Higher Incidence of Secondary AML and Adverse Molecular Markers, Together with Lower CR and Higher AML Related Death Rates in Elderly Compared to Younger Patients: Results from 2435 Patients Included in the Two German AML Intergroup Studies

Abstract Background The German AML Intergroup conducted two randomized studies in younger (<60 years) and elderly (≥60 years) patients in which the study arms were compared to a common standard arm. Here, we compared the two studies in younger and elderly patients focusing on disease characteristics and outcome. Patients and Methods The East German Study Group (OSHO) and the Acute Myeloid Leukemia Cooperative Group (AMLCG) each entered patients from 18 to 59 years into one study and patients aged 60 years and older into another. Each study group randomized upfront 10% of all AML patients into a common standard arm and 90% in the study group specific arm. All patients with de novo AML or AML after myelodysplastic syndrome or cytotoxic treatment were eligible. Chi-squared and Mann-Whitney-U tests were used to detect significant differences between the age groups regarding demographic, clinical and cytogenetic characteristics at baseline. Complete Remission (CR) at 90 days and cumulative probabilities of death were determined for outcome. To avoid bias due to the higher probability of death in older patients, cumulative probabilities of death were calculated for relapsed patients or those who did not achieve CR after 90 days. Other deaths were considered as a competing risk. Results A total of 2435 AML patients were analyzed, 1132 in the study <60 years and 1303 in the study ≥60 years. Significant differences in patient characteristics were noted between the studies. The elderly patient group contained a higher proportion of males than the younger group (55% vs 49% respectively, p=0.0031) and a higher percentage of secondary AML (40% vs 21% respectively, p<0.0001). In contrast, younger patients had higher median WBC count [13x109/L (range 0.03-798) for <60 years and 6.9x109/L (range 0.23-450) for ≥60 years, p<0.0001] and higher median lactate dehydrogenase [442U/L (range 35-19,624) for <60 years and 350U/L (range 51-9,486) for ≥60 years, p<0.0001]. Cytogenetic risk was similarly distributed in both groups (favorable: 12% in both age groups, intermediate: 66% in <60 years and 63% in ≥60 years, adverse: 22% in <60 years and 25% in ≥60 years, p=0.1672). However, the favorable combination of FLT3-ITDwt and NPM1mut in normal karyotype was more common in the younger (35%) than in the older group (27%; p=0.0212). A higher rate of CR at 90 days was observed in the younger (66%) than in the older (51%) patients (p=<0.0001). Of the younger patients 14.8% died (3.8% with persisting AML, 3.3% without AML and 7.7% without evaluable disease status) while of the older patients 21.8% died (6.2% with persisting AML, 2.5% without AML and 13.1% without evaluable disease status) during this period (p=0.0001). Relapse at 90 days was seen in 1% of the younger and in 2% of the older patients. The cumulative probability of AML-related death was lower in younger patients than in older patients (p<0.0001). Of the younger patients 29% (95% CI: 26% to 31%) and 44% (95% CI: 40% to 46%) died after one and three years due to AML; in the older group the corresponding frequencies were 45% (95% CI: 42% to 48%) and 62% (95% CI: 59% to 65%; Figure 1a). The probability of dying from AML was lowest for the younger patients with de novo AML [27% (95% CI 24% to 29%) at 1 year and 41% (95% CI 38% to 44%) at 3 years] and highest for those with secondary AML [38% (95% CI 32% to 44%) at 1 year and 56% (95% CI 49% to 62%) at 3 years (p=0.0001)], with similar differences being observed in the older patients (p=0.0001, Figure 1b). In the younger patients, CR at 90 days was lower in the standard (58%) than in the study arm (66%, p=0.0558), while AML related death was 29% and 27% at 1 year and 44% and 39% at 3 years respectively. In the older patients CR at 90 days was 52% vs. 51%, AML related death at 1 year 45% and 45% and at 3 years 63% and 69% for study arm and standard arm, respectively (Figure 1c). Conclusion This analysis reveals significant differences in gender, laboratory characteristics and proportion of secondary AML in elderly compared to younger AML patients. While there was no clear difference in cytogenetic risk groups, favorable molecular markers were more frequent in younger patients. Clear differences in CR rates after 90 days of therapy and AML related death rate were seen in regard to age (<60 years and ≥60 years) and disease type (de novo and secondary AML). As the common standard arm in both of the studies was age adapted, the differences between the two age groups are likely to be related to disease biology. Disclosures Niederwieser: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hoffmann:Novartis Oncology Europe: Research Funding. Krug:Sunesis; Clavis Pharma; usa Pharma, Catapult Cell Therapy, Gilead, Roche: Membership on an entity's Board of Directors or advisory committees; Sunesis: Speakers Bureau; Boehringer Ingelheim: Research Funding; Novartis; BMS; Roche; Boehringer Ingelheim; Bayer: Honoraria. Hegenbart:Janssen: Honoraria, Other: travel support. Pfirrmann:Novartis Pharma: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Kraemer:TEVA: Other: travel support. Al-Ali:Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding.

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Comparison of Peripheral Blood Stem Cell Mobilization for Multiple Myeloma Patients over 70 Years of Age with Younger Patients

Blood ◽

10.1182/blood-2018-99-117498 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4554-4554

Author(s):

Ning Dong ◽

David S Siegel ◽

Phyllis McKiernan ◽

Noa Biran ◽

Alan P Skarbnik ◽

...

Keyword(s):

Board Of Directors ◽

Older Patients ◽

Research Funding ◽

Age Groups ◽

Disease Status ◽

Cell Yield ◽

Disease Stage ◽

Age Group ◽

Advisory Committees ◽

Younger Patients

Abstract Background: Autologous stem cell transplantation (ASCT) is increasingly offered to older patients with multiple myeloma (MM) based on clinical trials demonstrating improved outcome. Inherently, successful mobilization and collection of peripheral blood stem cells (PBSC) is necessary for ASCT. A direct comparison of the efficacy of mobilization between elderly and younger patients has not been reported. Retrospective studies demonstrated that older patients had lower CD34+ cell yield and a higher incidence of mobilization failure (Lee et al 2014, Muchtar et al 2016). In this retrospective study, we compared two age groups (>/=70 years and <70 years) in MM patients who received ASCT at the John Theurer Cancer Center. We compared the outcomes of PBSC mobilization and transplantation between the two groups. Methods: MM patients who received a single ASCT at our institution between 2005 and 2016 were included. More than 95% of patients received either cyclophosphamide-based chemotherapy with GCSF (CY-GCSF) or plerixafor with GCSF (Pleri-GCSF) and were included in the analysis. We identified 111 patients aged >/= 70 years and 315 patients <70 years. The total CD34+ cell yield, number of apheresis sessions and CD34+ yield per session were compared by age group and mobilization regimen using the student's t-test. Multivariate analysis was performed using the general linear model with age group, mobilization regimen, age and mobilization agent interaction, Durie-Salmon (DS) stage, disease status at mobilization, and mobilization within 12 months of diagnosis as covariates. Progression-free survival (PFS) and overall survival (OS) were compared using Cox proportional hazard model with the above-mentioned covariates. All analyses were done using SAS 9.4. Results: Patient characteristics and CD34+ cell yield by age group are summarized in Table 1. The majority of patients in both groups underwent mobilization within one year of diagnosis. Older patients were less likely to receive CY-GCSF and more likely to receive Pleri-GCSF compared to younger patients (p<0.001). Disease status at mobilization, time from diagnosis to mobilization and DS stage were not associated with choice of mobilization regimens (p>0.05 for all). The two groups had similar number of apheresis sessions regardless of mobilization regimen. When receiving Pleri-GCSF, the two age groups had similar CD34+ yield per apheresis (4.4x10e6 /kg and 3.9x10e6 /kg for age>/=70 and age<70, respectively, p=0.49). However when receiving CY-GCSF, the older patients had lower CD34+ yield per apheresis compared to the younger patients (5.4 x10e6 /kg and 7.5 x10e6 /kg, respectively, p=0.004). When comparing the CD34+ yield per session within the older cohort, the yields with CY-GCSF and Pleri-GCSF were similar (p=0.16). In the multivariate analysis including all patients, time from diagnosis to mobilization, disease stage and disease status at mobilization were not associated with CD34+ yield per session or total CD34+ yield. Neither age nor mobilization regimen was associated with PFS or OS, after adjusting for disease stage and disease status at ASCT (Table 2, Figure 1, Figure 2). Conclusions: CD34+ yield was comparable between younger patients and older patients receiving plerixafor + GCSF. In contrast, the CD34+ yield was lower in the older patients receiving cyclophosphamide + GCSF. The cause of the difference is not clear and warrants further study. The PFS and OS were comparable between the two groups after ASCT. The choice of mobilization regimen did not affect survival. We have previously advocated cyclophosphamide mobilization in most patients because of the higher CD34+ yield and lower cost compared to plerixafor + GCSF (Panchal et al., ASH 2017). However this study showed that the CD34+ yield was not significantly different for patients aged 70 years or older in response to the different mobilization regimens. It is reasonable to consider plerixafor + GCSF in the elderly when chemotherapy toxicity is of concern. Disclosures Siegel: Karyopharm: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Biran:Amgen: Consultancy, Speakers Bureau; Merck: Research Funding; Celgene: Consultancy, Honoraria, Speakers Bureau; BMS: Research Funding; Takeda: Consultancy, Speakers Bureau. Skarbnik:Gilead Sciences: Honoraria, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Speakers Bureau.

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Efficacy of Single-Agent Decitabine in Relapsed and Primary Refractory (rel/ref) Acute Myeloid Leukemia (AML)

Blood ◽

10.1182/blood.v126.23.2518.2518 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2518-2518

Author(s):

Andrew Hantel ◽

Niloufer Khan ◽

Richard A. Larson ◽

Lucy A. Godley ◽

Michael J. Thirman ◽

...

Keyword(s):

Board Of Directors ◽

Genetic Risk ◽

Research Funding ◽

De Novo ◽

Median Number ◽

Advisory Committees ◽

Secondary Aml ◽

Induction Regimen ◽

De Novo Aml ◽

Wbc Count

Abstract Introduction Improving therapy for rel/ref AML remains a challenge. Decitabine, a DNA methyl-transferase inhibitor, initially showed promise in AML as a 5-day, first-line induction regimen and more recently as a 10-day regimen in older and unfit patients (1). However, little is known about the activity of decitabine in the rel/ref patient population despite increased use. Therefore, we sought to analyze the outcomes of these pts treated at our institution. Methods To obtain data regarding decitabine efficacy in rel/ref AML, we performed a retrospective analysis of outcomes following decitabine treatment in 34 adult pts treated at The University of Chicago from January 2009 to June 2014. Permission to access patient charts was granted by the medical centerÕs Institutional Review Board. AML was defined by WHO criteria, genetic risk grouping and complete remission (CR) was according to ELN classification; PR was defined as >50% decrease in bone marrow blasts and normalization of blood counts. Rel/ref AML was defined as either having had a prior CR with recurrence of disease or having received a prior induction regimen (1-2 cycles) without CR. Results Median pt age was 62 yrs (range, 18-81) and 60% were male. Median Charlson comorbidity index (CCI) was 5 (range, 0-8); 29% had ECOG performance status 0-1 and 71% had >2. 21 pts (62%) had de novo AML (7 with myelodysplasia-related changes), 3 (9%) had therapy-related myeloid neoplasm (t-MN), and 10 (29%) had secondary AML after myelodysplastic syndrome. 6% were in the ELN favorable genetic group, 3% intermediate-I, 18% intermediate-II, and 67% adverse; 2 cases were unevaluable. The median number of prior treatment regimens was three. 9% had received prior azacitidine, 85% had received prior HiDAC, and 38% had a prior allogeneic stem cell transplant (SCT). 34 pts received a total of 71 cycles of decitabine, 20 mg/m2 daily, in 5 or 10-day cycles every 28 days. All patients received 10-day courses, 91% had an initial 10-day course, and 74% had only 10-day courses. The median number of cycles per pt was 2; 59% received >1 cycle. 7 (21%) achieved CR and 4 (12%) had a partial response (PR), for an overall response rate (OR) of 33%. Responses occurred in 24% of pts with de novo AML, 66% with t-MN, and 50% with secondary AML. Intermediate and adverse group pts had OR of 14% and 39%, respectively. All pts achieving CR did so after 1 cycle; PR required a median of 3 cycles. Pts who achieved CR or PR had a significantly lower pretreatment WBC count (median, 9.5 vs 49.5 x 103/µL in non-responders; p=0.015) and blast percentage (44 vs 59.4; p=0.035) than those who did not. Pts with secondary AML or t-MN had a higher probability of OR compared to those with de novo AML (54 vs 23%; p=0.042). Median overall survival (OS) of all pts was 256 days; prior SCT was associated with reduced OS (p=0.017). When comparing de novo to secondary AML & t-MN, 1-year OS was not significantly different (Figure 1). Responders had a significantly longer OS (median, 622 days vs 278 days for non-responders; p=0.012). Age, race, CCI, ECOG PS, genetic risk group, prior HiDAC, dysplasia, azacitidine, and number of prior treatments did not impact OR or OS. 16 (47%) pts proceeded to SCT. During treatment, 70% had a grade 3-4 non-hematologic toxicity (based on NCI CTACE v4.0); the most common was fatigue. The median number of hospitalizations for complications per patient was 2 (range, 0-7). Causes of hospitalization were febrile neutropenia (40%), infection (22%), cytopenias (18%), rash (6%), acute kidney injury (6%), and 8% were for other causes. Conclusion Decitabine treatment of 34 adults with rel/ref AML resulted in an OR of 33% (21% CR) and allowed nearly one-half of these pts to proceed to SCT. All pts achieving CR did so after 1 cycle. Responding pts had improved OS over those without response (p=0.012). Interestingly, secondary AML or t-MN were 7.8 times more likely to achieve a response compared to de novo AML (p=0.046); lower WBC count and marrow blast percentage also correlated with higher OR. Further delineation of molecular subsets associated with response to decitabine should be evaluated in a larger prospective trial in this high-risk AML population. Citation 1. Blum KA, et al. Phase I trial of low dose decitabine targeting DNA hypermethylation in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: dose-limiting myelosuppression without evidence of DNA hypomethylation. Br J of Haem. Jul 2010;150(2):189-195. Figure 1. Figure 1. Disclosures Off Label Use: Decitabine is indicated for treatment of MDS but is often used to treat newly diagnosed or relapsed/refractory AML. In this study we analyzed results of patients with AML who were treated with decitabine in the relapsed/refractory setting.. Thirman:AbbVie: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead: Research Funding; Merck: Research Funding; AbbVie: Research Funding; Gilead: Research Funding; Merck: Research Funding. Odenike:Sunesis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Liu:Astra Zeneca/Medimmune: Consultancy; Pfizer: Consultancy; Astra Zeneca/Medimmune: Consultancy; Pfizer: Consultancy. Stock:Gilead: Membership on an entity's Board of Directors or advisory committees.

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Comparison of Outcomes of Haploidentical Peripheral Blood Stem Cell Transplantation with Post-Transplant Cyclophosphamide in Older Versus Younger Patients

Blood ◽

10.1182/blood-2020-141966 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 27-27

Author(s):

Giacomo Adoncecchi ◽

Ambuj Kumar ◽

Rawan Faramand ◽

Hien D. Liu ◽

Farhad Khimani ◽

...

Keyword(s):

Board Of Directors ◽

Older Patients ◽

Research Funding ◽

Chronic Gvhd ◽

Age Groups ◽

Group Versus ◽

Survival Outcomes ◽

Advisory Committees ◽

Younger Patients ◽

Two Age Groups

Introduction: Previous studies have demonstrated that allogeneic haploidentical (haplo) peripheral blood stem cell transplantation (PBSCT) with post-transplant cyclophosphamide (PTCy) yields improved progression free survival (PFS) when compared to haplo bone marrow transplant (BMT) with PTCy, attributable to lower relapse without an increase in non-relapse mortality (NRM) (Bashey, et al. JCO. 2017). However, haplo PBSCT results in higher rates of graft-versus-host disease (GVHD) which may negate these benefits in older patients who are more susceptible to transplant related toxicity. Thus, evaluation of the outcomes of haplo PBSCT with PTCy in older patients is warranted. Methods: We retrospectively evaluated 121 adult patients with hematologic malignancies treated at the Moffitt Cancer Center with allogeneic T-cell replete PBSCT from a haplo donor followed by PTCy-based GVHD prophylaxis. Data were extracted from the Moffitt BMT Research & Analysis Information Network (BRAIN) database. Myeloablative (n=70, 58%) and reduced intensity (n=51, 42%) conditioning regimens were included. Transplant related outcomes were compared between two age groups: <60 years (n=66) versus >60 years (n=55). Associations with transplant related survival outcomes were assessed using univariate and multivariate Cox proportional hazard survival models. Fine and Gray regression models were used to assess associations of transplant related endpoints with competing risks. Kaplan-Meier curves and cumulative incidence function curves were also plotted. Results: The median age at the time of transplant was 42 years (range: 20-59) for the younger group and 66 years (range: 61-75) for the older group. The median follow-up was 17 months (range: 2-53) for the entire cohort. Younger patients were more likely to receive myeloablative conditioning (83% versus 27%, p<0.001). Baseline characteristics were otherwise similar. Neutrophil engraftment (>500/uL) by day 30 did not differ significantly between the younger and older group (98% versus 93%, p=0.26). However, the median time to neutrophil engraftment was faster in the younger group versus the older group (16 versus 21 days, p<0.001). Platelet engraftment (>20,000/uL) by day 90 was achieved in 92% in the younger group versus 76% in the older group (p=0.03). The time to platelet engraftment was faster in the younger group: 28 days versus 36 days (p=0.006). At day 100, the cumulative incidence (CuI) of grade II-IV acute GVHD in younger patients was 42% (95% CI 29-61%) and for older patients was 35% (95% CI 22-55%, p=0.82). The CuI for grade III-IV acute GVHD for the younger and the older groups were 8% (95% CI 4-25%) and 15% (95% CI 7-38%, p=0.23), respectively. At 2 years, the CuI of chronic GVHD was 67% (95% CI 55-82%) for younger patients versus 56% (95% CI 38-82%) for older patients (p=0.20). NRM for the younger group and the older group, respectively, was 6% (95% CI 2-16%) versus 19% (95% CI 11-34%) at 100 days and 14% (95% CI 6-30%) versus 22% (95% CI 13-37%) at 2 years (p=0.17). The CuI of relapse at 2 years was not significantly different between the two age groups, with the younger recipients having a CuI of 42% (95% CI 20-60%) and the older group 31% (95% CI 17-56%, p=0.70). The 2-year DFS was similar between the younger and older group, respectively: 51% (95% CI 36-66%) and 53% (95% CI 37-70%, p=0.72). Similarly 2-year overall survival (OS) for the younger group was 59% (95% CI 44-74%), while the older group was 66% (95% CI 52-80%, p=0.92). In multivariate analysis, NRM was superior in the younger group (HR=0.31, 95% 0.12-0.82, p=0.02). Otherwise, age was not associated with engraftment, risk of acute or chronic GVHD, relapse, DFS, or OS. Conclusion: Our results demonstrate that outcomes following allogeneic haplo PBSCT with PTCy in patients >60 years approximate outcomes in patients <60 years. While NRM was inferior in the older patient group, this difference did not result in significant differences in long term OS or DFS. Instead, other variables such as the hematopoietic comorbidity index and the disease risk index were better indicators of survival outcomes. Additionally, these survival outcomes with haplo PBSCT with PTCy appear to be similar to prior published data with haplo BMT with PTCy in older patients (Kasamon, et al. JCO. 2015). Based on this study, haplo PBSCT with PTCy is an appropriate transplant platform for elderly patients. Disclosures Khimani: Bristol Myers Squibb-Moffitt-Alliance: Research Funding. Nishihori:Novartis: Other: Research support to institution; Karyopharm: Other: Research support to institution. Pidala:Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Takeda: Research Funding; Janssen: Research Funding; Johnson and Johnson: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding; BMS: Research Funding. Bejanyan:Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees.

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Breaking the Glass Ceiling of Age in Transplant in Multiple Myeloma

Blood ◽

10.1182/blood-2019-124804 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 782-782 ◽

Cited By ~ 3

Author(s):

Pashna N. Munshi ◽

Parameswaran Hari ◽

David H. Vesole ◽

Artur Jurczyszyn ◽

Jan Zaucha ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Older Patients ◽

Research Funding ◽

Age Groups ◽

Karnofsky Performance Score ◽

Age Group ◽

Advisory Committees ◽

Younger Patients ◽

Equity Ownership

Background: Autologous hematopoietic cell transplantation (AHCT) is an effective treatment to achieve deep and durable remission in multiple myeloma (MM). Typically, AHCT is offered to patients <70 years of age, although the median age of diagnosis of MM is 70 years. We compared the outcomes of upfront AHCT across age groups for newly diagnosed MM in the era of novel therapies using the Center for International Blood and Marrow Transplant Research (CIBMTR) database. Methods: We analyzed the outcomes of 15,999 MM patients aged 20 years and older from the USA who received a single AHCT with melphalan conditioning within 12 months of diagnosis between 2013 and 2017 and reported to the CIBMTR. Multivariate analysis was performed for non-relapse mortality (NRM), relapse/progression (REL), progression-free survival (PFS) and overall survival (OS) using Cox proportional hazards model with age at transplant in decades as the main effect. Hazard ratio (HR) with 95% confidence intervals (CI) are reported. Because of the large sample size, a p-value of <0.01 was considered significant a priori. Results: Table 1 shows patient, disease and treatment characteristics by age group at diagnosis. All age groups had similar distribution of gender, race, ethnicity, Karnofsky performance score (KPS), comorbidity index (HCT-CI), stage III by Durie-Salmon/International Staging System. There was a higher proportion of high-risk cytogenetics in patients ≥70 years (30%), compared to age group 40-49 years (24%) and 20-39 years (20%) in this population. Older patients were more likely to be White compared to younger patients: 85% ≥70 compared to 64% 20-39 years. While 82% of the overall population received melphalan 200 mg/m2, 58% of the ≥70% received Mel 140 mg/m2. There were more ASCT performed in the ≥70-year age group in 2017 (28%) compared to 2013 (15%). Univariate outcomes by age groups shown in Table 2 revealed that 100-day NRM was higher in ≥70 years at 1% compared to younger patients (p <0.01) and 2-year OS was lower in ≥70 years at 86 (85-88)% compared to 60-69 years, 89 (88-89)% (p<0.01). When adjusted for other variables (Table 3), compared to reference age group of 60-69 years, patients ≥70 had similar NRM (HR 1.3, 95% CI 1, 1.7, p 0.06), REL (HR 1.03, 95% CI 0.9, 1.1, p 0.6), PFS (HR 1.06, 95% CI 1, 1.2, p 0.2), and OS (HR 1.2, 95% CI 1, 1.4, p 0.02). The leading cause of death across all age groups was primary disease. Among the ≥70 years cohort, melphalan dose was a surrogate for worse outcomes including NRM at 100 days (Mel 140, 1 (1-2)% vs Mel 200 0 (0-1)%, p 0.003, PFS at 2 years Mel 140 64 (60-67)% vs Mel 200 69 (66-73)%, p 0.003, and OS at 2 years (Mel 140 85 (82-87)% vs Mel 200 89 (86-91)%, p 0.01) (Figure). Conclusions: This is the largest study of AHCT in older adults with MM. More MM patients ≥70 years are being transplanted in the US over time. While our data may highlight referral and access biases regarding which older patients may be referred for ASCT, our results confirm that patients ≥70 years can undergo transplant safely and achieve similar benefits as 60-69 years' old patients. Our results also suggest that melphalan 200 mg/m2 may be given safely in the ≥70 years population. While melphalan conditioning dose 140 mg/m2 in the ≥70 group is associated with worse outcomes, this is likely a surrogate for higher frailty and comorbidities in this cohort of patients. Our analysis confirms that AHCT has similar benefits in terms of disease control (REL and PFS) in both young and older MM patients. This benefit is seen even in a contemporaneous era where proteasome inhibitors and/or immunomodulator drugs are used in upfront treatment. Thus, AHCT remains a safe consolidation therapy across all age groups of MM patients. Disclosures Hari: Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; Cell Vault: Equity Ownership; AbbVie: Consultancy, Honoraria. Kumar:Janssen: Consultancy, Research Funding; Takeda: Research Funding; Celgene: Consultancy, Research Funding. Shah:Poseida: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; University of California, San Francisco: Employment; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; Indapta Therapeutics: Equity Ownership; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees. Qazilbash:Genzyme: Other: Speaker; Bioclinical: Consultancy; Amgen: Consultancy, Other: Advisory Board; Autolus: Consultancy. D'Souza:EDO-Mundapharma, Merck, Prothena, Sanofi, TeneoBio: Research Funding; Prothena: Consultancy; Pfizer, Imbrium, Akcea: Membership on an entity's Board of Directors or advisory committees.

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Mutational Landscape of Pediatric Acute Myeloid Leukemia: A Report of the AML-BFM Study Group with a Targeted NGS Approach in 525 Patients Integrating De Novo, Relapsed and Secondary AML

Blood ◽

10.1182/blood-2019-129778 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1398-1398 ◽

Cited By ~ 1

Author(s):

Christiane Walter ◽

Markus Schneider ◽

Nils Von Neuhoff ◽

Helmut Hanenberg ◽

Dirk Reinhardt ◽

...

Keyword(s):

Research Funding ◽

Pediatric Patients ◽

De Novo ◽

Fine Tuning ◽

Study Group ◽

Secondary Aml ◽

Mutational Landscape ◽

Advisory Boards ◽

De Novo Aml ◽

Pediatric Aml

Background: Recent studies in adults revealed the complexity of the genetic profiles of AML blasts that are used for fine-tuning of the risk-adapted treatment regimens. It is known, that recurrent translocations detected at diagnosis are largely preserved at relapse in the AML blasts. However, the molecular landscape and clonal evolution of small indels and missense alterations in the blasts assessed by NGS has not been well analyzed yet for pediatric AML patients, neither for primary and relapsed children and adolescents nor for patients with secondary AML. Here, we present the implications of our amplicon-based targeted sequencing efforts in a large cohort of pediatric patients with de novo AML or secondary AML at diagnosis and relapse. Patients and Methods: In total, samples from 525 AML patients (age <18 years) registered by the AML-BFM study group in Germany from 11/2000 until 04/2019 were analyzed here (de novo AML, n=449; secondary AML, n=13; first relapse n=63). Paired diagnostic and relapse samples were available from 45 patients. Sequencing was performed using the TruSight Myeloid panel (Illumina) on a MiseqDX device detecting somatic alterations in 54 genes associated with myeloid malignancies. On average, we achieved a 500X coverage in ≥95% of the target regions. We excluded intronic, synonymous and variants with an allele frequency below 5% and a read depth below 50 reads. Five-year probabilities of overall survival (pOS) and event-free survival (pEFS) were determined by Kaplan-Meier analysis in SPSS (IBM SPSS Statistics version 25). Results: In this large population of 525 pediatric patients, 632 mutations were detected in 40 out of 54 genes (74%). In total, 448 (80%) mutations in 9 genes (ASXL1, CEBPA, FLT3, KIT, KRAS, NPM1, NRAS, PTPN11 and WT1) were present in ≥3% of de novo AML patients. In ≥3% of relapsed patients, 48 (78%) mutations have been identified in 10 genes (CEBPA, FLT3, KIT, NPM1, NRAS, PHF6, PTPN11, RUNX1, TP53 and WT1). Although patient numbers were limited for secondary AML, data indicate a largely overlapping profile of affected genes. The median number of mutations per patient was low (n=1) in all 3 subgroups. However, 20% of the patients with de novo AML and 12% of relapsed patients had ≥ 3 mutations. Patients with more than 4 mutations have been only identified in de novo AML. The number of mutations per patient did not have a prognostic impact, analyzed in an uniformly treated subgroup of patients (pEFS: p=0.358; pOS: p=0.261). The comparison of paired samples (diagnosis/relapse) revealed the presence of three categories: Mutations only present at diagnosis for de novo AML samples, mutations that persisted through relapse and mutations that were newly gained at relapse. 39% of initially detected mutations (28 out of 72) persisted in the respective relapse samples with the highest stability in CEBPA, FLT3, KIT and WT1. In contrast, 61% (44 out of 72 initial mutations) were not detected and 45% (25 out of 54 relapse mutations) have been gained within the disease progress. The genetic profile changed from de novo AML to relapse in most patients (n = 34; pOS= 41 ± 15%). However, it has been found to be stable in 24% (n = 11; pOS 21±17%; p= 0.49) of the patients. Conclusions: This analysis elucidates the mutational landscape of both pediatric de novo and secondary AML as well as the genetic evolution of pediatric relapsed AML. Very high numbers of mutations per patient only occurred in de novo AML patients. In contrast to the assumed stability of recurrent translocations, the mutational landscape changed during disease progression in most of the patients. Whether these altered clones detectable at relapse were already present at the initial diagnosis, albeit at low frequency, or occurred de novo during treatment is very challenging to answer in pediatric AML due to the often very limited sample sizes. Either new single-cell sequencing approaches and/or analysis after expanding the cells in xenotransplantation models will provide more insights. Of note, modification of the sequencing panel would be beneficial for future studies due to the fact, that 26% of genes included were not affected by mutations. Disclosures Reinhardt: Jazz: Other: Participation in Advisory Boards, Research Funding; Novartis: Other: Participation in Advisory Boards; Roche: Research Funding; CSL Behring: Research Funding.

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Patient Characteristics and Outcomes in Adolescents and Young Adults (AYA) with Acute Myeloid Leukemia (AML): Princess Margaret Cancer Centre Experience

Blood ◽

10.1182/blood-2019-125449 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2609-2609

Author(s):

Muhned Alhumaid ◽

Georgina S Daher-Reyes ◽

Wilson Lam ◽

Arjun Law ◽

Tracy Murphy ◽

...

Keyword(s):

Board Of Directors ◽

Older Patients ◽

Myeloid Leukemia ◽

Research Funding ◽

Age Groups ◽

Treatment Strategies ◽

Patient Characteristics ◽

Cancer Center ◽

Advisory Committees ◽

Disease Behavior

Introduction: Clinical outcomes of acute myeloid leukemia (AML) in adolescents and young adults (AYA) are rarely reported as an isolated subgroup. Treatments vary little across age groups, and treatment intensity depends upon comorbid conditions and performance status. Optimal treatment strategies focused on disease behavior, biological factors, and the distinct needs of this subset of AML patients remain elusive. The purpose of this retrospective analysis is to determine the characteristics and outcomes of AYA AML patients treated at a specialized adult leukemia cancer center in comparison to older adults with AML (40-60 years). Methods: A retrospective analysis was performed on all patients treated at Princess Margaret Cancer Center from 2008-2018. Patients with acute promyelocytic leukemia were excluded. Clinical characteristics, treatment strategies, and survival outcomes were recorded for all patients. Overall survival (OS) and disease-free survival (DFS) rates were calculated using the Kaplan-Meier product-limit method and the impact of covariates were assessed using the Log-rank test. Finally, we compared the outcomes of AYA patients treated at our centre between 2015-2018 with older patients. Results: A total of 175 patients aged 18-39 were identified. Patient characteristics are shown in (Table 1). Cytogenetic were available in 163 patients. Based on MRC criteria, 27 (16%) were favorable risk, intermediate in 95 (54%), adverse in 39 (22%), and missing/failed in 14(8%). NPM1 status was available in 110 patients of whom 38 (35%) were positive. FLT3-ITD was available in 67 patients with 24 (36%) positive. Both mutations were present in 13 (54%) patients. There were no significant differences in terms of risk stratification based on cytogenetic and molecular markers based on age (18-29 vs.30-39) (P= 0.98). Most patients 172 (98%) received induction, 157 (91%) with 3+7, and 15 (9%) with FLAG-IDA. Complete remission (CR) was achieved in 133 (77%) after first induction [120 (76%) after 3+7 and 11 (73%) after FLAG-IDA]. Induction related mortality was low (2%). Of the 39 who did not achieve CR, thirty-four patients received re-induction (13 FLAG-IDA, 16 NOVE-HiDAC, 5 others) with CR in 21 (62%). Overall, 154 (89.5%) achieved CR1. Sixty-four (42%) proceeded to hematopoietic stem cell transplantation (HSCT) in CR1. 59 (38%) patients relapsed in CR1 with 8 (12%) relapsing post HSCT. Fifty-five (5 post HSCT) patients received reinduction with 30 (51%) (2 after HSCT) achieving CR2. Fifteen patients received HSCT in CR2. OS and DFS at 2 years were 62% (95% CI 0.53-0.69) and 50% (95% CI 0.41-0.57), respectively. Stratified by cytogenetic risk, OS was 81% for favorable risk, 61% for intermediate, and 50% for adverse risk (P=0.0001), respectively. DFS in these groups was 85%, 57%, and 46 % (P=0.0025), respectively. We further compared outcomes in the 18-29y and 30-39y age groups. The OS was 61.9% compared to 62.5% (P=0.91) and DFS of 52.1% compared to 47% (P=0.65) respectively. On univariate analysis for OS and DFS, cytogenetic risk stratification was the only significant variable (P=0.0004 and P=0.0042). We then compared the outcomes 67 sequential patients aged I8-39 treated from 2014-2018, with those of 176 sequential patients aged 40-60 treated during the same period (table 2). OS at 2 years was not statistically higher in the younger group compared to the older group (66.7% vs. 61.2%, P=0.372). While relapse rate was lower in older patients (15.5% vs. 22.6%, P=0.093), NRM was higher in older patients (29.7% vs. 18.8%,P=0.094). Conclusion: AYA pts. occupy a unique niche amongst AML as a whole. While treatment responses have improved in general, there may be potential for further gains in these patients. Increased tolerance for more intense treatment strategies as well as the incorporation of novel agents into standard treatment protocols may provide a means to optimize care in AYA patients. Finally, research is needed to elucidate biological mechanisms and predictors of disease behavior instead of arbitrary, age-stratified treatment schema. Disclosures McNamara: Novartis Pharmaceutical Canada Inc.: Consultancy. Schimmer:Jazz Pharmaceuticals: Consultancy; Medivir Pharmaceuticals: Research Funding; Novartis Pharmaceuticals: Consultancy; Otsuka Pharmaceuticals: Consultancy. Schuh:Astellas: 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; Pfizer: 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; Teva Canada Innovation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees. Maze:Pfizer Inc: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yee:Astellas: Membership on an entity's Board of Directors or advisory committees; Millennium: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MedImmune: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Research Funding. Minden:Trillium Therapetuics: Other: licensing agreement. Gupta:Incyte: Honoraria, Research Funding; Celgene: 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, Research Funding; Sierra Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Disease Characteristics and Patterns of Care In Elderly Patients (80+ years) with Follicular Lymphoma (FL) In the United States (US); Are Older Patients Treated Differently? Report From the National LymphoCare Study (NLCS)

Blood ◽

10.1182/blood.v116.21.4152.4152 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4152-4152

Author(s):

Chadi Nabhan ◽

Michelle Byrtek ◽

Michael Taylor ◽

Jill Tydell ◽

Jamie H. Hirata ◽

...

Keyword(s):

Older Patients ◽

Research Funding ◽

Age Groups ◽

Treatment Patterns ◽

Disease Stage ◽

Younger Patients ◽

Disease Characteristics ◽

Significant Difference ◽

The Difference ◽

Grade 3

Abstract Abstract 4152 Background: While FL is the most common low-grade lymphoma in the US, median age was less than 60 in patients enrolled on pivotal studies that led to our understanding of disease biology and optimal therapy. It remains unclear whether similar disease characteristics, presentation, prognostic factors, treatment patterns, and outcomes pertain to older patients with FL. No clear guidelines exist on how older patients should be treated and data is lacking as to whether current practice patterns affect their survival and progression. Previous reports on FL in the elderly have been retrospective and single center-based. Methods: The NLCS is a prospective, longitudinal multicenter, observational study that enrolled consecutive newly diagnosed FL patients from 3/2004 through 3/2007 collecting data on disease and patients' characteristics, treatment patterns, and outcome. Using the NLCS data we analyzed information on disease stage, grade, FL International Prognostic Index (FLIPI), B symptoms, and treatment choice for patients <60 years, 60–69 years, 70–79 years, and 80+ years. Either Chi-square or Fisher's exact comparison was used to assess the correlations depending on the sample size of the test. Results: A total of 2,736 pts were enrolled, of which 1,215 (44%) were < 60, 708 (25%) were between 60–69, 549 (20%) were between 70–79, and 264 (9%) were >80. There was a significant difference in grade distribution across the different age groups (p < 0.0001), with 22% of pts 80+ having grade 3 FL vs 17% pts <60. No significant differences across age groups in B symptoms, extra nodal sites, or LDH values were observed. A significant difference in FLIPI score was seen across the age groups (p < 0.0001) where high-score FLIPI was present in 48% of pts 80+ as opposed to 16% of pts <60, although calculating FLIPI might be confounded by the fact that older patients were more likely to not have received a bone marrow (BM) exam with 66% of pts 80+ not having BM exam vs. only 40% of those <60 (p < 0.0001). The difference in FLIPI was mainly due to lower Hgb values as older patients were more likely to have had Hgb < 12 g/dL than younger patients (31% of pts 80+ vs. 15% of pts <60) and to age being a component of the FLIPI index. The difference in FLIPI score across age groups was also observed in patients with grade 3 FL where 53% of pts 80+ had poor FLIPI vs. 15% of pts <60 (p < 0.0001). A statistically significant difference in treatment patterns was found across age groups (p <0.0001). When treatment was implemented, older patients were more likely to have received rituximab (R) monotherapy (37% of 80+ vs. 12% of <60) and less likely to have received R+Chemotherapy (40% of pts 80+ vs. 64% of pts<60). In addition, more pts 80+ were observed compared to those <60 (23% vs. 16%). These differences persisted even in those with advanced stage (III/IV), grade 3 disease, region of diagnosis, and in poor-risk FLIPI. When chemotherapy was used, older patients were less likely than younger patients to receive anthracyclines (p < 0.0001) (31% of pts 80+ vs. 69% of pts<60). Anthracycline use remained significantly different regardless of disease stage, grade, or FLIPI score. Conclusions: To our knowledge, this is the largest prospective data collection available for FL pts 80+ years of age. We demonstrate that these pts have higher FLIPI score and grade 3 disease. When treatment is initiated, these patients receive R monotherapy more often than their younger counterpart. Anthracycline use in this population is also less common regardless of disease stage, grade, or risk profile. Whether these baseline differences translate into different outcomes remains to be seen. Disclosures: Nabhan: genentech: Research Funding, Speakers Bureau. Byrtek:Genentech: Employment. Taylor:Genentech: Employment. Hirata:Genentech: Employment. Flowers:Genentech/Biogen-Idec (unpaid): Consultancy; Celgene, Intellikine: Consultancy; Millennium: Research Funding.

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Sequential Intensified Conditioning Regimen Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients with High-Risk AML in Complete Remission: A Survey from the ALWP of the EBMT

Blood ◽

10.1182/blood.v126.23.3105.3105 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3105-3105

Author(s):

Florent Malard ◽

Myriam Labopin ◽

Gernot Stuhler ◽

Johanna Tischer ◽

Joerg Thomas Bittenbring ◽

...

Keyword(s):

Multivariate Analysis ◽

High Risk ◽

Research Funding ◽

Antithymocyte Globulin ◽

De Novo ◽

Conditioning Regimen ◽

Secondary Aml ◽

Off Label ◽

Advisory Boards ◽

De Novo Aml

Abstract Introduction. Allogeneic hematopoietic cell transplant (HCT) is an established treatment modality that is potentially curative for many patients with acute myeloid leukemia (AML). The development of reduced intensity conditioning (RIC) allows performing HCT in elderly and/or in heavily pretreated patients and in those with comorbidities precluding the use of standard myeloablative conditioning. Post-transplant relapse remains a challenge after RIC, particularly in patients with adverse prognosis factors.The so-called "sequential" transplant approach (e.g. FLAMSA regimen combining both intensive chemotherapy and RIC HCT within the same procedure) initially developed in patients with refractory AML, could be a promising strategy to improve disease control and decrease the risk of relapse in high-risk AML patients in complete remission (CR). Patients and methods. In the current study we analyzed transplantation outcomes in a cohort of 411 adults AML patients in CR at time of transplant, treated between 2002 and 2013. Patients received a "sequential" conditioning regimen based on Fludarabine 30 mg/m2/d, high-dose aracytine 1-2 g/m2/d, amsacrine 100 mg/m2/d for 5 days and after a 3 days rest, total body irradiation (TBI) 4Gy, cyclophosphamide 50-120 mg/kg, and antithymocyte globulin (ATG) for 2 to 3 days (TBI group, n=269 [65%]). In 142 (35%) patients, TBI was substituted by IV Busulfan 3.2 mg/kg/d for 2 days, or orally equivalent dose (Bu group). 323 patients (79%) had de-novo AML and 88 (21%) had a secondary AML (with prior myelodysplastic syndrome). At time of transplant, 300 (73%) patients were in CR1 and 111 (27%) in CR2. Cytogenetic study in de novo AML was favorable in 19 patients (6%), intermediate in 102 (32%) and poor in 41 (13%). Cytogenetic data were missing in 161 (50%). 104 (25%) patients received matched related donors (MRD) and 307 (75%) unrelated donor (URD) HCT. Majority of patients (94%) received mobilized peripheral blood stem cells graft. Results. Median follow-up of surviving patients was 28 months and median age at transplant was 54 years (18-76). ANC>500/μL was achieved at a median of 17 (range, 9-74) days after HCT. Sixteen patients (4%) failed to engraft. Two year cumulative incidence of relapse (RI) and non-relapse mortality (NRM) were 22% (95%CI, 18-26%) and 22% (95%CI, 18-27%), respectively. The Kaplan-Meier estimate of overall (OS) and leukemia-free survival (LFS) at 2 years were 59% (95%CI, 54-65%) and 56% (95%CI, 50-61%), respectively. Acute GVHD (grade II-IV) occurred in 109 (28%) patients. The 2-year cumulative incidence of chronic GVHD was 31% (95%CI, 26-36), extensive in 17% (95%CI, 12-21). Two years RI, NRM, LFS and OS in TBI vs. Bu patients were 21.8% vs 21.7% (p=0.69), 29.4% vs 18.3% (p=0.008), 48.8% vs 59.6% (p=0.045) and 51.2% vs 64.0% (p=0.013), respectively. In multivariate analysis adjusted for variable with different distribution between Bu and TBI groups, the type of conditioning (TBI vs Bu) has no impact on RI, NRM, LFS and OS. Age over 55 at transplant was an independent adverse prognostic factor in multivariate analysis for NRM (hazard ratio (HR: 1.61, 95% CI: 1.00-2.61, p=0.05)), LFS (HR: 1.39, 95% CI: 1.00-1.92, p=0.05) and OS (HR: 1.55, 95% CI: 1.11-2.18, p=0.01). Being treated in an experienced center (defined as having including 10 or more transplants in the study) was associated with a significant lower RI (HR: 0.84, 95% CI: 0.75-0.93, p=0.001) and better LFS (HR: 0.91, 95% CI: 0.84-0.98, p=0.01) and OS (HR: 0.91, 95% CI: 0.84-0.98, p=0.02). Finally, transplantation from an URD was associated with a significant increase in NRM (HR: 2.11, 95% CI: 1.14-3.91, p=0.02). Of note, CR1 vs. CR2 and de novo vs. secondary AML had no impact on patients' outcome. Conclusions. These results in a rather large cohort of patients with AML suggest that a FLAMSA "sequential" regimen provided an efficient disease control in high-risk AML patients including in CR2 and secondary AML. Furthermore Busulfan and TBI based FLAMSA "sequential" regimens provide a similar outcome. These results should be confirmed in a multicenter well design randomized study. Disclosures Off Label Use: off-label drug use: antithymocyte globulin (ATG) for allo-SCT conditioning. Tischer:Sanofi-Aventis: Other: advisory board. Schmid:Neovii: Consultancy; Janssen Cilag: Other: Travel grand. Mayer:Janssen: Research Funding. Hallek:Pharmacyclics: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Janssen: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Boehringher Ingelheim: Honoraria, Other: Speakers Bureau and/or Advisory Boards; Mundipharma: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Celgene: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Gilead: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Roche: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; AbbVie: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding.

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Exome Array Analyses Identify Low-Frequency Germline Variants Associated with Increased Risk of AML in a HLA-Matched Unrelated Donor Blood and Marrow Transplant Population

Blood ◽

10.1182/blood.v128.22.42.42 ◽

2016 ◽

Vol 128 (22) ◽

pp. 42-42

Author(s):

Alyssa I. Clay ◽

Theresa Hahn ◽

Qianqian Zhu ◽

Li Yan ◽

Leah Preus ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

De Novo ◽

Association Studies ◽

Low Frequency ◽

Hematologic Malignancies ◽

Unrelated Donor ◽

Advisory Committees ◽

De Novo Aml ◽

Normal Cytogenetics

Abstract Both genome wide association studies (GWAS) of common variation and exome wide association studies (EXWAS) of rare variation have successfully identified disease susceptibility variants for a variety of diseases. One GWAS of inherited susceptibility to Acute Myeloid Leukemia (AML) has been conducted, but no EXWAS have been performed to measure risk of AML attributable to low-frequency constitutional genetic variation. We performed the first EXWAS of risk of AML as a nested case-control study in the DISCOVeRY-BMT (Determining the Influence of Susceptibility Conveying Variants Related to one-Year mortality after BMT) cohorts. The DISCOVeRY-BMT parent study examined transplant-related mortality in leukemia patients undergoing unrelated donor allogeneic BMT. To identify low frequency variants and genes contributing to increased susceptibility to AML we used genotype data from the Illumina HumanExome BeadChip typed in the DISCOVeRY-BMT cohorts; the HumanExome BeadChip contains 242,901 variants, which are mainly protein-coding variants. The optimal sequence kernel association test (SKAT-O) was used to analyze gene-level associations with risk of AML. These gene-based tests evaluate the cumulative effects of multiple single gene variants on risk of AML. Analyses were performed in all European American AML cases and two subtypes: 1) de novo AML, 2) de novo AML with normal cytogenetics. Models were adjusted for age at transplant and principal components to control for population stratification. For gene-based tests at least 2 variants with minor allele frequency (MAF) ≤ 5%, were required to be present in the gene. This yielded a total of 13,687 genes tested, and a Bonferroni corrected significance level of P<3.65 x 10-6. Association tests were performed in 1,189 AML cases reported to CIBMTR 2000-08 (Cohort 1) and 327 AML cases reported to CIBMTR from 2009-11 (Cohort 2). Controls in Cohorts 1 (n=1,986) and 2 (n= 515) were 10/10 HLA-matched unrelated donors who passed a comprehensive medical exam and deemed healthy. We used metaSKAT to combine Cohorts 1 and 2 and obtain p-values of association with AML. We present the results of gene-level tests significant in both cohorts. The likely pathogenicity of these variants was determined in silico using SIFT, PolyPhen and MutationTaster. Patient characteristics are in Table 1. DNMT3A, on chromosome 2, was associated in the gene-based test with risk of AML (Pmeta=1.70x10-9, Table 2). Three missense variants at MAF <1% comprise both overall AML and de novo AML gene-based association: exm177559 (Asn->Ser), exm177507 (Arg->His), and exm177543 (Arg->Trp). Normal cytogenetics de novo AML gene-based assocations consisted of only 2 of these variants: exm177559 and exm177507 (Table 2). While prevalence of exm177507 is <1% for all AML cases, in de novo AML with normal cytogenetics the MAF was higher at 3%. The other 2 variants had a MAF<1% irrespective of subtype. Somatically, DNMT3A is most frequently mutated in hematologic malignancies, with >30% of de novo AML cases with a normal karyotype and >10% of MDS patients having DNMT3A mutations. Although these are germline gene associations all three of the variants found have been reported somatically in hematologic malignancies. In 200 AML cases from The Cancer Genome Atlas (TCGA) p.R882H (represented as exm177507 on the exome chip) was a frequent somatic mutation (25%). Exm177543 (p.R635W) and exm177559 (p.N501S) are reported in the Catalogue of Somatic Mutations in Cancer (COSMIC) as somatic mutations involved in hematopoietic and lymphoid tissue in both cell lines and humans. Exm177507 and exm177543 show evidence of pathogenicity in all three in silico tools, while exm177559 was reported as deleterious and disease causing by Sift and MutationTaster, respectively. Our results show that multiple potentially pathogenic missense germline variants in DNMT3A comprise the gene-based association with AML, specifically de novo AML with normal cytogenetics. Given the functional nature of these variants it is possible germline risk stratification could be informative in determining AML risk, and subsequently development of AML harboring DNMT3A mutations. Confirmation of these findings in additional cohorts could have implications for individualized risk screening, prediction and prognosis. Additional cytogenetic subgroup analyses, including treatment-related AML, are underway. Disclosures Hahn: Novartis: Equity Ownership; NIH: Research Funding. McCarthy:Sanofi: 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, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: 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; The Binding Site: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sucheston-Campbell:NIH/NCI: Research Funding.

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Optimal Conditioning for Older Patients with Acute Myeloid Leukemia (AML) Receiving Allogeneic Hematopoietic Stem Cell Transplantation: A Propensity Score Analysis

Blood ◽

10.1182/blood-2019-123699 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 42-42 ◽

Cited By ~ 1

Author(s):

Stefan O. Ciurea ◽

Ankur Varma ◽

Piyanuch Kongtim ◽

Samer Srour ◽

Qaiser Bashir ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Board Of Directors ◽

Hematopoietic Stem Cell ◽

Older Patients ◽

Research Funding ◽

Conditioning Regimen ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Secondary Aml

Introduction Allogeneic hematopoietic stem cell transplantation (AHSCT) is increasingly performed for older patients with AML; however, the optimal conditioning regimen for these patients remains unclear. Methods: We retrospectively evaluated outcomes of 404 patients with AML, ≥60 years receiving AHSCT at our institution between 01/2005-08/2018 who received 4 conditioning regimens: 1) fludarabine+melphalan 100mg/m2 (FM100, N=78), 2) fludarabine+melphalan 140mg/m2 (FM140, N=89), 3) fludarabine+IV busulfan x 4 days with Bu AUC≥5,000/day (equivalent dose 130mg/m2/day) (Bu≥5,000, N=131), 4) fludarabine+IV busulfan x 4 days with Bu AUC 4,000/day (equivalent dose 110mg/m2/day) (Bu4,000, N=106). To adjust for potential selection bias in choices of conditioning regimen, propensity score was calculated and used as a stratifying variable in a multivariable Cox regression model. Factors included in the propensity score calculation were age, secondary AML, ELN2017 genetic risk, remission status before transplant, induction failure, donor type, stem cell source and KPS. Results are presented for the FM100, FM140, Bu≥5,000 and Bu4000, respectively. Median follow-up survivors were 40, 74, 30 and 44 months, respectively (p=0.06). Donors are matched sibling, matched unrelated, haploidentical and mismatched unrelated donor in 126 (31%), 218 (54%), 40 (10%) and 20 (5%) patients, respectively. Patients in the FM100 group were significantly older and had lower KPS. The median age was 67, 64, 64 and 65 years, respectively (p=0.001), while 51%, 32%, 27% and 27% had KPS<90%, respectively (p<0.001). The HCT-CI of ≥3 was present in 57%, 62%, 56% and 70%, respectively (p=0.33), while 42%, 78%, 47% and 51% had high and very high-risk DRI, respectively (p<0.001), and 12%, 46%, 18% and 32% of the patients were transplanted in active disease (p<0.001). No significant differences were seen in both cytogenetic and ELN2017 genetic risk. More patients in FM100 group were treated using a standard of care protocol (73%, 64%, 25% and 31%, respectively, p<0.001). Grade 2-4 aGVHD at day 100 were 26% vs. 26%, 36% and 40% (p=0.04), and extensive cGVHD at 3 years 14% vs. 42%, 36% and 37%, respectively (p=0.07). The NRM at 3 years were 19%, 29%, 25% and 21% (p=0.06), and 3-year relapse rates were 32% vs. 32%, 30% and 55%, respectively (p=0.003). Among 4 groups, FM100 group had a significantly better PFS and GRFS with 5-year PFS for these 4 groups were 44%, 30%, 33% and 22% (p=0.02) and 5-year GRFS were 28%, 20%, 18% and 9% (p=0.006), respectively (Figure 1). For subgroup of patients with KPS <90%, 5-year PFS were 41%, 27%, 28%, 22%, respectively (p=0.007), while there was no significant difference between 4 conditioning groups in patients with high-risk AML defined as either secondary AML, induction failure or high-risk cytogenetics/high ELN2017 risk, suggesting that a more intense conditioning is not beneficial in this group of patients. The survival benefit of FM100 persisted after adjusted for baseline factors, transplant characteristics as well as propensity scores in a multivariable analysis (MVA). In MVA for PFS, HR was 0.57 (p=0.013) for FM100, 0.68 (p=0.056) for FM140 and 0.77 (p=0.137) for Bu> 5000 as compared with Bu 4,000 group (Figure 1). In the MVA for GRFS, HR for FM100, FM140 and Bu> 5000 was 0.53 (p=0.005), 0.78 (p=0.196), and 0.81 (p=0.178), respectively as compared with Bu 4,000 group. Other factors that independently predicted PFS were secondary AML (HR 1.68, p=0.001), remission status before transplant (HR 1.82, p=0.048 for CR with MRD positive, HR 1.87, p=0.043 for CR with unknown MRD status and HR 2.86, p=0.001 for active disease at transplant as compared with CR with MRD negative), KPS (HR 0.98, p=0.005) and use of a mismatched unrelated donor (HR 2.46, p=0.001 compared with matched related donor transplant). Conclusions: Older patients with AML benefit from a reduced-intensity conditioning with FM100 conditioning regimen, which was associated with better survival despite the fact that patients who could not receive more intense conditioning preferentially received this regimen. Higher intensity conditioning does not appear to improve survival in older patients. Alternative approaches to increase in conditioning intensity are needed to improve survival in patients with AML receiving allogeneic hematopoietic stem cell transplantation. Disclosures Ciurea: Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees, Other: stock holder; Miltenyi: Research Funding; Spectrum: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees. Bashir:Imbrium: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Acrotech: Research Funding; StemLine: Research Funding; Spectrum: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Oran:Astex pharmaceuticals: Research Funding; AROG pharmaceuticals: Research Funding. Popat:Bayer: Research Funding; Incyte: Research Funding; Jazz: Consultancy. Konopleva:Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding; Astra Zeneca: Research Funding; Agios: Research Funding; Ascentage: Research Funding; Calithera: Research Funding; Forty-Seven: Consultancy, Honoraria; Kisoji: Consultancy, Honoraria; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding.

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