Hogan, William J.

Abstract Abstract 3555 Background: Although treatment-related acute myeloid leukemia (tr-AML) has been identified as an independent marker of poor prognosis, it is important to determine how characteristics of the patient, primary malignancy, or treatment regimen affect the development and outcome of tr-AML. Taxane therapy has become essential in the management of breast cancer in light of its favorable effect on survival in short term studies. However, clinical trials fail to capture acute leukemias related to recently introduced agents since development of tr-AML occurs years after chemotherapy. Aim: To examine the effect of taxane therapy on clinical outcome of patients who were treated for breast cancer and subsequently developed tr-AML. Methods: This retrospective chart review considers patients diagnosed with AML at Mayo Clinic between 1990 and 2011. Patients were included if they had previously received chemotherapy for breast cancer, or if they had never received any chemotherapy. Demographic data, previous diagnosis and treatment regimen, CBC at diagnosis, pathology and cytogenetic information, therapy used, and response were collected for each patient. IRB approval was obtained. Comparison between two groups was done using t-test; survival estimates using Kaplan-Meier curves were constructed with software JMP 9. Results: A total of 88 adult females with AML were identified. Median age at AML diagnosis was 58 years (range 19–86). Median hemoglobin was 8.9 g/dL (4–14.5), white blood cell count (WBC) 9.7 x109/L (0.6–237), platelets 67 x109/L (1–361), peripheral blood (PB) blasts 13%, bone marrow blasts (BM) 44%, and BM cellularity 90%. Of the 88 patients, 23 (26%) had previously received treatment for breast cancer (tr-AML), the remainder had de novo AML. Taxanes were included in the initial treatment for breast cancer in 14 (61%, median age 57, group 1), compared to 9 (39%) patients with no history of taxane exposure (median age 58, group 2). Median hemoglobin was 9.7 g/dL, WBC 4.5×109/L, platelets 72×109/L, PB blasts 2%, BM blasts 40% in group 1, compared to 8.3, 7.1, 50, 28%, 47%, respectively, in group 2. Cytogenetic analysis of group 1 showed diploidy in 8%, complex karyotypes in 8%, and chromosome 11 abnormalities in 38%, compared to 50%, 0%, 33%, respectively, in group 2. In group 1, 14% had good risk cytogenetics, 57% had intermediate risk, and 29% had poor risk, compared to 17%, 83%, and 0%, respectively, in group 2. Cytogenetic analysis of de novo AML showed diploidy in 71%, complex karyotypes in 14%, and chromosome 11 abnormalities in 0%. Complete remission (CR) was achieved in 79% of group 1 and 83% of group 2 (p 0.8). Differences in survival of group 1 (375 days) and group 2 (222 days) did not reach statistical significance (p 0.12). Median survival was 584 days for patients with de novo AML, 375 days in group 1 (p 0.47), and 222 days in group 2 (p<0.001). Conclusion: In agreement with previous reports, we found that tr-AML is a poor prognostic factor overall (p 0.04). However, patients with a history of breast cancer who had been treated with taxanes as a part of their initial chemotherapy regimen demonstrated similar survival as patients with de novo AML (p 0.47). Tr-AML patients only did significantly worse than patients with de novo AML if they had never received taxanes as part of their breast cancer therapy (p<0.001). Disclosures: No relevant conflicts of interest to declare.

Abstract Background Familial myeloid neoplasms are rare causes of myeloid malignancies. Over the last few years germline mutations involving RUNX1, JAK2, GATA1, GATA2 and CEBPA genes have been associated with myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN) and acute myeloid leukemia (AML). We carried out this study to describe the spectrum of familial myeloid neoplasms seen at our institution. Methods After due IRB approval, the myeloid neoplasms data base (1990-2012) at the Mayo Clinic in Minnesota was queried for patients presenting with, or having a strong family history of myeloid neoplasms. Selective sequencing of germline DNA was done in appropriate patients. Germline mutations that were screened for included; RUNX1, JAK2, GATA1, GATA2 and CEBPA. In one family with none of the aforementioned gene mutations, exome sequencing was performed. Families with chromosomal breakage and primary telomere disorders were excluded. All patients had bone marrow and cytogenetic studies at diagnosis. Results We identified six families with familial myeloid neoplasms (table one). There were two with germline GATA2 mutations (no.1 and 2); one with a novel c1339A>C, pS447R, non-zinc finger gene abnormality. In this family nine members have developed MDS/AML. All members had profound B/NK cell deficiency, viral warts and one member had primary lymphedema (Embergers syndrome). Three of the 6 seen at the clinic have successfully undergone allo- SCT. The second GATA2 mutated family had a less extensive history of myeloid neoplasms. There was one patient (no.5) who presented with long standing thrombocytopenia, clinically diagnosed as ITP. She eventually developed MDS with trisomy 8. She had three first degree relatives with myeloid neoplasms. Germline sequencing identified a RUNX1 mutation. Platelet electron microscopy identified characteristic ultrastructural changes. There was one family (no.4) with a germline JAK2V617F mutation. The propositus was diagnosed to have primary myelofibrosis and then demonstrated clonal evolution to a concomitant BCR-ABL1 p190 driven chronic myeloid leukemia. His sister and mother have essential thrombocytosis (ET) and his brother has a detectable JAK2 mutation (no evidence for disease). The patient has successfully undergone an allo-SCT. The patient with a GATA1 mutation (no.3) presented with congenital anemia and had craniofacial anomaly, atrial septal defect and developmental delays. Red cell and platelet ultrastructural abnormalities lead to the diagnosis with an additional family member having chronic anemia and suspected MDS. One family (no.6) presented with seven first degree relatives affected by MDS/AML. Germline sequencing for the aforementioned genes was negative. Exome sequencing has been performed and results should be available at the time of the meeting. The prepositus has successfully undergone allo-SCT. Conclusion Familial myeloid neoplasms are uncommon but warrant early recognition. Clues to diagnosis include strong family history, associated primary immunodeficiency states, morphological/skeletal abnormalities and platelet ultrastructural defects (RUNX1, GATA2, and GATA1). Exome and whole genome sequencing is an exciting prospect for further discoveries. Disclosures: No relevant conflicts of interest to declare.

Abstract Background Predictors of outcomes after reduced intensity conditioning (RIC) stem cell transplantation (SCT) in chronic lymphocytic leukemia (CLL) are not well established. The Dana Farber (DF) investigators (Brown et al, leukemia 2013) developed a prognostic scoring model for overall survival (OS) and disease free survival (DFS) that assigned one point to each of comorbidity index, absolute lymphocyte count, LDH and disease status. The goals of the present study were to 1) validate the DF model 2) identify additional predictors of outcomes after SCT. Methods This study is a retrospective review of the Mayo Clinic CLL database and was approved by the Institutional Review Board. All CLL patients that underwent RIC-SCT were included. The prognostic significance of prognostic factors at time of RIC-SCT were analyzed, including the DF model. Survival was estimated and compared using the Kaplan Meier and Log Rank tests. Results From 2006 to 2012, 50 patients with CLL underwent RIC-SCT at the Mayo Clinic. Of these, 33 were male (66%) and the median age was 56 (29-69) years. The median time from diagnosis to RIC-SCT was 4.7 years (0.6-22.9). Indications for RIC-SCT were 17p deletion in 24 (48%) patients and purine nucleoside analogue (PNA) refractory disease in 26 (52%) patients. Transplant related mortality was 6% and non-relapse mortality at 5 years was 14%. Acute graft versus host disease (GVHD) developed in 30 (60%) patients and chronic (c) GVHD was noted in 32 patients (64%). The 5-year relapse rate was 38%. The DF prognostic score stratified three categories for OS (score of 0, 1-2, ≥ 3), but was not associated with DFS in this cohort. We next evaluated the impact of other patient, disease, and transplant characteristics on clinical outcome. Development of cGVHD post-transplant was the dominant predictor of both DFS (HR 0.26, 95% CI=0.10-0.69, P=0.006) and OS (HR 0.04, 95% CI=0.01-0.19, P<0.0001, figure 1). The presence of 17p deletion at time of RIC-SCT was associated with shorter DFS (HR 3.99, 95% CI=1.43-11.18, P=0.008), but did not impact OS. Developing cGVH but not DF score remained an independent predictor of OS on a multi-variate analysis including both factors. Given these findings, we evaluated what pre-treatment patient, disease, and transplant characteristics predicted for subsequent development of cGVHD. Patients with higher scores on DF prognostic model were less likely to develop cGVHD (score 0=66%, 1-2=76%, ≥3=31%; P=0.01). Three CLL characteristics (complete or partial remission at time of RIC-SCT, absence of 17p deletion, and absence of ZAP70 overexpression) were predictors for development of cGVHD while alemtuzumab exposure ≤3 months prior to RIC-SCT decreased likelihood of cGVHD. On multivariate modeling using these four predictors, only ZAP70 overexpression was an independent negative predictor of developing cGVHD (Table 1). Rates of cGVHD post RIC-SCT in ZAP 70 positive and ZAP70 negative patients were 50% and 92%, respectively (p=0.03). Conclusion This study found that while the DF prognostic score is an effective way to predict outcome prior to RIC-SCT, development of cGVHD post-transplant is ultimately the most significant predictor for both OS and DFS after transplant in patients with CLL. Pretransplant characteristics that predict subsequent cGVHD include DF prognostic score and ZAP70 status. This is the first report to identify biologic characteristics of CLL B-cells associated with development of cGVHD post-transplant. Disclosures: No relevant conflicts of interest to declare.

Abstract We retrospectively reviewed all patients receiving bortezomib, lenalidomide and dexamethasone induction followed by autologous stem cell transplantation (ASCT) within 12 months of diagnosis for multiple myeloma at the Mayo Clinic. 243 patients treated between January 2010 and April of 2017 were included in the study. Median age was 61 (interquartile range, 55-67) with 62% of patients being male. High risk cytogenetic abnormalities (HRA) were present in 34% of patients. 166 (68%) patients received some form of maintenance/other therapy post transplant (no maintenance (NM, n=77), lenalidomide maintenance (LM, n=108), bortezomib maintenance (BM, n=39) and other therapy (OT, n=19)). Overall response rate was 99% with complete response (CR) rate of 42% and 62% at day 100 and time of best response post transplant respectively. The four cohorts categorized by post transplant therapy were well matched for age, gender and ISS stage. HRA were more common amongst patients receiving bortezomib maintenance or other therapy post transplant (NM 18% vs LM 22% vs BM 68% vs OT 79%, p<0.0001). Two year and five year overall survival rates were 90% and 67% respectively with an estimated median overall survival (OS) and progression free survival (PFS) of 96 months and 28 months respectively for the whole cohort. OS was not significantly different when stratified by post-transplant therapy (Median OS 96 months for NM vs not reached for LM vs 62 months for BM vs not reached for OT, p=0.61), however post-transplant therapy was predictive of PFS (median PFS 23 months for NM vs 34 months for LM vs 28 months for BM vs 76 months for OT, p=0.01). High risk cytogenetics was associated with a worse OS but not PFS when compared to patients with standard risk (median OS: not reached for standard risk vs 60 months for HRA, p=0.0006; median PFS: 27 months for standard risk vs 22 months for HRA, p=0.70). In patients that did not receive maintenance therapy presence of HRA was a strong predictor of OS and PFS (median OS: not reached for standard risk vs 36 months for HRA, p<0.0001; median PFS: 24 months for standard risk vs 7 months for HRA, p<0.0001). Patients receiving maintenance therapy appeared to have a similar PFS and OS irrespective of cytogenetics (median OS: not reached for standard risk vs 62 months for HRA, p=0.14; median PFS: 35 months for standard risk vs 34 months for HRA, p=0.79).On multivariable analysis ISS stage III and achieving CR/stringent CR predicted PFS whilst the only independent predictors of OS were presence of HRA and achieving CR/stringent CR. The combination of bortezomib, lenalidomide and dexamethasone followed by ASCT is a highly effective regimen producing deep and durable responses in many patients. Maintenance therapy in this cohort may overcome the poor prognostic impact of high risk cytogenetic abnormalities. Table Table. Disclosures Dispenzieri: Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Lacy:Celgene: Research Funding. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Kapoor:Celgene: Research Funding; Takeda: Research Funding. Kumar:KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Gertz:Abbvie: Consultancy; Apellis: Consultancy; annexon: Consultancy; Medscape: Consultancy; celgene: Consultancy; Prothena: Honoraria; spectrum: Consultancy, Honoraria; Amgen: Consultancy; janssen: Consultancy; Ionis: Honoraria; Teva: Consultancy; Alnylam: Honoraria; Research to Practice: Consultancy; Physicians Education Resource: Consultancy.

Abstract Background : Pre-treatment determinants of survival in adult acute myeloid leukemia (AML) include performance status, age, karyotype, the distinction between primary and non-primary AML and FLT3-ITD/NPM1 mutational status. Current literature on AML natural history and risk factors is often based on information derived from stringent protocol studies. In the current series of 1,123 adult patients seen at the Mayo Clinic between 2004 and 2017, we examined long-term survival specified by a number of primarily established risk factors. Methods: Diagnosis of AML and its sub-classification was according to World Health Organization criteria. Study subjects were recruited from the Mayo Clinic AML database. Conventional response criteria were used for CR and CRi assignment; the latter met all criteria for CR with the exception of platelet count <100 x 109/l or absolute neutrophil cunt <1 x 109/l. Standard statistical methods were used for analysis of overall survival, calculated from the initial diagnosis of AML to date of death or last follow-up; analyses were performed both in the absence and in the presence of censoring of survival at time of allogenic stem cell transplant (ASCT). The JMP® Pro 13.0.0 software from SAS Institute, Cary, NC, USA, was used for all calculations. Results: 1,123 adult patients (median age 65 years, range 18-94; 61% males) with non-APL AML were considered; 61% were age >60 years. 351 (31%) patients were seen between 2004 and 2009 and 772 (69%) between 2010 and 2017. AML subcategories were primary (56%), post-myelodysplastic syndromes (post-MDS; 24%), therapy-related (10%), post-myeloproliferative neoplasm (post-MPN; 8%) and post-MDS/MPN (3%). Cytogenetic risk distribution, according to the European LeukemiaNet classification, was favorable in 47 (4%), intermediate in 650 (58%) and adverse risk in 426 (38%) patients. FLT3, NPM1 and CEBPA mutation information was available in 462 (24% mutated), 393 (27% mutated) and 228 (11% mutated) patients, respectively. Treatment included intensive chemotherapy (IC) in 766 (68%) patients, less aggressive chemotherapy, including the use of hypomethylating agents in 144 (13%) and supportive care alone in 213 (19%) patients. ASCT was utilized in 258 (23%) cases, almost all performed after achieving CR/CRi. Complete remission (CR) and CR with incomplete count recovery (CRi) were listed in 333 (30%) and 248 (22%) patients, respectively; the corresponding rates in IC-treated patients were 43% and 32%. Almost all cases of CR/CRi occurred in IC-treated patients; 2 (1.4%) CRs were listed for less aggressive chemotherapy. After a median follow-up of 11 months, 798 (71%) deaths were recorded. Median survival for all 1,123 patients was 14 months with 1-, 3- and 5-year survival rates of 54%, 29% and 23%, respectively; a slight but significant (p=0.01) improvement in survival was apparent in more recent years (Figure 1a). Figures 1b, 1c and 1d depict analysis stratified by AML subcategories, treatment received and response obtained, respectively. Similarly, figures 2a, 2b and 2c depict analysis stratified by karyotype, use of ASCT and age. Multivariable analysis of pre-treatment parameters evaluable in all 1,123 patients identified age >60 years (HR 2.2, 1.9-2.6), adverse karyotype (HR 2.9, 1.9-4.9), intermediate-risk karyotype (HR 1.6, 1.02-2.6), post-MPN AML (HR 1.9, 1.5-2.4) and other secondary AML (HR 1.3 (1.1-1.6), as risk factors for shortened survival; the inclusion in the model of FLT3/NPM1 mutational status in 392 informative cases confirmed the adverse prognostic effect of age >60 years (HR 1.8, 1.4-2.5), adverse karyotype (HR 3.7, 1.4-15.3), post-MPN AML (HR 2.8, 1.6-4.6), other secondary AML (HR 1.4, 1.0-1.9) and FLT3+NPM1- (HR 2.8, 1.6-4.9) and FLT3-NPM1- (HR 1.7, 1.2-2.7) profile. Results were unchanged when survival was censored at time of ASCT. Additional prognostic interaction with treatment strategy and ASCT is further elaborated in an accompanying abstract to be presented. Conclusions: The current study, the largest coming from a single institution, provides practically useful information that should assist with patient consultation on AML prognosis and treatment. The study confirms the primary prognostic importance of age, karyotype and FLT3/NPM1 mutational status, in real-life practice. Novel observations included comparable value of CRi vs CR and the particularly worse prognosis associated with post-MPN AML. Disclosures Al-Kali: Novartis: Research Funding.

Abstract Introduction: Outcomes in multiple myeloma have significantly improved in recent times owing to the availability of newer more effective therapies. Autologous stem cell transplantation (ASCT) has been used for over three decades to treat multiple myeloma. We aimed to evaluate the outcome of patients receiving ASCT at our institution between 1990 and 2015. Patients and Methods: A total of 2025 patients received ASCT at Mayo Clinic Rochester between 1st January 1990 and 31st December 2015. The patients were divided in to three cohorts of approximately equal time period, Cohort 1 (1990-1999, n=144), Cohort 2 (2000-2009, n=909) and Cohort 3 (2010-2015, n=972). Outcomes of interest were early mortality, progression free survival (PFS) and overall survival (OS). Disease characteristics were documented from time of diagnosis and PFS and OS were calculated from date of ASCT unless otherwise stated. Results: Median age for the whole cohort was 60 years (range 24-77) and increased over time (55 Cohort 1 vs 59 Cohort 2 vs 61 Cohort 3, p<0.0001). The proportion of males (60% for whole cohort) was not significantly different between the 3 time periods. Almost all patients (99%, n=2018) received chemotherapy prior to transplantation (median lines of therapy 1, range 0-6). The number of patients receiving >1 line of therapy prior to transplantation decreased over time (67% Cohort 1 vs 27% Cohort 2 vs 34% Cohort 3, p<0.0001). The use of novel agents was congruous with their availability and increased over time (0% Cohort 1 vs 59% Cohort 2 vs 100% Cohort 3, p<0.000). After a median follow up of 84 months (95% CI, 78-91 months), median PFS and OS for the whole cohort were 24 and 66 months respectively. Both PFS and OS improved significantly over time (median PFS: 12 months Cohort 1vs 18 months Cohort 2 vs 33 months Cohort 3, p<0.0001; median OS: 26 months Cohort 1vs 63 months Cohort 2 vs 83 months Cohort 3, p<0.0001), Figure 1. The improvement in PFS and OS over the 3 time periods was seen in patients receiving early (≤ 12 months from diagnosis) and delayed (>12 months) ASCT, Table 2. OS from diagnosis was no different for early versus delayed transplant in Cohort 1 and Cohort 2 (Cohort 1: median OS 57 months for early vs 56 months for delayed, p=0.24 and Cohort 2: median OS 81 months for early vs 82 months for delayed, p=0.70) and showed a trend towards a marginal benefit for delayed transplant in Cohort 3 (median OS 105 months for early vs 109 months for delayed, p=0.046).Treatment related mortality (100 days post transplant) improved over time (7.6% Cohort 1 vs 1.8% Cohort 2 vs 0.7% Cohort 3, p<0.0001), Figure 2A. Mortality within 12 months of ASCT also improved over time (24% Cohort 1vs 8% Cohort 2 vs 6% Cohort 3, p<0.0001). A landmark analysis of OS from 12 months post ASCT continued to reveal improved survival over time(median OS 26 months Cohort 1vs 63 months Cohort 2 vs 83 month Cohort 3, p<0.0001), Figure 2B. Conclusion: ASCT remains an important therapeutic option for eligible patients with multiple myeloma. There has been a marked improvement over time in PFS and OS and reduction in treatment related mortality and early mortality in myeloma patients receiving ASCT. This is likely to reflect the addition of novel agents to induction regimens and improved post transplant therapies. Despite these improvements myeloma remains incurable with patients continuing to relapse and die many years after ASCT. Disclosures Dispenzieri: Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Lacy:Celgene: Research Funding. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Kumar:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: 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, Research Funding. Gertz:Research to Practice: Consultancy; Physicians Education Resource: Consultancy; Amgen: Consultancy; spectrum: Consultancy, Honoraria; celgene: Consultancy; annexon: Consultancy; janssen: Consultancy; Alnylam: Honoraria; Abbvie: Consultancy; Ionis: Honoraria; Teva: Consultancy; Apellis: Consultancy; Medscape: Consultancy; Prothena: Honoraria.

Abstract Abstract 4804 Background: Chronic myeloid leukemia (CML) is one of the classic myeloproliferative neoplasms characterized by a reciprocal translocation of BCR and ABL t(9;22)(q34;q11). Tyrosine kinase inhibitors (TKI) have revolutionized the management of CML in inducing rapid and prolonged responses. However; clonal evolution (CE) is considered a poor prognostic factor and a criterion for accelerated phase (AP) CML by the World Health Organization (WHO). Deletion of chromosome Y (−Y) is frequently considered an age-related abnormality and the exact prognostic value has not yet been determined. Aim: To determine if –Y carries an impact on the clinical outcome of male pts with CML. Methods: All male patients diagnosed with chronic phase CML in our institution between 1993 and 2011 were screened for -Y. Data were collected in a retrospective manner and compared (using t-test) to male patients with sole BCR-ABL translocation after excluding patients with advanced stages (accelerated phase, blast phase). Demographics, laboratory tests, cytogenetic analysis, molecular testing and survival data were abstracted. Kaplan-Meier estimates of overall survival were used via JMP software v9.0. Institutional Review Board (IRB) approval was obtained for this study in accordance with the Helsinki Declaration. Results: 20 of 162 (12%) males with CML were found to have –Y abnormality (group 1). CML male patients with sole Philadelphia chromosome abnormality were the control cohort (group 2). In group1; the median age was 57 years, BMI 27.7, hemoglobin 12.2 g/dL, white blood cell count (WBC) 32.8 x109/L, platelet 270 x109/L, and peripheral blood blasts 1%. Sokal risk was low in 30%, intermediate in 65% and high in 5% of pts. Nine pts (45%) were treated with interferon (IFN) prior to TKI. In group 2; the median age was 54 years, hemoglobin 12 g/dL, WBC 57 x109/L, and platelet 282 x109/L. Sokal risk was low in 37%, intermediate in 47%, and high in 16%. 46 of 142 patients (32%) had received previous interferon therapy. All patients in both groups had chronic phase CML at the time of diagnosis, with a median bone marrow cellularity of 95%. In group 1, 14 of 20 pts (70%) received imatinib, all of whom achieved a complete hematological response (CHR), 7 of 14 pts (50%) had partial cytogenetic response, 2 of 14 pts (14%) achieved a complete cytogenic response (CCyR);1 (7%) pt achieved CCyR within 12 months and an additional 1 (7%) by 18 months). Two pts of 12 (16%) achieved at least a major molecular response (MMR); one of whom (8%) achieved a complete molecular response (CMR). In comparison, 107of 142 pts (75%) in group 2 received imatinib, all of whom achieved CHR. Twenty-one pts (20%) achieved partial cytogenetic remission. CCyR was more frequently achieved than group 1 (48/107 pts (45%), p 0.026); 24 pts (22%) achieved CCyR within 12 months of therapy and an additional 10 pts by 18-months. MMR and/or CMR was higher in group 2 compared to group 1 (34 /101 (34%), p 0.18); 16 (16%) of which were CMR. In group 1; 6 (30%) pts had disease progression; 4 of 20 pts (20%) progressed to blast phase (BP) and 2 pts (10%) progressed to AP, compared to 32 (22%) pts in group 2 (p 0.17); 22 (15%) of whom progressed to BP and 10 (7%) patients progressed to AP. Median overall survival was 110 months in group 1 compared to 155 months in group 2 (log rank p=0.48). On multivariate analysis, CCyR was an independent factor for a better OS (p 0.03), but not –Y (p 0.7). Conclusion: Loss of the Y chromosome in chronic myelogenous leukemia is an infrequent phenomenon (12%). Although patients with –Y had a statistically significant less chance to achieve CCyR, loss of the Y chromosome did not affect the progression rate or overall survival. Larger scale studies are needed to confirm our observations Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 3040 We have previously shown that both lymphocyte and monocyte recovery are strongly associated with improved survival post-myeloablative allogeneic hematopoietic stem cell transplant for acute leukemia (Thoma et al, Biology of Blood and Marrow Transplantation, in press). We hypothesized that rapid lymphocyte and monocyte recovery would have a similarly positive impact on overall survival in reduced intensity conditioning (RIC) HSCT with fludarabine/melphalan. To test our hypothesis, we analyzed 118 consecutive patients who underwent allogeneic HSCT with fludarabine/melphalan conditioning for AML (n=49) and MDS/MPN (n=38), ALL (n=7) and other lymphoid malignancies (n=24) at our institution from 2001–2010. The absolute lymphocyte counts and monocyte counts (ALC and AMC, respectively) derived from routine complete blood counts were determined longitudinally at days +15, +30, +60, +100 and correlated with clinical outcomes. At the day +30 time point, both ALC and AMC > 0.3 × 10(9) cells/L were strongly associated with improved survival (OS 29.6 months vs. 5.4 months, p=0.006 and 25.3 months vs. 5.1 months, p=0.01 respectively), a pattern that continued through the day +100 evaluation. Multivariate analysis including age, CD34+ cell dose, unrelated vs. related HSCT, presence of aGVHD, remission status, and longitudinal hematologic parameters revealed that day +100 ALC (RR 0.21, 95% CI 0.07–0.66, p= 0.0096) and day +100 AMC (RR 0.41, 95% CI 0.2–0.9, p=0.047) were the only independent predictors of survival in the model. Pairwise correlations showed moderate negative associations between aGVHD and day +60 and day +100 ALC and AMC. To further explore whether any inherent patterns in the timing of lymphocyte and monocyte recovery had prognostic value post-HSCT, we performed unsupervised hierarchical clustering on the longitudinal hematopoietic parameters studied in this cohort and identified four clusters of patients, clusters A-D. Patient clusters A and C both demonstrated improved ALC and AMC recovery at the day +60 and day +100 time points and had significantly improved OS compared with clusters B and D (not reached for A and C vs. 54.9 and 22.3 months, respectively, p<0.001). No patient in cluster D had a day +100 AMC > 0.3 × 10(9) cells/L, and these patients experienced more acute GVHD (p=0.006) and relapse (8 of 14 patients, p=0.002) compared with clusters A, B, and C (p=0.002). 29 patients who were unable to be clustered with this algorithm, predominantly due to early toxic deaths, had a median survival of 6 months. Consistent with previous observations in our myeloablative cohort, both lymphocyte and monocyte recovery are predictive of overall survival post-RIC HSCT. However, compared to the myeloablative cohort, monocyte recovery in this series appears slightly less strongly associated with survival. Our results also extend the observation of improved survival of ALC and AMC recovery post-HSCT to diseases beyond acute leukemia. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 3095 Background: Although HDM is the standard conditioning for pts with MM undergoing ASCT, it is not sufficient for cure. In an effort to improve upon this standard, we added escalating doses of Y-90 Zevalin (a murine IgG1 kappa monoclonal antibody Ibritumomab conjugated to Y-90) to HDM in a standard 3+3 phase I trial design. Y-90 is a beta-emitting radioisotope with a path length of 5 mm allowing it to target CD20+ cells and bystander cells within 5 mm. Methods: Eligibility included being a candidate for ASCT. Consenting patients (pts) received: day -22, rituximab 250 mg/m2 with In2B8 for scanning; day -14, rituximab 250 mg/m2 with escalating doses of Y90-Zevalin; day -2 and -1, melphalan 100 mg/m2/day; day 0, at least 2 × 10(6) CD34/kg stem cells; and GM-CSF until ANC engraftment. The 6 dose levels (DL) were (in Gy): 10; 12; 14; 16; 18; and 20. Dose limiting toxicity (DLT) was defined as: sustained pulmonary or liver toxicity (grade3; 96 hours duration or VOD that does not resove by day 30); delayed engraftment (ANC < 500 at day 21 or platelet transfusion dependence at day 35); and non-hematologic grade (gr) 4 toxicity excluding gastrointestinal or constitutional. Responses were according to IMWG criteria. Accrual was between May 2005 and June 2011. Data was frozen as of August 2, 2011. Results: Thirty pts have been accrued: DL1, 3; DL2, 3; DL3, 3; DL4, 6, DL5, 6; DL6, 6. The median age of patients was 59 (range 32, 73), and 70% were male. 60% had ASCT as primary therapy. The other patients were transplanted in chemosensitive relapse (n=3), chemoresistant relapse (n=7), and untested relapse (n=2). Median time from diagnosis to protocol therapy was 10.4 months (range 3.5, 94.3). Five pts had prior radiation therapy, and 11 had prior ASCT. Maximum tolerated dose (MTD) of Zevalin with fixed dose melphalan 200 mg/m2 was DL 5 (18 Gy) which amounted to 168 mCi (124, 182) administered. No DLTs were observed at DL 1, 2, 3, or 5. There was 1 DLT at DL 4, comprising hepatic failure (gr 5) CMV viremia (gr 3), and delayed engraftment, in a 73 yo patient with chemoresistant relapsed disease, and 2 DLTs at DL 6. These DL 6 DLTs included: 1) fatal bowel necrosis (day 12 post ASCT) in a 67 yo patient with relapsed refractory MM and history of CAD, ischemic colitis, DM; and 2) fatal biopsy proven venoocclusive disease (gr 5), which began day 91 post ASCT in a 62 yo patient with primary refractory MM, peri-mobilization S. aureus bacteremia with septic embolic, and line associated venous thrombosis. Overall, gr 3 or higher AEs were observed in 100% of pts. Non-heme gr 4 AEs were seen in: DL1, 1; DL2, 2; DL3, 0; DL4, 1; DL5, 0; DL6, 4. Median time to ANC >=500 and plts>=50 was 11 (range 8, 17) and 15 days (range 11, 89). Confirmed response rates from immediately pre-protocol to best confirmed response were: CR, 5; VGPR, 5; continued VGPR, 4, and continued PR, 7. If one includes best confirmed response from baseline for those patients using transplant as primary consolidation, 4 PRs are upstaged to VGPRs. Median follow-up for all pts is 24.5 months (0.8, 64.8), and 10 pts have died. The median PFS for pts proceeding to early and delayed ASCT was 30.4 months (95%CI 4.1-NR) and 10.3 months (95%CI 2.8–21.7), respectively. The median OS for pts proceeding to early and delayed ASCT was not attained and 11.4 months (95%CI 2.8-NA), respectively. Conclusions: For patients with multiple myeloma, the MTD of Zevalin with fixed high-dose melphalan is 18 Gy. The combination of a VGPR plus continued VGPR rate of 60%, a median PFS of 13.1 months, and a 73% 1 year OS rate make this a regimen worthy of further study. Disclosures: Kumar: Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Abstract Background The management of extramedullary relapse (EM) of acute myeloid leukemia (AML) after allogeneic stem cell transplant (allo-SCT) is not standardized. We present a single institution experience, describing the risk factors, outcomes and management of EM leukemia relapse in AML patients who underwent allo-SCT. Methods After due IRB approval, 351 patients with AML who underwent allo-SCT at Mayo Clinic, Rochester, from 1985 through 2012, were evaluated for EM relapse. All patients had BM biopsies and cytogenetic studies at diagnosis and at relapse. Extramedullary relapse was identified by clinical exams and radiological methods and confirmed where possible by biopsies and cerebrospinal analysis (CSF). Clinical, pathological and transplant related data was retrospectively abstracted. Results Of 351 patients, 26 (7%) had EM involvement at initial diagnosis (17 CNS, 9 non-CNS, 3 both). Forty-four (13%) patients had CNS disease detected prior to allo-SCT. Of these, 17 (39%) were detected at AML diagnosis due to clinical signs/symptoms, 11 (25%) were detected to have CNS involvement at the time of AML relapse and 16 (36%) were asymptomatic; diagnosed on routine pre transplant CSF studies. All patients with pretransplant EM disease received appropriate therapy prior to undergoing transplantation. After allo-SCT, 21 (6%; 12 male) of 351 patients sustained an EM relapse (11 CNS alone, 9 non-CNS, 1 both). The non-CNS EM relapse sites were cutaneous, skeletal, renal, breast, testicular, gastrointestinal tract and soft tissue. In 12 patients with CNS relapse, 8 (68%) presented with localizing signs and symptoms and 4 were asymptomatic. The median age at EM relapse was 42 years (range; 2 - 61 years) and the median time to EM relapse was 443 days (range; 90- 6069 days). Salvage therapy offered in 18 patients included, intrathecal chemotherapy (IT) alone in 2, IT + systemic chemotherapy (CTX) in 2, allo-SCT in 1, CTX alone in 6, IT + radiation therapy (XRT) in 1, CTX, IT and XRT in 1, and CTX + XRT in 5 patients, respectively. Three patients were ineligible for further therapy. Median survival after EM relapse was 136 days (18 – 819, days), with 4 patients alive at last followup. At the time of AML diagnosis; 6 (29%) of 21 patients had EM involvement (2 breast, 1 lymph node, 1 CNS and lymph node, 1 cutaneous), 8 (38%) patients had a monocytic differentiation (AML-M4/M5) and 6 of 9 tested, had CD56 expression. Three (14%), 8 (38%) and 10 (48%) patients were risk stratified based on cytogenetic and molecular status (FLT3/NPM1) into favorable, intermediate and high risk, respectively. Subsequently, all 21 patients underwent allo-SCT with 14 patients undergoing matched related donor (MRD) transplants. The transplant conditioning was myeloablative in 16 (76%) patients, of which 11 (69%) received total body irradiation (TBI). Grade II-IV acute graft versus host disease (GVHD) was noted in 11 (52%) patients, while chronic GVHD was noted in 8 (38). On univariate analysis, factors associated with shortened survival after EM relapse included; high risk karyotype at diagnosis (p=0.009), concurrent bone marrow involvement with EM relapse (p=0.01) and reduced intensity conditioning (RIC) (p=0.04). Importantly, CD56 expression (p=0.27), CNS involvement at diagnosis (p=0.76), and chronic GVHD (p=0.383) were not prognostic. On a multivariate analysis, high risk karyotype (p=0.04) and concurrent bone marrow involvement (p=0.04) retained their negative prognostic value. Conclusions Although uncommon, EM relapse after allo-SCT for AML is associated with poor outcomes. Pretransplant CSF screening identifies a significant number of asymptomatic patients with CNS disease. High risk karyotype at diagnosis and concurrent BM involvement with EM relapse are poor prognosticators. Disclosures: No relevant conflicts of interest to declare.