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The need for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in adults with Philadelphia chromosome–negative (Ph−) acute lymphoblastic leukemia (ALL) with high-risk (HR) features and adequate measurable residual disease (MRD) clearance remains unclear. The aim of the ALL-HR-11 trial was to evaluate the outcomes of HR Ph− adult ALL patients following chemotherapy or allo-HSCT administered based on end-induction and consolidation MRD levels. Patients aged 15 to 60 years with HR-ALL in complete response (CR) and MRD levels (centrally assessed by 8-color flow cytometry)

Prognosis for relapsed or refractory (R/R) acute myeloid leukemia (AML) despite salvage therapy is dismal. This phase I dose-escalation trial assessed the safety and preliminary clinical activity of selinexor, an oral exportin-1 (XPO1) inhibitor, in combination with FLAG-Ida in younger R/R AML patients. The aim was to find the recommended phase 2 dose (RP2D) and maximum tolerated dose (MTD). Fourteen patients were included, and selinexor dosage was 60 mg (3 patients), 80 mg (3 patients), and 100 mg (7 patients) weekly. No dose-limiting toxicities were reported. Grade ≥3 non-hematologic adverse events (AEs) occurred in 78.6% of patients. Two patients were non MTD evaluable due to early death, and overall, 3 out of 14 patients (21.4%) had fatal AEs. Five out of 12 (42%) response and MTD evaluable patients achieved a complete remission (CR; n=4) or CR with incomplete hematologic recovery (CRi, n=1), and 4 patients (33%) subsequently underwent allogeneic transplantation. The median overall survival (OS) and event-free survival (EFS) were 6.0 (range 0.9-19.3) and 1.1 months (range 0.7-19.3), respectively. Using selinexor 100 mg/weekly, CR/CRi rate of 66.7%, OS 13.6 months (range, 1.6-19.3), and EFS 10.6 months (range, 0.9-19.3). At last follow-up, 3 patients were alive. Selinexor 100 mg/weekly with FLAG-Ida combination in R/R AML showed acceptable tolerability and efficacy, establishing the RP2D of this regimen in future clinical trials. ClinicalTrials.gov Identifier: NCT03661515.

Native or pegylated (PEG) asparaginase (ASP) are commonly used in treatment of acute lymphoblastic leukemia (ALL), but have been scarcely compared in the same trial in adult patients. Native vs. PEG-ASP administered according to availability in each center were prospectively evaluated in adults with high-risk ALL. Ninety-one patients received native ASP and 35 PEG-ASP in induction. No significant differences were observed in complete remission, minimal residual disease levels after induction and after consolidation, disease-free survival, and overall survival. No significant differences in grades 3–4 toxicity were observed in the induction period, although a trend for higher hepatic toxicity was observed in patients receiving PEG-ASP. In this trial the type of ASP did not influence patient response and outcome., Supported in part with the grants PI10/01417 from Fondo de Investigaciones Sanitarias and RD12/0036/0029 from RTICC, Instituto de Salud Carlos III, 2014 SGR225(GRE), CERCA Program, Generalitat de Catalunya, Spain, and a funding from ‘La Caixa’ Foundation.

About 25–35% of adult patients with acute lymphoblastic leukemia show the Philadelphia (Ph) chromosome. Few series have evaluated the prognosis of additional cytogenetic alterations (ACA) to the Ph chromosome. We analyzed the frequency, type and prognostic significance ofACA in adults (18–60 years) treated in the ALL-Ph-08 trial. Fifty-two out of 74 patients (70%) showed ACA and 19 (26%) presented monosomies associated with t(9;22) (monosomal karyotype, MK). Similar complete response (CR) rate, CR duration, overall survival and event-free survival (EFS) were observed in patients with or without ACA, but patients with MK showed shorter CR duration and EFS than the remaining. On multivariate analysis, the only variable with prognostic impact for CR duration and EFS was the presence of MK (p = .003 and p = .036, respectively). Although ACA associated with the Ph chromosome are frequent, only monosomies were associated with poor prognosis in this group of patients.

Background. About 25-35% of adult patients with acute lymphoblastic leukemia (ALL) show the Philadelphia (Ph) chromosome. Their outcome has improved with the combination of tyrosine kinase inhibitors (TKI) and chemotherapy, generally followed by allogeneic hematopoietic stem cell transplantation (alloHSCT). However, few series have evaluated the prognostic value of the additional cytogenetic alterations (ACA) to the Ph chromosome, with contradictory results. The aim of this study was to analyse the frequency, type and prognostic significance of ACA to the Ph chromosome in young adults with Ph+ ALL treated with the ALL Ph-08 trial from the PETHEMA group. Patients and methods.Between 2008 and 2016, 95 patients with Ph+ ALL from 30 Spanish hospitals were included in the ALL Ph08 trial. This trial includes concurrent administration of imatinib (600 mg/d) and standard induction and consolidation chemotherapy, followed by alloHSCT (or autologous HSCT if alloHSCT not feasible) and maintenance chemotherapy with imatinib in cases of MRD persistence of reappearance after alloHSCT (Ribera et al, Br J Haematol 2012; 159: 78-81). The cytogenetic reports were centrally reviewed. Major molecular response (MMR) was defined as BCR-ABL/ABL ratio ²0.1% and complete molecular response (CMR) as BCR-ABL/ABL ratio ²0.01% or undetectable. Results. In 74 out of 95 patients the karyotype was evaluable after review (in the remaining 21 cases the diagnosis was carried out by FISH [n=9] or PCR [n=12]). The median age of the 74 patients was 39 years (limits 19-63) and 44 patients (59%) were males. The median WBC count was 17.6x109/L (limits 0.2-390) and 8 out of 66 evaluable patients had CNS involvement at diagnosis. The CR rate was achieved in 72/74 patients (97%) (1 patient did not achieve CR and 1 died during induction therapy). To date, 57 patients underwent to HSCT, of them 46 were in MMR, at least, at the time of HSCT. With a median follow-up of 1.89 years (limits 0.10-7.38) the probabilities of the CR duration, OS and EFS at 4 years were 69% (95%CI: 54%-84%), 39% (23%-55%) and 38% (23%-53%), respectively. Out of 74 patients, 52 (70%) showed at least one ACA and in the remaining 22 (30%) the t(9;22) was the only cytogenetic alteration. No clinical or biologic differences were observed on comparison of the two groups of patients. Twenty (27%) out of 73 evaluable patients showed trisomies and 19 (26%) monosomies. No differences in CR attainment were observed according the presence and type of ACA. The 4-yr. probability of CR duration in patients with t(9;22) and one or more monosomies (monosomal karyotype) vs. those without monosomies was 23% (95%CI: 0%;49%) vs. 88% (77%;99%) (p Conclusions. In young patients with Ph+ ALL treated within the ALL Ph08 trial, the frequency of ACA was high, being trisomies and monosomies shown in similar frequency. The monosomal karyotype was the most important unfavourable prognostic factor in this series of patients. Funded in part by grants PI10/01417 (FIS), RD12-0036-0029 from RTICC, Instituto Carlos III and RD14-SGR225(GRE), Generalitat de Catalunya. Figure Figure. Disclosures No relevant conflicts of interest to declare.

Background and objective. Asparaginase (ASP) is an essential drug for ALL treatment. Two types of E.coli ASP (native and pegylated) are used in clinical trials for treatment of children and adults with ALL, but to our knowledge direct comparison between these two types of ASP in the same protocol has not been performed. This study aimed to compare the efficacy and safety of native vs. PEG-ASP in adult patients with HR, Ph-negative ALL. Patients and methods. HR ALL included one or more of the following parameters at baseline: age 30-60 yr., WBC count >30x109/L for B-cell precursor ALL or >100x109/L for thymic T-ALL, pro-B, early or mature T-ALL, 11q23 or MLL rearrangements or complex karyotype. Induction therapy consisted of vincristine, prednisone, daunorubicin and ASP (native 10,000 IU/m2, i.v., days 16-20 and 23-27 or PEG 2,000 IU/m2, iv, day 15 depending on center decision) for 4 weeks (Induction-1). FLAG-Ida was administered as intensified induction (Induction-2) in patients not achieving CR or in those in CR with MRD≥0.1% at the end of induction, and those patients proceeded to allogeneic HSCT if CR was attained. Patients in CR and MRD Results. Ninety-onepatients received native ASP and 35 PEG-ASP in Induction-1. The two groups of patients were comparable for the main clinical and hematologic ALL parameters. No differences were observed in the CR rate (86% vs. 86%), in the frequency of MRD level Conclusions. In HR, Ph-negative adult ALL patients included in the PETHEMA ALL-HR 11 protocol the type of E.coli ASP (native vs. PEG) did not have impact on response and outcome. Allergic reactions were more frequently seen with native ASP and coagulation abnormalities and hepatic toxicity were most frequent with PEG-ASP. Most of the differences in toxicity can be explained by the schedule of ASP given in consolidation (single dose of native ASP vs. single dose of PEG-ASP in each cycle). Supported in part by grants RD12/0036/0029 (RTICC, FEDER), PI14/01971 FIS, Instituto Carlos III, and SGR225 (GRE), Spain Disclosures No relevant conflicts of interest to declare.

Introduction: Recent studies have shown that young to middle-aged adults who receive a pediatric-inspired chemotherapy regimen for treatment of Ph-neg ALL do not appear to require an alloHSCT if they achieve good response on MRD testing after induction therapy. Patients (pts) who are not good MRD responders achieve better outcomes with alloHSCT than their counterparts who do not receive alloHSCT. However, it is not clear if this approach can be translated to adult ALL pts with HR features at baseline. The aim of the prospective ALL-HR-11 trial from the Spanish PETHEMA Group was to evaluate the response to a differentiated post-induction therapy (chemotherapy or alloHSCT) according to MRD levels (assessed by 8-color, centrally-performed flow cytometry at the end of induction-week 5- and consolidation therapy-week 17-) in HR Ph-neg adult ALL patients. Patients and methods: HR ALL included one or more of the following parameters at baseline: age 30-60 yr, WBC count >30x109/L for B-cell precursor ALL or >100x109/L for thymic T-ALL, pro-B, early or mature T-ALL, 11q23 or MLL rearrangements or complex karyotype. Induction therapy included vincristine, prednisone, daunorubicin and asparaginase (E coli native or PEG according to center availability) for 4 weeks (Induction-1). FLAG-Ida was administered as intensified induction (Induction-2) in pts not achieving CR or those in CR with MRD≥0.1% at the end of induction. For pts in CR and MRD Disclosures No relevant conflicts of interest to declare.

Introduction Intensive chemotherapy in patients with acute myeloid leukemia (AML) who are 70 years of age or older leads to an overall survival (OS) lower than 30% at one year. This is due to low tolerability of intensive chemotherapy schedules and biological adverse features of this group of patients. Objectives To evaluate the therapeutic results in AML patients who are 70 years of age or older treated with intensive (2+5) or semi-intensive (FLUGA) chemotherapy. Methods Multicenter retrospective study based on data of the epidemiologic AML PETHEMA group Registry to evaluate the OS in patients who are 70 year of age or older that have followed the treatment recommendations of the group (LMA2007/2+5 protocol: idarrubicin 12 mg/m2 for 2 days plus IV cytarabine 200 mg/m2 for 5 days, and two cycles with IV cytarabine 100 mg/m2 for 5 days; LMA2011/FLUGA protocol: 3 induction courses with oral fludarabine 40 mg/m2 for 4 days plus subcutaneous cytarabine 75 mg/m2 for 4 days following maintenance treatment with an outpatient schedule of lower doses of fludarabine plus cytarabine. Patients diagnosed with acute promyelocytic leukemia and/or an ECOG of 4 were excluded. Results Of the 155 patients included from 30 hospitals, 78 were treated according to LMA2007/2+5 scheme and 77 to LMA2011/FLUGA recommendations. Median of age in the FLUGA vs 2+5 was 77 years [70-89] vs 74 years [70-81], p Conclusion In patients who are 70 years of age or older, therapeutic recommendations consisting in semi-intensive chemotherapy (FLUGA) led to an improved OS at 1 year compared with intensive chemotherapy (2+5). In this group of patients achieving CR should be a therapeutic goal because it significantly improves the prognosis. Disclosures: No relevant conflicts of interest to declare.

Background and objective ALL in elderly patients is associated with poor prognosis and many patients are not included in therapeutic trials. Consequently, the results of subtype-oriented protocols in elderly ALL are poorly known. We present the results of three prospective parallel subtype-oriented protocols from the Spanish PETHEMA group in ALL patients older than 55 years. Patients and Methods In 2008 three prospective phase II trials for ALL patients older than 55 yr with the Charlson Comorbidity Index ≤3 were activated: ALLOld07 (Ph-negative patients, NCT01366898, n=54), ALLOPh07 (Ph-positive patients, NCT01376427, n=48) and BURKIMAB08 (mature B-ALL, NCT00388193, n=18). The ALL0ld07 protocol included moderate-dose induction chemotherapy without genotoxic drugs, followed by consolidation and maintenance therapy for 2 years (Gökbuget et al, ASH 2008), the ALL OPh07 included imatinib and dexamethasone for induction followed by maintenance therapy with mercaptopurine and methotrexate and imatinib for 2 years, followed by imatinib for one additional year (Ribera et al, Br J Haematol 2012; 159: 485-488), and the BURKIMAB08 protocol included specific therapy for Burkitt’s lymphoma/leukemia together with rituximab (Ribera et al, Cancer 2013; 119:1660-8). The main outcomes (early death [ED], complete remission [CR], remission duration [RD] and overall survival [OS]) and toxicity (CTCAE v4.0) were compared. Results 40, 45 and 16 patients from ALLOld07, ALLOPh07 and BURKIMAB08, respectively, were evaluable for this study. Patients with mature B-ALL were more frequently male, with poorer general status, higher frequency of bulky disease and higher LDH serum levels, whereas no significant differences were observed on comparison of ALLOld07 and ALLOPh07 patients. The comparison of the main outcomes of the three trials is shown in Table 1. By multivariate analyses for RD the protocol and WBC count were identified as prognostic factors (BURKIMAB08 was considered as reference category), with HR [95%CI] of 6.8 [0.9-52.1], p=0.064, when compared with ALL Old07 and 3.1 [0.4-24.8], p=0.278 when compared with ALL OPh07, global p value=0.042, and HR [95%CI]: 1.004 [1-1.009], p=0.058 for the WBC count, respectively. The ECOG score was the only variable influencing OS (HR [95%CI]: 0.4 [0.2;0.8], p=0.003). Hematological toxicity in induction and consolidation as well as infections were significantly less frequent in ALLOPh07 than in other two trials, whereas renal toxicity was more frequent in BURKIMAB08. Conclusion Risk-adapted therapy in elderly patients with ALL was feasible and produced significantly different results in terms of CR duration, being the best for mature B-ALL and the poorest for Ph-negative ALL. Supported by the grants PI10/01417 from FIS and RD12-0036-0029 from Instituto Carlos III Disclosures: No relevant conflicts of interest to declare.

Plasma exchange (PE) with plasma infusion is the treatment of choice for Thrombotic Thrombocytopenic Purpura (TTP) but doubts remain as to whether all kinds of plasma are equally effective. Since October 2004, a multicentric prospective cohort study is being conducted in Spain to compare Methylene Blue Photoinactivated Plasma (MBPIP) with Fresh Frozen Plasma (FFP) in the treatment of TTP. Sixty-three first episodes of idiopathic TTP were included. MBPIP was used in 38 and FFP in 25. The treatment schedule consisted of daily PE (> 40 mL/kg of body weight) and costicosteroids (1.5 mg/kg/d). Response was defined as the achievement of a platelet count >= 150 x 109/L for at least three consecutive days, normal LDH level and absence of TTP-related symptoms and signs. Recurrence was defined as a fall in platelet count below 50 x 109/L or below 50% of the highest count achieved after response. Response lasting for more than 15 days was considered as remission. The prognostic significance of the kind of plasma used was investigated by logistic regression analysis after adjustment for other variables that had previously been found to influence on response to PE (gender; the Rock score; days from first medical attendance to PE; volume of plasma infused in the first 7 days of treatment). Both groups were comparable with regard to clinical and biological parameters at diagnosis. A severe deficit in ADAMTS13 activity was found in 9 out 12 (75%) patients treated with MBPIP and in 12 out of 16 (75%) patients treated with FFP. When compared to FFP, patients treated with MBPIP required a higher number of PEs (16±13 vs 9±7, p=0.004) and a larger volume of plasma (763±678 ml/kg vs 413±326 ml/kg, p=0.02) to achieve a remission and presented more recurrences while on PE treatment (21 out of 38 vs 6 out of 25, p=0.02). Splenectomy or rituximab was required in eight patients (21%) treated with MBPIP to achieve a remission vs in none out of the 25 patients treated with FFP (p= 0.02). After adjustment for other prognostic variables, patients in the MBPIP group had a lower likelihood of remission by the 8th treatment day (OR: 5.1; 95% CI: 1.6 – 15.9) and a higher risk of recurrence while on PE treatment (OR: 4.2; 95% CI: 1.3 – 13.5). In conclusion, MBPIP is less effective than FFP in the treatment of TTP.