approved for the treatment of adult chronic immune thrombocytopenia (ITP). The formation of antibodies (Abs) against romiplostim may lead to a loss of response, and a theoretical risk exists that an immune response against romiplostim might lead to the formation of Abs that bind both romiplostim and native TPO. We therefore examined Abs against romiplostim and TPO in adult patients (pts) enrolled in clinical trials and in a global postmarketing registry based on spontaneously submitted requests for Ab testing. Methods: The clinical trial population included adult pts (age ≥18 years at screening) with ITP who received ≥1 dose of romiplostim in any of 13 completed romiplostim clinical trials, including phase 1 (n=1), phase 2 (n=3), phase 1/2 (n=1), phase 3 (n=5), and open-label extension (n=3) studies. Duration of romiplostim treatment varied among the trials. The postmarketing global registry population included romiplostim-treated adult pts with ITP who had blood samples sent for Ab testing. Serum samples from the clinical trials and the registry were assessed for romiplostim and TPO binding Abs in a surface plasmon resonance (SPR)-based immunoassay, and samples positive for binding were assessed for neutralizing activity in a cell-based bioassay, as previously described (Jawa et al. Ann Hematol 2010). Pt characteristics were summarized for those who did and did not develop Abs in the clinical trials. Pts in the registry found to have romiplostim neutralizing Abs were to be followed every 3 months for up to 12 months. No formal statistical analyses were conducted. Results: A total of 1046 romiplostim-treated pts from clinical trials were available for analysis. At baseline, 958 pts had romiplostim Ab results: 35 pts (3.7%) were positive for binding Abs and 1 pt (0.1%) was positive for neutralizing Abs. Post-baseline, 961 pts had romiplostim Ab results: 80 pts (8.3%) were positive for binding Abs and 4 pts (0.4%) were positive for neutralizing Abs, independent of the baseline result. Sixty (6.2%) pts negative for anti-drug Abs at baseline developed romiplostim binding Abs during the clinical trials. Characteristics of the pts who did and did not develop romiplostim binding Abs are presented in Table 1. Development of romiplostim binding Abs was more frequent in pts with ITP duration >3 years at baseline (70.0% vs 57.4%), prior splenectomy (48.3% vs 37.5%), and a history of allergies (21.7% vs 8.4%). Pts who developed Abs also had lower baseline TPO levels (84.8 pg/mL vs 104.6 pg/mL), lower baseline platelet counts (12.5× 109/L vs 20.5 × 109/L), and a higher number of previous ITP treatments (median 3 vs 2). Four of the 60 pts with romiplostim binding Abs developed romiplostim neutralizing Abs after treatment (0.38% of 1046 pts overall; Table 2). The emergence of neutralizing Abs did not appear to be related to romiplostim dose or platelet count. The neutralizing Abs were directed against the peptide component of romiplostim and did not bind native TPO. Pts in the clinical trials were also tested for TPO Abs. At baseline, 956 pts had TPO Ab results: 31 pts (3.2%) were positive for TPO binding Abs and 1 pt (0.1%) was positive for neutralizing Abs. Post-baseline, 960 pts had TPO Ab results: 33 pts (3.4%) were positive for TPO binding Abs and no pts were positive for neutralizing Abs. Of the 184 adult pts in the registry, 9 (4.9%) were positive for binding Abs: 5 were positive for romiplostim binding, 2 for TPO binding, and 2 for romiplostim and TPO binding. No predose Ab results were available for these pts. One pt received romiplostim for 11 months at a dose of 2 µg/kg and then experienced an abrupt fall in platelet count even as romiplostim dose was increased to 10 µg/kg. The pt tested positive for romiplostim binding and neutralizing Abs. Romiplostim was discontinued, and the pt was switched to alternative therapy. Conclusions: An analysis of pts in 13 clinical trials shows that pts with indicators of more severe disease (longer duration of ITP, prior splenectomy, and a higher number of previous ITP treatments) may be at increased risk of developing romiplostim binding Abs. Development of romiplostim neutralizing Abs was uncommon in the clinical trials, and these Abs did not bind native TPO. Data from a postmarketing registry showed that the overall risk of clinically significant immunogenicity following exposure to romiplostim is low. Disclosures Barger: Amgen Inc.: Employment, Equity Ownership. Boshier:Sanofi: Other: rents a room to a Sanofi employee; Amgen Inc.: Employment, Equity Ownership. Kim:Amgen Inc.: Employment, Equity Ownership. Mytych:Amgen Inc.: Employment, Equity Ownership. Park:Amgen Inc.: Employment, Equity Ownership. Kuter:Amgen Inc.: Consultancy; Argenx: Consultancy; Rigel: Consultancy, Research Funding; Dova Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Principia: Research Funding; Protalex: Research Funding; Pfizer: Consultancy; Bioverativ: Consultancy, Research Funding; ONO: Consultancy; Syntimmune: Consultancy; BMS: Research Funding.

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Mutations in Triple-Negative Patients with Myeloproliferative Neoplasms

Blood ◽

10.1182/blood-2019-128764 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5395-5395

Author(s):

Maria Carolina Costa Melo Svidnicki ◽

Paula De Melo Campos ◽

Moisés Alves Ferreira Filho ◽

Caio Augusto Leme Fujiura ◽

Tetsuichi Yoshizato ◽

...

Keyword(s):

Essential Thrombocythemia ◽

Triple Negative ◽

Myeloproliferative Neoplasms ◽

Biological Significance ◽

Primary Myelofibrosis ◽

Prognostic Impact ◽

Hematopoietic Stem ◽

Missense Variants ◽

Myeloid Neoplasms ◽

Equity Ownership

Background Myeloproliferative neoplasms (MPNs) are chronic hematopoietic stem cell disorders, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (MF). JAK2, MPL, and CALR mutations are considered as "driver mutations" and are directly implicated in the disease pathogenesis by activation of JAK/STAT signaling. However, some patients do not harbor any of these mutations. Since such triple-negative MPNs are very rare, no specific molecular markers were established to use for a precise differential diagnosis yet. So far, the introduction of next generation sequencing (NGS) technologies in research of myeloid neoplasms has provided valuable contributions on the identification of new molecular biomarkers, establishing more accurate risk rating and selection of more specific therapeutic interventions. This study aimed to identify, through targeted deep sequencing, specific genetic variants in patients with triple-negative MPNs. Methods We performed NGS targeted sequencing in 18 Brazilian triple-negative patients (11 MF and 7 ET). The median age at diagnosis was 64 years for primary myelofibrosis (range 42-78), and 52 years for essential thrombocythemia (range 19-79). In 14 cases, we used the Illumina TruSight Myeloid Panel covering 54 genes and in 4 cases we used a custom Sure Select Agilent panel containing more than 300 genes previously reported to be related to myeloid neoplasm. The inclusion criteria for variant filtering was quality score>30, read count>50, minor allele frequency<0.05, frameshift, nonsense, splice site and 5`UTR variants, and missense variants described as deleterious for at least three prediction softwares. Results Possible pathogenic mutations were identified in 33 genes by Illumina and/or Agilent panels. Frameshift/nonsense or missense variants previously described as pathogenic correspond to 11 variants (Table 1). Out of these, mutations in TET2 were the most frequently identified (in 9/18 (50%) of the cases). In three MF patients with TET2 mutations no other considered pathogenic mutation was identified, indicating a possible role of TET2 as a driver gene. According to previous reports, the frequency of TET2 mutations in triple-negative MPNs patients were only 7%. Phenotypically, in our triple-negative MPNs, 6/11 (54.5%) MF and 3/7 (42.9%) ET patients harbored TET2 mutations. Clinically, the adverse prognostic impact of TET2 mutations in MPN had not been consistently shown by previous studies. In addition, mutations in SF3B1, CEBPA, and KMT2A genes were the second most frequent ones detected in 2/18 each (11%) of the patients, some of which were concomitant with TET2 mutations, suggesting additional clonal advantage due to these genetic events. Other potentially pathogenic variants were also detected is genes that have been reported to be related to other myeloid neoplasms (KMT2A, CDKN2A, TERT, DIS3, ZFPM1, PCDHA8, SAMD9, SAMD9L, DCLRE1C,ERBB3, SDHA, PCDHA6, SVEP1, MAP2K1 and EP300). Conclusions We have characterized the genomic alterations in 18 Brazilian patients with MPN triple-negative for either JAK2, CALR or MPL main mutations. Using a sensitive NGS platform, we identified significantly more frequent mutations in TET2 gene (in as many as a half of the cases) compared to JAK2, MPL, CALR mutation-positive MPN cases. We also uncovered mutations in genes not previously related with in MPN. Our novel findings call for further studies validating the frequencies, biological significance, and prognostic impacts of somatic mutations in triple-negative MPNs. Disclosures Ogawa: Qiagen Corporation: Patents & Royalties; RegCell Corporation: Equity Ownership; Kan Research Laboratory, Inc.: Consultancy; Asahi Genomics: Equity Ownership; ChordiaTherapeutics, Inc.: Consultancy, Equity Ownership; Dainippon-Sumitomo Pharmaceutical, Inc.: Research Funding.

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Clinical Relevance of Clonal Hematopoiesis in the Oldest-Old Population: Analysis of the "Health and Anemia" Study

Blood ◽

10.1182/blood-2018-99-114717 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 750-750

Author(s):

Marianna Rossi ◽

Manja Meggendorfer ◽

Matteo Zampini ◽

Mauro Tettamanti ◽

Emma Riva ◽

...

Keyword(s):

Somatic Mutations ◽

Clonal Evolution ◽

Oldest Old ◽

Vascular Diseases ◽

Employment Equity ◽

Clonal Hematopoiesis ◽

Increased Risk ◽

Equity Ownership ◽

The Relationship

Abstract Background. Age-dependent clonal expansion of somatic mutations in the hematopoietic system is associated with an increased risk of hematological cancers (including myelodysplastic syndromes, MDS) and other illnesses (coronary heart disease and stroke). However, the presence of clonal hematopoiesis per se in a given individual has only limited predictive power. We hypothesized that the study of oldest-old population can define more specifically the relationship between mutations in the hematopoietic system and risk for MDS, inflammation and vascular diseases. Methods. We analyzed 1004 oldest-old subjects (median age 84.2y, range 80-105) included in the "Health and Anemia" population-based study [Haematologica 2010;95:1849]. Using peripheral blood DNA, we looked for somatic mutations in 47 genes recurrently mutated in hematologic cancers. Results. Clonal mutations were observed in 32.8% of individuals (range 1-5). The majority of variants occurred in 3 genes: DNMT3A (36.4%), TET2 (24.3%) and ASXL1 (6.5%). Mutations in splicing genes, PPM1D and TP53 were found in 7.4%, 5% and 2% of cases, respectively. The mutation frequencies increased with age, up to 50% in individuals aged over 90 years (P=.011). Clonal hematopoiesis was associated with a lower 5-y probability of survival (P=.03), and prognosis was even poorer in patients carrying ≥2 mutations (P=.002) We first focused on the relationship between clonal hematopoiesis and MDS phenotype. Carrying a somatic mutation with a variant allele frequency (VAF) ≥.10, carrying ≥2 mutations, spliceosome gene mutations and co-mutation patterns involving TET2, DNMT3A had a positive predictive value for MDS (from .85 to 1.0). The most frequent early phenotypic changes in patients who developed MDS included an increasing red blood cell distribution width (RDW) and mean corpuscular volume (MCV). Preliminary analyses suggested that the combination of mutations and non-mutational factors (RDW, MCV, after excluding iron/vitamin depletion and thalassemia) may improve the capability to capture individual risk of developing MDS with respect to molecular data alone (P=.01) We studied clonal evolution in 72 patients with multiple samples available over a period of 5y. Clonal hematopoiesis was found at baseline in 22 cases: 2 individuals acquired additional mutations during follow-up, and 5 displayed significant increase in VAF. In 9 subjects without clonal hematopoiesis, mutations were acquired during follow-up. RDW and MCV changes, induction of unexplained cytopenia and overt MDS phenotype were significantly restricted to subjects displaying clonal evolution. We hypothesized that in oldest-old populations MDS could be underdiagnosed (many patients are not considered for bone marrow aspiration because of age). Cytopenia was a common finding in our cohort (20%) the underlying cause remaining unexplained in 27% of cases. In patients with unexplained anemia, carrying a somatic mutation had a positive predictive value for persistent, progressive, multilineage cytopenia (findings consistent with a MDS phenotype) and shorter survival (from .8 to .94). On this basis, 8% of all cytopenias might be undiagnosed MDS. Finally, we investigated the association between clonal hematopoiesis with inflammatory and vascular diseases. Mutations in DNMT3A, TET2, and ASXL1 were each individually associated with risk of coronary heart disease and death, and preliminary analyses suggest that clonal hematopoiesis is also associated with increased risk of rheumatological diseases (P from .03 to.009). We identified mutations in macrophages isolated from synovial fluid of 4/17 patients with rheumatoid arthritis and from atherosclerotic plaques of 3/25 patients with carotid stenosis. Functional studies of macrophages (expression of specific chemokine and cytokine gene patterns) are ongoing. All these findings are under validation in an independent cohort of 800 subjects enrolled in the "Monzino 80-plus" study [Alzheimers Dement 2015;11:258]]. Conclusion. Clonal hematopoiesis was associated with reduced survival in an oldest-old population. Specific mutational profiles define different risks of developing MDS and inflammatory/vascular diseases. Non mutational factors, such as early changes in red blood cell indices, may improve the capability to identify patients at increased risk of developing myeloid cancers. Disclosures Meggendorfer: MLL Munich Leukemia Laboratory: Employment. Bolli:Celgene: Honoraria. Vassiliou:KYMAB: Consultancy, Equity Ownership; Celgene: Research Funding. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

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Financial Burden of Myeloproliferative Neoplasms on Patients: Results from the MPN Landmark Survey in the United States

Blood ◽

10.1182/blood.v126.23.5561.5561 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5561-5561 ◽

Cited By ~ 1

Author(s):

Shreekant V. Parasuraman ◽

Ahmad B. Naim ◽

Dilan C. Paranagama ◽

Maureen Thyne ◽

Sara Goldberger ◽

...

Keyword(s):

Health Insurance ◽

Household Income ◽

Research Funding ◽

Myeloproliferative Neoplasms ◽

Financial Burden ◽

Work Hours ◽

Annual Household Income ◽

Employment Equity ◽

Equity Ownership ◽

The Mean

Abstract Background: Myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) are chronic myeloproliferative neoplasms (MPNs). Patients across all 3 MPNs experience marked disease burden in terms of symptoms and negative effects on quality of life (QoL), productivity, and activities of daily living (ADL). To improve the lives and health of patients with MPNs, it is also important to have a current understanding of these burdens from a financial standpoint. This analysis of MPN Landmark survey data examined the financial burden of patients who reported that their MPN affected their employment (ie, reduced work hours, discontinued employment, or went on medical disability) or experienced no such effects on their employment. Methods: Patients diagnosed with MF, PV, or ET were recruited to participate in a real-world retrospective study (MPN Landmark survey) in the US (fielded May - July 2014). Only respondents who were diagnosed before 2013 and were 16 to 65 years of age at the time of diagnosis were eligible for this analysis. Participants were asked if their MPN had an impact in terms of reduced work hours, discontinued employment, medical disability, or no impact; the first 3 categories were not mutually exclusive. Participants provided information on their annual household income in 2013 before taxes by selecting from the following categories: ≤$15,000, $15,001-$25,000, $25,001-$35,000, $35,001-$50,000, $50,001-$75,000, $75,001-$100,000, and >$100,000. The mid value of each range was used to calculate mean income levels within each subgroup evaluated. Results: A total of 813 patients completed the web-based Landmark survey and 369 eligible patients were included in this analysis (MF, 85; PV, 172; ET, 112). Median age among patients with ET was slightly lower than among patients with MF and PV at time of MPN diagnosis (ET, 48 years; MF, 56 years; PV, 53 years). The majority of respondents were women (MF, 62%; PV, 52%; ET, 75%). Almost all patients (99%) had health insurance, primarily group commercial insurance through an employer (MF, 46%; PV, 53%; ET, 57%) and Medicare (MF, 40%; PV, 34%; ET, 24%). Most patients had at least some college education (ie, some college, 4-year degree, or postgraduate degree): MF, 86%; PV, 90%; ET, 88%. The mean 2013 household income of patients with MF, PV, and ET were similar to each other ($79,800, $80,200, and $80,400, respectively) and slightly higher than the total 2013 US mean household income of $75,839. A notable proportion of patients in each MPN group reported that their disease led to reduced work hours, discontinued employment, and medical disability: MF, 38%, 35%, and 33%, respectively; PV, 33%, 28%, and 15%; ET, 28%, 21%, and 4%. Patient demographics, such as age and health insurance status, were similar among patients who reported MPN-associated effects on employment and patients who did not within each MPN. In each MPN group, the mean percentage household income loss in patients with reduced work hours, discontinued employment, and medical disability were: MF, 16%, 18%, and 28%, respectively; PV, 15%, 24%, and 17%; and ET, 0%, 24%, and 37%, compared with patients who did not experience any effects of their MPN on employment (Figure 1). Discontinued employment and medical disability tended to have a greater impact compared with reduced work hours across MPNs. Conclusion: Patients withMPNs may experience a considerable negative impact on their employment status, which in turn may be associated with reduced annual household income. Therefore, across all MPNs, forestalling or reversing discrete aspects of the diseases that negatively impact individual productivity is an important factor in the management of these chronic neoplasms. Disclosures Parasuraman: Incyte Corporation: Employment, Equity Ownership. Naim:Incyte Corporation: Employment, Equity Ownership. Paranagama:Incyte Corporation: Employment, Equity Ownership. Thyne:Incyte Corporation: Speakers Bureau. Mascarenhas:Incyte Corporation: Research Funding; Novartis Pharmaceuticals Corporation: Research Funding; Promedior: Research Funding; Roche: Research Funding; CTI Biopharma: Research Funding; Kalobios: Research Funding. Mangan:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Fazal:Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Ariad: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Miller:Incyte Corporation: Honoraria, Research Funding. Mesa:Promedior: Research Funding; Gilead: Research Funding; Incyte Corporation: Research Funding; NS Pharma: Research Funding; CTI Biopharma: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Genentech: Research Funding; Pfizer: Research Funding.

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Hematopoietic Stem Cells Develop in the Absence of Endothelial Cadherin 5 Expression

Blood ◽

10.1182/blood.v126.23.1165.1165 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1165-1165

Author(s):

Heidi Anderson ◽

Taylor Patch ◽

Pavan Reddy ◽

Elliott Hagedorn ◽

Owen J. Tamplin ◽

...

Keyword(s):

Stem Cells ◽

Endothelial Cells ◽

Hematopoietic Stem Cells ◽

Board Of Directors ◽

Research Funding ◽

Hemogenic Endothelium ◽

Employment Equity ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Equity Ownership

Abstract Rare endothelial cells in the aorta-gonad-mesonephros (AGM) transition into hematopoietic stem cells (HSCs) during embryonic development. Lineage tracing experiments indicate that HSCs emerge from Cadherin 5 (Cdh5, VE-cadherin)+ endothelial precursors, and isolated populations of Cdh5+ cells from mouse embryos and embryonic stem (ES) cells can be differentiated into hematopoietic cells. Cdh5 has also been widely implicated as a marker of AGM-derived hemogenic endothelial cells. Since Cdh5-/- mice embryos die before the first HSCs emerge, it is unknown if Cdh5 has a direct role in HSC emergence. Our previous genetic screen yielded malbec (mlbbw306), a zebrafish mutant for cdh5, with normal embryonic and definitive blood. Utilizing time-lapse imaging, parabiotic surgical pairing of zebrafish embryos, and blastula transplantation assays, we show that HSCs emerge, migrate, engraft, and differentiate in the absence of cdh5 expression. By tracing Cdh5-/- GFP+/+ cells inchimeric mice, we demonstrated that Cdh5-/- GFP+/+ HSCs emerging from E10.5 and E11.5 AGM or derived from E13.5 fetal liver not only differentiate into hematopoietic colonies but also engraft and reconstitute multi-lineage adult blood. These data establish that Cdh5, a marker of hemogenic endothelium in the AGM, is dispensable for the transition of hemogenic endothelium to HSCs. Disclosures Bauer: Biogen: Research Funding; Editas Medicine: Consultancy. Zon:FATE Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: Founder; Scholar Rock: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: Founder. Orkin:Editas Medicine: Membership on an entity's Board of Directors or advisory committees; Biogen: Research Funding; Pfizer: Research Funding; Sangamo Biosciences: Consultancy.

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