Patterns of Delivery of Chemoimmunotherapy to Patients with Follicular Lymphoma in the United States: Results of the National Lymphocare Study

Abstract Abstract 3702 Background: Both drug choice and delivered dose of intended treatment potentially influence outcome in patients treated for follicular lymphoma (FL). Historically, observational studies have solely evaluated drug choice. The National LymphoCare Study (NLCS) is a prospective, observational study that enrolled >2700 patients with FL in the United States between 2004 and 2007. We report on measures of delivered dose and its impact on outcomes for the most common first-line regimens. Methods: All evaluable patients treated with R-CHOP, R-CVP, or R-fludarabine (R-Flu)–containing regimens in the NLCS were included, except those with FL plus other lymphoma histology, non-FL histology, or those who progressed before first treatment or before being assigned to watchful waiting. Associations between baseline factors and choice of treatment (R-CHOP, R-CVP, or R- Flu–containing regimen), number of cycles received (≤4, 5–6, 7+), and completion of therapy were assessed using the Pearson chi-square test. Factors associated with risk of early discontinuation were assessed using logistic regression, and a generalized logits model was used to assess the relationship between baseline factors and number of cycles received. Kaplan-Meier methods and the log-rank test were used to estimate progression-free survival (PFS), overall survival (OS), and time to next treatment. Results: Among 1165 evaluable patients, a total of 648 received R-CHOP, 296 received R-CVP, and 221 received R-Flu combinations. Patient characteristics were similar between groups with the following exceptions: patients receiving R-CHOP were more likely to have grade 3 FL (38% vs 11% for R-CVP and 13% for R-Flu), and patients receiving R-CVP were older (25% ≥75 vs 8% for R-CHOP and 13% for R-Flu) and had higher Follicular Lymphoma International Prognostic Index (FLIPI) risk scores (50% poor FLIPI vs 41% for R-CHOP and 36% for R-Flu). The distribution of delivered cycles demonstrated a high degree of compliance with published regimens, with most patients receiving ≥5 cycles of treatment (R-CHOP 86%, R-CVP 81%, R- Flu 67%, P<.0001). The median cycle length was 21 days for both R-CHOP and R-CVP, and 29 days for the R-Flu regimens. Cycle intensity, defined as the expected cycle length (21 days for R-CHOP and R-CVP, and 28 days for R-Flu) divided by the actual cycle length, was between 0.9 and 1.1 for 68% of R-CHOP patients, 75% of R-CVP patients, and 45% of R-Flu patients. The percentage of patients with longer-than-expected time between cycles (cycle intensity <0.9) was similar for the 3 treatment groups; however, R-Flu patients were more likely to have shorter-than-expected time between cycles (24% vs 4% for R-CHOP and 3% for R-CVP). We sought to understand the reasons for patients receiving ≤4 cycles. Most patients who received ≤4 cycles were considered to have completed the intended duration of therapy (58% for R-CHOP, 62% R-CVP, and 75% R-Flu); rates of early discontinuation from the intended treatment were significantly less for patients receiving ≥5 cycles. Early discontinuation was associated with age ≥75 years and treatment with R-Flu (particularly in patients with grade 1–2 FL). Toxicity was the most commonly cited reason for early discontinuation (47% for R-CHOP, 46% for R-CVP, and 71% for R-Flu). The higher rate of R-Flu discontinuation due to toxicity is consistent with findings from other studies. Disease progression was rarely cited as the reason for early discontinuation. Time to retreatment was significantly shorter for patients receiving ≤4 cycles for patients receiving R-CHOP and R-CVP compared with patients receiving 5–6 cycles and 7+ cycles (P=.002 and P<.001 respectively; medians not yet reached). Delivery of ≤4 treatment cycles was associated with lower response rates (76% CR/PR vs 90% for 5–6 cycles and 92% for 7+ cycles) and worse PFS and OS, among patients who received R-CVP (all P<.01) but not among other regimens. Conclusions: Most patients with FL receiving chemoimmunotherapy in the NLCS completed ≥5 cycles of treatment. Most who received fewer cycles were considered to have completed therapy, and therapy commonly was given at or above the expected cycle intensity. Strategies to improve dose delivery appear unlikely to impact patient outcomes, except possibly in patients receiving R-CVP. Disclosures: Martin: Genentech: Speakers Bureau. Link:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees. Byrtek:Genentech: Employment. Dawson:Genentech, A Member of the Roche Group: Employment. Friedberg:Genentech: Membership on an entity's Board of Directors or advisory committees. Cerhan:Genentech: Membership on an entity's Board of Directors or advisory committees. Flowers:Genentech: Membership on an entity's Board of Directors or advisory committees.

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Donor Cell Acute Myeloid Leukemia after Transplant for Follicular Lymphoma

Blood ◽

10.1182/blood-2019-122932 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5697-5697

Author(s):

Lacey S. Williams ◽

Catherine E. Lai

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Follicular Lymphoma ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Donor Cell ◽

Cell Leukemia ◽

Advisory Committees ◽

Donor Cell Leukemia ◽

Acute Myeloid

Donor cell leukemia is postulated to account for up to 5% of all leukemia "relapses" after hematopoietic stem cell transplant (SCT), though in many cases this is the first leukemia diagnosis for the patient if their transplant was for non-leukemia primary diseases. The rarity of the condition and heterogeneity of disease create challenges in diagnosis and management. In the present case, donor cell leukemia (DCL) developed in a 68-year-old female after allogeneic SCT 18 years earlier for follicular lymphoma. Only one other case of DCL after transplantation for follicular lymphoma has been reported (Boulton-Jones et al., Bone Marrow Transplantation, 2005). Furthermore, this case is atypical in that the presentation occurred many years after transplantation, since very few cases of DCL occur more than 15 years after original transplant. Case In 1993, the patient was diagnosed with stage IIIA follicular lymphoma at age 50. She achieved a complete remission with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) for 4 years. She relapsed in 1998 and received treatment with fludarabine and mitoxantrone. In 1999, she enrolled in a toxitumomab clinical trial (NCT00268203) but discontinued therapy secondary to side effects. Due to persistent disease, she proceeded with SCT and received EPOCH-F (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and fludarabine) prior to allogeneic SCT from her brother in 2000 (6/6 HLA match), augmented with TH2 cells. She received graft versus host disease (GVHD) prophylaxis with cyclosporine, however her post transplant course was complicated by engraftment syndrome and gastrointestinal and skin GVHD. In 2019, she presented to hematology for evaluation of worsening chronic neutropenia and thrombocytopenia persistent for three years, noted during work-up for symptomatic cholelithiasis. Bone marrow biopsy revealed acute myeloid leukemia (AML) with a hypocellular marrow with 30% blasts and myelodysplasia related changes. Her cytogenetics showed 46XY, +1, der(1;7)(q10;p10)/47,sl,+8/46,XY. FISH analyses demonstrated deletion 7q31 D7S486 locus in 156/200 cells (78%). NGS panel showed IDH1 (VAF16%) and U2AF1 (VAF 26%) mutations. Based on cytogenetics and chimerism studies showing 100% donor, the patient was diagnosed with donor-derived AML secondary to allogeneic SCT from her brother. The brother currently has no known hematologic problems. The patient was treated with CPX-351 (liposomal cytarabine and daunorubicin) and achieved a complete remission, followed by consolidation with CPX-351. Given her complex cytogenetics and poor prognosis, the patient proceeded to non-myeloablative haploidentical peripheral blood SCT from her son, with post-transplant cyclophosphamide. She subsequently had complications of neutropenic fever and C. dificile colitis, with progressive colitis leading to her death on day 22 after SCT. Discussion Though cytogenetic and molecular studies along with functional status assist clinicians in treatment decisions for DCL patients, the benefits and risks of treatment remain difficult to balance for this unique subset of leukemia. Of patients that achieve remission for greater than 18 months, many undergo second allogeneic SCT, however a similar number of patients have remissions of at least 18 months treated with chemotherapy alone (Wiseman, Biology of Blood and Bone Marrow Transplantation, 2011). In 15 reported cases that went to SCT, approximately 50% lived longer than 12 months after their DCL diagnosis. Second allogeneic SCT is often favored after initial remission in patients with good performance status due to high risk for relapse. This case illustrates the challenge in management of donor cell leukemia, a rather rare entity with very few cases in the literature developing greater than 15 years after transplant. Limited robust evidence favoring a particular treatment supports the need for further prospective studies. Disclosures Lai: Agios: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Speakers Bureau; Astellas: Speakers Bureau.

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Predictors of Maternal Morbidity Among Participants Enrolled in the Sickle Cell Disease Implementation Consortium Registry

Blood ◽

10.1182/blood-2020-140743 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 3-3

Author(s):

Rita V Masese ◽

Dominique Bulgin ◽

Liliana Preiss ◽

Mitchell Knisely ◽

Eleanor Stevenson ◽

...

Keyword(s):

Board Of Directors ◽

Sickle Cell ◽

Research Funding ◽

Transfusion Requirement ◽

The United States ◽

Acute Chest Syndrome ◽

Maternal Outcomes ◽

Maternal Complications ◽

Advisory Committees ◽

Increased Risk

Introduction Pregnancy in sickle cell disease (SCD) is associated with an exacerbation of SCD-related complications and an increased risk of maternal complications. The increased risk is partly due to physiologic adaptations in pregnancy, which include increased metabolic demands and a hypercoagulable state. The maternal death rate for SCD is 629 per 100,000 deliveries, compared to 12 per 100,000 deliveries in black women and 6 per 100,000 deliveries in the general population (Raider et al., 2016). Studies on maternal and perinatal outcomes of patients with SCD present inconsistent and conflicting results. Some studies have reported an increase in maternal complications such as pre-eclampsia, acute chest syndrome and thromboembolic events, while other studies have reported no significant risk in adverse maternal outcomes. The inconsistent findings reported in prior studies may be attributed to small sample sizes and single-centered sites. Our study aims to determine the prevalence and predictors of maternal morbidity among participants enrolled in the SCD Implementation Consortium (SCDIC) registry, which is the largest, most geographically diverse SCD participant sample in the United States. Methods This cross-sectional study included women enrolled in the SCDIC registry who had at least one pregnancy event. The SCDIC is composed of eight academic SCD centers across the United States and one data-coordinating center. Participants were enrolled in the SCDIC registry if they were 18 to 45 years of age and had a confirmed diagnosis of SCD. Enrolled participants completed a series of surveys that collected sociodemographic information, SCD and pregnancy history and data abstractions of participants' medical records was completed. Medical complications queried during pregnancy included: vaso-occlusive episodes, acute chest syndrome, blood transfusion requirement, preeclampsia, maternal diabetes and deep venous thrombosis. Descriptive analysis of sociodemographic, clinical and maternal characteristics was conducted. Bivariate analysis was performed using Chi-Square test, Mann-Whitney U test, t-test, and logistic regressions, as appropriate. A p-value of ≤ 0.05 was considered statistically significant for all analysis. Results The study sample included 743 women who had at least one pregnancy event, and a total of 1066 live births. Almost all women (96.3%) were African American, with a median age of 21 years (inter-quartile range of 19 to 23 years) at first birth. The majority had Hb SS SCD genotype (69.5%; 513 of the 738 with SCD genotype data). Of all reported pregnancies, participants did not use hydroxyurea during conception (78%), and pregnancy (84.5%). Only 2.7 % of the women reported using fertility drugs or assisted reproductive procedures. Seventy five percent of the pregnancies that ended in live births had maternal complications. The leading complications were vaso-occlusive episodes (61.2%), pregnancy requiring blood transfusion(s) (33.2%), preeclampsia (15.4%), deep venous thrombosis (5.6%) and acute chest syndrome (7.7%). When the pregnancies were stratified by SCD genotype, women with Hb SS had a higher occurrence of acute chest syndrome (63.4% vs. 26.7%), transfusion requirement (70.8% vs. 21%) and preeclampsia (66.7% vs 22.4%). In the univariate logistic regressions, multiparous women, with a history of adverse maternal outcomes in a previous pregnancy, had higher odds of vaso-occlusive episodes (OR: 3.42; 95% CI: 2.42-4.94) acute chest syndrome (OR:4.99; 95% CI:2.56- 9.48), transfusion requirement (OR:3.86; 95% CI:2.64- 5.69), and pre-eclampsia (OR:3.36; 95% CI:2.05-5.45). Conclusion In this large multicenter registry, we found pregnant women with SCD have significant maternal complications. Early antenatal care by healthcare providers knowledgeable about risk factors for adverse maternal outcomes in SCD is essential improve maternal and fetal outcomes and reduce the maternal death rate for SCD. Disclosures Hankins: Novartis: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; MJH Life Sciences: Consultancy, Patents & Royalties; UptoDate: Consultancy; National Heart, Lung, and Blood Institute: Honoraria, Research Funding; LINKS Incorporate Foundation: Research Funding; American Society of Pediatric Hematology/Oncology: Honoraria. Treadwell:Global Blood Therapeutics: Consultancy; UpToDate: Honoraria. King:Amphivena Therapeutics: Research Funding; Bioline: Consultancy; Celgene: Consultancy; Cell Works: Consultancy; Incyte: Consultancy; Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novimmune: Research Funding; RiverVest: Consultancy; Tioma Therapuetics: Consultancy; WUGEN: Current equity holder in private company. Gordeuk:CSL Behring: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Imara: Research Funding; Ironwood: Research Funding; Novartis: Consultancy. Kanter:SCDAA Medical and Research Advisory Board: Membership on an entity's Board of Directors or advisory committees; AGIOS: Membership on an entity's Board of Directors or advisory committees; BEAM: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; GLG: Honoraria; Jeffries: Honoraria; Cowen: Honoraria; Wells Fargo: Honoraria; NHLBI Sickle Cell Advisory Board: Membership on an entity's Board of Directors or advisory committees; Medscape: Honoraria; Guidepoint Global: Honoraria; bluebird bio, inc: Consultancy, Honoraria; Sanofi: Consultancy. Glassberg:Pfizer: Research Funding; Global Blood Therapeutics: Consultancy; Eli Lilly and Company: Research Funding. Shah:Novartis: Consultancy, Research Funding, Speakers Bureau; Alexion: Speakers Bureau; CSL Behring: Consultancy; Bluebird Bio: Consultancy; Global Blood Therapeutics: Consultancy, Research Funding, Speakers Bureau.

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Radioimmunotherapy for Mantle Cell Lymphoma: 5-Year Follow-up of 90 Patients from the International RIT-Registry

Blood ◽

10.1182/blood-2019-124192 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5263-5263

Author(s):

Karin Hohloch ◽

Christine Windemuth-Kieselbach ◽

Pier Luigi Zinzani ◽

Roberto E. Cacchione ◽

Wojciech Jurczak ◽

...

Keyword(s):

Follicular Lymphoma ◽

Mantle Cell Lymphoma ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Primary Therapy ◽

First Line ◽

Advisory Committees ◽

Mantle Cell

To assess the efficacy of radioimmunotherapy (RIT) with 90yttrium-ibrutinib-tiuxetan (90Y-IT) in mantle cell lymphoma, data from 90 patients registered in the RIT Network with a median follow-up (FU) of 5.5 years after RIT were evaluated. 90Y-IT was given as first-line therapy in 45 (50%) (consolidation 44 pts., primary therapy 1 pt.) and at relapse in 45 (50%) patients (consolidation 24 pts., recurrence 12 pts., therapy refractory 3 pts., conditioning 2 pts., other 4 pts.). As a first-line treatment, 30 patients (pts.) (67%) achieved CR, 10 pts. (22%) PR%., 1 pt. (2%) PD, and for 4 pts. (9%) no response data was available. At relapse, CR was achieved in 17 pts. (38%), PR in 6 pts. (13%), SD in 2 pts. (4%), and 6 pts. (13%) had PD, while the response was not documented for 14 pts. (31%). After a median FU of 5.5 years, median PFS for all patients was 2.11 (95%CI: 1.03-2.32) years, and median OS was 4.05 (95%CI 2.79-7.21) years. Eleven pts. (12.2%) developed second malignancy. In conclusion, this is the largest report of MCL pts. treated with 90Y-IT to date. 90Y-IT was most often used as consolidation after first- and second-line chemotherapy and may improve the results achieved using chemoimmunotherapy alone. However, the results are less encouraging compared to treatment with small molecules such as ibrutinib. Disclosures Zinzani: TG Therapeutics: Honoraria, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: 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; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy. Jurczak:Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Roche: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bayer: Research Funding; Gilead: Research Funding; MorphoSys: Research Funding; Incyte: Research Funding; Novo Nordisk: Research Funding; Servier: Research Funding; TG Therapeutics: Research Funding; Celtrion: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Truemper:Seattle Genetics, Inc.: Research Funding; Takeda: Consultancy, Research Funding; Roche: Research Funding; Nordic Nanovector: Consultancy; Mundipharma: Research Funding; Janssen Oncology: Consultancy. Scholz:Janssen-Cilag: Consultancy; Hexal: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Pfizer: Speakers Bureau; Roche: Consultancy; GILEAD: Consultancy, Speakers Bureau; Daiichi Sankio: Consultancy. OffLabel Disclosure: Yttrium 90 (90Y) Ibritumomab Tiuxetan (Zevalin) is approved for treatment of patients with relapsed follicular lymphoma and as consolidation therapy after chemo(immuno)therapy of patients with follicular lymphoma.

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Emicizumab-Kxwh for Previously Untreated Patients with Haemophilia: The Conversation Begins

Blood ◽

10.1182/blood-2019-127270 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2409-2409

Author(s):

Tiffany Lin Lucas ◽

Shveta Gupta ◽

Joanna A. Davis ◽

Fernando F. Corrales-Medina

Keyword(s):

Board Of Directors ◽

Real World ◽

Research Funding ◽

Hemophilia A ◽

The United States ◽

Haemophilia A ◽

Advisory Committees ◽

Inhibitor Development ◽

Increased Risk ◽

Prophylaxis Therapy

Introduction: With the Federal Drug and Administration approval of the use of emicizumab from birth to adulthood, clinicians will now grapple with when to choose and offer emicizumab for routine prophylaxis, especially in previously untreated patients (PUPs). Given the overall limited real-world reported data and experience using emicizumab in PUPs, we created and administered a survey to medical providers in the United States who care for paediatric patients with haemophilia to investigate real-world practice strategies and treatment selection for PUPs. Methods: After review and endorsement by the Haemostasis and Thrombosis Research Society (HTRS), the survey was electronically distributed by e-mail to all providers included in the HTRS core member list. The survey was also sent to those providers included in a list of Haemophilia Treatment Centre (HTC) physicians (with duplicate emails reconciled). Providers needed to self-identify as ones that treat pediatric patients to be included. The survey was developed as a tiered survey with questions presented to each recipient based on their prior responses. Results: Seventy-seven completed surveys were included and analysed. All participants were active providers at a comprehensive HTC and the majority (93.4%) were practicing at an academically affiliated site. In terms of characteristics of those that answered the survey, forty-eight percent of responders reported that 1-20% of their patients had expressed interest in emicizumab. 46% of participants (34/74) reported that they would personally consider emicizumab as their prophylaxis recommendation for the majority (>50%) of their hemophilia A patients without inhibitors. 57% (44/76) reported that 1-10% of their non-inhibitor hemophilia A patients were already prescribed emicizumab prophylaxis. Each participant was then asked about his or her consideration of emicizumab as prophylaxis therapy for a 2 month old PUP. Just over the majority were unsure or said no to this consideration (51.3%) and their concerns were lack of information on safety and efficacy in this young age group and increased risk for inhibitor development. If the 2 month old PUP had a high risk of inhibitor, the majority of providers who initially were hesitant to start emicizumab prophylaxis would remain so. Of note, those providers went on to be asked if the patient had gone on to complete 50 exposure days without inhibitor development, they would then become more likely to initiate emicizumab prophylaxis therapy. Use of concurrent factor replacement was posed to all participants and there were varied responses. Discussion: Overall, our results reflect a widespread practice variation and a not yet well-standardized or defined approach for the use of emicizumab in PUPs with haemophilia A. In this survey, patient preference and individual bleeding risk were the top reasons for which a provider would consider using switching to emicizumab prophylaxis in both severe and mild/moderate haemophilia A patients. This pattern of practice reflects the current era of individualized medicine. Overall, our findings reinforce the need for more studies to investigate the outcomes of a combined treatment approach with FVIII concentrates and emicizumab focusing in the potential benefit of this approach in decreasing the risk for inhibitor development PUPs. Clinicians also feel the need for further data to help clarifying the safety of emicizumab in this population. Figure Disclosures Gupta: Novartis: Honoraria, Speakers Bureau; CSL Behring: Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda-Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Davis:Sanofi: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda Shire: Consultancy; Spark Therapeutics: Consultancy. Corrales-Medina:Kedrion: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees.

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Individualized Prediction of Follicular Lymphoma Risk Using a Combination of Blood t(14;18) Frequency Years before Diagnosis and a Polygenic Risk Score (PRS) of 9 SNPs Associated with Follicular Lymphoma Susceptibility

Blood ◽

10.1182/blood-2019-130618 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2775-2775

Author(s):

Herve Ghesquieres ◽

Youenn Drouet ◽

Manon Zala ◽

Paolo Vineis ◽

Gilles A. Salles ◽

...

Keyword(s):

High Risk ◽

Follicular Lymphoma ◽

Board Of Directors ◽

Roc Curve ◽

Genetic Variants ◽

Epidemiological Studies ◽

Polygenic Risk Score ◽

Healthy Individuals ◽

Advisory Committees ◽

Polygenic Risk

Introduction: The risk of developing a follicular lymphoma (FL) begins to be better understood with the identification in large epidemiological studies of familial predisposition, some occupational exposures and genetic factors. Genome wide-association studies (GWAS) identified constitutional single nucleotide polymorphisms (SNPs) at risk of FL in HLA region (rs12195582), in 11q23.3 (near CXCR5), in 11q24.3 (near ETS1), in 3q28 (near LPP), in 18q21.33 (near BCL2), and 8q24 (near PVT1); three suggestive loci are localized at 17q25.3 (near CYBC1), 3q13.33 (CD86), 18q12.3 (SLC14A2) (Skibola, Am J Hum Genet. 2014). High t(14;18) frequency in blood years before diagnosis from healthy individuals was also defined as a predictive biomarker for FL (Roulland, J Clin Oncol 2014). It is currently unknown whether any relationship exists between inherited genetic variants associated with FL susceptibility and t(14;18) frequency and if the combination of the two biomarkers could be useful for a better stratification of risk of FL development in healthy individuals. Methods: We used quantitative PCR assays to estimate t(14;18) frequency in prediagnostic blood samples from 105 individuals that were obtained on average 6.4 years before FL diagnosis (pre-FL group) together with 236 age and gender-matched individuals (control group) that were issued from the participants in the EPIC cohort ( European Prospective Investigation Into Cancer and Nutrition). Constitutional DNA was analyzed for the genotyping of the nine SNPs associated with FL risk (HLA, rs12195582; CXCR5, rs4938573; ETS1, rs4937362; LPP, rs6444305; BCL2, rs17749561; PVT1, rs13254990; CYBC1, rs3751913; CD86, rs2681416; SLC14A2, rs11082438). Genotyping were performed in duplicate using TaqMan® assays on Fluidigm platform. The nine SNPs were analyzed individually and combined in a polygenic risk score (PRS). PRS is a weighted average of the number of risk alleles with the weights being the log of the odds-ratio (OR) reported in the FL GWAS (Skibola, Am J Hum Genet. 2014). A model for FL risk was developed using multivariable logistic regression. Predictive ability was assessed by area under Receiver Operating Characteristic (ROC) curve, with 10-fold cross-validation. This work is supported by the French NCI (INCA, PRT-K16-167). Results: t(14;18) frequency as a log-transformed continuous variable is predictive of FL risk (OR: 1.50; 95%CI: 1.29-1.78, P<0.001); PRS is also strongly associated with FL risk (OR: 3.31; 95%CI: 2.01-5.62, P<0.001). Age at screening (OR: 0.98; 95%CI: 0.95-1.01, P=0.24) did not influence FL risk. A weak but statistically significant correlation between t(14; 18) frequency and PRS was observed (Pearson correlation=0.18, P=0.002). In multivariable analysis, both PRS (OR: 2.84, 95%CI: 1.66-4.99, P<0.001) and t(14;18) frequency (OR: 1.45, 95%CI: 1.18-1.84, P<0.001) remained statistically significant. No departure from log-linear effect was observed in the modeling nor statistical interaction between PRS and log-transformed t(14;18), confirming that t(14; 18) frequency and genetic markers (PRS) were two independent factors of FL risk. Sensitivity analyses showed that these results were not influenced by the delay between the date of the screening and the FL diagnosis. Combining t(14;18) frequency and the PRS in a prediction model allowed the identification of some individuals at very high risk of developing FL and a shiny web application was developed to provide an easy-to-use tool to obtain individualized risk predictions for new patients (Figure). Area under ROC curve (AUC) showed that the model that integrated t(14;18) frequency and PRS (AUC: 0.69, 95%CI: 0.62-0.76) had a better prediction of FL risk than t(14;18) frequency (AUC: 0.62, 95%CI: 0.55-0.70) and PRS alone (AUC: 0.68, 95%CI: 0.61-0.75). Conclusions: Genetic variants combined in PRS and t(14;18) frequency allowed the identification of individuals at high-risk of FL development and provided a better way, when these two biomarkers were combined, to discriminate healthy individuals from pre-FL cases many years before malignant transformation. These findings could be used for screening test of populations with some environmental exposures positively associated with FL development in epidemiological studies and may contribute in the future to monitoring or early intervention. Figure Disclosures Salles: Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Amgen: Honoraria, Other: Educational events; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Honoraria.

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Efficacy Outcomes of Treatments for Double Relapsed/Refractory Follicular Lymphoma (R/R FL): A Systematic Literature Review

Blood ◽

10.1182/blood-2020-136228 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 42-43

Author(s):

Brad S. Kahl ◽

Anik R. Patel ◽

Omer Zaidi ◽

Sonya J. Snedecor ◽

Anna G. Purdum

Keyword(s):

Clinical Trials ◽

Follicular Lymphoma ◽

Board Of Directors ◽

Clinical Data ◽

Research Funding ◽

Treatment Options ◽

Unmet Need ◽

Progression Free Survival ◽

Disease Stage ◽

Advisory Committees

ABSTRACT Introduction: Patients with indolent non-Hodgkin lymphomas (iNHL), including follicular lymphoma (FL), have high response to first-line treatment. However, retreatment is often required when relapses occur, and those with multiple relapses represent a patient population with an unmet need for effective treatment. Clinical data for several treatment options exist for the general relapsed and refractory (R/R) population; however, there are relatively fewer data specific to FL patients with ≥2 lines of prior treatment. This work systematically identified the available efficacy data in the double R/R FL population. Methods: The MEDLINE and EMBASE databases were searched through February 10, 2020. Studies were limited to interventional clinical trials of R/R FL patients (or mixed histologies with a predominance of FL) and articles published in English. Studies also must have reported one or more efficacy measures, such as overall response rate (ORR), complete response (CR), duration of response (DoR), time to next treatment (TTNT), progression-free survival (PFS), and overall survival (OS). Potential interventions of interest were lenalidomide ± rituximab (R), duvelisib, ibrutinib, venetoclax, polatuzumab vedotin + R, obinutuzumab, copanlisib, umbralisib, idelalisib, and tazemetostat. Results: Of 35 publications examining treatment outcomes in R/R FL patients, only 14 (representing 5 unique clinical trials) were specific to the ≥ 2-line population. These trials were: CHRONOS Part B (copanlisib), DAWN (ibrutinib), DELTA (idelalisib), DYNAMO (duvelisib), and Morschhauser et al. 2019 (tazemetostat) and included a total of 605 participants. All studies used similar inclusion criteria, and patients included were similar in age (median 62-65), disease stage (III/IV), and ECOG score (0-2). Patients in the CHRONOS study had a median number of prior treatments of 2, whereas those in the DELTA study had 5. ORR ranged from 21% (ibrutinib) to 59% (copanlisib) (Table). The DoR ranged from 8.3 months in tazemetostat patients with EZH2 gene mutation to 19.4 months for ibrutinib. PFS ranged from 5.7 months in tazemetostat patients with wild-type EZH2 to 11.2 months for copanlisib. Median TTNT was only reported in the DAWN study (16 months). Conclusions: Very few clinical data exist reporting efficacy outcomes specific to the double R/R FL population. The limited data indicate that current treatments do not produce durable responses for most double R/R FL patients, demonstrating an unmet need. Further research is needed to fully understand the efficacy and safety of other potential interventions for this population. Disclosures Kahl: Genentech:Consultancy;Pharmacyclics LLC:Consultancy;AstraZeneca Pharmaceuticals LP:Consultancy, Membership on an entity's Board of Directors or advisory committees;ADC Therapeutics:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Celgene Corporation:Consultancy;AbbVie:Consultancy;Roche Laboratories Inc:Consultancy;BeiGene:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Janssen:Consultancy, Membership on an entity's Board of Directors or advisory committees;Acerta:Consultancy, Research Funding.Patel:Kite, a Gilead Company:Current Employment.Zaidi:BMS:Consultancy.Snedecor:Pharmerit - an OPEN Health Company:Other: Employment at consultancy paid by Kite Pharma to conduct this work.Purdum:Kite, a Gilead Company:Current Employment.

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Clinical and Economic Burden Of Peripheral T-Cell Lymphoma In The United States

Blood ◽

10.1182/blood.v122.21.2963.2963 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2963-2963

Author(s):

Michele H. Potashman ◽

Chakkarin Burudpakdee ◽

Weiying Wang ◽

Yanyan Zhu ◽

Kenneth R. Carson

Keyword(s):

Board Of Directors ◽

Economic Burden ◽

Research Funding ◽

Index Date ◽

The United States ◽

Control Group ◽

Pharmacy Services ◽

Office Visits ◽

Peripheral T Cell Lymphoma ◽

Advisory Committees

Abstract Background Peripheral T-cell lymphoma (PTCL) is an aggressive and heterogeneous subtype of non-Hodgkin lymphoma (NHL). PTCL has a poor prognosis due to advanced stage at presentation, and generally poor response to standard chemotherapy. According to recent SEER estimates, PTCL accounts for about 4% of all NHL cases in the United States each year. To date, few studies have assessed the clinical and economic burden of PTCL. Methods MarketScan data for commercially insured and Medicare supplemental patients were used to retrospectively identify unique PTCL patients. Patients were identified by ICD-9-CM diagnosis codes between October 1, 2007 and June 30, 2011. The time of first PTCL diagnosis code served as the index date, and a second PTCL diagnosis date was used for confirmation. All patients were required to have at least 6 months of continuous enrollment before and 12 months of continuous enrollment after their index date. Patients were excluded if aged <18 years, date of birth or gender were missing, or if they had received a stem cell transplant (SCT) prior to PTCL diagnosis. The control group includes patients that may have any other malignant (excluding PTCL) or non-malignant condition and are considered to represent an average insured patient population from the payer perspective. The control group was matched based on age, sex, region, plan type, payer type, and length of enrollment. Mean cost per month was measured and annualized to provide average yearly costs. Healthcare costs included hospitalizations, pharmacy services, office visits, emergency room visits, hospice stays, SCT, and other patient-related costs (lab procedures, radiology procedures, blood transfusions, and other ancillary procedures). Results Of 2820 patients with ≥1 PTCL diagnosis, 1000 patients were identified that met all inclusion criteria (mean age 56 years, 58% male), and were matched to the control group. On an average annual basis, PTCL patients were hospitalized more often (0.9 vs 0.1 hospitalizations), and experienced a longer length of stay (6.4 vs 4 days) compared with matched controls. In addition, PTCL patients had a higher utilization of office visits (16.2 vs 4.1 visits), pharmacy services (34.2 vs 11.6 prescriptions), emergency room visits (0.8 vs 0.2 visits), and hospice care (0.6 vs 0.1 stays). PTCL patients also experienced higher comorbidities (mean Charlson Comorbidity Index of 1.72 vs 0.39, as determined at index date). Overall, PTCL patients incurred much higher average annual costs compared with matched patients ($75,934.08 vs $4660.64; Table), driven mainly by hospitalizations (32.2% of overall costs) and pharmacy services (19.6% of overall costs). Conclusions PTCL is associated with high resource utilization rates and high overall costs. The development of efficacious treatments for PTCL may offer better disease management and may reduce the clinical and economic burden of PTCL. Disclosures: Potashman: Millennium: The Takeda Oncology Company: Employment. Burudpakdee:Millennium: The Takeda Oncology Company: Consulting researcher Other. Wang:Millennium: The Takeda Oncology Company: Consulting researcher Other, Research Funding. Zhu:Millennium: The Takeda Oncology Company: Employment. Carson:Millennium: The Takeda Oncology Company: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Spectrum, Inc.: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin Pharma, Inc.: Research Funding.

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An Update On The Clinical Activity Of Resimmune, a Targeted Therapy Directed To CD3 Receptor, In Patients With Cutaneous T Cell Lymphomas--CTCL

Blood ◽

10.1182/blood.v122.21.4381.4381 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4381-4381 ◽

Cited By ~ 2

Author(s):

Arthur E. Frankel ◽

Jung H Woo ◽

Jeremy P Mauldin ◽

Francine M. Foss ◽

Madeleine Duvic ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Pichia Pastoris ◽

Cell Line ◽

Board Of Directors ◽

Research Funding ◽

Response Rate ◽

The United States ◽

Advisory Committees ◽

Systemic Therapies

Abstract Cutaneous T cell lymphoma—CTCL is a malignancy of skin-tropic T cells. CTCL cells have ubiquitous overexpression of CD3. Although uncommon, CTCL has been estimated to affect 1,500 patients per year in the United States. There are multiple approved systemic therapies for CTCL, but responses are brief lasting months. Allogeneic stem cell transplantation may provide long-term remissions, but is suitable for only rare CTCL patients. Overall, CTCL has a long clinical course with relentless progression over months to years with estimated median survival of 3-5 years for stage IB-IIB patients. The CD3 targeted agent, Resimmune, was synthesized and prepared for clinical use. It consists of the catalytic and translocation domains of diphtheria toxin fused to two anti-human CD3 Fv fragments. DNA encoding Resimmune protein was integrated into the Pichia pastoris genome, and recombinant protein was produced in Pichia pastoris via the secretory route (Woo, Protein Expr Purif 25, 270, 2002). Protein was purified by anion exchange and size exclusion chromatography. The CD3+ Jurkat cell line incubated with Resimmune yielded an IC50 for protein synthesis inhibition of 0.017pM. The CD3- Vero cell line incubated with Resimmune showed an IC50 >10pM. Mice, rats, and monkeys given total doses of >200mg/kg over four days showed only transient transaminasemia without histopathologic tissue injury or clinical signs or symptoms (Woo, Cancer Immunol Immunother 57, 1225, 2008). In a mouse model with human CD3e transfected lymphocytes, four logs of antigen positive cells were reproducibly depleted from nodes and spleen with 100mg/kg total dose of Resimmune (Thompson, Protein Eng 14, 1035, 2001). Based on these findings, a phase 1 study was initiated and this report serves to update the results of a single cycle of Resimmune given at 2.5-11.25mg/kg 15 min IV infusion twice daily for 8 doses to 18 CTCL patients. There were 10 females and 8 males with ages 20-81 years. Two patients were naïve to systemic therapies, and all others had failed 1-4 prior treatments including interferon, bexarotene, gemcitabine, vorinostat, chlorambucil, etoposide, pralatrexate, doxil, romidepsin, methotrexate, CHOP, and brentuximab vedotin. None of the Resimmune treated CTCL patients had dose-limiting toxicities. Side effects were mild-moderate and transient with fevers, chills, nausea, transaminasemia, hypoalbuminemia, lymphopenia, reactivation of EBV and CMV, and hypophosphatemia. Toxicities responded to antipyretics, anti-emetics, albumin infusions, rituximab treatment and valgancyclovir. Among measured patients, there was a 3 log decline in normal, circulating T cells by day 5 that recovered by day 14. Because of vascular leak syndrome toxicities in non-CTCL patients, the MTD was defined as 7.5mg/kg x 8 doses. Cmax ranged from 1.9-40.7ng/mL and half-life from 5-66min. Pretreatment anti-DT titers were 0.9-251mg/mL and day 30 post-therapy increased to 5-4059 mg/mL. 17 CTCL patients were evaluable for response. There were six responses for a response rate of 35%. There were four CRs (24% CR rate). Three of the CRs are over 4-years duration. Patients with IB or IIB disease and mSWAT<50 had an overall response rate of 86% and CR rate of 56%. The long time required to convert from a PR to a CR in the absence of any additional therapy beyond the four treatment days suggest an additional anti-tumor mechanism beyond immunotoxin-induced killing such as immunomodulation. Accrual of patients with mSWAT scores of 50 or less is ongoing. Disclosures: Woo: Angimmune: Patents & Royalties, Research Funding. Foss:celgene: Honoraria, Research Funding; millenium: Honoraria, Membership on an entity’s Board of Directors or advisory committees; eisai: Membership on an entity’s Board of Directors or advisory committees; spectrum: Research Funding; merck: Research Funding; seattle genetics: Research Funding. Neville:Angimmune: Employment, Equity Ownership, Patents & Royalties.

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Unrelated Donor KIR B/X Genotype Reduces Relapse and Improves Progression-Free Survival after HLA-Matched Allogeneic Transplantation for Relapsed/Refractory Non-Hodgkin Lymphoma

Blood ◽

10.1182/blood.v124.21.670.670 ◽

2014 ◽

Vol 124 (21) ◽

pp. 670-670

Author(s):

Veronika Bachanova ◽

Daniel J. Weisdorf ◽

Tao Wang ◽

Steven G.E. Marsh ◽

Elizabeth Trachtenberg ◽

...

Keyword(s):

Follicular Lymphoma ◽

Nk Cells ◽

Board Of Directors ◽

Cell Lymphoma ◽

Progression Free Survival ◽

Unrelated Donor ◽

Advisory Committees ◽

Free Survival ◽

Kir Genes ◽

Non Hodgkin Lymphoma

Abstract While allogeneic donor hematopoietic cell transplantation (HCT) can cure non-Hodgkin lymphoma (NHL) by inducing a graft-versus-lymphoma effect, 10-35% of patients experience progression or relapse. We investigated whether the genotype of allogeneic donor natural killer (NK) cell killer immunoglobulin-like receptors (KIR) impacts the survival of lymphoma patients. The importance of KIR genetics in unrelated donor (URD) HCT has been demonstrated in AML where donors with favorable KIR gene content reduced the risk of relapse by 30%. Because the consequence of donor KIR genotype in NHL is unknown, we evaluated its effect on transplant outcome in 614 adults with NHL (28% follicular lymphoma, 16% diffuse large B cell lymphoma, 17% mantle cell lymphoma, 37% other) who underwent T cell replete URD HCT between 1990-2009 with outcomes reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Donor samples from the NMDP/CIBMTR Repository were genotyped (15 KIR genes) by MALDI-TOF mass spectroscopy. KIR haplotypes (A/A or B/x) were determined by presence/absence of individual KIR genes. Multivariate regression models were used to test the associations between donor KIR genotype and clinical outcome. The median patient age was 50 years (range 19-72), 93% were Caucasians and 62% had chemosensitive lymphoma. Most (60%) were >1.5 years from diagnosis; 41% received myeloablative preparative regimens and 61% received peripheral blood derived grafts. Most transplants were 10/10 matched for HLA alleles (n=396), the remainder 9/10 matched (n=158) or ≤8/10 matched (n=60). The frequencies of KIR genotypes in donors reflected the Caucasian population: 70% (n=428) were KIR B/x and 30% (n=180) were KIR A/A. Patients receiving 10/10 HLA-matched grafts (65%) experienced significantly lower relapse at 5 years when donors were KIR B/x genotype (n=281; 26% [95%CI 21-32%]) compared to KIR A/A genotype (n=115; 37% [95% CI 27-46%] ;p=0.05; Figure left) leading to improved progression-free survival (PFS) (35% [95% 26-44] vs. 22% [95%CI 11-35%]; p=0.02; Figure right). After adjusting for significant clinical variables, KIRB/x donors conferred significant protection against relapse (RR 0.63 [95%CI 0.43-0.92]; p=0.02) and improved PFS (RR 0.71 [95% CI 0.55-0.91]; p=0.008) compared to KIR A/A donors. The relapse protection and improved survival associated with KIR B/x donors was highly significant in the 10/10 HLA matched cohort (n=396) but not in the HLA-mismatched transplants (n=218; PFS RR 1.21 [95%CI 0.86-1.7]; Relapse RR 1.49 [0.87-2.55], p=NS for both). Importantly, the use of KIR B/x donors was associated with improved clinical outcomes for patients after both myeloablative and reduced intensity conditioning. Donor KIR genotype had no effect on rates of acute graft-versus-host disease (HR 1.05; p=0.86), and treatment related mortality at 1 year was similar for both groups (28% [B/x] and 30% [A/A]). In multivariate analysis of the entire cohort, other factors adversely impacting PFS included chemoresistant lymphoma (HR 1.52; p=0.03), disease other than follicular lymphoma (HR 1.34; p=0.0001) and <1.5 years interval from diagnosis to HCT (HR 1.35; p=0.003). Our results demonstrate that donors with KIR B/x genotypes, whose NK cells express more activating KIR, are associated with decreased relapse and improved survival after 10/10 HLA-matched URD HCT for NHL. The results suggest that NK cells may contribute to graft-versus-lymphoma effects and support the consideration of KIR genotyping with HLA typing into URD search criteria for patients with NHL. Figure 1 Figure 1. Disclosures Miller: Coronado: Speakers Bureau; BioSciences: Membership on an entity's Board of Directors or advisory committees; SAB: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Survival Outcomes of Leukemias and Myelodysplastic Syndromes Occurring As Second Cancers in the United States: A SEER Registry-Based Population Analysis

Blood ◽

10.1182/blood.v126.23.2507.2507 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2507-2507 ◽

Cited By ~ 2

Author(s):

Surbhi Sidana ◽

Paul Elson ◽

Aaron T. Gerds ◽

Hetty E. Carraway ◽

Anjali S. Advani ◽

...

Keyword(s):

Board Of Directors ◽

Myelodysplastic Syndromes ◽

Myeloid Leukemia ◽

Hematologic Malignancies ◽

The United States ◽

Survival Outcomes ◽

Advisory Committees ◽

Acute Leukemias ◽

Second Cancers ◽

Better Than

Abstract Introduction Population level data about the survival outcomes of patients with hematologic malignancies occurring as second cancers is limited. We undertook one of the largest analyses of second hematologic malignancies (SHM) using the Surveillance, Epidemiology & End Results (SEER) registry to identify factors associated with survival. Methods SEER 9 &13 registries were queried to identify adult patients (pts>18 years) diagnosed with SHM that comprised of Acute Myeloid Leukemia (AML), Acute Lymphoid Leukemia (ALL), Myelodysplastic Syndromes (MDS), Chronic Myeloid Leukemia (CML) & Other Acute Leukemias (OAL, biphenotypic leukemias, myeloid sarcomas & leukemias NOS) > 1 year (yr) after diagnosis of a primary unrelated cancer, using ICD-O-3 codes over a 40 yr period (1973-2012). Data on demographics, follow up, primary tumor & survival were abstracted. Univariate & multivariate analyses were performed to identify factors influencing survival of SHM & compared with hematologic malignancies occurring as first cancers. Hazard ratios (HR) with 95% confidence intervals (CIs) are reported & significance was set at p< 0.01. Results SHM cases included 4665 AML, 3569 MDS, 1140 OAL, 1076 CML & 536 ALL pts. Median age at diagnosis of SHM was 73 yrs (range, 18-100) for AML, 79 yrs (18-100) for MDS, 74 yrs(20-99) for OAL, 74 yrs(18-98) for CML & 70 yrs(19-97) for ALL. Pts>60 yrs comprised 79.2% of AML, 92% of MDS, 88.7% of OAL, 82.9% of CML & 75.2% of ALL cases. Gender distribution was similar across all categories, with females comprising 48.5% of AML, 42.2% of MDS, 45.3% of OAL, 42.8% of CML & 50.2% of ALL cases. More than 85% of pts in each group were Caucasians. While the majority of pts had one primary unrelated cancer (82-89%), 14% of AML pts, 17.8% of MDS pts, 13.8% of OAL, 15.3% of CML pts& 10.6% of ALL pts had >1 primary unrelated cancer. Most common primary sites were prostate (19.1-29.6%), breast (16.1-21.9%) & colorectal (9.3-14.5%). Median survival (range) was as follows: AML 0.2 yrs (0-28.2); MDS 1.5 yrs (0-14); OAL 0.2 yrs (0-29.1); CML 2.5 yrs (0-27.1); & ALL 0.7 yrs (0-28.8). Median latency periods (range) for secondary cancers were as follows: AML 5.2 yrs (1.0-24.2); MDS 7.6 yrs (1.0-35.5); OAL 5.7 yrs (1.0-=34.3); CML 5.2 yrs (1.0-31.6); & ALL 6.2 yrs (1.0-35.5). In univariable analyses, age <60 yrs predicted for better survival (p<0.0001) for all SHM, as did diagnosis in recent yrs (2001-2012) (p< 0.0001 for AML, OAL, CML & ALL). Effect of time period on survival for MDS was not done, as it became formally reportable in 2001. Having >2 primaries was associated with an unfavorable outcome for subsequent AML (HR=1.15; 1.08-1.23; p < 0.0001), MDS (HR=1.13; 1.05-1.22: p=0.001) & CML (HR=1.30; 1.13-1.48: p=0.0002). In multivariable analyses, advancing age was an independent adverse prognostic factor for all secondary leukemias & MDS, both as a continuous variable & when categorized as <60 yrs vs. >60 yrs (p<0.001). Race & gender did not impact survival. Using breast cancer as a referent primary, AML pts had worse outcomes following colorectal (HR=1.31; 1.14-1.5; p=0.0002) or lung (HR=1.46; 1.22-1.74; p< 0.0001) primaries, while MDS pts fared worse with prior lung (HR=1.61; 1.22-2.12; p=0.0007) or Non-Hodgkin lymphoma (HR=1.58; 1.3-1.92: p< 0.0001). Of all 2ndCML cases, those after colorectal cancer had worst survival (HR=1.54; 1.12-2.13; p=0.008). Among SHM pts, MDS pts had better survival than those with AML (HR=0.42; 0.4-0.44: p< 0.0001), as did pts with CML (HR=0.37; 0.35-0.41: p< 0.0001) & ALL (HR=0.64; 0.58-0.70; p< 0.0001). Out OAL had similar outcomes compared to AML (HR=0.99; 0.92-1.05; p=0.66). Pts with CML fared better than MDS (HR=0.47; 0.41-0.54; p< 0.0001) & OAL (HR=0.37; 0.34-0.41: p< 0.0001). Pts with ALL had worse survival than CML (HR=1.8; 1.6-2.03: p< 0.0001) & MDS (HR=1.28; 1.11-1.48: p=0.0005), but better than OAL (HR=0.65; 0.58-0.73: p< 0.0001). (Figure 1) Patients with all SHM, except CML, had worse outcomes compared to those with primary hematologic cancers (Figure 2). Conclusion The prolonged latencies for SHM in this study suggest that they are likely therapy-related. Our findings show that type & number of primary cancers influence survival of subsequent leukemias & MDS. SHM have worse survival compared to those with primary hematologic malignancies except CML where non-separation of survival curves suggest that CML as SHM does not behave like a therapy-related neoplasm. Disclosures Sekeres: TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees.

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