ALBERT

Description: Introduction: Patients with aggressive peripheral T-cell lymphoma (PTCL) often undergo induction with anthracycline-based chemotherapy followed by autologous stem cell transplantation in fit patients. Up to 40% of patients have primary refractory disease, and even for those who respond to induction, 5-year overall survival (OS) is 32% with the exception of ALCL. This results in a significant number of patients who need treatment in the relapsed and refractory (R/R) setting. While there is no standard approach for this group, multiagent chemotherapy regimens are often used, particularly in those who may be transplant candidates. Several novel single agents have shown activity in R/R PTCL and can often be given in a more continuous fashion than combination chemotherapy. In order to explore the potential benefits of single agents in comparison to combination chemotherapy in R/R PTCL, we examined treatment outcomes in a prospectively enrolled cohort of PTCL patients. Methods: Patients were enrolled in the Comprehensive Oncology Measures for Peripheral T-cell Lymphoma Treatment (COMPLETE), a multinational prospective cohort of 500 newly diagnosed PTCL patients. Demographics, treatments, and outcomes were recorded until death or for at least 5 years. Analysis was restricted to 6 subtypes of PTCL: PTCL-NOS, AITL, ALCL, EATL, NKT, HSTCL. Primary refractory was defined as lack of a complete response (CR) to initial treatment. Relapsed was defined as a CR to initial treatment with progression at a later date. Patients in whom initial treatment was ≤4 days, unreported, or began 〉30 days before or after informed consent were excluded. Single agents were pralatrexate, romidepsin, brentuximab vedotin (BV), bendamustine, alisertib, denileukin diftitox, and lenalidomide. Combinations were any multiagent chemotherapy regimen excluding the above agents. Results: Of 462 patients with locked records, 57 met the above eligibility criteria and had treatment and followup data available for analysis. As first treatment in R/R disease, 26 patients received combination therapy (by subtype: PTCL-NOS [10], AITL [6], ALCL [3], EATL [1], NKT [5], HSTCL [1]) and 31 received single agents (by subtype: PTCL-NOS [13], AITL [5], ALCL [7], EATL [2], NKT [2], HSTCL [2]). The most common combination regimens had an ifosfamide-, gemcitabine-, or platinum-based backbone. Single agents used were: BV (12), romidepsin (8), pralatrexate (5), alisertib (3), bendamustine (1), denileukin diftitox (1), and lenalidomide (1). The objective response rate (ORR) for single agents was higher than for combination therapy (59% [17/29] vs. 46% [12/26], P=0.36), as was the CR rate (41% [12/29] vs. 19% [5/26], P=0.02). In those with R/R ALCL who received BV, ORR was 83% (5/6) and CR was 67% (4/6). Given these expected high response rates of BV in R/R ALCL, a subtype analysis excluding ALCL patients who received BV (ALCL-BV) was conducted and showed similar ORR between single and combination therapy (52% [12/23] vs. 46% [12/26], P=0.26), though CR still favored single agents (35% [8/23] vs. 19% [5/26], P=0.07). Excluding the ALCL-BV group, CRs were observed with BV (3/6), romidepsin (2/8), pralatrexate (1/5), bendamustine (1/1), and alisertib (1/3). Median progression-free survival (PFS) favored single over combination therapy (11.2 vs. 6.7 months, P=0.02). PFS in the ALCL-BV group was comparable at 11 months. Stem-cell transplantation occurred more frequently after single agent use than combination therapy (25% [8/31] vs. 7% [2/26]). Conclusion: Our analysis confirms the unmet need for better therapies in R/R PTCL. This data shows a trend towards increased CR and PFS with single agents in comparison to combination therapy, while maintaining the potential to bridge to transplantation. It is unclear whether the differences were driven by reduced toxicity and longer treatment duration with single agents, increased efficacy from BV in CD30-expressing cancers, or patient factors that led to therapy selection. However, despite the small size and exploratory nature of this analysis, single agents do not appear inferior to combination therapy with respect to disease control or ability to bridge to transplant with intent to cure. Our data can serve as a foundation for larger datasets or randomized trials which are needed to identify the truly superior strategy. In the meantime, the optimal approach for R/R PTCL remains unclear. Disclosures Schwartz: MS Biostatistics, LLC: Employment. Acosta:Spectrum: Employment. Pro:Seattle Genetics: Consultancy, Other: Travel expenses, Research Funding; kiowa: Honoraria; portola: Honoraria; Takeda Pharmaceuticals: Honoraria, Other: Travel expenses. Shustov:Seattle Genetics: Research Funding. Horwitz:Aileron Therapeutics: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Mundipharma: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Spectrum: Research Funding; Trillium: Consultancy; Corvus: Consultancy; Forty Seven: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Innate Pharma: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Portola: Consultancy; Kyowa-Hakka-Kirin: Consultancy, Research Funding. Foss:Seattle genetics: Consultancy; Miragen: Consultancy, Speakers Bureau; Mallinkrodt: Consultancy; Spectrum: Consultancy.

Description: Background Recommendations on erythropoiesis-stimulating agents (ESAs) for the management of chemotherapy-induced anemia (CIA) are well established (Schrijvers D et al. Ann Oncol 2010;21[suppl 5]:v244-7). Iron supplementation can further improve treatment response of CIA, particularly in the case of iron deficiency (Pedrazzoli P et al. J Clin Oncol 2008;26:1619-25; Auerbach M et al. J Clin Oncol 2004;22:1301-7), but is under-used. Objective To evaluate the effect of epoetin alfa biosimilar, with or without iron, on CIA in current oncology and hematology practice. Methods SYNERGY was an observational, longitudinal, prospective, multicenter study conducted in France, from a representative, random sample of oncologists and hematologists. Patients of these clinicians were aged ≥18 years with solid tumors, lymphoma and/or myeloma and CIA, eligible for treatment with epoetin alfa biosimilar and followed for 12-16 weeks. A subanalysis describing the treatment response to epoetin alfa biosimilar in patients with/without iron supplementation and their target hemoglobin (Hb) levels is presented here. Results Overall, 2167 patients were enrolled by 195 French oncologists/hematologists during June 2012-December 2014. The analysis included 2076 patients, of whom half were male. At inclusion, mean age ± standard deviation (SD) was 67±12 years and 75.7% (n=1517) of patients had a World Health Organization performance status of 0 or 1. Most patients had not received any blood transfusions (90.0%, n=1867) or ESAs (93.1%, n=1932) in the year before the inclusion visit. A total of 31.6% (n=655) patients received iron supplementation, of whom 58.9% (n=386) received intravenous (IV) iron, 40.5% (n=265) had oral iron and 0.6% (n=4) were prescribed both oral and IV iron. An iron status assessment was more common in patients who were given iron supplementation, while over a third of patients who did not have an iron status were prescribed iron (Table). At follow-up, over 70% of patients had a maximum Hb level above 11 g/dL, regardless of iron status (Table). For patients with and without added iron, the mean change in Hb level was 2.26 g/dL and 2.22 g/dL at maximum during the study and 1.71±1.52 g/dL and 1.59±1.60 g/dL at final visit, respectively. Iron status results were used to define patients as having absolute iron deficiency (coefficient of saturation of transferrin [CST]

Description: Salvage chemotherapy followed by high dose therapy (HDT) and autologous stem cell transplantation (ASCT) is the standard of treatment for chemosensitive relapses in diffuse large B cell lymphoma. Improvement of salvage chemotherapy was suggested with the association rituximab, Ifosfamide, etoposide, carboplatinum, R-ICE. What is the optimal chemotherapy regimen and can we reduce the post ASCT relapses rate? The ongoing CORAL trial was designed to answer these questions. DLBCL CD 20+ in first relapse or pts refractory after first line therapy were randomized between rituximab plus DHAP and R-ICE. Stratification was made on centers, prior rituximab exposure and refractory/12months, 108 refractory/early relapses; 97 pts with prior exposure to rituximab; Stage 3-4 107 pts; elevated LDH 88 pts; secondary IPI 0–1 112 pts; sIPI 2-3 63pts. The two arms were well balanced. In the prior rituximab cohort exposure more pts had refractory disease and adverse prognostic factors. However, at inclusion patients characteristics were not significantly different in the stratified subgroups. The overall response rate was 68%, with 41% complete remission rate. Toxicity was similar to what is expected with intensive therapy, 72 SAE were reported with 12 deaths during the initial salvage regimens. In univariate analysis factors significantly affecting response rate (p1 54% vs 77% and prior exposure to rituximab 54% vs 82%. In a logistic regression model only refractory/early relapse and secondary IPI remain significant for response rate. Intent to treat 2 yrs EFS and OS were 50% (CI 42–57%) and 69% (CI 61–75%) respectively. Only 107 pts in this prospective study received, per protocol ASCT. For patients transplanted, 2 yrs EFS was 75% (CI 63–84%) with OS 89%. Two yrs EFS was affected by: prior treatment with rituximab, 34% vs 66% (p=.0001); refractory/early relapse 36% vs 68% (p

Description: Diffuse large B-cell lymphomas (DLBCLs) are heterogeneous in clinical presentation, histopathological and biological findings, and outcome. Today, risk-adapted treatment decisions are mainly based on the International Prognostic Index (IPI). Recently, molecular profiling has been shown to correlate with survival in DLBCL patients treated with conventional chemotherapy. Immunohistochemistry (IHC) has been proposed as a surrogate of molecular profiling (« phenotypic profiling»). Besides, we and others have shown that early response evaluation (after 2 cycles) with 18FDG-PET scanning is predictive of patient outcome in DLBCL, independently of IPI (Haioun & al, Blood2005; 106: 1376). We retrospectively investigated the phenotypic profile of 81 patients (pts) from our recently published series with a confirmed diagnosis of DLBCL and available material for extensive IHC analyses. Diagnosis was based on a nodal (n=45), extranodal (n=25) or mediastinal (n=11) specimen. IHC was performed with the markers bcl2, CD10, bcl6 and MUM1, and scored by two observers. Pts were classified as having a germinal center (GC) or non germinal center (nGC) profile using the following algorithm: GC pts were to be CD10+ or bcl6+ and MUM1−, and all others were nGC (Hans & al, Blood2004; 103: 275). Bcl2 was positive in 53%, CD10 in 36%, bcl6 in 58% and MUM1 in 45% of interpretable cases. Seventy-four pts (91%) had an interpretable profile, 39 (52%) were in the GC group, 35 (48%) in the nGC group. All pts received a doxorubicin-containing regimen as induction treatment, with rituximab for 46% of them. Pretreatment characteristics and early response by 18FDG-PET according to phenotypic profile are shown in the table below. With a median follow-up of 33 months, estimated 2-y OS and EFS were 75% and 67%. Survival analysis confirmed the poor prognostic value of a positive early 18FDG-PET scan: 2-y EFS was 46% in the PET-positive group and 80% in the PET-negative group (p = 0.0003). Two-year EFS was 61% and 73% in the bcl2-positive and negative groups, respectively (p = 0.08). We could not observe any prognostic influence of the GC vs nGC profile: Two-year EFS was 72% in the GC and 64% in the nGC group (p=0.62). In this limited series, we confirm the high predictive value of early response evaluation with 18FDG-PET scanning, but did not observe any significative influence of phenotypic profile, contrarily to several published reports. The reasons for this discrepancy, be they related to treatment type (including rituximab), disease presentation (many pts with extranodal disease) or IHC evaluation (fixation, scoring), remain to be understood. Meanwhile, 18FDG-PET should be an early guide for first-line strategies in DLBCL. Characteristics according to phenotypic profile GC (n=39) nGC (n=35) p Age

Description: Abstract 880 On behalf of the German Low-Grade Lymphoma Study Group (GLSG) and the European MCL Network Background: In younger patients with mantle cell lymphoma (MCL), autologous stem cell transplantation (ASCT) significantly prolonged response duration with a trend towards improved overall survival in a randomized trial of the European MCL Network (Dreyling et al., ASH 2008). A recently updated clinical trial of the German Low-Grade Lymphoma Study Group (GLSG) also reported a significantly prolonged response duration by the addition of Rituximab to first-line CHOP (Hoster et al., ASH 2008). By pooled analysis of these trials we investigated whether Rituximab and ASCT independently prolong response duration. Methods: The analysis included all advanced stage MCL patients of the trials “CHOP vs. MCP” (Nickenig et al., Cancer 2006), “CHOP vs. R-CHOP” (Lenz et al., JCO 2005) and European MCL trial 1 (Dreyling et al., Blood 2005) with complete or partial remission to either CHOP or R-CHOP first-line induction and randomization between ASCT and Interferon-α maintenance. Response duration was defined as time from the end of successful induction chemotherapy to relapse or death from any cause, overall survival from the end of successful induction chemotherapy to death from any cause. Stratified Kaplan-Meier curves for response duration and overall survival were calculated for the four treatment groups (CHOP without ASCT, CHOP with ASCT, R-CHOP without ASCT and R-CHOP with ASCT). By multiple Cox regression we tested whether the impact of Rituximab (R) and ASCT was independent and additive. Results: One-hundred and eighty patients with MCL were evaluable, 80 treated with R-CHOP, 78 with ASCT (CHOP without ASCT: 56, CHOP with ASCT: 46, R-CHOP without ASCT: 44 and R-CHOP with ASCT: 34). Median age was 55 years (range 34-65), the MIPI classified 71% as low risk, 22% as intermediate risk, and 6% as high risk, and baseline characteristics were comparable between treatment groups. With a median follow-up of 63 months, median response duration was 16 months after CHOP without ASCT, 26 months after R-CHOP without ASCT, 39 months after CHOP with ASCT, and 41 months after R-CHOP with ASCT. In multiple Cox regression including R and ASCT, the hazard ratios of R (0.60, 95% CI 0.42-0.86, p = 0.0056) and ASCT (0.50, 95% CI 0.35-0.70, p = 0.0001) were independently significant. There was no interaction between R and ASCT (p=0.43). Median overall survival was 54 months after CHOP without ASCT, 66 months after R-CHOP without ASCT, 90 months after CHOP with ASCT, and not reached after R-CHOP with ASCT. The hazard ratios for OS were 0.70 (95% CI 0.44-1.12, p = 0.14) for R and 0.63 (95% CI 0.41-0.97, p = 0.0379) for ASCT. Conclusions: Our results indicate an additive effect of ASCT and Rituximab in combination with CHOP on response duration in advanced stage MCL patients and support strategies of several study groups to combine Rituximab-containing induction therapies with ASCT in younger MCL patients. However, even after combined treatment approaches, delayed relapses have been observed, supporting the use of maintenance therapy and the introduction of molecular targeted therapeutical strategies. Disclosures: Hoster: Roche: Travel Support. Off Label Use: Rituximab in Mantle Cell Lymphoma. Pfreundschuh:Roche: Membership on an entity's Board of Directors or advisory committees. Dührsen:Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Gisselbrecht:Roche: Research Funding, Speakers Bureau. Unterhalt:Roche: Travel Support. Dreyling:Roche: Honoraria, Research Funding.

Description: To evaluate the prognostic significance of clinicobiologic and pathological features in angioimmunoblastic T-cell lymphoma (AITL), 157 AITL patients were retrieved from the GELA LNH87-LNH93 randomized clinical trials. One hundred forty-seven patients received a cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)–like regimen with intensified courses in half of them. Histologically, 41 cases were classified as “rich in large cells” and 116 as “classic” (including 19 rich in epithelioid cells, 14 rich in clear cells, and 4 with hyperplastic germinal centers). Sixty-two cases were scored for CD10 and CXCL13 expression according to the abundance of positive lymphoid cells. Median age was 62 years, with 81% advanced stage, 72% B symptoms, 65% anemia, 50% hypergammaglobulinemia, and 66% elevated LDH. Overall 7-year survival was 30%. In multivariate analysis, only male sex (P = .004), mediastinal lymphadenopathy (P = .041), and anemia (P = .042) adversely affected overall survival. Increase in large cells and high level of CD10 and CXCL13 did not affect survival. Intensive regimen did not improve survival. In conclusion, AITL is a morphologically heterogeneous T-cell lymphoma commonly expressing CXCL13 and CD10 and carrying few prognostic factors. It portends a poor prognosis even when treated intensively. However, AITL is not always lethal with 30% of patients alive at 7 years.

Description: Abstract 406 Introduction: In 2000, the Gela demonstrated the survival advantage of adding Rituximab to CHOP21 over CHOP21 in the treatment of diffuse large B-cell lymphoma (DLBCL) in elderly patients. Two consecutive studies from the German group have shown an improvement of survival with CHOP14 compared to CHOP21, and then after with R-CHOP14 compared to CHOP14. Here, we report the results of the planned interim analysis of the LNH03-6B, a multicentric, phase III open-label, randomized trial evaluating the efficacy of R-CHOP given every 14 days compared to R-CHOP given every 21 days, held after the inclusion of the first 202 patients, with a median follow-up of 24 months. Patients and methods: Patients between 60 and 80 years old with DLBCL and aaIPI ≥ 1 were eligible. They were randomized between two immunochemotherapy regimens combining Rituximab and CHOP given every 2 (R-CHOP14, arm A) or 3 weeks (R-CHOP21, arm B) for 8 cycles. They were subsequently randomized between a prophylactic treatment with Darbepoetin alfa and a conventional treatment of chemotherapy-induced anemia. G-CSF was given according to physician decision. The primary objective was to evaluate the efficacy of R-CHOP14 compared to R-CHOP 21 as measured by the EFS, events being defined as death from any cause, relapse for complete responders and unconfirmed complete responders, progression during or after treatment and changes of therapy during allocated treatment. Secondary objectives were OS, PFS, DFS, response rate and analysis of dose-intensity and toxicity. According to previous LNH98-5 protocol, sample size was calculated to demonstrate an improvement of 2-year EFS from 55% to 65% with R-CHOP14. Six-hundred patients, randomized 1:1 between the two treatment groups recruited over 4 years and followed for a minimum of one year, will provide 80% power at the overall 5% (2-sided) significance level to detect the expected difference. Results: In this planned interim analysis, 202 patients were randomized and 201 received study treatment, 103 with R-CHOP14 and 98 with R-CHOP21. Median age was 72 years. Patients' characteristics were similar in both groups with a slightly higher proportion of patients with aaIPI 2-3 in R-CHOP14 arm (67% vs 59%) whereas a higher proportion of patients in R-CHOP21 arm presented with B symptoms (43% vs 37%). The median interval between cycles was 15 days in R-CHOP14 group and 21 days in R-CHOP21 group; 73 patients (71%) in R-CHOP14 group and 74 patients (76%) in R-CHOP21 group completed 8 cycles without progression. In the R-CHOP14 group, the increase of dose-intensity at the end of treatment, calculated according to 3-week interval as a reference, was 125% for cyclophosphamide and doxorubicin. Ninety percent of patients treated with R-CHOP14 received G-CSF, whereas only 66% in R-CHOP21 group. Response rate (CR+CRu) was 67% in R-CHOP14 arm and 75% in R-CHOP21 arm (p=NS). The 2-year EFS was 48% in R-CHOP14 arm compared with 61% in R-CHOP21 (p=NS). A similar trend was observed for 2-year PFS (49% vs 63%), 2-year DFS (57% vs 70%) and 2-year OS (67% vs 70%) (p=NS for all). Grade 3-4 hematological toxicity was more frequent in R-CHOP14 group, with a higher proportion of patients receiving red cell or platelet transfusions and/or experiencing febrile neutropenia, resulting in higher proportion of patients hospitalized for adverse events. In contrast, there was no difference for extra-hematological grade 3-4 toxicities. Conclusions: The results of this interim analysis of the LNH03-6B trial favor treatment with R-CHOP21 in elderly patients with DLBCL, with trends toward higher efficacy and lower toxicity compared to R-CHOP14. These results should be confirmed by the final analysis, concerning the 602 patients included, planned in 2010. Disclosures: No relevant conflicts of interest to declare.

Description: Actually, the prognosis of localized Hodgkin’s lymphoma (HL) patients may be assessed by different scoring systems. Although many similar characteristics have been identified, these scoring systems are not easy to relate to advanced stage HL. The aim of the present study was to refine the assessment of risk using the published scoring systems and to construct a statistical model for predicting risk of death. We report here the results of the EORTC, GHSG and Canadian-ECOG scoring systems obtained in 1156 patients for whom hematological data were available among the 1390 patients with localized HL prospectively treated within GELA centres in H8 (518 pts) and H9 (638 pts) trials. The International prognostic score (IPS) was available only for the H9 subset. All patients have been treated with radio-chemotherapy of different intensity or duration according to their prognostic factors. Median age was 30 yr [14–69] and age≥45yr.: 18%, female 50%; stage 1: 25%; stage 2: 75%; B symptoms with elevated ESR: 40%; number of nodal sites 1–2: 52%; ≥3: 48%; extra nodal involvement: 8%, bulky mediastinum〉 0.35, 28%; elevated ESR〉 50:33%; Hb〈 10.5 g/dl: 7%; Lymphocytes 〈 600/μl: 6%; WBC 〉 15000/μl:11 %; albumin〈 40g/l: 37%. With the EORTC scoring system 36% of patients had favourable HL, with GHSG 35% and with Canadian-ECOG 38%. The IPS was 0 in 19% and 1 in 45%. With a median follow up of 42 months, 54 patients died. Survival curves according to the different scoring systems significantly discriminated favourable and unfavourable patients outcomes (5 yrs OS 95% vs 92%, p=0.01). By multivariate Cox analysis, age 〉 45yr (RR=2.0), sex male (RR=2.5), haemoglobin

Description: [§ share last authorship] Background: In 2000-2010, the first large prospective trials in peripheral T-cell lymphoma (PTCL) showed outcomes burdened by high failure rates during induction. Concurrently, trials with the anti-CD52 monoclonal antibody alemtuzumab (ALZ) yielded promising responses in PTCL while demonstrating the feasibility of combining ALZ with CHOP. Hence, the Nordic Lymphoma Group initiated the randomized ACT-1 trial to test, in younger patients (pts) (18-65yrs), the addition of ALZ to CHOP + autologous stem cell transplant (ASCT). Primary endpoint was the 3 years event-free survival (EFS). Here, we present the final analysis of the ACT-1 trial (ClinicalTrials.gov: NCT00646854). Patients and Methods: Overall, 136 pts were randomized (43% of planned sample size due to slow accrual), five did not receive study treatment, and 131 were analyzed (ALZ-CHOP: 65; CHOP: 66). Due to lack of tumoral CD52 expression, anaplastic large cell lymphomas (ALCL) were not included in the ACT-1 trial. An amendment tapering ALZ dose from 360 mg (30 mg on days 1+2 of each CHOP course) to 120 mg (30 mg on day 1 of CHOP courses 1-4) was introduced early on due to systemic fungal infections in 2 pts. Of the 65 pts treated with ALZ-CHOP, 4 received the pre- and 61 (94%) the post-amendment dose. Monitoring for CMV- and EBV-DNA and antimicrobial prophylaxis were mandatory. Results: The median observation time for the Full Analysis Set was 66 months and the median age 51 yrs. The ALZ-CHOP and CHOP cohorts were well balanced with regard to classical prognostic factors and histological subtypes (PTCL-NOS 58% vs 54%, AILT 21% vs 25%, other 21% vs 21%). Feasibility: Neither CHOP nor ALZ-CHOP pts experienced substantial treatment delay. ALZ exposure did not affect stem cell harvest nor hematopoietic recovery. Grade 4 leucopenia was more frequent in ALZ-CHOP pts (73% vs 35%; p=0.001), whereas the occurrence of grade 3-4 anemia and thrombocytopenia did not differ significantly. After ALZ dose amendment, the frequency of bacterial and fungal infections of grade ≥3 was similar in both treatment arms. ALZ treated pts had more viral events (22/57=42% vs 4/23=17%), mainly due to asymptomatic CMV reactivations. The ratio of serious adverse events per ALZ-CHOP treated patient dropped markedly (from 3.25 to 0.86, comparable with 0.46 for CHOP) after dose amendment. Additional toxicity was mild and similar in both arms. Treatment related mortality was 4% (5% vs 3%). Efficacy: Complete remission (CR) was 52% in ALZ-CHOP vs 42% in CHOP. Primary refractory disease occurred for ALZ-CHOP and CHOP in 23% and 38% of pts, respectively. Overall, females had a significantly better outcome than males (p=0.004), also after adjustment for classical prognostic factors. Analyzing time-related endpoints without knowledge of CD52 expression, 3-years EFS, progression-free, and overall survival (PFS, OS) did not differ significantly between ALZ-CHOP and CHOP (EFS 35% vs 26%, PFS 37% vs 26%, OS 52% vs 50%). Fig.1A shows EFS by treatment arm, by gender, and by gender and treatment arm. Although not significantly different, EFS, PFS and OS values of ALZ-CHOP treated females in the ACT-1 trial were consistently higher than those of non-ALZ treated females or of males regardless of treatment group. RNA sequencing from evaluable pre-therapeutic tumor biopsies defined a signature of differentially expressed genes to be predictive of clinical outcome in ALZ-CHOP but not CHOP treated pts (n=33). Tumor microenvironment genes were prominent in determining response to ALZ. Tumors rich in B-cell milieu showed good responses, while the opposite was observed in tumors with signatures enriched with high endothelial cell genes (p

Description: Abstract 1675 Poster Board I-701 Background Chemotherapeutic agents may be associated with early-onset toxicities (eg, bortezomib peripheral neuropathy) or late-term/cumulative-dose toxicities (eg, doxorubicin cardiotoxicity, platinum nephrotoxicity). The rationally designed antifolate, pralatrexate, has high affinity for reduced folate carrier-1 (RFC-1) and is an efficient substrate for polyglutamation by folylpolyglutamyl synthetase, resulting in increased drug uptake and retention by cells. As with all new agents, strategies must be learned and employed to maximize efficacy and minimize toxicities. The pivotal, international, Phase 2 PROPEL study of pralatrexate in patients with relapsed or refractory PTCL showed an overall response rate of 28% (30/109) by independent central review. Patients received pralatrexate for a mean of 112 days (range, 1-558). Patients accrued to PROPEL had received a median of 3 prior therapies, and 68% had received combination chemotherapy or stem cell transplant just prior to inclusion in the study. The objectives of this analysis were to assess the safety profile of pralatrexate according to duration of treatment, to evaluate both early and late-onset toxicities, and to assess the impact of dose modification. Methods Eligibility criteria included histologically confirmed PTCL by central review, disease progression after ≥ 1 prior treatment, and ECOG performance status £ 2. Response was assessed centrally using the International Workshop Criteria. All patients received pralatrexate 30 mg/m2 IV once weekly for 6 weeks in 7-week cycles with supplementation of vitamin B12 (1 mg IM q8-10 wks) and folic acid (1.0-1.25 mg PO daily). If a patient had Grade 3 thrombocytopenia, Grade 3 neutropenia (± fever), Grade 3 non-hematologic toxicity, or Grade 2 mucositis, that week's pralatrexate dose was omitted. Pralatrexate dose was decreased to 20 mg/m2 for all cycles after grade 3 non-hematologic toxicity or two occurrences of the following: Grade 4 thrombocytopenia, Grade 4 neutropenia, Grade 3 febrile neutropenia, or Grade 2 mucositis. Results In the PROPEL Trial, 111 patients received pralatrexate and were evaluable for safety. Patients received pralatrexate for a mean of 112 days (range, 1-558). Nineteen patients received pralatrexate for ≥180 days, including 10 who received pralatrexate for ≥300 days. Sixty-four patients received 2 or more cycles of therapy, including 43 patients who received 3 or more cycles. The median cumulative dose of pralatrexate was 207.9 mg/m2 (range, 26.7-1900). The incidence by cycle of the most common Grade 3-4 adverse events for patients who received 3 or more cycles are presented in the Table. Seventy-seven (69%) patients maintained the starting dose at 30 mg/m2 without dose reduction to 20 mg/m2. Of the 34 (31%) patients with a dose reduction at any time during the study, 20 had their dose reduced in cycle 1, 8 in cycle 2, and 6 in cycle 3 or later. Mucositis was the most common reason for dose reduction. In these 34 patients the frequency of Grade 2-4 mucositis before vs. after dose reduction was 28 vs. 15. Conclusions Despite pretreatment with a median of 3 prior therapies, the majority of patients with relapsed or refractory PTCL tolerated full dose pralatrexate. The most common Grade 3-4 adverse events for patients who initiated cycle 3 were observed at a similar rate in cycles 1-2 vs. cycles 3 or later, and no single adverse event increased in incidence in these patients, suggesting no cumulative-dose toxicity effects. Dose reduction to 20 mg/m2 per the protocol effectively reduced the occurrence of mucositis. Adherence to pralatrexate dose modification guidelines allowed for minimization of toxicity with continued therapy. Disclosures Pinter-Brown: Allos Therapeutics, Inc.: Consultancy. Horwitz:Allos Therapeutics, Inc: Consultancy, Research Funding. Pro:Allos Therapeutics, Inc.: Research Funding. Gisselbrecht:Allos Therapeutics, Inc.: Research Funding. Fruchtman:Allos Therapeutics, Inc.: Employment.