Lin, Tasha

Abstract Background: Adult relapsed/refractory acute lymphoblastic leukemia/lymphoma (rALL) carries a very poor prognosis with limited options for effective salvage therapy. To date, there has been only a single retrospective report on the use of clofarabine in adult rALL demonstrating CR rate of 31% in this setting (Barba P et al. 2012). Aim: To evaluate the efficacy and toxicity of clofarabine based therapy in a relatively large cohort of adult rALL patients. Method: After IRB approval, a retrospective single institution study of all patients (pts) diagnosed with rALL treated with a clofarabine based regimen at Mayo Clinic between 2000 - 2014 was performed. Categorical variables were analyzed using Pearson's chi-squared test while continuous variables were analyzed using the Wilcoxon / Kruskal-Wallis test with P < 0.05 considered statistically significant. Survival estimates were calculated using Kaplan-Meier method and means were compared using log ranks. Results: Presenting features: We identified a total of 22 pts with a diagnosis of rALL who received clofarabine based therapy. 20 patients were evaluable and 2 were excluded (one received clofarabine as salvage for positive MRD and the other as systemic maintenance with CNS directed therapy for an isolated CNS relapse). Among evaluable pts, median age at time of Clofarabine based chemotherapy was 39 years (range 19-65) and 50% were males. Thirteen had B-ALL while 7 had T-ALL. Median leukocyte count was 6 x109 (0.2-28.7), hemoglobin 9.8 g/dL (7-12.9), platelet 65 x109 (12-493), peripheral blood blast 4% (0-88) and bone marrow blasts 80% (0-95) while five pts had extramedullary disease. Median number of prior regimens was 2 (1-7).. 8 (40%) pts were post allogeneic transplant Treatment and Response: 10 pts (50%) received clofarabine monotherapy, 7(35%) clofarabine and cytarabine, and 3 (15%) had clofarabine, etoposide and cyclophosphamide. Overall response rate (CR/CRi + PR) was 35%. Five (25%) achieved CR/CRi, and 2 achieved PR. Among those who achieved CR, 4 out 5 proceeded to further therapy; 2 to allogeneic stem cell transplant and two additional patients received donor lymphocyte infusion (DLI). One pt with PR also proceeded to allogeneic stem cell transplant. In comparative analysis, there were more males 6 (86%) vs 1(14%) in the responding arm (P = 0.014), otherwise the number of regimens prior to clofarabine, type of clofarabine regimen, transplant status, T vs B cell ALL, did not impact response. Median overall survival was 2.4 months (1.3-2.9) in non-responders vs. 12.8 months (3-27.4) in responders (P =0.0007) (Figure 1). All pts who proceeded to transplant or DLI relapsed with a median time to relapse of 6.4 (4.8-13.7) months. Toxicity: Rash/Hand Foot syndrome was observed in 3 pts (19%), Grade III-IV liver toxicity occurred in 4 (26%) with no permanent sequela. Opportunistic infection occurred in 3 pt (17%). Conclusion: Clofarabine based chemotherapy was a well-tolerated salvage regimen in heavily pretreated patients and was an effective bridge to definitive therapy in a significant proportion of cases. Prospective evaluation of these findings is warranted. Figure 1. Figure 1. Disclosures Al-Kali: Celgene: Research Funding.

Abstract Background: Adult T-cell acute lymphoblastic leukemia / lymphoma (T-ALL) is an rare and aggressive hematological malignancy with overall survival (OS) according to the UKALL XII/E2993 of 48% at 5 years (Marks et al, Blood 2009). Over the last decade, the incorporation of L-asparaginase, dose intensification (similar to pediatric protocols), availability of newer agents such as clofarabine (Dec 2004) and nelarabine (Oct 2005) have been shown to improve outcomes. We carried out this study to see if the above mentioned changes in treatment have translated to an OS benefit. Methods: After due IRB approval, adults diagnosed with T-ALL from 1990-2014 at Mayo Clinic were identified. All clinical and pathologic data was retrospectively reviewed Comparative analysis was performed based on year of diagnosis before and after 2005 (Group 1, diagnosis prior to 2005, and Group 2, diagnosis post 2005). Survival was estimated using the Kaplan-Meier Method and log-rank test. Chi-square test was used to compare variables. Results: A. Patient Characteristics: Between 1990 and 2014, a total of 92 consecutive patients (pts) with T-ALL were identified. Median age at diagnosis was 33 years (range; 18-88 years) with 72% males. Distribution of pts by year of diagnosis was as follows: Group 1(n= 47) (51%), and Group 2 (n=45) (49%). Median overall survival was 97.2 months. Median follow up for Group 1 was 50 months, during which time 23 (39%) deaths were documented, and 22.8 months (0.9 - 115.4) for Group 2 at which time19 deaths (42%) were documented (p= 0.04). Pts in Group 2 were older than Group1 (median age 41 vs 27 years (p= 0.004). Apart from age, the two groups were similar in other characteristics (Table 1). B. Therapy received by patient groups: We observed a high use of L-asparaginase containing regimens in Group 1 vs Group 2 [35(74%) pts vs 19 (42%), p=0.0013]. In contrast there was an increase in use of Hyper-CVAD in Group 2; 23(51%) vs. 3 (6%) (p<0.0001). There was no difference in the use of intensive pediatric protocols (p=0.11). There was a trend of increased use of nelarabine in Group 2, however clofarabine usage was not different (p=0.09, and p=0.6 respectively) (Table1). Allogenic stem cell transplant was offered more in Group 2 compared to Group 1, 16 (36%) patients vs. 10 (21%) patients (p=0.0009). In contrast, 7 (19%) patients underwent autologous transplantation in group 1 vs. none in group 2 (p=0.0009). C. Overall outcome by patient groups: We did not observe any difference in CR, or relapse rates among the two groups. The median OS and time to relapse were also not statistically different among Group 1 and 2 [102.6 vs 61.8 months Figure A, and 7.1 vs 14.1 months respectively]. Furthermore, age adjusted survival analysis was also not statistically significant. Conclusion: In this large cohort of adult T-ALL patients, in spite of significant advances in treatment strategies over the last two decades, we observed no difference in overall and relapse free survival prior to and after 2005. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Al-Kali: Celgene: Research Funding. Thompson:Kite Pharma: Research Funding. Witzig:Spectrum: Research Funding; Novartis: Research Funding; Celgene: Research Funding; Amgen: Honoraria; Valeant Pharma: Equity Ownership.

Abstract Background: Diffuse large B-cell lymphoma (DLBCL) is curable for the majority of patients treated with anthracycline based immunochemotherapy (IC). However, up to 40% of patients will relapse or require retreatment of DLBCL and outcomes are poor in this setting. Here we examine the incidence, treatment patterns and outcomes of relapsed DLBCL in the R-CHOP era. Methods: Patients were prospectively enrolled in the University of Iowa / Mayo Clinic SPORE Molecular Epidemiology Resource (MER) within 9 months of diagnosis and followed for relapse, retreatment, and death. Clinical management at diagnosis and subsequent therapies were per treating physician. This analysis includes patients with DLBCL or primary mediastinal B-cell lymphoma (PMBCL) who underwent front-line anthracycline based IC; patients with primary CNS lymphoma or PTLD were excluded. All relapse and re-treatments were verified by medical record review. Response to front-line therapy was retrospectively classified per 2007 Revised Response Criteria for Malignant Lymphoma from available clinical and radiology records. Unplanned consolidative radiation (RT) without biopsy proven disease after achieving PR from IC (N=21) was not classified as a relapse. Results: 1039 patients with newly diagnosed DLBCL or PMBCL and treated with IC were enrolled in the MER from 2002-2012. Median age at diagnosis was 62 years (range 18-92) and 577 patients (56%) were male. 647 patients (63%) had stage III/IV disease and IPI at diagnosis was 0-1 in 350 patients (34%), 2 in 305 patients (29%), 3 in 250 patients (24%) and 4-5 in 134 patients (13%). At a median follow-up of 59 months (range 1-148), 258 patients had relapse or retreatment of DLBCL of which 184 (71%) died. Incidence of relapse was 21.7% (95% CI: 19.3%-24.4%) at 2 years and 25.5% (95% CI: 22.9%-28.5%) at 5 years. In addition, the incidence of lymphoma related death without documented relapse or retreatment was 4.7% (95% CI: 3.6%-6.2%) at 2 years. At first relapse, 174 patients (67% of relapsed) received platinum based salvage therapy with 90 (52%) subsequently proceeding to autologous stem cell transplant (ASCT). 22 patients received CNS directed systemic therapy at relapse with 9 (41%) proceeding to transplant, and 43 received non-platinum-based salvage systemic therapy with 7 proceeding to transplant (17%), 15 patients received RT only as 2nd line therapy, and 4 were untreated. At a median follow-up of 56 months (range 6-121) post-transplant, 39 of 107 patients who underwent transplant remain in remission with a 2-year post-transplant progression-free survival of 45% (95% CI 37%-56%). Response to front-line IC was predictive of post-relapse outcome. Survival post-relapse was superior in the 162 patients with responsive disease (CR or PR) at the end of front-line IC (median OS 21.0 months) compared to the 88 patients who had stable or progressive disease (median OS 6.8 months, HR = 2.33, 95% CI: 1.73-3.14 p<0.0001). Transient response in midst of front-line IC was similar to no response. Patients achieving a CR or PR to front-line IC were more likely to proceed to ASCT at relapse (55%) compared to patients with either SD or PD at the end of front-line IC (25% and 17% respectively, p<0.0001). Other factors associated with poor survival at first relapse were relapse within 12 months of diagnosis (HR = 2.24, 95% CI: 1.57-3.18, p<0.0001), IPI at diagnosis of 3-5 (HR=1.51, 95% CI: 1.13-2.03, p=0.0058), and age > 60 (HR =1.51, 95% CI: 1.12-2.03, p=0.0064). There was no difference in survival at first relapse by cell of origin (HR = 1.13, 95% CI: 0.74-1.72, p=0.59). Conclusions: Most patients undergo therapy after relapsed/refractory DLBCL but only one-third receive ASCT. Outcomes following all treatments for relapsed/refractory DLBCL remain poor. Factors associated with adverse outcomes include refractory to front-line therapy, early relapse, baseline IPI and advanced age. These outcomes provide relevant historical control for the many novel agents being tested in this unmet need. Figure 1. Figure 1. Disclosures Farooq: Kite Pharma: Research Funding. Maurer:Kite Pharma: Research Funding. Cerhan:Kite Pharma: Research Funding. Link:Genentech: Consultancy, Research Funding; Kite Pharma: Research Funding. Thompson:Kite Pharma: Research Funding.

Abstract Background: Adult T-cell acute lymphoblastic leukemia / lymphoma (T-ALL) is a rare and aggressive hematological malignancy. Unlike B-cell ALL, apart from age and presenting WBC, additional prognostic factors remain largely unknown. Additionally, the prognostic impact of a monosomal karyotype, which has a negative impact on survival in myeloid neoplasms, remains to be determined in T-ALL (Kenderian et al, BCJ 2013) Aim: To study predictors of survival including the role of a monosomal karyotype in T-ALL. Methods: After due IRB approval, adults diagnosed with T-ALL from 1990-2014 at Mayo Clinic Rochester were identified. All clinical and pathologic data including FISH studies and cytogenetics were retrospectively reviewed. Chi-square test was used to compare variables. Survival was estimated and compared using the Kaplan-Meier Method and log-rank test. Univariate and multivariate analysis was performed using the Cox regression model. Results: Between 1990 and 2014, a total of 92 consecutive patients (pts) with T-ALL were identified, 41 had acute lymphoblastic lymphoma (LBL), and 51 (55%) acute lymphoblastic leukemia (ALL). Median age at diagnosis was 33 years (range; 18-88 years) with 72%males. Median follow up of our cohort was 25 months (range; 0.9-260 months) during which time 42 deaths (45%) were documented. A. Baseline characteristics: Fifty six (67%) had constitutional symptoms, and 63 (77%) had lymphadenopathy at diagnosis. Mediastinal mass was identified in 49 (55%) pts with palpable splenomegaly in 16 (20%) pts. Fifty one (58%) pts had extranodal disease, and 17 (19%) pts had CNS involvement. Pleural and pericardial effusion were evident in 16 (19%), and 6 (7%) pts, respectively. Median laboratory values included; LDH 288 U/L (115-6590), hemoglobin (Hb) 12.8 g/dl (4.5-18.2), WBC 8.65 x109 (1.4-406), platelets 169 x109 (8-485), bone marrow blasts 29% (0-99). B. Treatments: Induction therapies were variable and included; 11 (12%) CHOP like regimens, 7 (8%) modified NHL regimens (Asparginase+CHOP), 54 (58%) ALL like regimens (CALGB 9111, E2993, or HyperCVAD), 13 (14%) Pediatric regimens (ALL 10403, CCG 1961, BFM, Augmented BFM, GRAALL 2003, or Hoelzer regimen), with 7 (8%) patients' receiving palliative care only. Seventy-one (77%) pts achieved complete remission (CR1) during induction therapy while eight pts had refractory disease (8%). Thirty-three (35%) pts underwent stem cell transplant; 7 (21%) autologous and 26 (79%) allogeneic. Forty one (44%) pts had disease relapse and median time to relapse was 10.8 months (range; 8.2-16 months) C. Predictors of survival: In univariate analysis, that included age > 60 years, leukocyte count Hb, Plt, Blast percentage, mediastinal mass, LDH and CNS involvement, only age >60 and CNS involvement were predictors of inferior survival and both retained significance in the multivariable analysis with HR 3.9 (CI 1.5 - 9; p=0.0055) and 2.8 (1.3 - 5.7; p =0.0085), respectively (Figure 1 and 2). In this cohort age >60 was a better stratification that the conventionally used age above 40 (p = 0.1). Among 56 pts with evaluable cytogenetics data, 7 (13%) pts had MK which did not have an impact on survival with HR 1.9 (CI 0.4-5.6; p=0.33). Conclusion: In this large cohort of adult T-ALL patients, we observed that age >60 years and CNS involvement were independent predictors of inferior survival. MK was infrequent, but unlike in myeloid neoplasms, does not seem to impact overall survival. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Al-Kali: Celgene: Research Funding. Thompson:Kite Pharma: Research Funding. Witzig:Novartis: Research Funding; Celgene: Research Funding; Amgen: Honoraria; Spectrum: Research Funding; Valeant Pharma: Equity Ownership.

Abstract Background: Acute T-cell lymphoblastic leukemia (T-ALL)/ lymphoma (T-LBL) are immature T-cell malignancies with very poor outcomes. In patients with relapsed disease, survival is often < 12 months (Marks et al, Blood, 2009). Prognostic correlates and treatment outcomes after relapse remain largely unknown. Aims: To evaluate prognostic correlates and treatment outcomes in patients with relapsed T-ALL/LBL. Methods: After IRB approval, 92 consecutive patients with T-cell ALL/LBL were identified. 41 patients with relapsed disease after achieving a first complete remission (CR1) were included in the study group. Features at the time of relapse were retrospectively abstracted and analyzed. Survival time after relapse was calculated from the time of relapse until death or last follow-up. Conventional methods were used for statistical analysis. Results: A. Baseline characteristics of all patients 92 patients were identified [41 LBL, 51 ALL]. Median age was 33 years (range; 18-88) and 66 (72%) were males. Median follow-up was 25 months (range 0.9-260). 13(14%) received palliative care or were lost to follow-up before treatment initiation. At last follow-up, there were 41 (52%, n = 79) relapses and 42 (46%, n = 92) deaths. Of 79 patients, 71 (90%) achieved a CR1 and 8 (10%) had primary refractory disease. Comparisons between ALL and LBL revealed expected differences in presenting features such as frequency of primary mediastinal mass at presentation in LBL and high leukocyte count in ALL. Significant differences in treatment were seen. Asparaginase-based and ALL-directed therapy were more common in the ALL group (71% vs. 45%, p = 0.009; 88% vs. 71%, p = 0.04). 13 (81%) LBL and 14 (27%) ALL underwent allogeneic SCT. The remaining three in each group underwent autologous SCT in CR1. B. Characteristics of relapsed patients 41 relapsed after achieving CR1 [23 LBL, 18 ALL]. Median time to relapse was 8.0 months (range 2.3-130), with no difference between ALL and LBL groups. Median age was 34 years (range 19-71) and 29 (71%) were males. Median follow-up after relapse was 7.2 months (range 0.3-207). At time of last follow-up, there were 30 (73%) deaths, 25 (61%) achieved a second complete remission (CR2) and 14 (34%) had persistent disease. 12 (48%) had relapse following CR2. 34 (83%) relapsed following CR1 after induction chemotherapy alone. 6 (15%) and 1 (2%) relapsed following allogeneic and autologous SCT respectively. 27 (66%) had BM involvement, 5 (12%) had CNS involvement, 13 (32%) had mediastinal involvement, and 3 (7%) had isolated extramedullary relapse. Ten (43%) patients with LBL relapsed with ALL. Of 27 patients with available data, 9 (33%) had high-risk cytogenetics at relapse, defined as ≥ 5 chromosomal abnormalities and/or markers known to confer an unfavorable prognosis. 16 of these 27 patients had follow-up cytogenetic studies performed, of which 8 (50%) had evidence of clonal evolution. Patients were treated with up to five regimens. 12 (31%) received asparaginase-based therapy and 13 (33%) received nelarabine with CR2 rates of 75% and 25% respectively. Median number of regimens needed to achieve CR2 was one. 18 (46%) went onto SCT following CR2: 14 (allogeneic), 3 (autologous), and 1 (donor lymphocyte infusion). The majority received myeloablative conditioning (92%). C. Outcomes and prognostic correlates for survival after relapse Median survival following relapse was 8.2 months (IQR 4.1-21.3) and did not differ between LBL and ALL. Nine (36%) who achieved CR2 are alive at time of last follow-up. 25 (61%) achieved CR2, but 12 (48%) relapsed following CR2, with median time to second relapse of 7.6 months (IQR 4.7-14). Nine of 18 who underwent SCT following CR2 had disease relapse (8 allogeneic, 1 autologous). Only BM involvement at relapse significantly correlated with post-relapse survival (HR 2.4 [1.1, 5.1], p = 0.03). Clonal evolution, high-risk cytogenetics, nelarabine therapy, achieving CR2, and SCT were not independent predictors of survival in our small subset of patients. Conclusion: Patients with relapsed T-ALL/LBL have dismal outcomes, in spite of advances in therapy with newer agents such as nelarabine and the use of allogeneic SCT. Regardless of T-ALL/LBL subtype, BM involvement at relapse appears to be a significant factor negatively impacting post-relapse survival. Further studies are needed to validate these findings. Disclosures Al-Kali: Celgene: Research Funding. Thompson:Kite Pharma: Research Funding.

Abstract Background. Diffuse large B-cell lymphoma (DLBCL) is curable for the majority of patients treated with anthracycline based immunochemotherapy (IC). While most patients achieve response to initial therapy, a subset of patients are refractory to initial IC or become refractory to subsequent salvage therapies. Prognosis in this setting is very poor. Here we determine the incidence of refractory disease from a large cohort of DLBCL prospectively followed from diagnosis in the IC era and assess outcomes in these patients. Methods. Patients were prospectively enrolled in the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource (MER) within 9 months of diagnosis. Patients were followed for relapse, retreatment, and death; all events were validated by medical record. This analysis includes patients with DLBCL or primary mediastinal B-cell lymphoma (PMBCL) who received initial treatment of anthracycline based immunochemotherapy; patients with primary CNS lymphoma or post-transplant lymphoproliferative disorders were excluded. Response to therapy was retrospectively classified per 2007 Revised Response Criteria for Malignant Lymphoma from available clinical and radiology records. Refractory disease was defined as having a best response to any systemic therapy of stable disease (SD), progressive disease (PD), or relapse within 12 months of autologous stem cell transplantation (SCT). We also examined patients with transient response to IC as defined by achieving an interim response (CR or PR) but having progressive disease at or prior to the end of the planned number of cycles of IC. Results. 1039 patients with DLBCL or PMBCL lymphoma were enrolled in the MER from 2002-2012 and treated with R-CHOP or comparable IC. Median age at diagnosis was 62 years (range 18-91) and 577 (56%) were male. At a median FU of 60 months (range 1-148), 136 patients developed refractory disease. The median age at diagnosis of patients with refractory disease was 62 years (range 19-87). The cumulative incidence of refractory DLBCL was 11.3% at 2 years (95%: CI: 9.5-13.4) and 13.1% at 5 years (95% CI: 11.2-15.4). The median overall survival after becoming refractory was 4.7 months (95% CI: 4.1-5.5) with a 1 year survival rate of 21% (95% CI: 15%-30%). The median number of therapies before becoming refractory was 2 with 35 patients becoming refractory following their first therapy (i.e. IC), 83 patients becoming refractory after their 2nd therapy, and 23 patients becoming refractory after their 3rd or later therapy; 27 patients had received stem cell transplant prior to becoming refractory. Outcomes were poor regardless of when patients became refractory (figure). Patients received a median (range) of 2 (0-8) treatments after becoming refractory with 40% (N=54) attempting subsequent platinum based salvage therapy and 14% (N=9) proceeding to ASCT, of which only 6 remain alive in long-term remission. 41 patients (30%) were treated on clinical trials after becoming refractory. Response rate for the first therapy after becoming refractory was 21%, while 29% of patients had a response to any subsequent therapy. Once patients became refractory, there was no difference in survival based on response at end of initial IC (p=0.33), cell of origin at diagnosis (p=0.64), IPI at diagnosis (p=0.33), or age when refractory (p=0.66). Outcomes in patients with transient response to IC (n=58) were poor, with the majority (N=37, 63%) becoming refractory to subsequent therapy. Median OS after first relapse was 6.7 months in patients with transient response to IC, which was equivalent to patients refractory to IC (p=0.99). The majority of patients with transient response to IC (69%) were next treated with platinum based salvage therapy which had a response rate of 40%. Ultimately 15 of the 58 patients (26%) proceeded to transplant, of which only 5 (9%) achieved long-term remission. Conclusions. Approximately 13% of patients with DLBCL become refractory to treatment in their disease course. Outcomes once patients become refractory are extremely poor regardless of when patients become refractory. Standard prognostic factors are no longer predictive of outcome and stem cell transplant had limited benefit in this group of patients. Patients with transient response to initial immunochemotherapy should be included when classifying patients as refractory. New therapy strategies are needed in the refractory setting. Figure 1. Figure 1. Disclosures Maurer: Kite Pharma: Research Funding. Thompson:Kite Pharma: Research Funding. Farooq:Kite Pharma: Research Funding. Cerhan:Kite Pharma: Research Funding. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Link:Genentech: Consultancy, Research Funding; Kite Pharma: Research Funding.

Summary This study aimed to describe the patterns of care and outcomes of diffuse large B cell lymphoma ( DLBCL ) after failure of front line anthracycline‐based immunochemotherapy ( IC ). Patients with newly diagnosed lymphoma were prospectively enrolled in Molecular Epidemiology Resource ( MER ) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellzence. All DLBCL and primary mediastinal B‐cell lymphoma ( PMBL ) patients treated with front‐line anthracycline‐based IC were followed for relapse. Patients with relapse on follow‐up and subsequently retreated were included in this analysis. 1039 patients received anthracycline‐based IC between 2002 and 2012, of which 244 relapsed and were subsequently retreated. Across all therapies, overall survival at 4 years ( OS 4) from relapse was 28% and 103 patients ultimately underwent autologous haematopoietic cell transplant (auto HCT ) with OS 4 from auto HCT of 51%. Patients relapsing after 12 months from initial diagnosis had OS 4 of 47% but those with a transient or no response to initial therapy had OS 4 of only 13%. Outcomes of relapsed or refractory DLBCL differ substantially when categorized by response to initial therapy, timing of relapse and opportunity to undergo auto HCT . The design and interpretation of uncontrolled trials should account for this heterogeneity in patients with relapsed DLBCL .