Management of Myeloproliferative Neoplasms during Pregnancy: A Systematic Review

Abstract Introduction: Myeloproliferative neoplasms (MPN) include essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF). Pregnancy in the presence of MPN increases the risk of thrombosis, hemorrhagic events, pre-eclampsia, progression to myelofibrosis (MF) or acute myeloid leukemia (AML) leading to poor fetal outcome. Methods: We conducted a literature search on PubMed, Embase, Web of Science, and Clinicaltrials.gov using MeSH terms and key words for MPN, PV, and ET from date of inception to January 2021. We excluded studies reporting less than 10 patients and those not in English language. Results: ET studies: How et al. (121 pregnancy (P)/52 women (W)) reported Aspirin (ASA) was protective and was used in 51.2% P (n=62/107) with OR (odd's ratio) of 0.304 (p=0.048; 90% CI 0.102-0.795). Similar benefit of ASA was also reported by Gangat e t al.(2009) (63P/36W ; P loss 21% in 24 patients receiving ASA vs 75% in 12 patients not receiving ASA), Niittyvuopio et al. (40P/16W; live births (LB) in all 13 P treated with ASA or ASA with prior cytoreduction therapy vs 67% complications and 56% loss of P in patients not treated with ASA), Randi et al. (1999) (16P/13W; 7/13 LB occurred on ASA, and only one P was lost on ASA), Bangerter et al.( 17P/9W; 100% P treated with ASA resulted in LB vs 45% LB in P without any treatment, p=0.04), and Pagliaro et al. (15P/9W; ASA monotherapy (n=3/15P) or ASA+ subcutaneous heparin (n=7/15P) resulted in nine LB). Cincotta e t al. (30P/12W) reported 79% LB with ASA or IFN-α vs 38% LB without any treatment (p=0.06). Among the treatment cohort, 5/7 patients on ASA had a LB, and all 4/4 patients on IFN-α had a LB. However, Beressi et al. (31P/18W) reported 4/8 untreated and 10/19 ASA treated P were lost with no statistically significant benefit. Palandri et al. reported 24P/13W treated with IFN-α (n=1), IFN-α + ASA (n=2) and ASA alone (n=9). The LB rate was not influenced significantly with treatment at conception (treated vs. untreated: 8/12 vs. 7/12, P=0.99). Melillo e t al. (122P/92W) reported no benefit with ASA. IFN-α had positive outcomes with 95% LB than patients not receiving IFN-α with 71.6% LB (OR 0.10 (95%CI: 0.013-0.846, p=0.034)). JAK2 mutation was associated with poorer outcomes (OR 6.19; 95%CI: 1.17-32.61; p=0.038). Wright et al. (43P/20W) reported no statistically significant difference between no treatment (n=16/43), ASA alone (n=24/43), ASA+cytoreduction (n=2/43), and low molecular weight heparin (LMWH) (n=1/43) groups. Passamonti et al.( 96P/58W ) reported statistically significant worse outcomes in JAK2 negative patients, no statistically significant benefit in JAK2 positive patients (p=0.05) with ASA and higher complications with conception while on cytoreduction therapy (n=6/13 abortion, n=3/13 pre-eclampsia). ET + Other MPN studies: Gangat et al. (2020) reported (152W ET and 36W PV) that in 95P/55W with ET, 60% pregnancy loss occurred without ASA vs 27% with ASA (p=0.02). All 4/36W with PV who were treated with one or more of ASA, enoxaparin, and hydroxyurea delivered LB, and 50% developed venous thromboembolism. Sokolowska et al. reported 104P/60W with MPN (47 ET, 3 PV, and 10 PMF) treated with various combinations of cytoreduction therapy (IFN-α in 48P, apheresis in 1P and anticoagulation (LMWH+ASA in 10, LMWH alone in 19 and ASA alone in 24P) during the pregnancy with 72.1% LB. Lapoirie et al. stratified 27P/14W (ET 19P/9W, PV 8P/5W) with MPN into high risk (67%) and standard risk and found significant P loss in all high-risk P that did not receive ASA (n=2). Maternal complications occurred in 3 high-risk P that received ASA. 77% of P treated with ASA, LMWH, or both resulted in a LB. Alimam et al. (58W; ET 47, PV 5, PMF 5, MPN-unclassified 1) reported better than predicted outcomes in 88% of women receiving ASA during P, 38% receiving ASA + prophylactic LMWH and 3% receiving ASA + therapeutic LMWH resulting in 58 LB with a P loss rate of 1.7/100 (95% CI; 0.04-9.24). PV studies: Irene et al. (24P/15W) reported a 40% incidence of P loss without antithrombotic therapy vs 10.5 % P loss receiving ASA, LMWH, or both. Willie e t al. divided 32P/14W with PV into two groups (treatment group: 18 P, treated with ASA during P and LMWH for six weeks postpartum; non-treatment group: 14 P) with 72% vs 14% LB respectively. Conclusion: Use of ASA, LMWH and cytoreductive therapy is the existing practice for pregnancies with MPN. However, proper evidence via a RCT is an unmet need. Figure 1 Figure 1. Disclosures Anwer: Janssen pharmaceutical: Honoraria, Research Funding; BMS / Celgene: Honoraria, Research Funding; Allogene Therapeutics: Research Funding; GlaxoSmithKline: Research Funding.

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Cytogenetic Characteristics and Outcomes of Patients Receiving CTL019 CAR T Cell Therapy

Blood ◽

10.1182/blood-2019-130060 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1464-1464 ◽

Cited By ~ 2

Author(s):

Allison Barz Leahy ◽

Kaitlin J. Stanley ◽

Regina M. Myers ◽

Amanda M. DiNofia ◽

Lisa Wray ◽

...

Keyword(s):

T Cell ◽

High Risk ◽

Research Funding ◽

Risk Category ◽

Intermediate Risk ◽

Car T Cell ◽

Advisory Boards ◽

Significant Difference ◽

Car T ◽

Scientific Advisory

Background: CTL019 is a therapy derived from autologous T cells expressing a CD19-specific chimeric antigen receptor (CAR) that was approved by the FDA in August 2017 (tisagenlecleucel). Complete and durable remissions have been seen in the setting of pediatric and young adult patients with relapsed and refractory B cell acute lymphoblastic leukemia (ALL) (Maude NEJM 2018). Initial case reports suggested that there may be differential outcomes mediated by cytogenetic characteristics of the leukemia at CAR T cell infusion. Here, we report results from a single institution experience of 112 patients. Methods: Patients with relapsed/refractory ALL were identified as having received CTL019 either in the context of a clinical trial (NCT02906371) or commercial product (tisagenlecleucel) at Children's Hospital of Philadelphia from October 2016 to April 2019. Patients who received prior CAR T therapy were excluded. Demographic, cytogenetic, and outcome data were manually abstracted from the medical record or clinical trial datasets. High risk lesions were defined as MLL(KMT2A) rearrangements, Philadelphia-chromosome (Ph+), Ph-like, hypodiploidy, and TCF3/HLF fusion. Favorable cytogenetics were defined as the presence of hyperdiploidy or ETV6/RUNX1fusion and intermediate were defined as iAMP21, IKZF1deletion, or TCF3/PBX1. Patients were classified according to their highest risk cytogenetic characteristic and stratified by cytogenetic risk category present at CAR T cell infusion. Relapse-free survival (RFS) and overall survival (OS) was described for cohorts with more than 10 patients. Results: One hundred and twelve patients were included in the analysis, with a median age of 11 years (range 1-29) at infusion, of which 32% had had a previous allogeneic hematopoietic stem cell transplant (alloHSCT). Disease burden at the time of CTL019 infusion was heterogenous, with 61% having detectable disease in the bone marrow and 21% having more than 25% blasts by flow cytometry. Thirty-six patients (32%) had leukemias with high-risk genetic lesions at infusion, including 12 with MLL rearrangements and 18 with Ph+ or Ph-like lesions (Table 2). Thirty-one patients (28%) had hyperdiploidy or ETV6/RUNX1; 3 additional were in conjunction with high-risk cytogenetics (t(17;19) and 2 with Ph+), and 3 in the setting of intermediate-risk cytogenetics (iAmp21, TCF3/PBX1, IKZF1deletion). Figure 1 demonstrates RFS for those patients in remission at day 28 following infusion, stratified by cytogenetic risk category. Complete remission (CR) rate in the high-risk cytogenetics group was 94%. RFS at 12 months was 69% (0.50-0.82), 69% (0.40-0.86), and 67% (0.48-0.80) for non-informative, favorable, and high-risk cytogenetic groups, respectively. Figure 2 shows OS of patients infused with CTL019, again stratified by cytogenetic categories of interest, with a maximum follow-up time of 30 months. OS at 12 months was 84% (0.68-0.93) and 76% (0.56-0.88) for the non-informative and high-risk cytogenetic groups, respectively. There were no deaths in that time period for the favorable risk category. There was no statistically significant difference in RFS or OS for patients with high-risk cytogenetics. The intermediate-risk cytogenetics group (n<10) was excluded from these analyses. Conclusion: Durable remissions can be achieved with CTL019 across several high-risk cytogenetic subtypes of B-ALL. Stratifying outcomes by cytogenetic risk category in this unadjusted analysis does not show a statistically significant difference in either RFS nor OS. Further investigation is needed to parse out the contribution of individual cytogenetic lesions as well as the effects of other relapse and survival risk factors at play. Figure Disclosures Rheingold: Novartis: Consultancy; Pfizer: Research Funding. Callahan:Novartis: Consultancy. Hunger:Bristol Myers Squibb: Consultancy; Amgen: Consultancy, Equity Ownership; Jazz: Honoraria; Novartis: Consultancy. Grupp:Novartis: Consultancy, Research Funding; Roche: Consultancy; GSK: Consultancy; Cure Genetics: Consultancy; Humanigen: Consultancy; CBMG: Consultancy; Novartis: Research Funding; Kite: Research Funding; Servier: Research Funding; Jazz: Other: study steering committees or scientific advisory boards; Adaptimmune: Other: study steering committees or scientific advisory boards. Maude:Kite: Consultancy; Novartis: Consultancy.

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Alemtuzumab Plus Oral Dexamethasone, Followed by Alemtuzumab Maintenance or Allogeneic Transplantation in Ultra High-Risk CLL: Interim Analysis of a Phase II Study of the GCLLSG and fcgcll/MW

Blood ◽

10.1182/blood.v118.21.2854.2854 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2854-2854 ◽

Cited By ~ 2

Author(s):

Stephan Stilgenbauer ◽

Florence Cymbalista ◽

Véronique Leblond ◽

Alain Delmer ◽

Dirk Winkler ◽

...

Keyword(s):

High Risk ◽

Research Funding ◽

Response Rates ◽

Long Term Results ◽

High Dose ◽

Significant Difference ◽

Ultra High Risk ◽

Grade 3 ◽

The Impact

Abstract Abstract 2854 Alemtuzumab (A) proved to be efficacious in CLL patients (pts) with very poor prognosis, either due to fludarabine (F) refractoriness or due to unfavorable cytogenetics (17p-). However, rate and duration of remissions still remain unsatisfactory. Therefore, the French and German CLL study groups jointly embarked on this trial, trying to achieve higher overall response rates (ORR) by adding high-dose dexamethasone (D) to A and, simultaneously, investigating the consolidation effect of prolonged A maintenance or allogeneic stem-cell transplantation (allo-SCT), respectively. Induction treatment consisted of subcutaneous A 30 mg weekly × 3 for 28 days, combined with oral D 40 mg on days 1–4 and 15–18, and prophylactic pegfilgrastim 6 mg on days 1 and 15. Depending on the remission status, pts were treated for up to 12 weeks. If CR was documented at 4 or 8 weeks, or at least SD was achieved at 12 weeks, consolidation was scheduled with either allo-SCT or A maintenance with 30 mg every 14 days for up to 2 years (y), at the discretion of pt and physician. Between January 2008 and July 2011, 124 pts were recruited at 26 centers, 120 of whom were eligible. Pts were generally subdivided into three cohorts: 55 pts were refractory (i.e. no response or relapse within 6 months) to regimens containing F or a similar drug (i.e. pentostatin, cladribine, bendamustine). Non-refractory pts all exhibited 17p- and had either untreated (n=39) or relapsed CLL (n = 26) requiring therapy. The median age was high with 66/64/66 y in 17p- 1st line, 17p- relapse, and F-refractory pts, respectively. The three cohorts had 46/54/75% Binet C disease, 41/35/27% B symptoms, 38/42/53% reduced performance status (ECOG 1/2), median thymidine kinase levels of 35/49/24 U/L, median ß2MG levels of 3.8/5.5/4.6 mg/L, and IGHV was unmutated in 89/96/87%. In the F-refractory group, 53% exhibited 17p deletion and 22% had 11q deletion. Pretreated patients had received a median of 3 (F-refractory) or 2 prior lines (17p- relapse). 5 pts had previously undergone autologous and 1 pt allo-SCT. Treatment and efficacy data are currently available for 87 pts who completed induction therapy :17p- 1st-line (n=30), 17p- relapse (n=17), and F-refractory (n=40). Of these, 80/53/55% received the full induction of 12 weeks. ORR (best observed status) was generally high with 97/76/70%. CR was achieved in 20/0/5%. After a median follow-up of 11.8 months (mo), median progression-free survival (PFS) was 16.9/10.4/8.4 mo. Deaths are recorded in 13/27/36% of pts, with median overall survival (OS) not yet reached (>24 mo) in the 17p- 1st line group, and 15/12 mo in 17p- relapse/F-refractory pts. Consolidation treatment was performed as maintenance A (median duration 32 weeks, range 2 – 89) in 34%, and allo-SCT in 30%, with a median age of 66 and 61 y in these subgroups. The main reasons for going off-study without consolidation were death due to infection (14%, n=11, of these 6 without response, and 10 in the F-refractory cohort), CLL progression (12%), and other toxicity (5%). Among the 28 pts not receiving consolidation, there were 19 (68%) deaths, 15 of them in the F-refractory cohort. When comparing A maintenance and allo-SCT for consolidation, there were 9 (35%) and 7 (30%) PD events, respectively and there was so far no significant difference in PFS (median 17 mo in both groups) or OS. During induction, grade 3/4 hematotoxicity consisted of anemia in 28%, neutropenia in 47%, and thrombopenia in 44%. Grade 3/4 non-CMV infection occurred in 29% of 17p- 1st-line, 15% of 17p- relapsed, and 56% of F-refractory pts. CMV reactivation was observed in 54/25/40%, without severe sequelae recorded. During A maintenance, grade 3/4 toxicity consisted of neutropenia in 39% pts and thrombopenia in 4% pts with 6 SAEs (ITP, diarrhea, infection, erythema, tachycardia, and thrombosis). Conclusions: The combination of A and D shows high response rates in ultra high-risk CLL, with promising preliminary findings for PFS and OS, despite the high median age of the pts. The results compare favorably to ORR/CR of 68%/5%, and median PFS of 11.3 mo in the 17p- subgroup of the CLL8 study treated with FCR, consisting of younger pts (median 61 y). In F-refractory CLL however, when compared to the preceding CLL2H study with single agent A, the improved initial response by adding dexamethasone does not seem to translate into improved long-term results. More mature follow-up is needed, especially with respect to the impact of allo-SCT. Disclosures: Stilgenbauer: Amgen: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding. Off Label Use: Alemtuzumab in 1st line CLL treatment. Cymbalista:Roche (d) Mundipharma (e) Genzyme (e): Honoraria, Research Funding. Hinke:WiSP (CRO): Employment.

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Impact of Molecular Mutations on Treatment Response to Hypomethylating Agents in MDS

Blood ◽

10.1182/blood.v118.21.461.461 ◽

2011 ◽

Vol 118 (21) ◽

pp. 461-461 ◽

Cited By ~ 5

Author(s):

Fabiola Traina ◽

Anna M Jankowska ◽

Valeria Visconte ◽

Yuka Sugimoto ◽

Hadrian Szpurka ◽

...

Keyword(s):

Treatment Response ◽

Predictive Value ◽

Research Funding ◽

Myeloproliferative Neoplasms ◽

Progression Free Survival ◽

Predictive Biomarker ◽

Median Number ◽

Categorical Variables ◽

Hypomethylating Agents ◽

Significant Difference

Abstract Abstract 461 Aberrant DNA methylation is a hallmark of myelodysplastic syndromes (MDS), MDS/myeloproliferative neoplasms (MDS/MPN) and secondary acute myeloid leukemia (sAML). It provides a rationale for treating these malignancies with hypomethylating agents like 5-azacitidine (AZA) and decitabine (DAC). However, treatment outcomes remain limited and heavily weighed on morphologic/cytogenetic results. The discovery of novel mutations has provided important insight into the pathogenesis of MDS and related disorders. Genes implicated in epigenetic regulation, including DNMT3A, TET2, IDH1/IDH2, EZH2, ASXL1 and UTX have been found mutated in MDS, while others have also been implicated in MDS pathogenesis. There is limited data on the predictive value of these genetic defects for treatment response and disease outcome. We hypothesized that these defects are important biomarkers predictive of response to hypomethylating agents. We studied 88 patients with MDS (RCUD=2, RARS=6, RCMD=11, MDS-U=3, RAEB-1/2=29, CMML1/2=16, MDS/MPN-U=5, RARS-T=5, AML from MDS=11) who received hypomethylating agents (AZA=53, DAC=24, both=11). The median number of cycles was 7 [range 1–35], median age was 69 years (range 42–82) and median follow-up was 18 months (range 0–76). Responses were scored according to IWG criteria. DNMT3A, TET2, IDH1/2, EZH2, ASXL1, UTX, KRAS, NRAS, CBL, RUNX1, TP53 and SF3B1 were sequenced using standard techniques. Categorical variables were analyzed using Chi-square statistics. Overall survival (OS) was analyzed using Kaplan-Meier; p-values ≤ 0.05 were considered statistically significant. Mutated patients were older than wild type (WT) cases (72 vs. 68 years, p=.01) but were well matched for marrow blast %, cytogenetic risk group and cycles of hypomethylating agents received. We found mutations in 40/88 (45%) patients. Mutations were most frequent in SF3B1 (6/11; 55%), ASXL1 (13/50; 26%), TET2 (18/88; 20%), KRAS (3/34; 9%), and DNMT3A (7/88; 8%). Less common were mutations in EZH2 (2/43; 5%), TP53 (1/23; 4%), IDH1 (4/88; 5%), IDH2 (3/88; 3%), and UTX (1/36;3%). No mutations were found in CBL, NRAS or RUNX1. Based on single mutations, overall response rate (ORR) was higher in mutated vs WT patients for DNMT3A (6/7 [86%] vs 33/81 [41%]; p=.02), ASXL1 (11/13 [85%] vs 14/37 [38%]; p=.003), and TET2 (12/18 [67%] vs. 27/70 [39%]; p=.03). All heterozygous DNMT3A mutants responded to hypomethylating agents. Differences remained significant when stratified to AZA treatment alone for DNMT3A (6/7 [86%] vs 21/56 [38%]; p=.01) and ASXL1 (9/11 [82%] vs 12/29 [41%]; p=.02) but not TET2 (6/10 [60%] vs 21/53 [40%]; p=0.22). The predictive value of combined mutations were analyzed for DNMT3A, TET2 and/or IDH1/2, showing better response to hypomethylating therapy in patients who had a mutation; ORR (mutated: 18/28 (64%) vs WT: 21/60 (35%); p=.01). This difference remained significant in patients receiving only AZA (n=53); ORR was 11/18 (61%) in mutant and 11/35 (31%) in WT patients (p=.03). No differences in ORR were noted for KRAS, EZH2 and IDH1/2 mutant and WT patients. No SF3B1 mutants responded to treatment while both patients with UTX and TP53 mutations responded. The frequency of AML evolution was also analyzed and showed no difference between mutant and WT cases for TET2 (7/18 [39%] vs 22/70 [31%];p=.52), ASXL1 (4/10 [40%] vs 11/35 [31%]; p=.61), and DNMT3A (3/7 [43%] vs 26/81 [32%];p=.56). No differences in OS and progression free survival (PFS) were noted between responders and non-responders to hypomethylating therapy (28 vs 17 mos, p=.25; 16 vs 8 mos, p=.54). Comparison of survival outcomes for mutant and WT patients showed no significant difference for DNMT3A (OS: 30 vs 21 mos, p=0.43; PFS: 20 vs 11, p=.53), ASXL1 (OS: 28 vs 22, p=.68; PFS: 16 vs 10, p=.88), and TET2 (OS: 30 vs 20 mos, p=.30). PFS was better in TET2 mutants compared to WT (19 vs 9, p=.03). No survival differences were noted between mutant and WT cases who responded to hypomethylating agents for DNMT3A (OS: 25 vs 28,p=.84; PFS: 14 vs 16, p=.78), ASXL1 (OS: 10 vs 18, p=.48; PFS: 10 vs 6, p=.76) TET2 (OS: 27 vs 16, p=.79; PFS: 18 vs10, p=.19). In conclusion, DNMT3A, ASXL1 and TET2 mutations were independently associated with a better response to hypomethylating drugs. Moreover, combined mutations in DNMT3A/TET2/IDH1/IDH2 may influence the response to hypomethylating agents, especially AZA supporting its role as a predictive biomarker in MDS treatment. Disclosures: Maciejewski: Celgene and Eisai, NIH, AA&MDS Foundation: Research Funding. Tiu:MDS Foundation Young Investigator Award: Research Funding.

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Activity and Tolerability of Azacitidine in Patients Who Relapse after Allogeneic Stem Cell Transplantation (allo-SCT) for Acute Myeloid Leukemia (AML) and Myelodysplasia (MDS): a Survey from the European Society for Blood and Marrow Transplantation (EBMT

Blood ◽

10.1182/blood.v124.21.2506.2506 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2506-2506 ◽

Cited By ~ 1

Author(s):

Charles Craddock ◽

Myriam Labopin ◽

Mohamed Houhou ◽

Marie Robin ◽

Juergen Finke ◽

...

Keyword(s):

High Risk ◽

Research Funding ◽

Survival Rates ◽

Conditioning Regimen ◽

Multivariable Analysis ◽

Unrelated Donor ◽

Disease Relapse ◽

Post Transplant ◽

Significant Difference ◽

Grade 3

Abstract Disease relapse is the most common cause of treatment failure after allo-SCT for high risk AML and MDS. Treatment options for patients with recurrent disease are extremely limited and re-induction chemotherapy, when administered, is often either poorly tolerated or ineffective. Azacitidine (AZA) is a DNMT inhibitor which is well tolerated and clinically active in high risk AML/MDS. Of interest AZA also up-regulates the expression of tumor antigens and plausibly augments a graft-versus-leukemia effect. A number of small studies have suggested clinical activity of AZA in patients who relapse after an allograft for AML/MDS but both overall response rate and predictors of response remain unknown. We report the first systematic study of the activity and tolerability of AZA in patients who relapsed after allo-SCT for AML/MDS. 204 patients who relapsed at a median of 6.5 months (range, 1-49) after an allograft for AML (n=130) or MDS (n=74) were studied. The median age was 58 years (range 22-76). 89 patients were transplanted using a matched sibling donor and 115 from an adult unrelated donor. 47 patients received a myeloablative and 157 a reduced intensity conditioning regimen. AZA was administered for 5-7 consecutive days every month. The median duration of AZA treatment was 68 days (inter-quartile range 24-154 days). 66 patients received additional donor lymphocyte infusions (DLI) at a median of 43 days after commencement of AZA. AZA was well tolerated in the majority of patients. 57 patients developed Grade 3-4 non-hematological toxicities 47 of which were infectious complications and likely also attributable to relapsed disease. 4 patients developed Grade 3-4 acute GVHD after AZA treatment. 45 (22%) patients achieved a complete remission (CR) or partial remission after AZA administration at a median of 114 days after commencement of treatment. 31 (15%) patients achieved a CR. The median number of courses of AZA to achieve a clinical response was three. In multivariable analysis the only significant factor determining improved response to AZA was relapse occurring more than 12 months post-transplant. The median overall survival (OS) for all patients was 6 months after the commencement of AZA therapy. In patients who achieved a CR the 2 year OS after commencement of AZA was 38.5% versus 11% for the whole population (p= 0.001). In multivariable analysis OS was determined by the occurrence of disease relapse more than 6 months post-transplant and achievement of a CR after AZA therapy. Of note, there was no significant difference in response rates to AZA between patients with relapsed AML or MDS. Concurrent administration of DLI did not improve either response or survival rates. In conclusion, these data confirm the ability of AZA to salvage a proportion of patients with AML or MDS who relapse after an allogeneic SCT and identify prognostic factors of response. The response and survival rates achieved with salvage AZA are comparable to those previously reported with either intensive chemotherapy or DLI. We conclude AZA represents an important and relatively well-tolerated new treatment option in the management of selected patients with AML and MDS who relapse after allo-SCT. Disclosures Craddock: Celgene: Grants Other, Honoraria. Kroger:Celgene: Research Funding. Mohty:Celgene: Research Funding.

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MyPRSR Molecular Subtypes of Multiple Myeloma Represent All High-Risk FISH Translocations Included in the mSMART 2.0 and R-ISS Guidelines

Blood ◽

10.1182/blood.v128.22.3264.3264 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3264-3264 ◽

Cited By ~ 1

Author(s):

Ryan K Van Laar ◽

Ivan Borrelo ◽

David Jabalayan ◽

Ruben Niesvizky ◽

Aga Zielinski ◽

...

Keyword(s):

Gene Expression ◽

Multiple Myeloma ◽

High Risk ◽

Gene Expression Profiling ◽

Expression Profiling ◽

Research Funding ◽

Plasma Cells ◽

Molecular Subtypes ◽

Risk Status ◽

Significant Difference

Abstract Background: There is a global consensus that multiple myeloma patients with high-risk disease require additional monitoring and therapy compared to low/standard risk patients in order to maximize their chances of survival. Current diagnostic guidelines recommend FISH-based assessment of chromosomal aberrations to determine risk status (i.e. t(14;20), t(14;16), t(4;14) and/or Del17p), however, studies show FISH for MM may have a 20-30% QNS rate and is up to 15% discordant between laboratories, even when starting from isolated plasma cells. In this study we demonstrate that MyPRS gene expression profiling reproduces the key high risk translocations for MM risk stratification, in addition to having other significant advantages. Methods: Reproducibility studies show that MyPRS results are less than 1% discordant starting from isolated plasma cells and return successful results in up to 95% of cases. 270 MM patients from Johns Hopkins University (MD) and Weill Cornell Medicine (NY) had both FISH and MyPRS gene expression profiling performed between 2012 and 2016 using standard and previously published methodology, respectively. Results: Retrospective review of the matched FISH and MyPRS results showed: 25/28 (89%) patients wish FISH-identified t(4;14) were classified as MMSET (MS) subtype. 10/10 (100%) patients with t(14;16) or t(14;20) were classified as MAF-like (MF) subtype 62/67 (93%) patients with t(11;14) were assigned to the Cyclin D (1 or 2) subtype. Patients with FISH hyperdiploidy status were classified as the Hyperdiploid (HY) subtype or had multiple gains detected by the separate MyPRS Virtual Karyotype (VK) algorithm, included in MyPRS. TP53del was seen in patients with multiple molecular subtypes, predominantly Proliferation (PR) and MMSET (MS). Assessment of TP53 function by gene expression is a more clinically relevant prognostic marker than TP53del, as dysregulation of the tumor suppressor is affected by mutations as well as deletions. Analysis of the TP53 expression in the 39 patients with delTP53 showed a statistically significant difference, compared to patients without this deletion (P<0.0001). Conclusion: Gene expression profiling is a superior and more reliable method for determining an individual patients' prognostic risk status. The molecular subtypes of MM, as reported by Signal Genetics MyPRS assay, are driven by large-scale changes in gene expression caused by or closely associated with chromosomal changes, including translocations. Physicians who are managing myeloma patients and wishing to base their assessment of risk on R-ISS or mSMART Guidelines may obtain the required data points from either FISH or MyPRS, with the latter offering lower QNS rates, higher reproducibility, assessment of a larger number of cells and a substantially lower price point ($5,480 vs. $1,912; 2016 CMS data). A larger cohort study is now underway to further validate these observations. Figure GEP-based TP53 expression in patients with and without Del17p. P<0.0001 Figure. GEP-based TP53 expression in patients with and without Del17p. P<0.0001 Disclosures Van Laar: Signal Genetics, Inc.: Employment. Borrelo:Sidney Kimmel Cancer Institute: Employment. Jabalayan:Weill Cornell Medical Center: Employment. Niesvizky:Celgene: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Onyx: Consultancy, Research Funding, Speakers Bureau. Zielinski:Signal Genetics, Inc.: Employment. Leigh:Signal Genetics, Inc.: Employment. Brown:Signal Genetics, Inc.: Employment. Bender:Signal Genetics, Inc.: Employment.

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Prognostic Molecular Stratification in Relapsed/Refractory Multiple Myeloma - Results of the Pomalidomide Mukseven (NCT02406222) Biomarker Trial

Blood ◽

10.1182/blood-2019-123640 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4327-4327

Author(s):

James Croft ◽

Andrew Hall ◽

Amy L Sherborne ◽

Katrina Walker ◽

Sidra Ellis ◽

...

Keyword(s):

Multiple Myeloma ◽

Flow Cytometry ◽

T Cell ◽

High Risk ◽

Real World ◽

Research Funding ◽

Unmet Need ◽

Employment Equity ◽

Equity Ownership

Background Treatment of relapsed/refractory multiple myeloma (RRMM) remains challenging as durable remissions are achieved in patient sub-groups only. Identifying patients that are likely to benefit prior to or early after starting relapse treatments remains an unmet need. MUKseven is a trial specifically designed to investigate and validate biomarkers for treatment optimization in a 'real-world' RRMM population. Design In the randomized multi-center phase 2 MUKseven trial, RRMM patients (≥2 prior lines of therapy, exposed to proteasome inhibitor and lenalidomide) were randomized 1:1 to cyclophosphamide (500 mg po d1, 8, 15), pomalidomide (4 mg days 1-21) and dexamethasone (40 mg; if ≥75 years 20 mg; d1, 8, 15, 21) (CPomD) or PomD and treated until progression. All patients were asked to undergo bone marrow (BM) and peripheral blood (PB) bio-sampling at baseline, cycle 1 day 14 (C1D14, on-treatment) and relapse. For biomarker discovery and validation, IGH translocations were profiled by qRT-PCR, copy number aberrations by digital MLPA (probemix D006; MRC Holland), GEP by U133plus2.0 array (Affymetrix), PD protein markers by IHC and PB T-cell subsets by flow cytometry for all patients with sufficient material. Primary endpoint was PFS, secondary endpoints included response, OS, safety/toxicity and biomarker validation. Original planned sample size was 250 patients but due to a change in UK standard of care during recruitment with pomalidomide becoming available, a decision was made to stop recruitment early. Results In total, 102 RRMM patients were randomized 1:1 between March 2016 and February 2018. Trial entry criteria were designed to include a real-world RRMM population, permitting transfusions and growth factor support. Median age at randomization was 69 years (range 42-88), 28% of patients had received ≥5 prior lines of therapy (median: 3). Median follow-up for this analysis was 13.4 months (95% CI: 12.0-17.5). 16 patients remained on trial at time of analysis (median number of cycles: 19.5; range 8-28). More patients achieved ≥PR with CPomD compared to PomD: 70.6% (95% CI: 56.2-82.5%) vs. 47.1% (CI: 32.9-61.5%) (P=0.006). Median PFS was 6.9 months (CI: 5.7-10.4) for CPomD vs. 4.6 months (CI: 3.5-7.4) for PomD, which was not significantly different as per pre-defined criteria. Follow-up for OS is ongoing and will be presented at the conference. High-risk genetic aberrations were found at following frequencies: t(4;14): 6%, t(14;16)/t(14;20): 2%, gain(1q): 45%, del(17p): 13%. Non-high risk lesions were present as follows: t(11;14): 22%, hyperdiploidy: 44%. Complete information on all high-risk genetic markers was available for 71/102 patients, of whom 12.7% had double-hit high-risk (≥2 adverse lesions), 46.5% single-hit high-risk (1 adverse lesion) and 40.8% no risk markers, as per our recent meta-analysis in NDMM (Shah V, et al., Leukemia 2018). Median PFS was significantly shorter for double-hit: 3.4 months (CI: 1.0-4.9) vs. single-hit: 5.8 months (CI: 3.7-9.0) or no hit: 14.1 months (CI: 6.9-17.3) (P=0.005) (Figure 1A). GEP was available for 48 patients and the EMC92 high-risk signature, present in 19% of tumors, was associated with significantly shorter PFS: 3.4 months (CI: 2.0-5.7) vs. 7.4 (CI: 3.9-15.1) for EMC92 standard risk (P=0.037). Pharmacodynamic (PD) profiling of cereblon and CRL4CRBN ubiquitination targets (including Aiolos, ZFP91) in BM clots collected at baseline and C1D14 is currently ongoing. Preliminary results for the first 10 patients demonstrate differential change of nuclear Aiolos (Figure 1C), with a major decrease in Aiolos H-scores in 7/10 patients from baseline to C1D14 and reconstitution at relapse. T-cell PB sub-sets were profiled at baseline and C1D14 by flow cytometry. Specific sub-sets increased with therapy from baseline to C1D14, e.g. activated (HLA-DR+) CD4+ T-cells, as reported at last ASH. CD4+ T-cell % at baseline was associated with shorter PFS in these analyses in a multi-variable Cox regression model (P=0.005). PD and T-cell biomarker results will be updated and integrated with molecular tumor characteristics and outcome. Discussion Our results demonstrate that molecular markers validated for NDMM predict treatment outcomes in RRMM, opening the potential for stratified delivery of novel treatment approaches for patients with a particularly high unmet need. Additional immunologic and PD biomarkers are currently being explored. Disclosures Croft: Celgene: Other: Travel expenses. Hall:Celgene, Amgen, Janssen, Karyopharm: Other: Research funding to Institution. Walker:Janssen, Celgene: Other: Research funding to Institution. Pawlyn:Amgen, Janssen, Celgene, Takeda: Other: Travel expenses; Amgen, Celgene, Janssen, Oncopeptides: Honoraria; Amgen, Celgene, Takeda: Consultancy. Flanagan:Amgen, Celgene, Janssen, Karyopharm: Other: Research funding to Institution. Garg:Janssen, Takeda, Novartis: Other: Travel expenses; Novartis, Janssen: Research Funding; Janssen: Honoraria. Couto:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties. Wang:Celgene Corporation: Employment, Equity Ownership. Boyd:Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Pierceall:Celgene: Employment. Thakurta:Celgene: Employment, Equity Ownership. Cook:Celgene, Janssen-Cilag, Takeda: Honoraria, Research Funding; Janssen, Takeda, Sanofi, Karyopharm, Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen, Bristol-Myers Squib, GlycoMimetics, Seattle Genetics, Sanofi: Honoraria. Brown:Amgen, Celgene, Janssen, Karyopharm: Other: Research funding to Institution. Kaiser:Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses; Celgene, Janssen: Research Funding; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy.

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Platelet-Dependent Thrombin Generation Induced By ADP or Activated Factor X Does Not Contribute to Increased In Vivo Thrombin Formation in Myeloproliferative Neoplasms

Blood ◽

10.1182/blood-2018-99-118487 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4336-4336

Author(s):

Christina Berens ◽

Heiko Rühl ◽

Jens Müller ◽

Johannes Oldenburg ◽

Peter Brossart ◽

...

Keyword(s):

Plasma Levels ◽

Research Funding ◽

Thrombin Generation ◽

Myeloproliferative Neoplasms ◽

Final Concentration ◽

Factor X ◽

Prothrombinase Complex ◽

Significant Difference ◽

Thrombin Formation

Abstract Introduction: Myeloproliferative Neoplasms (MPN), including the clinical entities Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF), are characterized by an increased thrombotic risk, the pathomechanisms of which are not well-understood. It has been suggested that an increased sensitivity of platelets to adenosin diphosphate (ADP) contributes to the hypercoagulable state in PV and ET through increased thrombin generation. In the present study we analyzed plasma levels of thrombin and platelet-dependent thrombin generation in MPN patients with an additional focus on prothrombin activation by the prothrombinase complex. Methods: A total of 33 blood samples were obtained from patients with MPN (PV, n=18; ET, n=5; PMF, n=10) and from 33 healthy blood donors that served as controls. In vitro thrombin generation in platelet-rich plasma (PRP) and platelet-poor plasma (PPP) was assessed using the Calibrated Automated Thrombogram (CAT) assay. To induce thrombin generation either ADP (1 µmol/L final concentration) or activated factor X (FXa, 10 ng/mL final concentration) were applied. To further characterize the MPN-associated hypercoagulable state in vivo, plasma levels of free thrombin were measured using an oligonucleotide-based enzyme capture assay (OECA). Prothrombin activation fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT), and D-dimer were measured additionally. Results: In PRP of MPN patients a slightly higher ADP-induced peak thrombin concentration (Cpeak) was observed than in the healthy controls, with 106 (79-130) vs. 84 (65-110) nmol/L (median and interquartile range, p=.026). There was no statistically significant difference in the ADP-induced endogenous thrombin potential (ETP) in MPN patients (1445, 1194-1643 nmol/L·min) compared with the controls (1417, 1258-1814 nmol/L·min). There was no statistically significant difference in the FXa-induced Cpeak and ETP between MPN patients and controls, with 106 (79-127) vs. 97 (82-128) nmol/L, and 1424 (1165-1560) vs. 1641 (1193-1841) nmol/L·min, respectively. With 0.68 (<0.46-1.20) pmol/L, plasma levels of free thrombin were significantly higher (p=.025) in MPN patients than in the control group, in which median thrombin levels were below the limit of detection. Plasma levels of F1+2 and TAT were also higher in the MPN group than in healthy controls, with 0.31 (0.17-0.50) vs. 0.18 (0.13-0.25) nmol/L (p=.002) and 4.36 (2.53-6.76) vs. 2.36 (<2.00-2.68) ng/mL (p=.003), respectively. Conclusion: Increased plasma levels of thrombin, F1+2, and TAT indicate enhanced in vivo thrombin formation in MPN patients. Despite a slightly increased ADP sensitivity of MPN-platelets, the total amount of thrombin generated in PRP from MPN patients is not increased. This makes it unlikely that a 'hyperreactivity' of MPN platelets, resulting in increased activities of the prothrombinase complex on the platelet surface, contributes to the increased thrombin formation in MPN patients. Disclosures Berens: Shire: Research Funding; Biotest: Research Funding; Pfizer: Research Funding; Sanofi Genzyme: Research Funding; CSL-Behring: Research Funding. Rühl:Shire: Research Funding; Swedish Orphan Biovitrum: Consultancy, Research Funding; Grifols: Research Funding; Sanofi Genzyme: Research Funding; CSL-Behring: Research Funding. Müller:Swedish Orphan Biovitrum: Consultancy, Research Funding. Oldenburg:Roche: Honoraria, Research Funding; Grifols: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Novo Nordisk: Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Shire: Honoraria, Research Funding; Octapharma: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Biogen: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Swedish Orphan Biovitrum: Honoraria, Research Funding.

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Myelodysplastic/Myeloproliferative Neoplasms Unclassified (MDS/MPN-U) Overlap: Can We Alter the Natural History?

Blood ◽

10.1182/blood.v128.22.3125.3125 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3125-3125 ◽

Cited By ~ 4

Author(s):

Kaitlin Hendrix ◽

Najla Alali ◽

Eric Padron ◽

David Sallman ◽

Alan F. List ◽

...

Keyword(s):

High Risk ◽

Myeloproliferative Neoplasms ◽

Unmet Need ◽

Low Risk ◽

World Health ◽

Cell Transplant ◽

Sequencing Data ◽

Modest Improvement ◽

Baseline Characteristics ◽

Health Organization

Abstract Introduction: The 2008 World Health Organization classification recognized a unique overlap category that combines features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). The least well characterized of the 4 overlap diseases is a rare entity known as MDS/MPN Unclassifiable (MDS/MPN-U), comprising <5% of myeloid disorders. The outcome of this subtype has been reported to be poor. The response to and impact of hypomethylating agents (HMA) on outcome is not well studied. Methods: We identified MDS/MPN-U patients within the Moffitt MDS database, baseline characteristics were reviewed, and responses to HMA utilizing IWG 2006 response criteria were assessed. The Kaplan-Meier method was applied to estimate overall survival (OS). Results: Among 127 patients with MDS/MPN-U, 62 patients received HMA treatment. There was no difference in baseline characteristics among those who received HMA or not, except that those treated with HMA were less likely to have low risk disease by IPSS, MD Anderson model or very low risk by revised IPSS (R-IPSS). Among 16 patients who had NextGen sequencing data, the 5 most common mutations were ASXL-1 (56%), TET2 (31%), JAK2 (33%), SRSF2 (25%), as well as SETBP1, DNMT3A, and EZH2(19%). The best overall response to HMA (hematological improvement [HI] or better) according to the International Working Group (IWG) 2006 criteria was 26%. Only 11 patients (low risk) underwent allogeneic stem cell transplant (allo-SCT) with no improvement or decrease in OS. The median OS was 33 months (mo). Among patients with IPSS low/int-1 risk disease, the median OS was 39 and 33 mo respectively for those treated with HMA vs. HMA untreated. (p=0.50). For Int-2/high risk IPSS, the median OS was 11 and 5 mo for those who received HMA and those who did not. (p=0.02). Based on R-IPSS the median OS for very low/low risk was 47 and 39 mo respectively for those treated with HMA and without (p=0.96), for intermediate risk, the median OS was 39 and 25 mo respectively (p 0.75), and for high and very high risk the median OS was 13 and 5 mo respectively for those treated with HMA and those who did not. (p < 0.005). The median OS for patients with HI+, stable disease or progressive disease was 68, 59, and 36 mo respectively (p=0.08). Conclusions: Treatment with HMA is associated with modest improvement in OS among higher risk MDS/MPN-U, reinforcing the unmet need to improve outcomes in this group. Targeted therapy may prove to be of benefit as allo-SCT does not appear to be beneficial for patients even with low risk disease. Furthermore, these data demonstrate the need for prospective analysis of the outcomes of allo-SCT in patients with MDS/MPN-U to determine potential benefit to high risk patients. Disclosures Komrokji: Novartis: Consultancy, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Abstract 3220: Bivalirudin Monotherapy Provides Similar One-Year Survival Compared to Heparin plus GP IIb/IIIa Inhibitors in Diabetic Patients with Acute Coronary Syndromes: Results from the Randomized ACUITY Trial

Circulation ◽

10.1161/circ.116.suppl_16.ii_724-b ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Frederick Feit ◽

Stuart V Manoukian ◽

George D Dangas ◽

A. M Lincoff ◽

E. M Ohman ◽

...

Keyword(s):

Treatment Group ◽

High Risk ◽

Major Bleeding ◽

Acute Coronary Syndromes ◽

Diabetic Patients ◽

Significant Difference ◽

Coronary Syndromes ◽

One Year ◽

The Impact ◽

Ischemic Events

Background: Among diabetic patients with acute coronary syndromes (ACS) in the ACUITY trial, bivalirudin (Biv) monotherapy (Mono) provided similar survival and protection from ischemic events with significantly less major bleeding compared to heparin (unfractionated or enoxaparin) plus GP IIb/IIIa inhibitors (Hep+GPI) at 30 days. Whether this protection from ischemic events persists to one year is unknown. Methods: In the ACUITY trial, patients with moderate and high risk (ACS) were randomized to Hep+GPI, Biv+gPI, or Biv Mono. We evaluated the impact of treatment group on composite ischemia (death, MI, or unplanned revascularization) and mortality at one year in diabetic patients using Kaplan Meier survival analysis and log rank tests. Results: Of patients enrolled in the ACUITY trial, 3852 were diabetic (28.1%) and 9857 (71.9%) were non-diabetic. Compared with non-diabetics, diabetics had higher rates of mortality at one year (6.1% vs 3.4%, p<0.001). There was no significant difference in the rate of composite ischemia at one year for diabetic patients who received Biv Mono vs Hep+GPI (19.7% vs 18.9%, p=0.39) or Biv+GPI vs Hep+GPI (20.9% vs 18.9%, p=0.16). Mortality rates for diabetic patients by treatment group are shown below. Conclusions: In the ACUITY Trial, diabetic patients had lower survival rates at one year than non-diabetics. Among diabetic patients, treatment with Biv Mono resulted in similar rates of composite ischemia and survival at one year compared to those treated with Hep+GPI. Combined with the early reduction in major bleeding, these findings indicate that Biv Mono is a suitable alternative to Hep + GPI for diabetic patients with moderate and high risk ACS.

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Long-Term Maintenance with Lenalidomide Improves Progression Free Survival In Myeloma Patients with High-Risk Cytogenetics: An IFM Study

Blood ◽

10.1182/blood.v116.21.1944.1944 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1944-1944 ◽

Cited By ~ 7

Author(s):

Hervé Avet-Loiseau ◽

Denis Caillot ◽

Gerald Marit ◽

Valerie Lauwers-Cances ◽

Murielle Roussel ◽

...

Keyword(s):

High Risk ◽

Research Funding ◽

Prognostic Value ◽

Plasma Cells ◽

Chromosomal Abnormalities ◽

Progression Free Survival ◽

High Dose ◽

Poor Outcome ◽

Significant Difference ◽

Chromosomal Changes

Abstract Abstract 1944 Cytogenetic abnormalities have been associated with specific outcome in myeloma, as in many other hematologic malignancies. Among the large spectrum of chromosomal changes observed in myeloma, at least two of them are clearly associated with a specific poor outcome, both in terms of PFS and OS, i.e., t(4;14) and del(17p). Recent data suggested that bortezomib can at least partially overcome the prognostic value of t(4;14). However, t(4;14) remains a prognostic factor in the IFM series. Deletion 17p is rare (< 10%), but is associated with a very poor outcome, whatever the treatment proposed to these patients. In 2005, the IFM designed a clinical trial aiming to test the role of lenalidomide maintenance until relapse in patients under 65 years of age treated with a VAD or bortezomib/dexamethasone induction, followed by high-dose melphalan. Six hundred and fourteen patients have been enrolled, and the clinical results of this trial are presented in another abstract. Chromosomal data focused on t(4;14) and del(17p) were available for 488 of those patients, as analyzed at diagnosis by FISH on sorted plasma cells. The t(4;14) was observed in 13.3% of the patients and del(17p) (defined by presence in at least 60% of the plasma cells) was present in 6.6% of them, incidences that are in agreement with previous reports. The median PFS (calculated from the date of randomization) for patients with t(4;14) were 15 months and 27 months for patients in the placebo and lenalidomide arms, respectively. The median for patients with del(17p) were 14 months and 29 months for patients in the placebo and lenalidomide arms, respectively. The comparison of PFS in the lenalidomide arm for patients with t(4;14) or del(17p), as compared with those lacking the chromosomal abnormalities shows a significant difference, in favor of the “no abnormality” group. In conclusion, lenalidomide maintenance very significantly improves the PFS of patients with high-risk cytogenetics, albeit these chromosomal changes retain their prognostic value. Disclosures: Facon: celgene: Consultancy, Research Funding; johnson and johnson: Consultancy. Attal:celgene: Consultancy, Research Funding; johnson and johnson: Consultancy, Research Funding.

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