The Impact of gain1q on Mutational Structure and Clonal Evolution in a Uniformly Treated High-Risk Series of Patients at First Relapse

Abstract Introduction In Multiple Myeloma (MM) the emergence of treatment resistant clones is a characteristic feature of relapse and this is particularly so for high-risk cases. A key driver event mediating progression, risk status and relapse is gain(1q) (1q+). We report on the impact of 1q+ on the genetic profile seen at first relapse in a uniformly treated, newly diagnosed series of 56 patients enrolled to the NCRI Myeloma XI Trial. Methods We included 56 high risk patients, defined as relapse within 30 months of maintenance randomisation (median 19 months, range 8-51). Of the 56 patients, 30 received lenalidomide maintenance and 26 were observed. Whole exome sequencing was conducted at presentation and relapse to a median depth of 122x for tumour samples and 58x for controls. Libraries were prepared using the SureSelectQXT sample prep kit and SureSelect Clinical Research Exome kit. MuTect was used to determine gene variants and SciClone clustering was undertaken to map mutation variant allele frequencies. MANTA was used to determine translocations and Sequenza for copy number aberrations. Clonal structure and mechanisms of clonal evolution were assessed using kernel density estimation of the cancer clonal fraction for all mutations. Wilcoxon matched-pairs signed rank tests (2-sided) were used to determine the significance between paired data sets, including mutational load. Fishers exact test was used to determine the difference between two nominal variables. Results We looked at mutational, structural and clonal evolution events in all patients based on 1q+ status at relapse. At diagnosis, 34% (19/56) patients had evidence of 1q+, increasing to 46% (26/56) at relapse, with all patients harbouring 1q+ at presentation having the lesion at relapse. There was a significantly higher non-synonymous mutational load at relapse in patients with 1q+, 107 vs 126 (p=0.047), compared to those without 1q+, 36 vs 44 (p=0.140). Twenty two genes known to be significant in MM and mutations within the genes known to be important in IMiD mechanism of action were reviewed. Of the patients with 1q+, 92% (24/26) had at least one mutation during the course of the disease, compared to 77% in those without 1q+ (p=0.15). The impact on tumour suppressor gene regions including deletions of chromosome 1p, 13, 14 and 17p was analyzed. Of the patients with 1q+, 77% (20/26) of patients had a deletion of one of these regions during the disease course, compared to 57% (17/30) of patients without 1q+ (p=0.16). At relapse a change in the profile of these lesions was noted in 23% (6/26) patients with 1q+, compared to 20% (6/30) patients without 1q+ (p=1). Translocations involving MYC (t MYC) were also determined and found in 27% (7/26) of patients with 1q+ and 27% (8/30) of patients without (p=1). As with 1q+, t MYC was always preserved at relapse. Mechanisms of evolution leading to relapse were established for all patients. Branching and linear evolution predominated, noted to be the mechanism leading to relapse in 88% (23/26) patients with 1q+ and 83% (25/30) without (p0.71). Stable evolution was noted in the remaining patients. 1q+ occurring as a new event at relapse was associated with branching or linear evolution in all patients (n=7), consistent with a change in clonal structure. Conclusion These data reveal that 1q+ is conserved throughout the disease course, suggesting it imparts a survival advantage and treatment resistant phenotype to the clone(s) containing it. The presence of 1q+ is associated with a significant increase in mutational load at relapse and a greater incidence of tumour suppressor gene structural deletions, mechanisms that may contribute to clonal evolution and therapeutic escape. Disclosures Jones: BMS/Celgene: Other: Conference fees; Janssen: Honoraria. Pawlyn: Celgene / BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Weinhold: Sanofi: Honoraria. Walker: Sanofi: Speakers Bureau; Bristol Myers Squibb: Research Funding. Cairns: Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding; Celgene / BMS: Other: travel support, Research Funding. Kaiser: AbbVie: Consultancy; Seattle Genetics: Consultancy; BMS/Celgene: Consultancy, Other: Travel support, Research Funding; Amgen: Honoraria; Karyopharm: Consultancy, Research Funding; Pfizer: Consultancy; Janssen: Consultancy, Other: Educational support, Research Funding; GSK: Consultancy; Takeda: Consultancy, Other: Educational support. Cook: Pfizer: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria. Drayson: Abingdon Health: Current holder of individual stocks in a privately-held company. Jackson: oncopeptides: Consultancy; takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; J and J: Consultancy, Honoraria, Speakers Bureau; celgene BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; amgen: Consultancy, Honoraria, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau. Davies: BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Morgan: BMS: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees.

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The Impact of Combination Chemotherapy and Tandem Stem Cell Transplant on Clonal Substructure and Mutational Pattern at Relapse of MM

Blood ◽

10.1182/blood.v126.23.372.372 ◽

2015 ◽

Vol 126 (23) ◽

pp. 372-372 ◽

Cited By ~ 1

Author(s):

Christoph Heuck ◽

Niels Weinhold ◽

Erich Allen Peterson ◽

Michael Bauer ◽

Caleb K. Stein ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Clonal Evolution ◽

Advisory Board ◽

Proliferation Index ◽

University Of Arkansas ◽

Medical Sciences ◽

Advisory Committees ◽

The Impact

Abstract Introduction: Next generation sequencing of over 800 newly diagnosed multiple myeloma (NDMM) cases has established the mutational landscape and key cancer driver pathways. The mutational basis of relapse has not been systematically studied. Two previous studies (Keats et al.; Bolli et al.) identified 4 patterns of clonal evolution. Neither study included uniformly treated patients and looked at the impact of therapy on clonal structure at relapse. Understanding the mutational patterns underlying relapse and how they relate to specific therapies is crucial in order to improve MM outcomes, especially for high-risk (HR) MM. In this study we compare the clonal structure at presentation (PRES) and at relapse (REL), after exposure to Total Therapy (TT). Materials and Methods: We studied 33 pairs of tumor samples collected at PRES and REL. 9 patients were treated on TT2, 13 on TT3, 10 on TT4 and 1 on TT5-like regimen. Eleven patients had HR disease at PRES. DNA was extracted from CD138+ selected cells from random bone marrow aspirates. Germline controls were obtained from leukapheresis products. Whole exome sequencing libraries were prepared using the Agilent qXT kit and the Agilent SureSelect Clinical Research Exome kit with additional baits covering the Ig and MYC loci. All samples were sequenced on an Illumina HiSeq2500 to a median depth of 120x. Sequencing data were aligned to the Ensembl GRCh37/hg19 human reference using BWA. Somatic variants were called using MuTect. Translocations were identified using MANTA. Copy number variations were inferred using TITAN. Gene expression profiles (GEP), generated using the Affymetrix U133plus2 microarray, were available for all tumor samples. Nonnegative matrix factorization (NMF) was used to define mutation signatures. Results: The median time to progression was 30 months with a median follow up of 9.5 years. 22 cases achieved a complete remission (CR) or near CR. There were 11 cases of HR at PRES. Of the 22 cases with low risk (LR) MM, 7 relapsed with HR disease. There were on average 478 SNVs per sample at PRES and 422 at REL. All but 2 cases had evidence of new mutations at REL. There were no consistent patterns or number of mutation associated with REL or GEP-defined risk. Patients of the MF molecular subgroup had more mutations compared to other molecular subgroups (657 vs. 379) and were enriched for mutations with an APOBEC signature. We did not detect any mutation signature consistent with chemotherapy-induced alterations, providing evidence that TT itself does not cause additional mutations. Primary recurrent IgH translocations called by MANTA were confirmed by GEP data. A number of new translocations were identified , several only at REL. In particular we demonstrate a case with a newly acquired MYC translocation at relapse, indicating that it contributed to progression. We identified 5 patterns of clonal evolution (Figure 1): A) genetically distinct relapse in 3 patients, B) linear evolution in 8 patients, C) clonal selection in 9 patients, D) branching evolution in 11 patients, and E) stable clone(s) in 2 patients. Patterns A (distinct) and B (linear) were associated with low risk and longer survival, whereas patterns D (branching) and E (stable) were associated with high risk and shorter time to relapse and overall survival (Table 1). Conclusion: This is the first study to systematically analyze the pattern of clonal evolution using NGS in patients treated with combination chemotherapy and tandem ASCT. We identified 5 patterns of evolution, which correlate with survival. We identified 3 cases with a loss of the original clone and emergence of a new clone, suggesting high effectiveness of Total Therapy for those patients. The persistence of major clones despite multi agent chemotherapy in most other cases supports a concept of a tumor-initiating cell population that persist in a protective niche, for which new therapies are needed. Table 1. Pattern of Evolution GEP70 Pres.(high risk: ≥0.66) Proliferation Index Pres. GEP70 Rel.(high risk: ≥0.66) Proliferation Index Rel Mean OS Mean TTR A: distinct (n=3) -0.690 -3.34 -0.015 2.04 8.18 5.00 B: linear (n=8) -0.171 -0.34 0.618 9.22 5.70 4.05 C: selection (n=9) 0.366 3.20 0.569 6.97 3.95 2.64 D: branching (n=11) 0.710 5.17 1.173 11.15 3.84 2.21 E: stable (n=2) 1.532 7.42 1.124 2.54 0.96 0.35 Pres.: Presentation; Rel.: Relapse; OS: Overall Survival; TTR: Time to Relapse Figure 1. Patterns of Relapse Figure 1. Patterns of Relapse Disclosures Heuck: Foundation Medicine: Honoraria; Millenium: Other: Advisory Board; Janssen: Other: Advisory Board; Celgene: Consultancy; University of Arkansas for Medical Sciences: Employment. Weinhold:Janssen Cilag: Other: Advisory Board; University of Arkansas for Medical Sciences: Employment. Peterson:University of Arkansas for Medical Sciences: Employment. Bauer:University of Arkansas for Medical Sciences: Employment. Stein:University of Arkansas for Medical Sciences: Employment. Ashby:University of Arkansas for Medical Sciences: Employment. Chavan:University of Arkansas for Medical Sciences: Employment. Stephens:University of Arkansas for Medical Sciences: Employment. Johann:University of Arkansas for Medical Sciences: Employment. van Rhee:University of Arkansa for Medical Sciences: Employment. Waheed:University of Arkansas for Medical Sciences: Employment. Johnson:University of Arkansas for Medical Sciences: Employment. Zangari:University of Arkansas for Medical Sciences: Employment; Millennium: Research Funding; Onyx: Research Funding; Novartis: Research Funding. Matin:University of Arkansas for Medical Sciences: Employment. Petty:University of Arkansas for Medical Sciences: Employment. Yaccoby:University of Arkansas for Medical Sciences: Employment. Davies:University of Arkansas for Medical Sciences: Employment; Millenium: Consultancy; Janssen: Consultancy; Onyx: Consultancy; Celgene: Consultancy. Epstein:University of Arkansas for Medical Sciences: Employment. Barlogie:University of Arkansas for Medical Sciences: Employment. Morgan:Weismann Institute: Honoraria; MMRF: Honoraria; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; University of Arkansas for Medical Sciences: Employment; CancerNet: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Prognostic Impact of Bone Marrow Fibrosis in Primary Myelofibrosis: A Study of Agimm Group on 540 Patients

Blood ◽

10.1182/blood.v126.23.351.351 ◽

2015 ◽

Vol 126 (23) ◽

pp. 351-351 ◽

Cited By ~ 1

Author(s):

Paola Guglielmelli ◽

Giada Rotunno ◽

Annalisa Pacilli ◽

Elisa Rumi ◽

Vittorio Rosti ◽

...

Keyword(s):

Bone Marrow ◽

Multivariate Analysis ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Primary Myelofibrosis ◽

Driver Mutations ◽

Prognostic Impact ◽

Advisory Committees ◽

The Impact

Abstract Background. The prognostic significance of bone marrow (BM) fibrosis grade in pts with primary myelofibrosis (PMF) is debated. A fibrosis grade greater than 1 was associated with a 2-fold higher risk of death compared with pts with early/prefibrotic MF (grade 0) [Thiele J, Ann Hematol 2006]. Recent data suggest that more accurate prediction of survival is achieved when fibrosis grade is added to IPSS [Verner C, Blood 2008; Giannelli U, Mod Pathol 2012]. Aim. To analyze the prognostic impact of fibrosis in diagnostic BM samples of 540 WHO-2008 diagnosed PMF pts with extensive clinical and molecular information collected in 6 Italian centers belonging to AGIMM (AIRC-Gruppo Italiano Malattie Mieloproliferative). Methods. The clinical variables assessed were those previously identified as prognostically relevant in the IPSS score. Published methods were used to screen mutations of JAK2, MPL, CALR, EZH2, ASXL1, IDH1/2 and SRSF2. European consensus scoring system was used to grade fibrosis (on a scale of MF-0 to MF-3). The prognostic value of fibrosis with regard to overall survival (OS) was estimated by Kaplan-Meier method and Cox regression. Results. Pts' median age was 61y; median follow-up 3.7y; median OS 10.5y; 184 pts (34.1%) died. IPSS risk category: low 33.7%, Int-1 27.7%, Int-2 19.1%, High-risk 19.5%. Mutational rate: JAK2 V617F 62.6%, CALR 20.7% (type-1/1-like 77.7%, type2/2-like-2 21.4%), MPL W515 5.9%; 62 (11.5%) were triple negative (TN). 171 pts (31.7%) were High-Molecular Risk (HMR) category (Vannucchi AM, Leukemia 2013); mutation rate: EZH2 7.2%, ASXL1 22.2%, IDH1-2 2.4%, SRSF2 8.3%. According to fibrosis grading, 50 pts were MF-0 (9.3%), 180 MF-1 (33.3%), 196 MF-2 (36.3%), 114 MF-3 (21.1%). Compared with both MF-0 and MF-1, MF-2 and MF-3 pts presented more frequently constitutional symptoms (P<.0001), larger splenomegaly (P<.0001), greater risk of developing anemia (P<.0001) or thrombocytopenia (P=.003). We found a significant association (P<.0001) between IPSS higher/Int-2 risk categories and MF-2 and -3 (20.5% and 37.8%, respectively, vs 14.8% and 6.0% for MF-0 and -1). There was no correlation between fibrosis grade and phenotypic driver mutations; in particular, TN pts were equally distributed among MF fibrosis grades (10%, 10.6%, 14.3% and 8.8% from MF-0 to -3, respectively). Conversely, the frequency of HMR pts increased progressively according to fibrosis grade: 8 pts MF-0 (16%), 46 MF-1 (25.6%), 66 MF-2 (33.7%) and 51 MF-3 (44.7%) (P<.0001). In particular, we found a significant association between fibrosis grade and ASXL1 (12%, 15%, 23.5% and 36% from MF-0 to -3; P<.0001) and EZH2 (2%, 3.9%, 8.2%, 13.2%; P=.01) mutations. Also, pts with 2 or more HMR mutated genes were preferentially MF-2 or -3 ( 0%, 4.4% 10.2% and 10.5% from MF-0 to -3; P=.001). Median OS was significantly shorter in pts with MF-2 (OS 6.7y, HR 7.3, IC95% 2.7-20.0; P<.0001) and MF-3 (OS 7.2y, HR 8.7, IC95% 3.1-24.2; P<.0001) compared with MF-1 (14.7y; HR 3.9, IC95% 1.4-10.9, P=.008) and MF-0 (P<.0001) used as reference group (OS not reached) (Figure). Excluding MF-0, MF-2 and -3 maintained negative prognostic impact with HR 1.9 (1.3-2.6; P=.001) and 2.2 (1.5-3.3; P<.0001) respectively vs MF-1. The impact of fibrosis on OS was maintained when analysis was restricted to younger (≤65y) pts. In multivariate analysis using the individual IPSS variables, grade MF-2 and -3 were independently predictive of survival (HR 3.9 (1.4-10.8), and HR 4.2 (1.5-12.0), respectively, P=.008 for both). The negative impact on survival of MF-2/-3 was maintained regardless of IPSS category, HMR status, number of HMR mutated genes and driver mutations, included as covariates (Table). In low, Int-1 and Int-2, but not high-risk IPSS categories, MF-2/-3 associated with reduced survival (P<.03). Conclusions. Overall, these results indicate that higher grades (MF-2 and MF-3) of fibrosis correlate with defined clinical and molecular variables and independently negatively impact on OS in PMF, suggesting the opportunity to explore its value in the setting of clinical and molecular prognostic scores for PMF. Table. Multivariate Analysis Variables HR 95% CI P value HMR status 2.4 1.5-3.7 <.0001 HMR≥2mutations 4.3 2.8-6.4 .009 IPSS scoring Int1 2.9 1.6-5.1 <.0001 Int2 10.0 5.6-17.7 <.0001 High 9.7 5.5-17.2 <.0001 Driver mutations CALR type2 3.4 1.3-8.6 .010 JAK2/MPL 2.4 1.4-4.3 .003 TN 4.5 2.3-8.8 <.0001 Fibrosis MF-2/MF-3 3.8 1.4-10.6 .010 Figure 1. Figure 1. Disclosures Passamonti: Novartis: Consultancy, Honoraria, Speakers Bureau. Barbui:Novartis: Speakers Bureau. Vannucchi:Shire: Speakers Bureau; Novartis: Other: Research Funding paid to institution (University of Florence), Research Funding; Baxalta: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Genetic Alterations at Diagnosis Predict Outcome of AML Patients Age 60 or Older Undergoing Allogeneic Transplantation in First Remission

Blood ◽

10.1182/blood-2019-125967 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 48-48 ◽

Cited By ~ 1

Author(s):

H. Moses Murdock ◽

Haesook T. Kim ◽

Bryan Hambley ◽

Pankit Vachhani ◽

Nathan Denlinger ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Genetic Risk ◽

Research Funding ◽

Gene Mutations ◽

Genetic Alterations ◽

Advisory Committees ◽

Genetic Characteristics ◽

The Impact ◽

Advisory Role

Background: Older age is associated with inferior outcomes after allogeneic hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia (AML). High risk genetic characteristics are common among older patients and linked to poor outcomes in the non-transplant setting. An enhanced understanding of genetic risk may thus provide a basis for improving transplant outcomes in these patients. We evaluated the impact of leukemia genetic characteristics at diagnosis on HSCT outcomes in a multi-center cohort of AML patients age 60 or older receiving HSCT in first complete remission (CR1). Methods: We performed targeted sequencing of 112 genes on diagnostic leukemia samples from 257 patients with AML age 60 or older who received allogeneic HSCT in CR1 at 5 US transplant centers. Median age at diagnosis and HSCT were 65 (range 59-76) and 66 (range 60-76), respectively. 31% had clinically defined secondary AML, 11% had therapy-related AML, and 23% had adverse cytogenetics by 2017 ELN classification. Most (84%) were treated with anthracycline-based induction chemotherapy, while 16% received non-intensive induction. Conditioning was either reduced-intensity or non-myeloablative in 94% of patients. Median follow-up for survivors was 3.7 years; 3-year overall survival (OS) and leukemia-free survival (LFS) were 48% and 44%, respectively. Results: All patients had recurrent genetic alterations at the time of diagnosis, including 251 (98%) with gene mutations and 6 with only cytogenetic abnormalities. The most frequent gene mutations were DNMT3A (25%), NPM1 (23%), FLT3-ITD (22%), ASXL1 (21%), TET2 (21%), RUNX1 (20%), and SRSF2 (18%). Secondary-type mutations associated with antecedent MDS occurred in 42%, and 10% had TP53 mutations. As expected, secondary-type and TP53 mutations were associated with clinically-defined secondary AML (p<0.001), need for reinduction (p=0.03), and CR with incomplete count recovery (p= 0.03). Despite the older age at leukemia diagnosis, putative germline pathogenic variants were identified in 22 (8.6%) patients, including 17 (6.6%) with DDX41 mutations (13/17 with somatic mutation of the second allele), and 5 with TERT or TERC variants not found in population databases. We evaluated the impact of gene mutations on LFS using univariable and multivariable Cox models and developed a hierarchical model of 3 molecular genetic risk groups according to the hazard ratios (Fig 1A): (1) patients with TP53 mutation or JAK2 mutation or FLT3-ITD/NPM1-WT (high risk), (2) patients without high risk mutations who have DNMT3A or GATA2 or DDX41 mutations (low risk) (3) patients without high- or low-risk mutations (intermediate risk), with 3-year LFS of 8%, 65%, and 47% (p<0.001), respectively. Next, we combined molecular genetic and cytogenetic risk to derive a final genetic model comprised of 4 groups with distinct 3-year LFS (69%, 50%, 27%, and 0%) (Fig 1B). Poor LFS in the very high-risk group was due almost entirely to relapse (3-year relapse rate > 90%), but was driven by a combination of relapse and non-relapse mortality in the intermediate and high-risk groups (Fig 2). Conclusion: Genetic characteristics at diagnosis are highly associated with OS and LFS in AML patients age 60 or older who undergo allogeneic transplantation in CR1. We identify patients with low genetic risk and remarkably good outcomes who may be candidates for strategies aimed at reducing toxicity, and those with very high-risk genetics who have limited benefit from current transplant approaches. Among intermediate and high-risk patients, the impact of disease genetics on LFS is mostly due to relapse, suggesting that a model incorporating measurement of residual disease in CR1 and after transplantation could enable a more dynamic estimation of risk. Disclosures Perales: Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; NexImmune: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Medigene: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyte/Gilead: Research Funding; Miltenyi: Research Funding. Koreth:Equillium: Consultancy; Amgen: Consultancy; Cugene: Consultancy. Ho:Jazz Pharmaceuticals: Consultancy. Soiffer:Mana therapeutic: Consultancy; Kiadis: Other: supervisory board; Juno, kiadis: Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Gilead, Mana therapeutic, Cugene, Jazz: Consultancy; Jazz: Consultancy; Cugene: Consultancy. Carroll:Astellas Pharmaceuticals: Research Funding; Incyte: Research Funding; Janssen Pharmaceuticals: Consultancy. Vasu:Boehringer Ingelheim: Other: Travel support; Seattle Genetics: Other: Clinical trial support. Wang:Abbvie: Other: Advisory role; Kite: Other: Advisory role; Jazz: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role; Pfizer: Other: Advisory role, Speakers Bureau; Stemline: Other: Advisory role, Speakers Bureau; Daiichi: Other: Advisory role; Amgen: Other: Advisory role; Agios: Other: Advisory role. Devine:Kiadis Pharma: Other: Protocol development (via institution); Bristol Myers: Other: Grant for monitoring support & travel support; Magenta Therapeutics: Other: Travel support for advisory board; My employer (National Marrow Donor Program) has equity interest in Magenta. Lindsley:Jazz Pharmaceuticals: Research Funding; Takeda Pharmaceuticals: Consultancy; Medlmmune: Research Funding.

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Chronic Exposure to Cytoreductive Treatment Shapes Clonal Evolution in Myeloproliferative Neoplasms

Blood ◽

10.1182/blood-2021-152622 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3620-3620

Author(s):

Lin-Pierre Zhao ◽

Nabih Maslah ◽

Rafael Daltro De Oliveira ◽

Emmanuelle Verger ◽

Juliette Soret-Dulphy ◽

...

Keyword(s):

Board Of Directors ◽

Mutation Rate ◽

Chronic Exposure ◽

Research Funding ◽

Myeloproliferative Neoplasms ◽

Clonal Evolution ◽

Advisory Committees ◽

Cytoreductive Treatment ◽

The Impact

Abstract Introduction: Myeloproliferative neoplasms (MPN) are a heterogeneous group of chronic myeloid malignancies resulting from the combination of a driver mutated gene (JAK2, MPL or CALR) and a variety of acquired additional somatic mutations. Although next-generation sequencing (NGS) has identified high molecular risk mutations associated with adverse prognosis (Vannucchi et al., Leukemia, 2013 , Guglielmelli et al., Leukemia, 2014 ), the clonal evolution of these mutations remains poorly described. Chronic exposure to cytoreductive treatment, especially genotoxic drugs such as hydroxyurea (HU), could impact clonal evolution. A previous study suggested that Interferon-α (IFN) could limit the accumulation of cytogenetic abnormalities compared to HU (Mondello et al., Blood, 2018). The objective of our study was to describe the long-term evolution of the mutational landscape in the era of NGS in a large cohort of MPN patients. Methods: A total of 1538 consecutive patients were diagnosed with MPN according to WHO criteria and followed in our hospital between January 2011 and January 2021. This study included 1039 of them in whom a NGS molecular analysis targeting 36 myeloid genes with a sensitivity of 1% was performed at diagnosis and/or during follow-up. Patients with only one NGS (n=588), AML/MDS transformation at either the first (n=3) or the second NGS (n=2) were excluded from the analysis. Serial NGS data obtained in chronic MPN phase were thus analyzed for 446 patients. Clinical and biological characteristics at time of diagnosis and follow-up were collected from medical charts and electronic medical records. Mutation rates per year were calculated for each gene as the difference in the number of mutations between first and last NGS divided by the time interval (in years) between both NGS. Results : Median age at MPN diagnosis in our whole cohort was 51 years [IQR 41-60]. Our cohort included 167 (37%), 205 (46%) and 64 (14%) patients with Polycythemia Vera (PV), Essential thrombocythemia (ET) and primary myelofibrosis (MF) respectively. 279 patients (63%) had at least one additional mutation at first NGS, and respectively 27 (6%) and 104 (23%) patients had TP53 and high molecular risk mutations. Median interval between MPN diagnosis and the first NGS was 6.5 years [IQR 1.7-13] while median time between the first and the last NGS was 2.5 years [IQR 1.6-4, range 0.3-14.3]. Overall, 178 patients (39.9%) acquired an additional mutation at last NGS evaluation, most frequently involving TET2, DNMT3A, ASXL1, TP53 and NFE2 genes . To study the impact of chronic MPN therapy on clonal evolution, we focused on patients who electively received HU (n=112) or IFN (n=92) as a monotherapy, or did not receive any cytoreductive treatment (n=119) between the first and the last NGS. The remaining patients received ruxolitinib (n=44), anagrelide (n=10), vercyte (n=7) or polytherapy (n=62). At last follow-up, 74 patients receiving IFN (80.4%) and 65 (58%) treated with HU had a complete hematological response. When combining all additional mutations, the global mutation rate per year did not significantly differ between treatment groups. When analyzing individual genes, TP53 mutation rate was higher in patients treated with HU compared to the patients receiving IFN (p=0.014) or not treated (p=0.008) (Figure). MDS/AML evolution occurred in 4 patients (3.6%) treated with HU, 2 (1.7%) without cytoreductive therapy versus none of the 92 patients treated with IFN (ns). In the whole cohort, MDS/AML evolution was significantly increased in patients harboring TP53 mutations (p= 0.004). In contrast, DNMT3A mutation rate was significantly increased in patients receiving IFN compared to patients treated with HU (p=0.045) (Figure). The latest result is in line with previous observations showing that loss of DNMT3A could confer resistance to IFN in a JAK2-V617F mouse model (Stetka et al., Blood, 2020). Conclusion: Our results highlight the impact of chronic cytoreductive therapy on clonal evolution shaping in MPN. IFN limits the emergence of TP53 mutated clones compared to HU, thus potentially reducing the risk of leukemogenesis. Emergence of DNMT3A mutated clones under IFN therapy requires further exploration and could potentially play a role in therapeutic resistance. This study on a large clinically and biologically annotated cohort illustrates how serial NGS analysis may guide therapeutic options for MPN patients. Figure 1 Figure 1. Disclosures Raffoux: PFIZER: Consultancy; ASTELLAS: Consultancy; ABBVIE: Consultancy; CELGENE/BMS: Consultancy. Kiladjian: AbbVie: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Taiho Oncology, Inc.: Research Funding; PharmaEssentia: Other: Personal fees. Benajiba: Pfizer: Research Funding; Gilead: Research Funding.

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Characteristics of Different Splicing Factor Mutation Hotspots in Myelofibrosis

Blood ◽

10.1182/blood-2020-140145 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 37-37

Author(s):

Franco Castillo Tokumori ◽

Chetasi Talati ◽

Najla E. Al Ali ◽

David A. Sallman ◽

Seongseok Yun ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Splicing Factor ◽

World Health ◽

Severe Thrombocytopenia ◽

Leukemic Transformation ◽

Advisory Committees ◽

Splicing Mutations ◽

The Impact

CONTEXT: Splicing factor mutations (SRSF2, U2AF1, SF3B1, and ZRSR2) are present in ~50% of myelofibrosis (MF) patients. SRSF2 and U2AF1 Q157 are considered to be high-risk mutations, while the prognostic significance of ZRSR2 and SF3B1 has not been well established. As a group, splicing mutations are associated with cytopenias, the management of which is an area of unmet clinical need in MF. OBJECTIVE: To describe the clinical characteristics, treatment approaches, and outcomes in MF patients with splicing mutations. DESIGN: This is a single-institution, retrospective analysis of 133 MF patients with splicing mutations who presented to our institution between 2006 and 2019. PMF, post-ET MF, and post-PV MF were defined according to the World Health Organization and International Working Group criteria, respectively. Baseline variables were compared between patients harboring different splicing factor mutations and different mutations within the same splicing gene. Median overall survival (OS) was measured from time of diagnosis to date of death or censored at last follow up or date of transplant. Kaplan-Meier plots were created to compare LFS and OS among treatment cohorts, and differences were assessed using Log-rank tests. RESULTS: Among 133 MF patients with a splicing mutation, SRSF2 mutations were most common (n = 48), followed by U2AF1 (n = 36), SF3B1 (n = 27) and ZRSR2 mutations (n = 24). Most SRSF2 mutations occurred at P95 (90%). Thirty (83%) U2AF1 mutations occurred at Q157, with 5 (14%) at S34. Fourteen (63%) SF3B1 mutations occurred K666, with 9 (33%) at K700. Thirteen (54%) ZRSR2 mutations were in-frame insertions/deletions, 4 (17%) frameshift mutations, 3 (13%) nonsense mutations and 4 (17%) missense. All frameshift/nonsense ZRSR2 mutations occurred in males. Spliceosome mutations were mutually exclusive but for 2 cases (one had U2AF1 and SRSF2 mutations and the other had SF3B1 and ZRSR2 mutations). Baseline characteristics were similar between splicing mutations. The presence of a U2AF1 mutation correlated with lower hemoglobin (p 0.018) and U2AF1 Q157 mutations were associated with thrombocytopenia p=0.051) and higher DIPSS-plus scores (p=0.006). Severe thrombocytopenia (platelets < 50 x 109/L) was present in 20 (17%) patients and enriched in those with U2AF1 mutations (n = 9). ASXL1 mutations rarely occurred in conjunction with SF3B1 mutations (p = 0.007). Among all patients with splicing mutations, median OS was 60.6 months. Median OS was decreased in patients with SRSF2 mutations (33 vs 106 months, p=0.001) compared to those with other splicing mutations. Median OS was increased in patients with SF3B1 mutations compared to patients with other splicing mutations (181 mo vs 42 mo, p = 0.002). Median OS for patients with U2AF1 and ZRSR2 mutations was 44 and 106 months, respectively. Among patients with U2AF1 mutations, the presence of severe thrombocytopenia was associated with inferior survival (13.9 mo vs not reached, p = 0.045). The presence of an SRSF2 mutation was associated with an increased risk of leukemic transformation (24% vs 3%, p = 0.002). Among patients with SRSF2 mutations, median OS in those with documented leukemic transformation was 32.9 mo compared to 48.7 mo in those without (p = 0.17). CONCLUSIONS: Splicing mutations in MF have unique phenotypic and prognostic correlations. While SRSF2 mutations appear detrimental, SF3B1 mutations correlate with favorable outcomes. While U2AF1 and SRSF2 mutations are considered high-risk in MF, the impact appears driven by cytopenias in the former and leukemic transformation in the latter. This may hold relevance when considering therapeutic approaches in these patients. Disclosures Talati: AbbVie: Honoraria; Jazz: Speakers Bureau; Astellas: Speakers Bureau; BMS: Honoraria; Pfizer: Honoraria. Sallman:Celgene, Jazz Pharma: Research Funding; Agios, Bristol Myers Squibb, Celyad Oncology, Incyte, Intellia Therapeutics, Kite Pharma, Novartis, Syndax: Consultancy. Sweet:Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Stemline: Honoraria; Agios: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria. Padron:Incyte: Research Funding; Kura: Research Funding; BMS: Research Funding; Novartis: Honoraria. Lancet:Abbvie: Consultancy; Agios Pharmaceuticals: Consultancy, Honoraria; Astellas Pharma: Consultancy; Celgene: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; ElevateBio Management: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy. Komrokji:Geron: Honoraria; Novartis: Honoraria; Acceleron: Honoraria; Incyte: Honoraria; Abbvie: Honoraria; Agios: Speakers Bureau; BMS: Honoraria, Speakers Bureau; Jazz: Honoraria, Speakers Bureau. Kuykendall:Blueprint Medicines: Research Funding; BMS: Research Funding; Incyte: Research Funding; Novartis: Research Funding.

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Comorbidities Are Frequent in Older Patients with De Novo Acute Lymphoblastic Leukemia (ALL) and Correlate with Induction Mortality: Analysis of More Than 1200 Patients from GMALL Data Bases

Blood ◽

10.1182/blood-2018-99-111954 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 660-660 ◽

Cited By ~ 3

Author(s):

Wiba Keke Wermann ◽

Andreas Viardot ◽

Sabine Kayser ◽

Nael Alakel ◽

Ahmet Elmaagacli ◽

...

Keyword(s):

Clinical Trials ◽

Board Of Directors ◽

Research Funding ◽

Intensive Therapy ◽

Risk Groups ◽

Advisory Committees ◽

Group 3 ◽

Group 2 ◽

The Impact ◽

Support Research

Abstract Outcome of adult ALL has improved considerably during the past decades by intensive chemotherapy, which still remains a challenge in older pts. This may be partly due to comorbidities. So far there are no standards to differentiate pts who will be able to tolerate even age-adapted chemotherapy (fit vs unfit). In addition, little is known about the prevalence of comorbidities. Clinical trials with new compounds often represent a selection of pts w/o comorbidities. There is also no generally accepted tool for comorbidity scoring. The goal of this analysis is to provide reference data for pre-existing comorbidities in a large set of adult ALL pts, to compare two different tools and to evaluate the impact on early death (ED) in older pts. The German Multicenter Study Group for Adult ALL (GMALL) has collected data from trials for younger (18-55 y) and older (>55 y) pts and from a prospective registry. Trials had very limited exclusion criteria and in the registry there are no exclusion criteria. The Charlson Comorbidity Index (CCI) was assessed in the GMALL Elderly trial, whereas the Sorror Score (HCT-CI) was used in trials for younger pts and in the registry. 879 pts had a documented HCT-CI score from GMALL 08/2013 trial (N=282;group 1) and 3 groups from the registry: >55 y but eligible for intensive therapy (N=56, group 2), > 55 y in GMALL Elderly protocol (N=505, group 3) and >55 y in GMALL Frail protocol (N=36; group 4) (Table 1). In addition the CCI was documented in 333 pts treated in the GMALL Elderly Trial. HCT-CI-Score: The most frequent comorbidities were infections (17%), prior malignancies (16%), diabetes (16%), cardiac (14%) and moderate pulmonary disease (12%), obesity (11%) and mild liver disease (10%). Arrhythmias (<1%, 5%, 12% and 22% resp. in groups 1, 2, 3, 4), cardiac disease (2%, 7%, 19% and 42% resp.), prior malignancies (2%, 11%, 25% and 22% resp.) and diabetes (4%, 16%, 22% and 22% resp.) increased with age. Infections (15%, 18%, 22% and 22% resp.) or obesity (9%, 7%, 11% and 14% resp.) were not strongly correlated to age. Comorbidity rates were lower in pts >55 y (group 2) considered eligible for intensive therapy (57%) compared to those considered for the Elderly protocol (76%) (group 3). The proportion of low risk (LR) scores decreased with age (54%, 43%, 25% and 8% resp.;p=.01), whereas high risk (HR) increased (18%, 25%, 50% and 59% resp; p=.01). CCI: The most frequent comorbidities were prior malignancy (14%), diabetes (25%) with (3%) or w/o (22%) end organ damage, cardiac (11%) and vascular disease (8%). The incidence of prior malignancy within the last 5 y was 7%. Risk classification was: LR (0) 51%, intermediate risk (IMR) (1-2) 42% and HR (≥3) 7%. HCT-CI vs CCI in pts >55 y: With HCT-CI the incidence of heart diseases (21% arrhythmias, cardiac disease or valve damage) was higher compared to CCI (9%), which differentiated better into cardiac failure (7%) and myocardial infarction (4%). Peripheral vascular disease (8% with CCI) is not assessed by HCT-CI. Liver disease was less frequent with CCI (1.5%) vs HCT-CI (14%) due to different definitions, whereas moderate pulmonary disease (12%) or infections (18%) are not assessed by CCI. The incidences of prior malignancies and diabetes were comparable. Of note, the overall incidence of distinct comorbidities e.g. cardiac was lower than the sum of subentities because some pts had several comorbidities. ED in pts >55 y: ED rates in pts >55 y in group 3 and in GMALL Elderly trial were comparable (13% vs 12% resp). In group 3 ED rates in risk groups (HCT-CI) were 7% vs 13% vs 15% (p>.05). In the GMALL Elderly trial ED in risk groups (CCI) were 9%, 12% and 35% (p=.05; p=.003 LR/IMR vs HR). Overall the analysis reveals a high incidence of comorbidities in older (57-92%) and even in younger pts (46%), which partly would represent contraindications in clinical trials with novel compounds; thus real world data in pts with comorbidities are required after marketing authorisation. HCT-CI and CCI have a different focus and shortcomings. For ALL pts a more specific score with different organ modules would be helpful. Comorbidity is significantly correlated to ED risk. CCI allows to identify a small HR group (7%) with a mortality of 35%. HCT-CI (24% of pts) and even more CCI (51% of pts) allow to identify LR groups with <10% early mortality. It will be of interest to analyse the impact of individual comorbidities on ED rate. Overall structured comorbidity assessment should be part of all clinical trials in ALL. Disclosures Viardot: Gilead Kite: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen: Consultancy; BMS: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Fiedler:Teva: Other: support for meeting attendance; Gilead: Other: support for meeting attendance; Amgen: Other: support for meetíng attendance; Pfizer: Research Funding; Amgen: Research Funding; Amgen: Patents & Royalties; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; ARIAD/Incyte: Membership on an entity's Board of Directors or advisory committees, support for meeting attendance; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSO: Other: support for meeting attendance; JAZZ Pharmaceuticals: Other: support for meeting attendance; Daiichi Sankyo: Other: support for meeting attendance. Stelljes:JAZZ: Honoraria; MSD: Consultancy; Amgen: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Honoraria. Serve:Bayer: Research Funding. Goekbuget:Kite / Gilead: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Other: Travel support, Research Funding; Pfizer: Consultancy, Other: Travel support, Research Funding; Amgen: Consultancy, Other: Travel support, Research Funding.

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Clonal Hematopoiesis Driven By MDM4 Amplification Defines a Canonical Route Towards Secondary MDS/AML in Fanconi Anemia Patients

Blood ◽

10.1182/blood-2021-147811 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 860-860

Author(s):

Marie Sebert ◽

Stéphanie Gachet ◽

Thierry Leblanc ◽

Alix Rousseau ◽

Olivier Bluteau ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Clonal Evolution ◽

Point Mutations ◽

Advisory Committees ◽

P53 Pathway ◽

Clonal Hematopoiesis ◽

Mutational Signature ◽

Secondary Mds ◽

Support Research

Abstract Introduction Fanconi anemia (FA) is the most frequent inherited DNA-repair disease in human, driving hematopoietic stem cell (HSC) failure in children and a major predisposition to poor-prognosis myelodysplastic syndrome (MDS) and acute leukemia (AML) in children or young adults. MDS/AML secondary to FA have a dismal prognosis in this frail population with a high chemotherapy-related toxicity. How bone marrow (BM) cells progress to myeloid malignancies in a background of cell intrinsic genomic instability and stem cell exhaustion is still poorly understood. Here we aimed to identify the molecular and functional determinants of BM progression to MDS/AML in FA patients. Methods We studied a cohort of 335 FA patients, representing virtually all FA patients seen in France from 2002 to 2020. We performed longitudinal clinical studies (cytopenia, BM morphology and staging, HSCT, survival), somatic genomics (karyotype, myeloid cancer gene panel, aCGH, WES, WGS), expression analysis by RNAseq on clonal cells, and functional studies (gene modulation in HSPCs, transgenic MDM4 mice, CFU and competitive engraftment experiments). Paired clonal BM and skin fibroblasts samples were available for 62 MDS/AML FA patients; WES and WGS files from age-matched non FA MDS/AML were used as controls. Results 98 out of 335 patients (29%) experienced clonal evolution, first seen at a median age of 13y, including 51 (15%) with blastic evolution (>5% BM blasts, median age 16y). Unbalanced chromosomal translocations rather than point mutations underlaid clonal evolution in comparison to age-matched, sporadic (non-FA) AML cases. The most prominent driver lesion was chromosome 1q duplication (1q+), found in 52% of the clonal FA patients, while other recurrent lesions were gain of 3q (3q+/EVI1; 40%), translocations/del/mut involving the RUNX1 gene (35%), monosomy 7/7q- (31%), and signaling gene mutations (18%). Based on longitudinal studies and ranking models, we evidenced that 1q+ occurred early, yielding preleukemic clonal hematopoiesis, whereas 3q+, -7/del7q, RUNX1 and signaling mutations occurred later along with BM transformation. Regarding genomic instability, WGS analysis of FA AML cells revealed a unique mutational signature that shares features with BRCA-related solid cancers [homologous recombination deficient (HRD)-type substitution signature, accumulation of small/intermediate-size deletions and large structural variants (SV)]. SV breakpoint analysis identified microhomology-mediated end joining (MM-EJ, also known as Alt-EJ) as the preferential DNA repair mechanism in the FA context. Specifically, a fragile site in the 1q pericentromeric repeated region underlaid 1q+ translocations. Next, we found that the MDM4 oncogene, a negative modulator of p53 response located in the minimal 1q duplicated region, was overexpressed in 1q+ but not in clonal non-1q FA cells. We hypothesized that 1q+ may attenuate the FA-associated p53 pathway hyperactivation through increased gene dosage of MDM4. Consistently, RNA-seq of patient cells before and after clonal progression showed p53 pathway activation before clonal evolution and subsequent p53 downregulation along with 1q+. When evaluated in vitro by CFU assay, lentiviral overexpression of MDM4 rescued clonogenicity defect of HSCPs from both FA patients and Fanc-/- mice, at the same level as TP53 knockdown. We produced a transgenic mouse bearing a duplicated Mdm4 locus and showed that MdM4 overexpression conferred an advantage to FA-like HSPCs in competitive transplant experiments, modeling clonal hematopoiesis. Exposure of 1q+ FA cells to Mdm4 inhibitors raised therapeutic potential. Conclusions The somatic genomic landscape of FA MDS/AML reveals a unique FA mutational signature, characterized by structural rearrangements and copy number abnormalities rather than point mutations. Our results define a canonical oncogenic route towards secondary MDS/AML in FA patients, in which the early modulation of the p53 pathway through 1q+/MDM4 oncogene overexpression plays a pivotal role, raising novel monitoring and therapeutic prospects for the FA patients. Disclosures Sebert: BMS: Consultancy; Abbvie: Consultancy. Dalle: Jazz Pharmaceuticals: Honoraria. Socie: Alexion: Research Funding. Peffault De Latour: Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Amgen: Consultancy, Other, Research Funding; Jazz Pharmaceuticals: Honoraria; Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding.

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PET-CT Defined Focal Lesions at Baseline and Day 7 Predict Outcome in GEP 70 Defined High Risk Multiple Myeloma Patients

Blood ◽

10.1182/blood.v124.21.3407.3407 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3407-3407

Author(s):

Yogesh Jethava ◽

Rachel Hunter-Merrill ◽

Gareth J Morgan ◽

Rashid Z Khan ◽

Aasiya Matin ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Cox Regression ◽

Focal Lesions ◽

Advisory Committees ◽

Early Therapy ◽

Time Points ◽

The Impact

Abstract Introduction: Fluoro-deoxy-glucose (FDG) positron emission tomography (PET) scanning is an important state-of-the-art imaging tool in the initial workup of patients with multiple myeloma (MM). We evaluate the impact of PET focal lesions (FL) at baseline (BL), 7 days after starting induction therapy (D7) and prior to first autologous transplant (pre-ACST) in gene expression profiling (GEP 70) defined high risk (HR) multiple myeloma (MM) patients. Patients and methods: 48 GEP 70 HR MM patients were treated uniformly on IRB approved protocol consisting of tandem transplants with dose reduced Mel-80-VRD-PACE (melphalan, velcade, revlimid, dexamethasone, cisplatin, adreamycin, cyclophosphamide and etoposide) and interspersed Mel-20-VTD-PACE (melphalan, velcade, thalidomide, dexamethasone, cisplatin, adreamycin, cyclophosphamide and etoposide) consolidation and VRD (velcade, revlimid, dexamethasone) maintenance. PET examinations were performed at (BL), D7 and pre-ASCT, enumerating FDG-avid FL, their SUV max and extra-medullary disease (EMD).Of the 48 GEP 70 HR patients, 39 had BL, 28 had D7 and 42 had pre-ASCT PET examinations. 20 patients had examinations at all 3 time points. At BL, there were 24 (50%) patients with B2M >5.5mg/L and 26 (54%) with albumin <3.5g/dL. Metaphase cytogenetic abnormalities were documented in 36 (75%) patients, including deletion 13/hypodiploidy in 30 (63%). EMD was present in 3 (8%) patients, 28 (58%) had diffuse SUV <= 2 (median 2.4; range 1.4 to 9.5) and 14 (29%) had FL max SUV >3.9 (median 4.6; range 1.6 to 14.4). Results: From BL, the 3-yr PFS estimate was 46% for the group with no FL and 29% for those with FL (Figure 1a). The corresponding PFS data for the D7 was 53% for no FL at D7 as opposed to 11% for those with FL (Figure 1b), and for pre-ASCT it was 34% for no FL and 33% for those with FL (Figure 1c). Joint consideration of BL and D7 landmark revealed 3-yr PFS of 54% for those with no FL at BL, compared to 40% for those with resolution of BL FL by D7 and 18% for those whose FL did not resolve (log rank p-value=0.09), confirming the significance of FL resolution. Cox regression of PFS revealed that those with FL at BL had 2.34 times the risk of progression or death compared to those with no FL at BL (p=0.075), while those with FL at D7 had 3.27 times the risk (p=0.033). Diffuse SUV and SUV max had no impact on PFS at the three time points. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Fig 1a- PFS from baseline PET Fig 1b- PFS from D7 PET Fig 1c- PFS from pre-ASCT PET Conclusion: The prognosis of GEP 70 HR MM is dominantly affected by BL indicators of MM metabolism, as revealed by FDG uptake in FL. Our analysis in HR GEP70 MM patients confirms that early suppression of FL by D7 was key to improved PFS. MM patients who had absence of FL resolution from BL to D7 had poorer PFS and are candidates for early therapy change. Disclosures Morgan: Celgene Corp: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Myeloma UK: Membership on an entity's Board of Directors or advisory committees; International Myeloma Foundation: Membership on an entity's Board of Directors or advisory committees; The Binding Site: Membership on an entity's Board of Directors or advisory committees; MMRF: Membership on an entity's Board of Directors or advisory committees. Zangari:Norvartis: Membership on an entity's Board of Directors or advisory committees; Onyx: Research Funding; Millennium: Research Funding. van Rhee:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees.

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Retrospective Analysis of 149 Unselected Patients with Mantle Cell Lymphoma Confirms Prognostic Relevance of Mantle Cell Lymphoma International Prognostic Index: Single Center Experience

Blood ◽

10.1182/blood-2018-99-120370 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5331-5331

Author(s):

Guldane Cengiz Seval ◽

Bahar Ulas ◽

Onur Tascı ◽

Fulya Ozel ◽

Buğu Bulat ◽

...

Keyword(s):

High Risk ◽

Mantle Cell Lymphoma ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

International Prognostic Index ◽

Single Center ◽

Advisory Committees ◽

Mantle Cell ◽

Support Research

Abstract Introduction: Mantle cell lymphoma (MCL) is an uncommon subtype of non-Hodgkin lymphoma with distinguishes clinical, biologic, and molecular characteristics. The MCL-International Prognostic Index (MIPI) incorporates age, EGOC performance status, normalized LDH level and WBC and has improved discriminatory power. The aim of this retrospective single-center study was to evaluate the clinical characteristics and response to treatment of patients with mantle cell lymphoma. Methods: This single center retrospective study included 297 adult patients diagnosed with MCL between December 2005 and May 2018. The diagnosis of MCL was rendered in accordance with the later World Health Organization (WHO) classification. Outcome was determined as response to treatment, progression free survival (PFS) and overall survival (OS) by Kaplan-Meier analysis using SPSS (IBM SPSS Statistics 21; IBM Corp., Chicago, IL) statistical tool kit. We also compared the PFS and OS according to simplified MIPI (s-MIPI) index. Results: All clinical data were available in 149 cases and these patients were further evaluated. There were 38 (26%) female and 208 (74%) male patients. The median age at diagnosis of MCL was 66 years (range, 31-93 years). The median time of follow-up was 14.5 months (range, 3-139.3 months). The median s-MIPI was 6 points (range 2-11). Most patients were in the high-risk group (62.2%). Induction chemotherapy was administered in 128/146 patients and remaining two patients had deceased after diagnosis of MCL. Altogether 115 out of 146 patients (78.8%) were treated with a combination of chemotherapy and anti-CD20 monoclonal antibody rituximab.One elderly patient received Rituximab immunotherapy only. The majority (56.5%) of the patients received CHOP with rituximab as induction chemotherapy. Thirty-one patients underwent ASCT after remission was obtained in relapse setting. Sixty-four patients (43.8%) had bone marrow involvement and 23 patients (15.7%) had extra-nodal involvement. In total 40 patients (41.2%) achieved a complete remission (CR) with an overall response rate of 63.9% after the induction therapy. During follow up, 20 relapses and 28 deaths were noted. Infection was the most common cause of death (50%). Following ASCT, OS was significantly improved; estimated median OS in transplant cohort was 115.7 months vs. 60 months compare with non-transplant group (p=0.013) (Figure-2). According to the long-rank test, estimated 5-year OS was not significantly different between intermediate-risk and high-risk s-MIPI categories (72.4%±1.2% vs. 72.6%±0.7%; p=0,202). Estimated 5-year PFS was significantly different between intermediate-risk and high-risk s-MIPI cohorts (47.1%±1.3% vs. 33%±10.3%; p=0,05). Among the transplanted patients, there is no differences between the OS of s-MIPI groups (p=0.952). No patient died or progressed in the low-risk group. Conclusion: We have confirmed the validity of the MIPI and simplifed MIPI for the prognosis of patients with MCL even in the era of rituximab. e general results of both indexes are fully comparable, facilitating the broad application of s-MIPI as a simple bedside prognostic tool. Disclosures Civriz Bozdag: MSD: Research Funding; TAKEDA: Consultancy; NOVARTIS: Consultancy. Özcan:Janssen: Other: Travel Support, Research Funding; Abbvie: Other: Travel payment; Novartis: Research Funding; Takeda: Honoraria, Other: Travel payment, Research Funding; Bayer: Research Funding; BMS: Honoraria; Celgene: Other: Travel support, Research Funding; Roche: Honoraria, Research Funding; Archigen: Research Funding; MSD: Other: travel support, Research Funding; MSD: Research Funding; Jazz: Other: Travel support; Jazz: Other. Beksac:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Deva: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ilhan:Roche: Speakers Bureau; BMS: Speakers Bureau; Celgene: Speakers Bureau; Alexion: Speakers Bureau.

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The Impact of Letermovir (LTV) Prophylaxis on Early Cytomegalovirus Infection (CMVi) and Outcomes in the Adult Allogeneic Hematopoietic Cell Transplantation (alloHCT) Recipients with High-Risk Donor Type

Blood ◽

10.1182/blood-2021-153784 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1776-1776

Author(s):

Sanjeet S Dadwal ◽

Dongyun Yang ◽

Guido Marcucci ◽

Sally Mokhtari ◽

Bernard Tegtmeier ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Standard Of Care ◽

Advisory Committees ◽

Donor Type ◽

The Impact ◽

Grade Iii

Abstract CMV recipient seropositivity (R+) and CMVi are independent risk factors for increased mortality after alloHCT. Preemptive therapy (PET) was standard of care until LTV approval by the FDA in November 2017 for CMVi prevention in CMV R+ alloHCT patients (pts). In a registration trial, LTV led to a significant reduction in clinically significant CMVi (CS-CMVi) defined as CMVi requiring PET in both high-risk (HR) or low-risk (LR) recipients. In the HR-group, defined as mismatched related / unrelated donor with at least one mismatch in one of the four HLA-gene loci of HLA-A, -B, -C or -DRB1, haploidentical donor, umbilical cord source or grade ≥2 acute graft-versus-host disease (aGVHD) at randomization, the impact of LTV on CS-CMVi was more robust. Small studies have confirmed the positive impact of LTV on CS-CMVi. Here, we compared the natural history of CMVi and CS-CMVi between the pre-LTV and LTV era in the first 100 days after HR-alloHCT. We also explored the impact on non-relapse mortality (NRM), overall survival (OS), disease free survival (DFS), and incidence of aGVHD between the two eras. In this IRB approved retrospective study, we identified 450 consecutive HR-alloHCT pts who underwent their first HCT from 1/1/2016 to 12/31/2020 at our center. Pre-LTV era was from 1/1/2016 to 2/28/2018 and LTV era was from 3/1/2018 onwards when prophylaxis became standard of care (SOC) for all R+ alloHCT at our institution. In the HR-alloHCT, the uptake of the new SOC was consistent in all HR-R+ pts beginning LTV prophylaxis on day +7 post-HCT. We defined R+ HR-alloHCT pts at high-risk for CMVi or CS-CMVi as described above except for aGVHD (not recorded at time of institution of LTV). CMVi was defined as first time viral load (VL) of >500 genomic copies/ml (gc/ml). CS-CMVi was defined as a VL >500 gc/ml (910 IU/ml) on two consecutive tests done atleast 48 hours apart, that triggered PET (ganciclovir, valganciclovir, foscarnet, cidofovir), or had identification of CMV end organ disease . The incidence of CMVi and CS-CMVi in R+ allo-HCT was compared by LTV era using Gray test. Kaplan-Meier curves and log-rank tests were used for OS and DFS by LTV era. NRM, relapse, acute and chronic GVHD were compared using cumulative incidence curves and Gray test. All tests were 2-sided at 0.05 level. Of the 450 HR-alloHCT pts, 146 were R+ in pre-LTV vs. 246 R+ in LTV era. R+ patient, their eligible underlying disease, and HCT characteristics are shown in Table 1. There was a significant reduction in both CMVi and CS-CMVi in LTV era vs pre-LTV era (24.1% vs 45.2%, and 22.3% vs 44.5% respectively; p <0.001 for both outcomes) in the first 100 days. Compared to pre LTV era, LTV era was associated with significantly reduced CS-CMVi among R+ pts (HR=0.39, 95%CI: 0.26-0.58, p <0.001) in the multivariable Fine and Gray model adjusted for primary diagnosis, donor type and acute GVHD. CMVi was also reduced in the multivariable model (HR=0.41 and 95%CI: 0.28-0.61, p<0.001). Although there were no significant differences in OS, DFS, NRM, relapse, and chronic GVHD between the two eras at 6, 12, and 18 months post-HCT in R+ pts, a trend towards improved OS and DFS in LTV era was noted (p=0.06 and p=0.07) in this patient population. There was a significantly lower rate of grade III-IV acute GVHD in the LTV era (9.2% vs 17.8% at day 100, p=0.012 with HR = 0.49). No case of CMV disease was identified in the first 100 days. LTV has substantially reduced CS-CMVi in the first 100 days post-HCT in HR-R+ pts and resultant burden from PET. We identified a significant reduction in grade III - IV aGVHD in LTV era suggesting that with reduced CMVi, LTV may have a salutary impact on development of aGVHD; this is in agreement with studies showing bidirectional relationship between CMVi and onset of aGVHD. We did not observe a significant difference in OS, DFS, NRM amongst the two eras but there was trend towards higher OS and DFS in LTV era that requires further assessment in a larger multicenter cohort. Lastly, significant burden persists from CS-CMVi in this patient population during the first 100 days of alloHCT that underscores the need of efforts to identify other novel methods to mitigate it. One of the limitations in the LTV era is identifying the clinical scenarios surrounding the CMVi and CS-CMVi that may relate to compliance, absorption from gastrointestinal tract, and affordability or coverage of LTV after discharge from hospital. Figure 1 Figure 1. Disclosures Dadwal: Astellas: Speakers Bureau; Aseptiscope: Consultancy; AlloVir: Research Funding; Shire/Takeda: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Other: Investigator; Karius: Other: Investigator. Marcucci: Novartis: Other: Speaker and advisory scientific board meetings; Agios: Other: Speaker and advisory scientific board meetings; Abbvie: Other: Speaker and advisory scientific board meetings. Taplitz: Merck: Membership on an entity's Board of Directors or advisory committees. Artz: Radiology Partners: Other: Spouse has equity interest in Radiology Partners, a private radiology physician practice. Stein: Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; Stemline: Speakers Bureau. Forman: Allogene: Consultancy; Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company. Al Malki: Neximmune: Consultancy; Jazz Pharmaceuticals, Inc.: Consultancy; CareDx: Consultancy; Rigel Pharma: Consultancy; Hansa Biopharma: Consultancy.

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