Litzow, Mark R.

Abstract Aim: The autonomic nervous system plays an essential role in homeostasis and the response to stress. The peri-transplant period can be a challenging time for homeostatic responses due to the fluid shifts, sepsis and cardiac dysrhythmias that can occur. Patients with AL amyloidosis may have significant autonomic neuropathy (AN) that renders the peri-transplant care problematic. The purpose of this study was to compare a cohort of patients with AL amyloidosis complicated by AN with a matched cohort without AN to determine the outcome of patients with AN during and after stem cell transplantation (PBSCT). Methods: We performed a nested case-control study by searching the Mayo Clinic dysproteinemia transplant database for all patients with AL amyloidosis who underwent autologous PBSCT. Patients with proven AN were identified and compared to a large cohort of matched controls. We have complete follow-up on all the patients. The main outcome variables were overall survival (OS), the duration of hospitalization, incidence of sepsis, peri-transplant atrial fibrillation (AF) and engraftment kinetics. Comparisons between groups were performed with the Mann Whitney U test for continuous variables and the chi squared test for nominal variables. Overall survival was determined by the Kaplan-Meier method. A stepwise Cox proportional hazards model was used to evaluate the impact of various parameters on OS. Results: We identified 13 patients with AN who underwent PBSCT and compared them to a control group of 94 patients. The two cohorts were well matched for many of the relevant clinical and laboratory characteristics prior to PBSCT. Notable differences included (i) patients with AN tended to have more organs involved (2.5 versus 1, p<0.001) and as a result (ii) the conditioning dose of melphalan was often reduced (p=0.0015). There was no difference in the number of apheresis sessions required for CD34+ cell collection (2.5 versus 2.0, p=0.99), or the number of CD34+ cell collected (6.75 versus 8.15 x106/kg, p=0.99) between the two cohorts. The median hospital duration was 10 (1 – 78) and 8 (0 – 78) days (p=0.99) respectively. Engraftment kinetics, as measured by the time to reach a neutrophil count > 500/ml (p=0.85), a platelet count > 20,000/ml (p=0.99) and a platelet count > 50,000/ml (p=0.99) were similar in the two cohorts. Culture positive sepsis was more common in patients with AN (75% versus 47%, p=0.014). Atrial fibrillation occurred in all patients with AN but in only 1 patient from the control group (p<0.0001). The median OS from PBSCT was 45.2 months for all the combined groups. However, the median OS for patients with AN was 29 months but not yet reached for the controls (p<0.0001). On univariate analysis, cardiac involvement (p=0.0132), AN (p=0.0011), GFR (p=0.038), number of organs involved (p=0.0064) and NT-pro-BNP (p=0.039) all had an impact on OS. On multivariate analysis, AN remained an independent adverse determinant of OS. Conclusion: Patients with autonomic neuropathy secondary to AL amyloidosis can undergo PBSCT safely with similar engraftment kinetics. They are at a higher risk of peri-transplant atrial fibrillation and sepsis although their hospitalizations are not longer compared to controls. Patients with AN generally have more organ involvement by AL amyloidosis. However, AN is an independent, adverse determinant of OS in AL amyloidosis.

Abstract Background: Autologous stem cell transplantation is an effective therapy for patients with multiple myeloma. We and others have previously reported the influence of lenalidomide based regimens on the ability to harvest adequate number of stem cells for successful transplantation. In order to identify factors predicting for poor mobilization we studied a large group of patients who underwent an attempt at stem cell mobilization after receiving lenalidomide and dexamethasone as primary therapy for myeloma. Methods: We identified sequential patients who received lenalidomide and dexamethasone as initial therapy for their myeloma and then underwent stem cell mobilization for immediate or future stem cell transplantation. Patients who received any other regimen prior to the stem cell mobilization were excluded. Between July 2004 and May 2008, 106 patients, satisfying the above criteria were identified from the Mayo Clinic transplant database. Medical records and collection sheets were examined for the data. Results: The median (range) age at mobilization was 60 yrs (29–75); 34 (32%) were over 65 yrs and 59 (55%) were males. The median duration of lenalidomide therapy was 4 months (range; 1–13). The strategy for stem cell mobilization was GCSF alone in 92 patients (87%), cyclophosphamide (CTX) and GCSF in 11 pts and 3 pts received AMD3100 and GCSF. Among the GCSF mobilized patients, 10 pts (11%) failed to collect at least 2.5 million cells required for one transplant, including 8 patients who never achieved the minimum peripheral count threshold to initiate the collection. Two of the 11 pts undergoing primary mobilization with CTX/GCSF failed to collect any cells, while all of the 3 pts mobilized with AMD3100 were successful. Five of these pts subsequently underwent successful salvage mobilization with CTX/GCSF, 1 with AMD3100, one failed to mobilize with CTX and the rest did not repeat mobilization. Given that the total CD34 collection and the number of days of collection are influenced by the CD34 goal, we examined patient characteristics that correlated with the CD34 collections over the first 2 days. Increasing patient age and the duration of lenalidomide therapy, both correlated with decreasing 2-day CD34 collection, while the time between last dose of lenalidomide and the start of GCSF had no effect. We then performed ROC analysis to find best cut-off points that predicted the inability to collect adequate (2.5 million) CD34 cells in 3 days. Lenalidomide therapy of more than 4 months (P =0.03) and age > 63 yrs (P = 0.04) best predicted inability to achieve this endpoint. In addition, a peripheral blood CD34 count < 5/uL on day 5 after start of GCSF was highly predictive of failure to reach this endpoint. Conclusions: Inability to collect adequate stem cells with lenalidomide appears to be related to patient age and the duration of lenalidomide therapy. We recommend early stem cell collection and storage, if a delayed transplantation approach is taken. Patients receiving more than 4 cycles of therapy and those over 65 years should undergo mobilization with CTX+G-CSF, rather than G-CSF alone. Majority of the patients who fail G-CSF based collection can be mobilized using CTX and G-CSF. Early identification of failures after G-CSF administration using the peripheral CD34 counts can potentially allow salvage using strategies such as AMD3100.

Background: Therapy-related MDS/AML (t-MDS/AML) is a common and devastating complication of treatment with alkylating agents and topoisomerase II inhibitors, often employed with curative intent, in standard or high-doses, in the treatment of hematological malignancies and solid tumors. Allogeneic HSC transplant is considered the standard treatment for t-MDS/AML but its applicability is limited by the unavailability of donors, comorbidities in the recipient and risk of acute and chronic graft-versus-host disease. Patients carrying diseases commonly treated with high-dose chemotherapy and autologous HSC transplant (such as multiple myeloma and non-Hodgkin lymphoma) who latter develop t-MDS/AML occasionally have stored HSC harvested prior to the diagnosis of the secondary malignancy (hereafter called early-stored HSC). The benefit of using early-stored HSC to support myeloablative therapy for the treatment t-MDS/AML is unknown. Methods: Retrospective, single center analysis of patients with t-MDS/AML receiving myeloablative chemotherapy with or without irradiation supported with early-stored HSC. Results: Six patients received early-stored HSC transplant for treatment of t-MDS/AML between 2000 and 2007. Median age at the time of the transplant was 57 years (range 15–71). Three patients had been primarily diagnosed with follicular lymphoma, 2 with multiple myeloma and 1 with Ewing’s sarcoma. One patient had received prior autologous HSC transplantation. Two patients developed AML, 1 patient CMML, 1 patient RCMD, 1 patient RAEB1 and 1 patient RAEB2. Median time from diagnosis of primary malignancy to HSC harvesting was 26 (2–122) months and from harvesting to development of t-MDS/AML 44 (7–79) months. Conditioning regimen was Cy/TBI in three patients, BuCy in 2 patients and Samarium + Melphalan in one patient. Five patients engrafted neutrophils and 4 patients engrafted platelets 10–34 and 13–126 days after transplant respectively. In 3/6 patients there was disappearance of the pre-transplant chromosomic abnormality (2 patients -7 and 1 patient -7 and t(1;7)). Two patients obtained hematologic CR and two patients obtained CR without full recovery of platelets. One patient died of sepsis 230 days after transplant, one died with refractory disease on day 103 after transplant and one patient is alive with recurrence of t-MDS. Three patients are alive and free of disease 7, 73 and 87 months after transplant. Conclusion: Myeloablative conditioning followed by autologous, early-stored HSC transplant can provide prolonged survival to patients with tMDS/AML not suitable to allogeneic SCT.

Abstract Abstract 3094 The HLA class II DRB1 antigen DR15 is an important immunobiologic marker in immune mediated marrow failure states. DR15 has also been reported in small studies to be associated with favorable outcomes (reduction in acute GVHD and reduced relapse resulting in improved overall survival) after allogeneic hematopoietic cell transplant. To elucidate the impact of DR15 on major transplant outcomes, we conducted a retrospective study of 2, 891 recipients of first marrow or mobilized peripheral blood stem cell transplantation for the treatment of acute myeloid leukemia (n=1038), acute lymphoblastic leukemia (n=700), chronic myeloid leukemia (n=948), or myelodysplastic syndrome (n=205) between 1990–2008 and reported to the CIBMTR registry. Selection was confined to HLA-identical sibling transplantation to avoid HLA-disparity as a driving force for observed differences. All patients received conventional myeloablative conditioning, T-replete grafts and cyclosporine plus methotrexate- based GVHD prophylaxis. DNA-based HLA typing allowed categorization of 732 (25.3%) patients as positive and 2159 (74.7%) patients as negative for DRB1*15 :01 or *15 :02 (DR15). There were no significant differences in baseline characteristics between the HLA DR15-positive and -negative groups. In univariate analysis, HLA-DR15 status had no impact on neutrophil engraftment, acute graft-versus-host disease (GvHD) II-IV or III-IV, chronic GVHD, treatment related mortality, relapse, disease-free survival or overall survival. Confining the univariate analysis to myeloid malignancies did not alter these findings. Multivariate analysis models were constructed with DR15 status forced into the models in all steps of model building and the final model regardless of its statistical significance. Other variables tested included: donor/recipient age, CMV status, disease, disease stage, graft source, Karnofsky score, race and year of transplant. Variables that attained a p-value ≤0.05 were held in the final multivariate models. In multivariate analysis, DR15 status showed no significant difference in the primary outcomes of acute GVHD II-IV or III-IV, chronic GVHD, overall survival, or relapse. In conclusion, DR15 status had no impact on major HLA-matched sibling donor hematopoietic cell transplantation outcomes in this large and homogenous cohort of leukemia and MDS patients. 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.

Abstract Background Allogeneic stem cell transplantation (allo-SCT) is a potentially curative option for patients with myelodysplastic syndromes (MDS). However, allo-SCT can be associated with significant morbidity and mortality along with a risk for post-transplant disease relapse. While many MDS prognostic models exist, a prognostic model specifically designed to predict post-transplant disease relapse is yet to be developed. Therefore, we carried out this single institution study. Methods After due IRB approval, the Mayo Clinic MDS database (1995-2012) was retrospectively reviewed. This database contains comprehensive information on MDS clinical and pathological characteristics, treatments and SCT. Primary outcomes analyzed included disease free survival (DFS), overall survival (OS) and relapse rates at five years post allo-SCT. In addition, we evaluated transplant related mortality (TRM), non-relapse mortality (NRM), and rates of acute and chronic graft versus host disease (GVHD). DFS and OS were calculated from the time of transplantation. The prognostic relevance of several disease and transplant specific characteristics were analyzed, including: age, gender, World Health Organization (WHO) categories, therapy related MDS, cytogenetics, International Prognostic Scoring System (IPSS) and IPSS-Revised (IPSS-R) at the time of MDS diagnosis, transfusion dependence, bone marrow and circulating blast count at transplant, serum ferritin levels, SCT Co-morbidity Index, donor source, HLA matching, CMV serostatus, and conditioning regimen. Multivariate analysis was performed using the Cox Proportional Hazard Model. Survival was estimated and compared using the Kaplan Meier and Log Rank tests, respectively. Results From 1995 through 2012, 96 consecutive patients with MDS underwent allo-SCT at the Mayo Clinic, Rochester. Of these, 62 were male (65%) with a median age of 54 (24-68 years). The median follow up was 31 (1-181) months. Twenty seven patients (28%) had therapy related MDS and 39 (40%) had MDS with a monosomal karyotype. IPSS-R risk stratification identified 55 (57%) patients with very high, 20 (21%) with high and 21 (22%) with intermediate/good risk disease. Fifty (52%) patients received a reduced intensity conditioning. The TRM was 8% and NRM at 5 years was 22%. Acute (grade 2 to 4) GVHD developed in 57 (59%) patients and chronic extensive GVHD was noted in 52 (54%) patients. Five-year relapse, DFS and OS rates were 24%, 42%, and 44%, respectively. In a univariate analysis, IPSS-R (high/very high, P=0.005), therapy related MDS (P=0.009), bone marrow blast count at transplant (≥10%, P=0.01), and the presence of a monosomal karyotype (P=0.05) were significantly associated with worse DFS. On a multivariable analysis, only high or very high risk IPSS-R category (HR 7.8, P=0.005) and therapy related MDS (HR 3.9, P=0.04) retained their negative prognostic impact. Based on this finding, we developed a prognostic model that assigned one point to each of these two factors (low risk-0, intermediate-1 and high risk-2). This model successfully stratified patients based on DFS, with a 5-year DFS of 67%, 40% and 23% for low, intermediate and high risk categories respectively, P=0.0012. This model was also successful in risk stratifying patients with regards to OS (table 1, figure 1). The presence of chronic GVHD was associated with a significantly improved DFS (62% vs 24%, P<0.0001) and OS (78% vs 19%, P<0.0001), however, as this is a post-transplant outcome, it was not included in the analysis/model. Conclusions Although the IPSS-R has not been validated in therapy related MDS or in patients who have received MDS directed therapy, the high/very high risk categories along with therapy related MDS, serve as independent predictors of OS and disease relapse after allo-SCT. Using these two variables, our prognostic model efficiently stratified patients with regards to DFS, relapse rates, and OS. Given the smaller sample size validation in a larger patient cohort will be needed. Disclosures: No relevant conflicts of interest to declare.

Abstract Introduction: FISH is able to recognize chromosomal deletions and translocations with a greater sensitivity than conventional cytogenetics. Specific abnormalities have been associated with prognosis. Initial observations suggest a poor outcome for patients with -17p13.1, chromosome 13 abnormalities (Δ13) and t(4;14)(p16.3;q32). In contrast a good outcome has been shown in some series for patients with t(11;14)(q13;q32). We analyzed the value of FISH in patients receiving high dose therapy . Patients and Methods: We studied by cIg-FISH 226 patients undergoing high dose therapy at Mayo Clinic between 1/1990 and 9/2001. All patients had a pretransplant cIg-FISH done on cytospin slides from marrow aspirates for t(11;14)(q13;q32), t(4;14)(p16.3;q32), and -17p13.1(p53). Information was available regarding Δ13 for all patients (+ in 52%). Results: The prevalence of the abnormalities were: t(11;14)(q13;q32) 17% (n=197), t(4;14)(p16.3;q32) 13% (n=153), and -17p13.1 11% (n=168). The overall survival (OS)was significantly shortened in patients with t(4;14)(p16.3;q32) (18.2 vs. 43.3 mo, p=0.001) (figure) and patients with -17p13.1 (14.7 vs. 38.6 mo, p=.01). OS was not different for patients with the t(11;14)(q13;q32) (36.2 vs. 34.8 mo, p=ns). Likewise time to progression (TTP) was shortened in patients with t(4;14)(p16.3;q32) (8.5 vs 17.7 mo, p=.001) and -17p13.1 (8.3 vs. 16.2 mo, p=0.005). TTP was also not affected significantly by the t(11;14)(q13;q32) (20.7 vs. 14.9 mo, p=NS). To dissect the specific contribution of t(4;14)(p16.3;q32) we did a subset analysis of patients who also had Δ13, since 85% of patients with t(4;14)(p16.3;q32) are expected to have Δ13. Of 84 studied for both abnormalities 22 had both Δ13 and t(4;14)(p16.3;q32). The OS was significantly shorter in patients with both abnormalities versus those with Δ13 alone (26.6 vs. 18.2 months, p=0.001). When a multivariable analysis of the impact of Δ13 and t(4;14)(p16.3;q32) were placed into a Cox model the hazard function for t(4;14)(p16.3;q32) was greater than Δ13 (2.6 versus 1.6). Δ13 had only borderline significance in this model (p=0.06). Conclusion: We have been unable to corroborate the improved outcome after transplant for patients with t(11;14)(q13;q32). As has been reported in patients with conventional and high dose therapy -17p13(p53) and t(4;14)(p16.3;q32) have clinical importance for estimation of OS and TTP. In this patient group the t(4;14)(p16.3;q32) carried a greater adverse impact than did Δ13, and identifies a subset of patients whose time to progression is 8.5 months. These patients likely do not benefit from autologous transplant and are candidates for novel therapeutic approaches. Outcome Successful determination Patients with translocation or deletion Survival (months) with/without abnormality Time to Progression (months) with/without abnormality * p<0.01;**p<0.001 t(11;14)(q13;q32) 197 34(17%) 36.2/34.8 20.7/14.9 p53 168 18(11%) 14.7/38.6 * 8.3/16.2 * t(4;14)(p16.3;q32) 153 26(17%) 18.2/43.3 **figure 8.5/17.7 ** t(4;14)(p16.3;q32)/Δ13+ patients 84 22(26%) 18.2/26.6 8.2/12.8 * Figure Figure

Abstract Abstract 4259 Background: Patients with defective DNA repair mechanisms are at higher risk for developing cancer. BRCA1 and BRCA2 are proteins that coordinate DNA repair by homologous-recombination. Mutations in BRCA1 and BRCA2 are associated with an increased risk of cancers, namely breast, ovarian, and pancreatic, thus making these patients more likely to receive chemo- or radiation therapy. Additionally, secondary malignancies can be an unfortunate consequence of treatment with chemo- or radiation therapy. Although tumors with defective DNA repair mechanisms may be more susceptible to therapy, we hypothesized that patients with BRCA mutations that underwent chemotherapy or radiotherapy for treatment of breast or ovarian cancer would be at a higher risk of developing therapy- related myelodysplastic syndrome (t-MDS) or acute myeloid leukemia (t-AML). Methods: We accessed patient data from our institution maintained by the Mayo Clinic Life Sciences System using the Data Discovery and Query Builder. We searched for patients whose notes and diagnoses included the terms BRCA, and breast or ovarian cancer, and myelodysplastic syndrome or acute myeloid leukemia. We searched our records from 1/1/1995–7/15/2011. We cross-referenced our findings to a database of patients who were diagnosed with a BRCA mutation through our department of medical genetics. Secondly, we searched the National Cancer Institute's Surveillance Epidemiology and End Results (SEER) database for female patients who developed AML after the diagnosis or breast or ovarian cancer from the years 1973–2008 using ratio and multiple primaries standardized incidence ratios sessions. Results: We identified 220 patients with a BRCA mutation, of which 73 received chemotherapy. There were two patients with BRCA mutations that developed t-AML following treatment for breast cancer, and one patient with a BRCA mutation who developed t-AML following treatment for ovarian cancer (Table 1). Manual data extraction from the list of patients with BRCA mutations diagnosed at our institution only identified one of these patients, as two obtained their testing through another institution. We did not identify any patients with BRCA mutations who developed t-MDS following treatment for breast or ovarian cancer. The latency between diagnosis of the primary cancer and the diagnosis or t-AML was 24 months for two patients, and 22 years for the other. From our search of the SEER database we found 649 patients who developed AML after a diagnosis of breast cancer, and 98 patients who developed AML after a diagnosis of ovarian cancer. These patients represented 0.1% and 0.2% of evaluable breast and ovarian cases respectively. The latency from time of diagnosis of the primary cancer to that of AML was 58 months (29–113 interquartile range) for breast cancer and 47 months (29–91) for ovarian cancer. The observed number of patients with AML following the diagnosis of breast or ovarian cancer was 1.68 and 4.74 times higher than that expected of the general population, respectively (both p<0.05). We were not able to stratify patients based on the presence of a BRCA mutation due to the limitations of the database. Conclusions: We identified three patients with confirmed BRCA mutations and t-AML at our institution. Although this does not represent a strong association, patients at risk for BRCA mutations do not always undergo testing. Thus, our results may not fully represent whether there is an association with BRCA mutations and t-MDS or t-AML. Using the SEER database, we confirmed that patients who were diagnosed with breast or ovarian cancer subsequently had a higher incidence of AML than the general population, although we were not able to test if patients with BRCA mutations are at higher risk of t-MDS or t-AML. Disclosures: No relevant conflicts of interest to declare.