ALBERT

Description: Background: Azacitidine (AZA) therapy is the standard of care for higher-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients not eligible for intensive treatment. Although nearly 50% of patients respond to AZA treatment, most of them experience disease progression within 2 years of remission. The prognosis of patients after AZA failure is dismal with a median overall survival (OS) reaching 3-6 months. Interestingly, recent studies have demonstrated clinical efficacy of cladribine combined with cytarabine in newly diagnosed AML patients. In view of epigenetic properties of cladribine and known synergy with cytarabine, it may be speculated that combination of cladribine and low-dose cytarabine (LD-AraC) exerts some clinical activity also in the setting of relapsed/refractory AML/MDS. Aim: The aim our study was to assess activity and toxicity of combination of cladribine and LD-AraC in patients with MDS/AML after AZA failure. Methods: This retrospective analysis included patients with AML with 20% to 30% blasts, high and intermediate-2 risk MDS and CMML patients with AZA failure who were treated with combination of cladribine and LD-AraC in centers of the Polish Adult Leukemia Group (PALG). Therapy started with induction phase consisting of 2 cycles of cladribine 5 mg/m2 iv on days 1-5 (cycle 1) and on days 1-3 (cycle 2) in combination with LD-AraC 40 mg/m2 sc (days 1-10). Patients who achieved remission moved on to maintenance therapy with LD-AraC 40 mg/m2 sc, days 1-10), every 4 weeks. The treatment was continued for as long as tolerated and there was a clinical benefit. Treatment response was determined in accordance with the 2017 European Leukemia Net (ELN) and the 2006 International Working Group (IWG) criteria after each cycle. Results: Overall, 16 patients (8 patients with diagnosis of AML, 7 with diagnosis of MDS, and 1 with diagnosis of CMML myelodysplastic subtype at AZA therapy initiation) who had been treated with combination of cladribine and LD-AraC at AZA failure in 3 centers of PALG between 2014 and 2019 were identified. There were 9 males and 7 females, with median age of 72 years (range 64 - 78). The patients had previously received a median of 15 cycles of AZA (range 4 - 33). At the initiation of cladribine and LD-AraC therapy the median number of blasts was 27,5% (range 15,5 - 77) with 13 patients fulfilling the criteria of AML. At the data cut-off the median of administered chemotherapy cycles reached 4 (range 1-14), with 4 patients continuing treatment. The regimen was relatively well tolerated with no treatment related deaths and the most common non-hematological adverse events of grade 3 or worse being neutropenic fever and pneumonia. Response assessment revealed that nine patients (56%) achieved a remission, including 6 complete remissions (CR) and 3 complete remissions with incomplete recovery (CRi). The median time to response was 1 cycle. Median progression-free survival was 8 months, and the median OS reached 10.6 months. The estimated 6-months and 12-months OS probability were 79.3% and 44.6%, respectively. Conclusions: The combination of cladribine and LD-AraC appears to be an attractive option in the therapy of AML/MDS patients after AZA failure. Although prospective studies are needed to confirm these findings such treatment seems to be associated with an improvement in OS compared to the historical data. Disclosures Gora Tybor: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Description: Introduction: As previously reported, the combination of brentuximab vedotin with doxorubicin, vinblastine and dacarbazine (A+AVD) demonstrated a statistically significant improvement in modified progression free survival (modified PFS) compared with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) in patients with newly diagnosed Stage III or IV classical HL in the phase 3 ECHELON-1 trial (NCT01712490). The benefit of A+AVD in the ITT population observed in the primary analysis was maintained at 3-years median follow-up [3-year PFS: A+AVD: 83.1% (79.9-85.9), ABVD: 76% (72.4-79.2)] and appears independent of interim PET status, disease stage, and prognostic risk factors. Here we present the efficacy and safety results of longer follow-up at a median 43.3 months. Methods: Newly diagnosed patients with Stage III or IV cHL were randomized 1:1 to receive A+AVD (n=664) or ABVD (n=670) intravenously on days 1 and 15 of each 28-day cycle for up to 6 cycles. The primary endpoint of the study was modified PFS per independent central review. The present follow-up PFS analysis is exploratory and per investigator assessment, with a cutoff date of June 17th, 2019. Patients with ongoing peripheral neuropathy (PN) at end of treatment were followed for resolution or improvement (defined as improved by ≥1 grade from worst grade as of the latest assessment) during the post-treatment follow-up period. Results: With a median follow-up of 43.3 months, the 42-month PFS per investigator for all patients was 82.4% (95% CI, 79.1-85.2) on the A+AVD arm and 76.2% (95% CI, 72.6-79.4) on the ABVD arm [overall HR 0.697 (95% CI, 0.547-0.890)]. Exploratory subgroup analyses of PET2(+) and PET2(-) patients showed a treatment effect in favor of A+AVD. The 42-month PFS in PET2(-) patients was 85.0% (95% CI, 81.6-87.7) for A+AVD and 79.6% (95% CI, 75.9-82.8) for ABVD [overall HR 0.695 (95% CI, 0.526-0.919)]; in PET2(+) patients 42-month PFS was 68.3% (95% CI, 54.5-78.7) for A+AVD and 51.5% (95% CI, 38.2-63.4) for ABVD [overall HR 0.552 (95% CI, 0.308-0.989)]. Upon continued follow-up, 81% (356/442) of patients with PN in the A+AVD arm had either complete resolution (64%, 283/442) or improvement (17%, 73/442) of their PN events compared with 83% (236/286) with either complete resolution (74%, 212/286) or improvement (8%, 24/286) in the ABVD arm. Among patients with ongoing PN after continued follow-up, the majority were Grade 1/2 events, with 89% (141/159; 59% Grade 1) and 95% (70/74; 65% Grade 1) on the A+AVD and ABVD arms, respectively. Overall survival data are not yet mature; per protocol, the final analysis will be performed after 112 deaths have occurred. Additional follow-up at an estimated median of ~4 years, including data from prespecified subgroups, will be presented. Conclusions: With a median follow-up of 43.3 months, A+AVD continues to provide a robust, durable benefit for patients with previously untreated Stage III or IV cHL compared with ABVD; the benefit is evident regardless of patient status at interim PET [PET2(+) or PET2(-)] and without the need for treatment intensification. PN continued to completely resolve or improve in patients on the A+AVD and ABVD arms. Together, these data further support the clinical advantages of A+AVD versus ABVD as treatment for patients with previously untreated Stage III or IV cHL. Disclosures Bartlett: Affimed Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Dynavax: Research Funding; Forty-Seven: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Medimmune: Research Funding; Merck: Research Funding; Millennium: Research Funding; Novartis: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Straus:Elsevier (PracticeUpdate): Consultancy, Honoraria; Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria. Dlugosz-Danecka:Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Macrogenomics: Research Funding; Roche: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Illes:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Feldman:Takeda: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Cell Medica: Research Funding; Amgen: Research Funding; Viracta: Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; Pfizer: Research Funding; Portola Pharma: Research Funding; Roche: Research Funding; Eisai: Research Funding; Corvus: Research Funding; Roche: Research Funding; AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; Kyowa Hakko Kirin: Research Funding; Trillium: Research Funding. Smolewski:Roche: Other: Travel Expenses. Savage:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding; BMS, Merck, Novartis, Verastem, Abbvie, Servier, and Seattle Genetics: Consultancy, Honoraria. Walewski:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Takeda: Honoraria, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria; Gilead: Other: Travel Expenses; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Zinzani:Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Honoraria, Speakers Bureau. Hutchings:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Novartis: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding. Radford:AstraZeneca: Equity Ownership, Research Funding; Novartis: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; GSK: Equity Ownership. Munoz:AstraZeneca: Speakers Bureau; Kite Pharma: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Fosunkite: Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Portola: Research Funding; Incyte: Research Funding. Kim:Roche: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; J&J: Research Funding; Mundipharma: Research Funding; Celltrion: Research Funding; Donga: Research Funding. Advani:Cell Medica, Ltd: Consultancy; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Kura: Research Funding; Infinity Pharma: Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Celmed: Consultancy, Membership on an entity's Board of Directors or advisory committees; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agensys: Research Funding; Stanford University: Employment, Equity Ownership; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Research Funding; Kyowa Kirin Pharmaceutical Developments, Inc.: Consultancy; Regeneron: Research Funding; Millennium: Research Funding; Janssen: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences, Inc./Kite Pharma, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forty-Seven: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ansell:Mayo Clinic Rochester: Employment; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Trillium: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment. Younes:Roche: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Abbvie: Honoraria; Takeda: Honoraria; Pharmacyclics: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding; Biopath: Consultancy; Xynomics: Consultancy; Epizyme: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; HCM: Consultancy; BMS: Research Funding; Syndax: Research Funding. Gallamini:Takeda: Consultancy; Roche: Consultancy. Miao:Millennium Pharmaceuticals, Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership. Liu:Takeda: Employment. Fenton:Seattle Genetics, Inc.: Employment, Equity Ownership. Forero-Torres:Seattle Genetics: Employment, Equity Ownership, Honoraria, Research Funding.

Description: Key Points HDAC6 inhibition represents a novel strategy to improve the efficacy of anti-CD20 mAbs. HDAC6 inhibition increases CD20 levels by enhancing CD20 protein synthesis without affecting the gene expression.

Description: Background: Interleukin-10 (IL-10) is an important immunoregulatory cytokine modulating the balance between cell-mediated and humoral response. It has been suggested that dysregulation and different IL-10 level resulting from single-nucleotide polymorphisms (SNPs) in IL-10 gene promoter play a role in pathogenesis of lymphoid disorders, and may increase a risk of non-Hodgkin lymphomas (NHL) development, especially diffuse large B-cell lymphoma subtype. The aim of this study was to investigate whether functionally important IL-10 promoter region SNPs IL-10: −1082A〉G and IL-10: − 3575T〉A contribute to the incidence and clinical course of B-cell chronic lymphocytic leukemia (CLL). Patients and Methods: We genotyped IL-10: −1082A〉G and IL-10: − 3575T〉A SNPs in 85 patients with B-CLL and 94 ethnically-matched healthy individuals by direct sequencing using 3130xl Genetic Analyzer (Applied Biosystems). Sequence data were based on the NCI SNP500 website http://snp500cancer.nci.nih.gov. Haplotype analysis was performed using version 2.0.2 PHASE software (http://www.stat.Washington.edu/stephens/). For the clinical features, p values were calculated using χ2 test. Survival probabilities were estimated using the Kaplan-Meier method and comparison of survival was based on log-rank testing. Results: The IL-10: −1082A〉G or IL-10: −3575T〉A allelic frequencies and distributions were consistent with Hardy-Weinberg equilibrium, and did not differ significantly between CLL patients and the control group. Four distinct haplotypes, including IL-10: −1082G, −3575A, IL-10: −1082A, −3575T, IL-10: −1082G, − 3575T, and IL-10: −1082A, −3575A, inferred in healthy controls and CLL patients. There were no significant differences in estimated frequencies of these haplotypes between CLL patients and controls. No association was found between IL-10: −1082A〉G or IL-10: − 3575T〉A allelic, genotype or haplotype distribution and clinical characteristics of CLL patients at diagnosis, including age, clinical stage according to Rai classification, surface CD38 expression, serum LDH and β2-microglobulin levels. In patients with IL-10: − 1082G allele (IL-10: −1082GG or IL-10: −1082GA genotypes) there was a trend towards higher frequency of autoimmune complications during CLL course as compared to those carrying IL-10: −1082AA genotype (13% vs 0%, p=0.04, χ2 test). The patients with IL-10: −1082G allele had significantly shorter time from diagnosis to treatment (log-rank test, p=0.02) as compared to individuals carrying IL-10: −1082AA genotype. However, neither of assessed IL-10 SNPs was associated with response to first-line treatment or freedom from progression time. With a median follow-up of surviving patients of 80 months (range 8–209), no correlation was found between IL-10: −1082A〉G or IL-10: −3575T〉A alleles, genotypes or haplotypes and overall survival in CLL patients. Conclusions: The study suggests the influence of IL-10: −1082G allele, predisposing to higher IL-10 production, on activation of immune system towards more aggressive course of CLL requiring earlier treatment intervention. Similarly to other low-grade NHL studies, our findings did not support an important role of IL-10 SNPs in CLL occurrence and survival however larger studies are needed to confirm these results.

Description: Introduction: In normal B lymphocytes, B-cell receptor (BCR)-induced activation of PI3K-AKT kinases and subsequent inactivation of FOXO1 is a critical pro-survival component of tonic BCR signaling. In murine models, conditional deletion of FOXO1 protected quiescent peripheral B cells from apoptosis mediated by inducible loss of the BCR, demonstrating that PI3K-AKT-FOXO1 axis plays a central role in B-cell homeostasis. Disruption of the BCR signaling by SYK inhibitor leads also to the apoptosis of BCR-dependent DLBCLs, at least in part via a mechanism involving decreased activity of PI3K/AKT axis. Herein, we investigated the role of FOXO1 in toxicity of BCR pathway/SYK inhibition in human BCR-dependent lymphomas. Methods: BCR-dependent DLBCL cell lines (DHL4, DHL6, Ly1, Ly7) were incubated with SYK inhibitor R406 (4 µM) and AKT phosphorylation, FOXO1 activation and transcriptional activity were assessed by phospho-specific flow cytometry, Western Blot and qPCR. Toxicity of active FOXO1 was assessed by transducing DLBCL cells with a constitutively nuclear FOXO1 mutant. FOXO1 knock-down in DLBCL cell was achieved with shRNA. DREAM cleavage and HRK expression were assessed by Western Blot and qPCR, respectively, in the absence or presence of caspase inhibitors. DLBCL cell viability and apoptosis after incubation with SYK and/or AKT inhibitors R406 and MK2206, were assessed by MTS assay and Annexin V/PI staining. Drug interactions were quantitated by CompuSyn software. The expression of p-SYK and FOXO1 in DLBCL samples was assessed by immunohistochemistry (IHC) in 60 DLBCL patients. Results: Since FOXO1 is a major effector of tonic BCR signaling, we assessed the activity of FOXO1 in DLBCL cells after SYK inhibition. In all tested cell lines, AKT and FOXO1 phosphorylations decreased after incubation with SYK inhibitor. Diminished FOXO1 phosphorylation resulted in its nuclear relocalization and induction of FOXO1-dependent expression of p27, BIM, TRAIL and GADD45A. To assess whether the increased activity of FOXO1 is sufficient to induce apoptosis of DLBCL cells, we transduced DHL4 cells with a constitutively nuclear and transcriptionally active FOXO1-3A mutant. The mutant induced G1/S cell cycle arrest and triggered apoptosis, whereas wild-type FOXO1 did not change proliferation or cellular viability, demonstrating that FOXO1 activation is sufficient to induce apoptosis of DLBCL cells. Next, we assessed the toxicity of SYK inhibitor in cells lacking FOXO1. Cells with depleted FOXO1 exhibited 70% lower sensitivity to SYK inhibitor than control cells (p

Description: Abstract 2138 In a previous study by the Polish Adult Leukemia Group (PALG 4–2002) we demonstrated that status of minimal residual disease (MRD) during induction-consolidation is the most important factor predicting long-term outcome of adult ALL (Br J Haematol 2008). In a new PALG 5–2007 protocol the treatment was intensified for patients with MRD level 〉0.1% of bone marrow cells and adjusted to age. Induction consisted of Epirubicine(4×), Vincristine(4×), Prednisone and PEG-asparaginase. Patients with complete remission (CR) but MRD 〉0.1% obtained additional 2nd phase of induction: AraC+Cyclophosphamide(Ctx) + 6MP. Consolidation consisted of 2 courses of Methotrexate(Mtx) + Etoposide + Dexamethasone and subsequent 2 cycles of Ctx + high dose AraC, asparaginase, intrathecal prophylaxis and CNS irradiation. Doses of Mtx were 500 mg/m2 for patients with MRD35y and 1500 mg/m2 for all remaining ones. For Ph+ ALL imatinib 600 mg/d was administered in parallel to chemotherapy. Patients with standard risk disease continued with 2 years maintenance while those with high-risk were referred for alloHSCT. High risk was defined as the presence of at least one of: initial WBC 〉30×10e9/L, age 〉35y, pro-B, early-T, mature-T, late CR, t(9;22), t(4;11) or MRD 〉0.1% at any time during induction-consolidation. Results of PALG 5–2007 protocol (N=108, median age 32y, range 16–55y) were compared to PALG 4–2002 (N=253, age 28y, range 16–55y), in which MRD status was not taken into account for treatment decisions. CR rate was 92% for PALG 5–2007 compared to 89% for PALG 4–2002. The probability of the overall survival at 36 months was 56% vs. 33% (p=0.02), while leukemia-free survival was 53% vs. 28% (p=0.04), respectively. The probability of relapse decreased from 54% in PALG 4–2002 to 16% in PALG 5–2007 (p=0.002). In a multivariate analysis adjusted to age, initial WBC and the presence of t(9;22) treatment according to PLAG 5–2007 protocol was associated with decreased risk of mortality (HR=0.57, p=0.02), relapse (HR=0.37, p=0.006) and treatment failure (HR=0.64, p=0.049). We conclude that individualized therapeutic approach with treatment intensity adjusted to MRD status and age may result in improved outcome of adults with ALL. *This multi-institutional study was supported by Polish Ministry of Sciences Grant NN-402366433 Disclosures: Off Label Use: Dasatinib as first line therapy in Ph ALL.

Description: Abstract 3269 Poster Board III-1 Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a potentially curative treatment for patients (pts) with chronic myeloid leukemia (CML). AlloHSCT is associated with long-term disease-free survival in 40% to 80% pts transplanted in early chronic phase of disease. The probability of relapse for pts transplanted in first chronic phase is 10% to 20% at 5 years, and is even higher (30% – 60%) for pts who received transplant in advanced phases of CML. The significance of minimal residual disease (MRD) in this clinical setting is uncertain. We enrolled 63 consecutive pts with CML who had received an alloHSCT between 1995 and 2007 and had BCR-ABL transcript quantity measured by RQ-PCR method on at least 2 occasions during follow-up in the period starting 6 months after alloHSCT. The reverse transcription was preformed using SuperScriptIII and random hexamers. Quantification of BCR-ABL was performed by RQ-PCR assay according to ‘Europe Against Cancer' protocol. BCR-ABL expression was normalized with endogenous control ABL gene and expressed as a ratio BCR-ABL/ABL. According to the amount of BCR-ABL transcript detected in blood or bone marrow after alloHSCT pts were allocated into 3 categories, including pts with no-detectable or stable very low-level of BCR-ABL transcripts (ratio BCR-ABL/ABL below 0.005%), pts with fluctuating-low level of BCR-ABL transcripts (0.005 – 0.01%) and pts with high-level of BCR-ABL transcripts (0.01 – 0.1%). We didn't find any relationships between different BCR-ABL levels after alloHSCT and clinical parameters at the time of CML diagnosis or transplantation, including Sokal, Hasford and Gratwohl scores. Median time from alloHSCT to molecular relapse (MR) was 38 months (range, 8.5 – 88.5 months). The 3-year progression rate into cytogenetic or hematological relapse of CML since MR was 70%. This progression occurred at a median time of 1.4 months (range, 0 – 3.2 months). We found strong correlation between the levels of BCR-ABL transcripts after alloHSCT and a risk of relapse. The incidence of MR was 0%, 26%, 71% for the low-level, fluctuating-low level and high-level of BCR-ABL transcript (p

Description: Introduction: Central nervous system involvement (CNSi) in acute myeloid leukemia (AML) can be found both at the time of diagnosis and during the AML course, with an incidence of 5-15%. However, there is lack of precise clinical characteristics and commonly recommended therapies for AML patients with the CNSi. Such patients demonstrate worse prognosis and reduced survival compared to those without CNSi, therefore allocation them to the allogeneic hematopoietic stem cell transplantation (allo-HSCT) regardless of their cytogenetic risk seems to be the best treatment option. Aims: The aim of the study was to assessed clinical characteristics and treatment outcome of patients with AML and the CNSi who were treated between 2004 and 2014 in 8 hematology departments of the Polish Adult Leukemia Group (PALG). Results: The analysis comprised 65 patients (62% males and 38% females) with the median age of 45 years (range 20-81 years). The CNSi was observed in 33 (51%) patients at the time of AML diagnosis (group 1) and in 32 (49%) subjects during the course of AML (group 2). The most common neurological symptoms were headaches (47% vs 48%, p= 0.99) and altered mental status (21% vs 30%, p= 0.32) observed in the group 1 and 2, respectively. Higher rates of paraparesis (39% vs 9%, p= 0.002) and motor deficits (33% vs 9%, p= 0.011) were noted in the group 2 compared to the group 1. The CNSi was the most frequently found in the AML not otherwise specified (AML NOS) subtype (61% in the group 1 and 50% in the group 2; p= 0.39). The AML subtype with recurrent cytogenetic abnormalities was diagnosed in 30% of patients form the group 1 and 28% of subjects from the group 2 (p= 0.85). The therapy and dysplasia related AML subtype was diagnosed in 6% of patients from the group 1 compared to the 16% of patients from the group 2 (p= 0.21). Using the FAB classification of AML, the CNSi in the group 1 occurred more often among patients with the M4 (42%) and the M5 (30%) subtype, whilst in the group 2 it was found in the M2 (25%) and the M5 (22%) subtype. The cytogenetic risk distribution according to the SWOG (ie. favorable, intermediate and poor) were 13%, 28% and 16% in the group 1 and 18%, 15% and 21 % in the group 2, respectively (p=0,39). The group 1 was more likely to have abnormal cytogenetics involving the chromosome 8 or 16 compared to the group 2 (62% vs 27%, p= 0.012). After the diagnosis of the CNSi, systemic chemotherapy was administered to 100% of patients from the group 1 and to 80% of patients from the group 2. Intrathecal chemotherapy was administered to 94% patients in both groups, whereas 19% of patients were subjected to subsequent brain radiation therapy. The cytarabine with methotrexate with corticosteroid was given intrathecally to 83% of patients, whilst the cytarabine monotherapy, the methotrexate with or without corticosteroid and liposomal cytarabine were given intrathecally to 1.5%, 9.1% and 18.2% patients, respectively. The CNS remission rate was higher in the group 1 compared to the group 2 (72% vs 39%, p= 0,003). Allo-HSCT in the first complete remission (CR1) as well as allo-HSCT after the AML relapse were performed with similar frequency in the both groups (21% vs 25%; p= 0.72 and 12% vs. 16%; p=0.73, respectively). The probability of a 1-year overall survival (OS) between the group 1 and 2 was not significantly different (52% vs 58% , p= 0.8). However, the OS rate was significantly higher in patients who underwent allo-HSCT in their CR1 compared to that in the patients without allo-HSCT (94% vs 39%; p

Description: Background: CD37 is a tetraspanin protein expressed on the surface of normal and transformed B cells across a wide range of maturational stages that mediates death signaling via SHP1. Otlertuzumab is a CD37-specific therapeutic protein built on the ADAPTIRTM (modular protein technology) platform that has shown significantly greater direct killing of CLL cells than rituximab and higher levels of Fc mediated cellular cytotoxicity of CLL cells than either alemtuzumab or rituximab in pre-clinical models. Preclinical in vitro and in vivo models showed significant activity of otlertuzumab with bendamustine (benda). In phase 1 of this study involving 12 relapsed and/or refractory CLL patients (pts), otlertuzumab plus benda was well tolerated and showed activity. This phase 2 trial was conducted to investigate the activity of this combination compared to benda alone. Methods: Pts with relapsed-refractory CLL who had 1-3 prior treatments, adequate organ function, ECOG performance status ≤2, ANC ≥1200/μL and CrCl 〉40 mL/min were eligible. Pts were stratified at randomization (1:1) based on Cumulative Illness Rating Score (CIRS), CrCl, and deletion or mutation of 17p13.1. Pts in the study drug arm received otlertuzumab(20 mg/kg) weekly (1st dose split over 2 days) by IV infusion for two 28-day cycles then every 14 days for four 28-day cycles. In both arms, benda (70 mg/m2) was administered IV on Days 1 and 2 of each cycle for up to six 28-day cycles. Safety was evaluated using CTCAE, v4.03 and IWCLL 2008 Grading scale for Hematologic Toxicity in CLL Studies. Response was determined using the 1996 NCI and 2008 IWCLL Criteria. Results: 65 pts were treated; 32 with otlertuzumab plus benda and 33 with benda alone. Pt characteristics, response, and adverse events (AEs) are shown in the table. All but 4 patients have been followed for 2 years. Overall response rate was higher in the otlertuzumab+benda arm compared to benda alone (69% vs 39%, p=0.025) and median progression-free survival (PFS) was longer (14 m vs 10 m, p=0.016) in the otlertuzumab+benda arm. The frequency of all AEs was similar between treatment arms with hematologic and infection AEs being the most frequent. The imbalance in serious AEs appeared to be driven by CLL-related events in the benda alone arm. The half-life of otlertuzumab is 10 days and there were no pts with detectable antidrug antibody in the 14 pts tested to date. Pts were followed for 18 months. Conclusions: The combination ofotlertuzumab and bendamustine was well tolerated and significantly prolonged response rate and PFS over single agent bendamustine. The overall incidence of AEs was similar between the 2 treatment cohorts, but there was a higher incidence of pyrexia, neutropenia, and thrombocytopenia with the combination. However, the addition of otlertuzumab did not appear to increase the number of serious adverse events. The activity and safety profile of otlertuzumab warrants continued development. A trial in combination with obinutuzumab is underway and a trial in combination with a pi3k inhibitor is slated to start shortly. TableOtlertuzumab + Benda (n=32)Benda (n=33)Baseline CharacteristicsAge, median (range)65 (44-82)60 (48-79)CIRS 〉619%18%CrCl 〈 60 mL/min19%15%FIT75%67%Bulky disease*25%18%Prior rituximab81%64%Refractory16%12%≥ 2 Prior regimens63%39%del(17p13.1)13%18%TP53 mutation16%27%del(11q)47%30%Mutated IGVH25%21%Rai III/IV28%36%Efficacy IWCLL ORR**69%39%IWCLL CR9%3%IWCLL CRi3%0DOR, months (80% CI)13 (11-18)8 (7-10)PFS, months (80% CI)***14 (14-19)10 (9-11)%, All Adverse Events/All / ≥ Grade 3 Adverse EventsAny Event91/66100/76 Events in ≥5 patients in either armNeutropenia59/5639/39Any Infection59/1361/27Thrombocytopenia34/1927/15Pyrexia34/312/0Anaemia28/1333/15Nausea19/030/0Diarrhea16/321/0Fatigue16/015/3Pruritus16/03/0Upper respiratory tract infection16/09/0Cough13/021/0Bronchitis13/021/9Vomiting13/015/3Pneumonia9/615/12Headache6/015/0Constipation6/024/0Febrile neutropenia0/06/6%, Serious Adverse Events in ≥2 patientsAll serious events3146Pneumonia912Pyrexia99Febrile neutropenia06Bronchitis09 *nodes ≥7 cm or 3 adjacent/confluent nodes ≥3 cm **p=0.025 ***p=0.016 FIT = CIRS ≤6 and CrCL ≥60 mL/min, ORR = overall response rate, CR = complete response rate, Cri = CR with incomplete bone marrow recovery, PFS = median progression free survival, DOR = median duration of response Disclosures Robak: Emergent Product Development: Research Funding. Mato:Emegent Product Development: Honoraria. Byrd:Emergent Product Development: Research Funding. Awan:Lymphoma Research Foundation: Research Funding; Boehringer Ingelheim: Consultancy. Hill:Emergent Product Development: Research Funding. Stromatt:Emergent Product Development: Employment.