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Treatment options for patients with secondary and myeloid related changes acute myeloid leukemia (sAML and AML-MRC) aged 60-75 years old are scarce and unsuitable. A pivotal trial showed that CPX-351 improved complete remission with/without incomplete recovery (CR/CRi) and overall survival (OS) as compared with standard 3+7. We retrospectively analyze outcomes of 765 patients with sAML and AML-MRC aged 60-75 years treated with intensive chemotherapy (IC), reported to the PETHEMA registry before CPX-351 became available. The CR/CRi rate was 48%, median OS 7.6 months (CI95%, 6.7-8.5) and event-free survival (EFS) 2.7 months (CI95%, 2-3.3), without differences between IC regimens and AML type. Multivariate analyses identified age ≥70 years, ECOG≥1 as independent adverse prognostic factors for CR/CRi and OS, while favorable/intermediate cytogenetic risk and NPM1 were favorable prognostic factors. Patients receiving allogeneic stem cell transplant (HSCT), auto-HSCT, and those who completed more consolidation cycles showed improved OS. This large study suggests that classical intensive chemotherapy could lead to similar CR/CRi rates with slightly shorter median OS than CPX-351.

In a context of therapeutic revolution in older adults with AML, it is becoming increasingly important to select patients for the various treatment options by taking account of short-term efficacy and toxicity as well as long-term survival. Here, the data from three European registries for 1,199 AML patients aged 70 years or older treated with intensive chemotherapy were used to develop a prognostic scoring system. The median follow-up was 50.8 months. In the training set of 636 patients, age, performance status, secondary AML, leukocytosis, and cytogenetics, as well as NPM1 mutations (without FLT3-ITD), were all significantly associated with overall survival, albeit not to the same degree. These factors were used to develop a score that predicts long-term overall survival. Three risk-groups were identified: a lower, intermediate and higher-risk score with predicted 5-year overall survival (OS) probabilities of ≥12% (n = 283, 51%; median OS = 18 months), 3–12% (n = 226, 41%; median OS = 9 months) and n = 47, 8%; median OS = 3 months), respectively. This scoring system was also significantly associated with complete remission, early death and relapse-free survival; performed similarly in the external validation cohort (n = 563) and showed a lower false-positive rate than previously published scores. The European Scoring System ≥70, easy for routine calculation, predicts long-term survival in older AML patients considered for intensive chemotherapy.

The outcome of acute myeloid leukemia patients aged 70 years or older is poor. Defining the best treatment option remains controversial especially when choosing between intensive chemotherapy and hypomethylating agents. We set up a multicentric European database collecting data of 3 700 newly diagnosed acute myeloid leukemia patients ≥70 years. The primary objective was to compare overall survival in patients selected for intensive chemotherapy (n = 1199) or hypomethylating agents (n = 1073). With a median follow-up of 49.5 months, the median overall survival was 10.9 (95% CI: 9.7–11.6) and 9.2 months (95% CI: 8.3–10.2) with chemotherapy and hypomethylating agents, respectively. Complete remission or complete remission with incomplete hematologic recovery was 56.1% and 19.7% with chemotherapy and hypomethylating agents, respectively (P

A significant proportion of adult patients with acute myeloid leukemia (AML) fail to achieve complete remission or will relapse later on after achieving it. Prognosis for relapsed or refractory (R/R) AML patients remains discouraging, with the main curative option still relying on hematopoietic stem cell transplant (HSCT) for those who are eligible. Beyond morphological bone marrow and peripheral blood assessment, evaluation of patient performance status and comorbidities, as well as genetic/molecular characterization, is crucial to make an accurate diagnosis and prognosis, which will be useful to select the most appropriate treatment. Emerging strategies are mainly focusing on the development of immune- and molecular-based approaches. Novel targeted therapies are generally well tolerated, potentially allowing them to be administered alone or in combination with classical chemotherapy agents. Enrolment in clinical trials should be considered first option for R/R AML patients, either as a bridge to HSCT or to benefit from novel therapies that eventually may prolong survival and improve quality of life. An Iberian expert panel has reviewed the recent advances in the management of R/R AML with the aim to develop updated evidence and expert opinion-based recommendations.

Next-Generation Sequencing has recently been introduced to efficiently and simultaneously detect genetic variations in acute myeloid leukemia. However, its implementation in the clinical routine raises new challenges focused on the diversity of assays and variant reporting criteria. To overcome this challenge, the PETHEMA group established a nationwide network of reference laboratories aimed to deliver molecular results in the clinics. We report the technical cross-validation results for next-generation sequencing panel genes during the standardization process and the clinical validation in 823 samples of 751 patients with newly diagnosed or refractory/relapse acute myeloid leukemia. Two cross-validation rounds were performed in seven nationwide reference laboratories in order to reach a consensus regarding quality metrics criteria and variant reporting. In the pre-standardization cross-validation round, an overall concordance of 60.98% was obtained with a great variability in selected genes and conditions across laboratories. After consensus of relevant genes and optimization of quality parameters the overall concordance rose to 85.57% in the second cross-validation round. We show that a diagnostic network with harmonized next-generation sequencing analysis and reporting in seven experienced laboratories is feasible in the context of a scientific group. This cooperative nationwide strategy provides advanced molecular diagnostic for acute myeloid leukemia patients of the PETHEMA group.

Background and objective SARS-CoV-2 infection has bimodal distribution in Europe with a first wave in March to June 2020 and a second in September 2020 to February 2021. We compared the frequency, clinical characteristics and outcomes of adults with acute lymphoblastic leukemia (ALL) and infection in the first vs. second pandemic waves in Spain. Patients and Methods In this prospective study the characteristics of ALL and COVID-19 infection, comorbidities, treatment and outcome in the two periods were compared. The study ended when vaccination against SARS-CoV-2 was implemented in Spain. Results Twenty eight patients were collected in the first wave and 24 in the second. The median age was 46.5 years (range 20–83). Patients from the first wave had a trend to more severe ALL (higher frequency of patients under induction or submitted to transplantation or under immunosuppressive therapy). No significant differences were observed in need for oxygen support, intensive care unit (ICU) requirement, days in ICU and time to COVID-19 infection recovery. Seventeen patients (33%) died, with death attributed to COVID infection in 15 (29%), without significant differences in the 100 day overall survival (OS) probabilities in the two waves (68% ± 17% vs. 56% ± 30%). The only prognostic factor for OS identified by was the presence of comorbidities at COVID-19 infection (HR: 5.358 [95% CI: 1.875- 15.313]). Conclusion The frequency and mortality of COVID-19 infection were high in adults with ALL, without changes over time, providing evidence in favor of vaccination priority for these patients., Microabstract The characteristics and outcome of ALL in adults with COVID-19 infection in the first two waves of the pandemic in Spain were compared. The frequency and mortality of COVID-19 infection were high in adults with ALL, without changes over time. Comorbidities at COVID-19 infection was the only prognostic factor for survival.

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.

Context: There is a debate regarding the impact of t(1;19) (q23;p13) in adult BCP ALL. While the MD Anderson group suggests it may be a low-risk subtype, the German, English, and French study groups have shown no differential outcome, and Italian and SWOG groups have reported poor outcomes. Objective: To analyze the frequency and clinical impact of t(1;19) in a series of adult BCP ALL patients (pts). Design & Patients: A review of 513 adult BCP ALL pts (15 to 60 years) diagnosed between 2003 and 2017 and treated with MRD-oriented protocols of the PETHEMA Group. Interventions: G-banding and FISH were performed on BM samples. Measurable residual disease (MRD) was centrally assessed by multi-parametric flow cytometry. Main Outcomes Measures: Complete response (CR), overall survival (OS) and cumulative incidence of relapse (CIR), assessed by competing risk analysis. Results: Total of 26 pts with t(1;19)/TCF3-PBX1 (representing 5% of all BCP ALL). 9/23 (39%) cases showed isolated t(1;19) while 14/23 (61%) had additional chromosomal aberrations (ACA). Pts with t(1;19) were more likely to be female (73% vs 45%, p=0.006) and pre-B phenotype (63% vs 17%, p Conclusions: Although showing favorable initial treatment response, pts with t(1;19) experience a higher rate of relapse (especially those with ACA to t(1;19)) than the remaining BCP ALL pts, without differences in OS. A deeper genetic analysis may identify markers of poor outcome enabling a more precise risk stratification of t(1;19) pts.

PETHEMA, HOVON, PALG, GATLA cooperative groups., [Objective] The obesity/overweight may have an influence on APL outcomes., [Methods] This is the biggest multicentre analysis on 1320 APL patients treated with AIDA‐induction and risk‐adapted consolidation between 1996 and 2012. Patients body mass index (BMI) was classified as underweight (, [Results and conclusions] Relationship between male gender, older age, and other known laboratory abnormalities in overweight/obese patients was significant. The induction mortality rate was significantly higher in APL with BMI ≥25 vs BMI, This work was partially financed with FEDER funds (CIBERONC (CB16/12/00284)) and with Instituto de Investigación Sanitaria La Fe funds (2014/0368).

Introduction Inv(3)(q21.3q26.2)/t(3;3)(q21.3;q26.2) is a rare poor prognosis cytogenetic abnormality present in acute myeloid leukemia (AML) and other myeloid neoplasms. Objective The aim of this study was to evaluate the outcome of a cohort of 61 patients with newly diagnosed AML with inv(3)/t(3;3) treated with homogeneous intensive chemotherapy protocols conducted by the Spanish PETHEMA and CETLAM cooperative groups between 1999 and 2017. Methods In this retrospective study the main clinical and biologic parameters were collected. The complete response (CR) rate, the cumulative incidence of relapse (CIR) and the overall survival (OS) were calculated. An analysis of prognostic factors for survival was performed. Results Sixty-one patients received induction and only 18 (29%) achieved CR (median age, 46 years). Allogeneic hematopoietic stem cell transplantation (alloHSCT) was performed in 36 patients (59%), 15 with active disease. One- and 4-year CIR were 52% and 56%. One- and 4-year OS probabilities were 41% and 13%. By multivariate analysis monosomal karyotype (MK) was associated with poorer OS (HR 2.0, P = .017). Conclusion Inv(3)/t(3;3) AML is a poor prognosis entity with low response to standard chemotherapy and to alloHSCT because of frequent and early relapse. MK was associated with a poorer prognosis. Improved therapeutic strategies are clearly needed.

After publication of this paper, the authors determined that an additional information in the funding section was missing.

Patients with primary refractory or relapsed-acute myeloid leukemia (RR-AML), particularly older adults, have dismal outcomes and limited therapy options [1]. Given the tolerability of hypomethylat...

Background and objective The standardization of treatment of older adults with Philadelphia chromosome negative (Ph-) acute lymphoblastic leukemia (ALL) is challenging, especially in the age range of 55–65 years. This study aimed to compare intensive, pediatric-inspired therapy with non-intensive therapy in this population of patients. Patients and methods The outcomes of 67 patients prospectively included in two consecutive pediatric-inspired intensive protocols (ALL-HR03 and ALL-HR11) from the Spanish PETHEMA Group were compared with those from 44 patients included in a contemporary semi-intensive protocol (ALL-OLD07). Results Baseline patient and ALL characteristics were similar in both groups, except for a younger median age in the intensive group (medians: 58 vs. 62 years). Patients treated intensively had a higher complete remission rate (85% vs. 64%, p = 0.005), a lower cumulative incidence of relapse (39% [95%CI, 25% to 52%] vs. 60% [95%CI, 38% to 77%], p = .003), a similar cumulative incidence of treatment-related mortality (28% [95% CI, 18%, 40%] vs. 21% [95% CI, 10%, 34%]) and superior event-free survival at 2 years (37% [95%CI, 25%–49%) vs. 21% [8%-34%], p = 0.002). On multivariable analysis the type of protocol was the only variable with independent significance for event-free survival (HR [95% CI]: 2 [1.3, 3], p = .002). Conclusions Compared with less intensive chemotherapy, pediatric-inspired intensive chemotherapy significantly improves the outcome of older adults with Ph-negative ALL in the age range of 55–65 years.

[Objective and methods]: Pediatric‐inspired regimens have been adopted by several groups as the treatment strategy for adult patients with acute lymphoblastic leukemia (ALL). Whether subsequent modifications of these protocols have led to an improvement in the outcome of patients is uncertain, especially in T‐cell ALL. We analyzed 169 patients with high‐risk T‐cell ALL included in two consecutive trials of the PETHEMA Group (HR‐ALL03 [n = 104] and the more contemporary HR‐ALL11 [n = 65]). [Results]: Patients and disease characteristics were balanced between both groups. Regarding efficacy, we observed a similar complete remission (CR) rate, relapse and disease‐free survival (DFS) between both protocols. Patients included in the HR‐ALL11 trial had better 2‐year overall survival (OS) compared with the HR‐ALL03 (65% [95% CI 51%‐79%] vs 44% [95% CI 34%‐54%], P = 0.026). Regarding toxicity, we observed a better safety profile in the HR‐11 protocol. Irrespective of the protocol, patients with good measurable residual disease (MRD) clearance had a promising outcome without allogeneic hematopoietic stem cell transplantation (allo‐HSCT) in CR1, with 2‐year OS of 67%. [Conclusion]: Patients with T‐cell ALL included in the HR‐11 trial showed better OS than patients in the HR‐03, mostly driven by a reduction of NRM., This work was supported in part by a grant from Generalitat de Catalunya (2017 SGR288 (GRC)); economical support from CERCA Programme/Generalitat de Catalunya and from Fundació Internacional Josep Carreras. The research leading to this invention has received funding from “la Caixa” Foundation. JMR was supported by PI14/01971 from Fondo de Investigaciones Sanitarias. PB was supported by the Instituto de Salud Carlos III FIS16/01433 and PERIS 2018‐2020 from Generalitat de Catalunya (BDNS357800) grants.

The name of Pau Montesinos was inadvertently presented as Pau Montesinos Fernández in the original article.The original version of this article was revised: The name of Pau Montesinos was inadvertently presented as Pau Montesinos Fernández.

Patients with primary refractory or relapsed acute myeloid leukemia (RR-AML) have very poor prognosis. Due to limited treatment options, some patients are treated with hypomethylating agents (HMAs) due to their tolerability. Little is known about the role of allogeneic hematopoietic stem cell transplantation (HSCT) following HMA therapy in this setting. We retrospectively analyzed an international cohort of 655 RR-AML patients who received HMA therapy to study patterns and outcomes with HSCT. Only 37 patients (5.6%) patients underwent HSCT after HMA therapy. The conditioning regimen was myeloablative in 57% and nonmyeloablative in 43%. Patients received matched unrelated donor, matched sibling, haploidentical and mismatched unrelated HSCT in 56%, 24%, 16% and 4% of cases, respectively. Acute GvHD and chronic GvHD were observed in 40% and 17% of patients. While the median OS for the entire cohort of patients was 15.3 months (95% CI 9.5 - 21.7 months), OS reached 29.7 months (95% CI 7.01 - not-reached) for patients who achieved a complete remission (CR) to HMA and no intervening therapies between HMA therapy and HSCT. Our study suggests that HMA therapy can effectively bridge some patients with RR-AML to HSCT. (C) 2018 American Society for Blood and Marrow Transplantation.

Although hypomethylating agents (HMAs) are frequently used in the frontline treatment of older acute myeloid leukemia (AML) patients, little is known about their effectiveness in relapsed or primary treatment–refractory (RR)-AML. Using an international multicenter retrospective database, we studied the effectiveness of HMAs in RR-AML and evaluated for predictors of response and overall survival (OS). A total of 655 patients from 12 centers received azacitidine (57%) or decitabine (43%), including 290 refractory (44%) and 365 relapsed (56%) patients. Median age at diagnosis was 65 years. Best response to HMAs was complete remission (CR; 11%) or CR with incomplete count recovery (CRi; 5.3%). Additionally, 8.5% experienced hematologic improvement. Median OS was 6.7 months (95% confidence interval, 6.1-7.3). As expected, OS differed significantly by best response, with patients achieving CR and CRi having a median OS of 25.3 and 14.6 months, respectively. In multivariate analysis, the presence of ≤5% circulating blasts and a 10-day schedule of decitabine were associated with improved response rates, whereas the presence of >5% circulating blasts and >20% bone marrow blasts were associated with decreased OS. A significant subset of RR-AML patients (16%) achieved CR/CRi with HMAs and experienced a median OS of 21 months. Outside of a clinical trial, HMAs represent a reasonable therapeutic option for some patients with RR-AML.

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.

This prospective multi-institutional phase II study was designed to assess the efficacy and safety of dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin) plus rituximab (DA-EPOCH-R) in untreated patients with poor prognosis large B-cell lymphomas. Eighty-one patients diagnosed with diffuse large B-cell lymphoma (DLBCL, n = 68), primary mediastinal DLBCL (n = 6) and follicular lymphoma Grade 3b (n = 7), with an age-adjusted International Prognostic Index >1, were eligible for analysis. Median age was 60 years (range: 21-77). Sixty-five patients (80·2%) achieved complete response. After a median follow-up time of 64 months, 10-year event-free survival and overall survival (OS) were 47·8% and 63·6%, respectively. None of the studied clinical and biological characteristics were associated with poorer outcome. Interestingly, patients with BCL6 rearrangement achieved a 10-year OS of 100%, while patients with BCL2 rearrangement exhibited a poorer outcome compared to activated B-cell tumours and germinal centre B-cell without BCL2 rearranged tumours. Results achieved with DA-EPOCH-R showed a good long-term outcome and a tolerable toxicity profile in high-risk large B cell lymphoma patients. Outcome was not affected by tumour cell proliferation or by cell of origin, highlighting the requirement of new biological markers for patient subclassification of high-risk DLBCL patients.

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.

The karyotype is an important predictor of outcome in acute lymphoblastic leukemia (ALL). Rearrangements of the 11q23 region involving the KMT2A gene confer an unfavorable prognosis. Forty-six adult ALL patients from the PETHEMA Group treated with risk-adapted protocols, with t(v;11q23) were selected for this study. Complete response (CR) was attained in 38 patients; 25 remained in CR after consolidation. Twelve (48%) received allogeneic hematopoietic stem cell transplantation (HSCT) and 13 delayed intensification and maintenance. The 5-year CR duration probability was 37% (95% CI, 19%-55%). A trend for a longer CR duration was observed in patients undergoing HSCT vs. those receiving chemotherapy. The 5-year overall survival (OS) probability was 20% (95% CI, 5%-35%). The OS was better, albeit not significant, in patients with a MRD level< 0.1% after induction (39% [95% CI, 14%-64%] vs. 13% [95% CI, 0%-36%]). Specific treatment approaches are required to improve the outcome of patients with KMT2A-rearrangements.

Previous studies have shown that clofarabine plus low-dose cytarabine (LDAC) could induce roughly 60 % of complete remissions (CR) with acceptable toxicity and induction mortality in elderly acute myeloid leukemia (AML) patients not suitable for intensive chemotherapy. The Programa Espanol de Tratamientos en Hematologia group conducted a trial for patients diagnosed with untreated AML aged 60 years and older, using the combination of clofarabine (20 mg/m2 × 5 days) plus low-dose cytarabine (20 mg/m2 × 14 days). The protocol was flexible regarding the use of antifungal and antibacterial prophylaxis, and outpatient induction therapy was allowed. Although the planned recruitment goal was 75 patients, only 11 patients were enrolled (median age, 74 years) after observing high toxicity and unacceptable mortality (46 and 73 % at 4 and 8 weeks, respectively). The response assessment showed three CR (27 %), three resistant diseases (27 %), and five induction deaths (46 %). Induction was administered in an outpatient modality in five patients, while antifungal and antibacterial prophylaxis was not given in seven and five patients, respectively. In our context, induction therapy with the combination of clofarabine (20 mg/m2) plus LDAC was associated with high toxicity and unacceptable mortality in elderly AML patients, leading to the early interruption of the trial. Tight patients’ clinical monitoring, follow-up, and intensive supportive care seem crucial to achieve at least acceptable clinical outcomes in elderly AML patients receiving clofarabine plus LDAC. This trial is registered at www.clinicaltrials.gov as no. NCT01193400.

Background Several evidences support the existence of cytokine deregulation in acute myeloid leukemia (AML) patients that may be associated with pathogenesis, disease progression and patient survival. Methods In the present study, we analyzed plasma levels of pro- and anti-inflammatory cytokines in AML patients and age-matched healthy donors. TNF-α, IL-6, IL-1β, IL-2, IFN-γ, IL-17A, IL-12p70, IL-8, IL-10, IL-4 and IL-5 were analyzed using fluorescent bead-based technology and TGF-β by ELISA technique. Because age-associated differences in cytokine profiles have been described, patients and healthy individuals were divided into two age groups: up to 65 years and over 65 years. Results Our results showed that plasma TNF-α, IL-6 and IL-10 levels were higher in AML patients from both groups of age. IL-8 was increased in AML patients less than 65 years while the plasma concentrations of IL-4, IL-5 and IL-12p70 were significantly higher only in elderly AML patients compared with aged-matched healthy controls. Moreover, plasma levels of IL-6 and IL-10 were associated with patient survival and event-free survival. Conclusions An aberrant production of the pro-inflammatory cytokines IL-6 and TNF-α and the anti-inflammatory cytokine IL-10 is observed in AML patients. Low levels of IL-6 and high levels of IL-10 represent favorable prognostic factors for survival in AML patients. These results support the idea that cytokine deregulation may be useful as a marker for predicting clinical evolution in AML patients.

Differentiation syndrome (DS) can be a life-threatening complication in patients with acute promyelocytic leukemia (APL) undergoing induction therapy with all-trans retinoic acid ( ATRA). Detailed knowledge about DS has remained limited. We present an analysis of the incidence, characteristics, prognostic factors, and outcome of 739 APL patients treated with ATRA plus idarubicin in 2 consecutive trials (Programa Espanol de Tratamientos en Hematologa [PETHEMA] LPA96 and LPA99). Overall, 183 patients (24.8%) experienced DS, 93 with a severe form (12.6%) and 90 with a moderate form (12.2%). Severe but not moderate DS was associated with an increase in mortality. A bimodal incidence of DS was observed, with peaks occurring in the first and third weeks after the start of ATRA therapy. A multivariate analysis indicated that a WBC count greater than 5 x 10(9)/L and an abnormal serum creatinine level correlated with an increased risk of developing severe DS. Patients receiving systematic prednisone prophylaxis (LPA99 trial) in contrast to those receiving selective prophylaxis with dexamethasone (LPA96 trial) had a lower incidence of severe DS. Patients developing severe DS showed a reduced 7-year relapse-free survival in the LPA96 trial (60% vs 85%, P = .003), but this difference was not apparent in the LPA99 trial (86% vs 88%). (Blood. 2009; 113: 775-783)

A previous report of the Programa de Estudio y Tratamiento de las Hemopatías Malignas (PETHEMA) Group showed that a risk-adapted strategy combining all-trans retinoic acid (ATRA) and anthracycline monochemotherapy for induction and consolidation in newly diagnosed acute promyelocytic leukemia results in an improved outcome. Here we analyze treatment outcome of an enlarged series of patients who have been followed up for a median of 65 months. From November 1999 through July 2005 (LPA99 trial), 560 patients received induction therapy with ATRA plus idarubicin. Patients achieving complete remission received 3 courses of consolidation followed by maintenance with ATRA and low-dose chemotherapy. The 5-year cumulative incidence of relapse and disease-free survival were 11% and 84%, respectively. These results compare favorably with those obtained in the previous LPA96 study (P = .019 and P = .04, respectively). This updated analysis confirms the high antileukemic efficacy, low toxicity, and high degree of compliance of a risk-adapted strategy combining ATRA and anthracycline monochemotherapy for consolidation therapy.

An understanding of the prognostic factors associated with the various forms of induction mortality in patients with acute promyelocytic leukemia (APL) has remained remarkably limited. This study reports the incidence, time of occurrence, and prognostic factors of the major categories of induction failure in a series of 732 patients of all ages (range, 2-83 years) with newly diagnosed APL who received all-trans retinoic acid (ATRA) plus idarubicin as induction therapy in 2 consecutive studies of the Programa de Estudio y Tratamiento de las Hemopatias Malignas (PETHEMA) Group. Complete remission was attained in 666 patients (91%). All the 66 induction failures were due to induction death. Hemorrhage was the most common cause of induction death (5%), followed by infection (2.3%) and differentiation syndrome (1.4%). Multivariate analysis identified specific and distinct pretreatment characteristics to correlate with an increased risk of death caused by hemorrhage (abnormal creatinine level, increased peripheral blast counts, and presence of coagulopathy), infection (age >60 years, male sex, and fever at presentation), and differentiation syndrome (Eastern Cooperative Oncology Group [ECOG] score >1 and low albumin levels), respectively. These data furnish clinically relevant information that might be useful for designing more appropriately risk-adapted treatment protocols aimed at reducing the considerable problem of induction mortality in APL.

Objectives: Angioimmunoblastic T-cell lymphoma (AIL) is a rare lymphoma with a poor prognosis and no standard treatment. Here, we report our experiences with 19 patients treated with high-dose chemotherapy and autologous stem cell transplantation (HDC/ASCT) within the GELTAMO co-operative group between 1992 and 2004. Methods: The median age at transplantation was 46 yr. Fifteen patients underwent the procedure as front-line therapy and four patients as salvage therapy. Most patients received peripheral stem cells (90%) coupled with BEAM or BEAC as conditioning regimen (79%). Results: A 79% of patients achieved complete response, 5% partial response and 16% failed the procedure. After a median follow-up of 25 months, eight patients died (seven of progressive disease and secondary neoplasia), while actuarial overall survival and progression-free survival at 3 yr was 60% and 55%. Prognostic factors associated with a poor outcome included bone marrow involvement, transplantation in refractory disease state, attributing more than one factor of the age-adjusted-International Prognostic Index, Pretransplant peripheral T-cell lymphoma (PTCL) Score or Prognostic Index for PTCL. Conclusions: More than half of the patients with AIL that display unfavourable prognostic factors at diagnosis or relapse would be expected to be alive and disease-free after 3 yr when treated with HDC/ASCT. Patients who are transplanted in a refractory disease state do not benefit from this procedure.

Therapeutic results in elderly patients with acute promyelocytic leukemia (APL) have been generally reported as less effective than for younger patients. Patients 60 years or older with APL who were enrolled in 2 successive multicenter PETHEMA studies received induction therapy with all-trans retinoic acid (ATRA) and idarubicin, consolidation with 3 anthracycline monochemotherapy courses with or without ATRA, and maintenance with ATRA and low-dose chemotherapy. Eighty-seven of 104 patients achieved complete remission (84%). Eighty-six proceeded to consolidation therapy (2 withdrew after the first and second courses). Deaths in remission occurred during consolidation and maintenance therapy in 3 and 4 patients, respectively. One patient showed molecular persistence after consolidation and 5 had a relapse. The 6-year cumulative incidence of relapse, leukemia-free survival, and disease-free survival were 8.5%, 91%, and 79%, respectively. A significantly higher incidence of low-risk patients found among the elderly, as compared to younger patients, may partially account for the low relapse rate observed. This study confirms the high antileukemic efficacy, low toxicity, and high degree of compliance of protocols using ATRA and anthracycline monochemotherapy for induction and consolidation therapy in elderly patients. (C) 2004 by The American Society of Hematology.

All- trans -retinoic acid (ATRA) increases the efficacy of chemotherapy when used for induction and maintenance treatment of acute promyelocytic leukemia (APL), but its role in consolidation is unknown. Since November 1996, 426 patients with newly diagnosed APL have received induction therapy with ATRA and idarubicin. Before November 1999 (LPA96 study), consolidation therapy consisted of 3 courses of anthracycline monochemotherapy. After November 1999 (LPA99 study), patients with intermediate and high risks of relapse received consolidation therapy with ATRA and increased doses of anthracyclines. Of the 384 patients who achieved complete remission (90%), 382 proceeded to consolidation therapy. Seven patients died in remission (1.8%). The 3-year cumulative incidence of relapse for patients in the LPA96 and LPA99 studies was 17.2% and 7.5%, respectively ( P = .008). Patients treated with ATRA in consolidation therapy showed an overall reduction in the relapse rate from 20.1% to 8.7% ( P = .004). In intermediate-risk patients the rate decreased from 14.0% to 2.5% ( P = .006). This improved antileukemic efficacy also translated into significantly better disease-free and overall survival. A risk-adapted strategy combining anthracycline monochemotherapy and ATRA for induction and consolidation therapy of newly diagnosed APL results in improved antileukemic efficacy and a high degree of compliance.

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.

Background: Diffuse large B-cell lymphoma (DLBCL) patients with relapsed or refractory disease after rituximab-containing first-line therapy have poor outcomes with current salvage regimens. Accordingly, prospective studies incorporating new agents are needed for these patients. We conducted a phase 1b/2 trial to analyze the safety and efficacy of lenalidomide in combination with R-ESHAP (LR-ESHAP) in patients with relapsed or refractory DLBCL. The phase 1b part of the trial has been completed and lenalidomide 10 mg/day was identified as the maximum tolerated dose (MTD) (Martín et al, Br J Haematol 2016; 173: 245-52). Here we present the preliminary results of the phase 2 (ClinicalTrials.gov Identifier: NCT02340936). Patients and methods: Eligible patients must be refractory to, or have relapsed following first-line treatment with rituximab in combination with an anthracycline-containing regimen and be eligible for autologous stem-cell transplantation (ASCT). Subjects received 3 cycles of lenalidomide 10 mg given on days 1 to 14 of every 21-day cycle, in combination with R-ESHAP salvage chemotherapy at standard doses (rituximab 375 mg/m2 day 1, etoposide 40 mg/m2 days 1-4, cisplatin 25 mg/m2 days 1-4, cytarabine 2000 mg/m2 day 5, and methylprednisolone 500 mg days 1-5). Responding patients received BEAM followed by ASCT. The primary endpoint was overall response rate (ORR) after 3 cycles of therapy. Secondary endpoints were complete remission (CR) rate, stem-cell mobilization activity, progression-free and overall survival, and toxicity. Results: Patient characteristics: 46 patients were included in the phase 2 analysis, of whom 12 were enrolled between January 2012 and March 2013, and had been given the MTD during phase 1; 34 were enrolled between January 2015 and November 2015. Median age was 58 (23-69) years, and 56.5% were male. Evaluable population per-protocol consisted of 44 patients because 2 patients were excluded during the first cycle due to withdrawal of consent and centralized diagnosis at relapse of lymphoblastic lymphoma, respectively. First-line treatment consisted of R-CHOP or similar in 38 patients, R-EPOCH in 3, VR-CAP in 1, and Burkitt lymphoma protocols in 2. Disease status at LR-ESHAP was: primary refractory disease in 67% of patients (partial response [PR] after first-line, n=13; and stable or progressive disease [ Feasibility and efficacy: 40 out of 44 patients (91%) received the planned 3 cycles of treatment (2 without lenalidomide in the third cycle due to toxicity) and 2 patients two cycles (due to persistent hematological and renal toxicities, respectively). Two patients discontinued treatment during the first cycle due to grade 3 infections (fungal pulmonary infection and mastoiditis, respectively). ORR to LR-ESHAP in the per-protocol population (n=44) was 68% (41% CR). Patients with relapsed disease had significantly better ORR and CR rates (87% and 67%, respectively) than patients in PR (77% and 31%) or Toxicity: 42 serious adverse events (SAEs) have been reported during 128 cycles of treatment, including 14 episodes of febrile neutropenia (11%), 12 infections (9%), 2 renal disorders, 3 cardiac disorders, 3 thrombosis, and 8 other toxicities. All of them recovered except 1 case of colon adenocarcinoma in a patient with previous adenoma in the same location. There were no treatment-related deaths during LR-ESHAP cycles. Conclusions: LR-ESHAP is safe, feasible and associated with high response rates in rituximab-pretreated relapsed or refractory DLBCL patients. Longer follow-up is needed to perform survival analysis. Efficacy analysis according to COO is ongoing. Disclosures Martín: Janssen: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sevier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. González-Barca:Sanofi: Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria. Lopez-Guillermo:Roche: Consultancy, Research Funding; Celgene: Consultancy; Gilead: Consultancy; Janssen: Consultancy; Mundipharma: Consultancy.

Introduction: Current recommendations for the treatment of AML in newly diagnosed elderly patients (≥ 65 years) include different therapeutic options (intensive or semi-intensive chemotherapy, low-dose chemotherapy, hypomethylating agents, and supportive care). Regardless of the selected treatment, the results are disappointing because of low overall survival (OS) rates and significant toxicity. Objectives: The primary objective of FLUGAZA trial is to compare the 1-year-OS in 350 patients aged ≥ 65 years diagnosed with AML assigned to azacytidine (n=175) or FLUGA (n=175) arms. Here we present the results of a pre-planned interim safety analysis for both outpatient treatment regimens. Methods Inclusion criteria: Patients diagnosed with de novo or secondary AML according to WHO classification (except for APL), previously untreated, age ≥ 65 years, ECOG 25 x109/L. Concomitant use of hydroxyurea was allowed in the AZA arm if WBC was between 15 and 50 x109/L. In patients with more than 50 x109/L WBC assigned to the AZA arm, the first induction cycle was FLUGA. An interim analysis to assess myelotoxicity, early mortality and response rate was planned in the trial when the last of the first 100 randomized patients completed the first 3 induction cycles. Results: From October 2014 to April 2016, 162 patients were enrolled in 26 Spanish centers from the PETHEMA group. Of them, 22 patients were screen failure and 16 patients did not receive the assigned treatment. The first 100 patients treated were analyzed (58 patients were assigned to AZA arm and 42 to FLUGA arm). Baseline characteristics are shown in Table 1. Median age was 75 [65;90] years in AZA arm vs. 77 [65;88] years in FLUGA arm; 36 (62%) vs. 19 (45%) males. Five patients from AZA arm (n=58) received the first cycle of FLUGA because of WBC > 50 x109/L. Outcomes: overall response rate (CR+CRu+PR) based on the best response accumulated with 3 cycles of treatment was 62% in the AZA arm and 57% in the FLUGA arm. CR+CRu was achieved in 14 patients (24%) from AZA arm and 15 (36%) from FLUGA arm. Early mortality rate (8 weeks) was 14% in AZA and 22% in FLUGA arm. Toxicities: there were no differences in hospitalization and non-hematological ≥ G3 serious adverse events (SAEs) between both arms. Overall, 71 patients (71%), 61 out of 79 (77%) vs. 41 out of 64 (64%) patients, developed neutropenia (< 0.5 x x109/L) after C1, C2 and C3, respectively. Median duration of neutropenia in the AZA arm was 14 days (6;40), 21 days (4;95) and 18 days (1;45) after in C1, C2 and C3, respectively, vs. 15 days (4;33), 15 days (3;36) and 20 days (7;41) after C1, C2 and C3, respectively, in the FLUGA arm (no statistically significant differences). Eighty-one (81%), 55 out of 79 (70%) vs. 40 out of 64 (62%) patients, developed thrombocytopenia (< 50 x109/L) after C1, C2 and C3, respectively. Median duration of thrombocytopenia was 14 days (5;29) after C1, 18 days (4;88) after C2 and 14 days (7;25) after C3 in the AZA arm; vs. 16 (3;63), 20 (6;42) and 13 days (7;56) after C1, C2 and C3, respectively, in the FLUGA arm (NS). Conclusions: Outpatient treatment with AZA or FLUGA was feasible. Both treatment arms showed a similar rate of early mortality and relatively low CR/CRu rates. The study is currently enrolling patients until the planned accrual goal (350 patients) to assess the primary end-point (1-year OS). The study is registered at www.ClinicalTrials.gov as NCT02319135. Disclosures No relevant conflicts of interest to declare.

Elacytarabine is the elaidic acid ester derivative of cytarabine, designed to enter cells independently of nucleoside transporters. Effects of elacytarabine on QT interval, serum lipid profile and clinical activity were investigated in 43 relapsed/refractory AML patients. Mean maximum increase in corrected QT interval of 24( ± 29)ms occurred 48 h after elacytarabine infusion without associated arrhythmias or clinical symptoms. A non-clinically significant, elacytarabine exposure-dependent increase in cholesterol was caused by a cholesterol rich lipoprotein depleted of apolipoprotein B formed by infused phospholipids complexing cholesterol. Elacytarabine is clinically active in relapsed/refractory AML: overall response rate (CR + CRi) was 44% (16/36 with 7 non-evaluable patients) and adverse events were manageable. Clinical Trials.gov Identifier: NCT01258816.

One hundred ten patients with multiple myeloma (MM) failing to achieve at least near-complete remission (nCR) after a first autologous stem cell transplantation (ASCT) were scheduled to receive a second ASCT (85 patients) or a reduced-intensity-conditioning allograft (allo-RIC; 25 patients), depending on the human leukocyte antigen (HLA)–identical sibling donor availability. There was a higher increase in complete remission (CR) rate (40% vs 11%, P = .001) and a trend toward a longer progression-free survival (PFS; median, 31 months vs not reached, P = .08) in favor of allo-RIC. In contrast, it was associated with a trend toward a higher transplantation-related mortality (16% vs 5%, P = .07), a 66% chance of chronic graft-versus-host disease and no statistical difference in event-free survival and overall survival. Although the PFS plateau observed with allo-RIC is very encouraging, this procedure is associated with high morbidity and mortality, and therefore it should still be considered investigational and restricted to well-designed prospective clinical trials. This trial is registered at ClinicalTrials.gov ID number NCT00560053

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: In recent years, the multiple myeloma (MM) treatment (Tx) landscape has evolved considerably, with the approval of effective novel agents, such as immunomodulatory drugs (thalidomide, lenalidomide, and most recently, pomalidomide) and proteasome inhibitors (bortezomib and carfilzomib; Chng et al, Leukemia, 2014). However, most patients relapse and patterns of relapse in MM can be heterogeneous (Alegre et al, Haematologica, 2002). Tx rescue for MM relapse should begin at symptomatic clinical relapse (clinR) and probably earlier at asymptomatic biological relapse (BR; specifically when significant paraprotein relapse), according to the International Myeloma Workshop Consensus Panel (Rajkumar et al, Blood, 2011). In the case of asymptomatic BR/progression, rescue Tx could be delayed in a subset of pts (Fernández de Larrea et al, Bone Marrow Transplant, 2014), particularly when M-component and hemoglobin levels are stable. Progressive increases of M-spike blood and/or urine could lead to rescue Tx, even in the absence of clinical symptoms, to avoid complications (ie, renal failure, plasmacytomas, bone lesions; Castelli et al, Clin Med Insights Oncol, 2013). This Spanish registry (EPA-MMBR) is an observational prospective study to describe MM relapse patterns, comparing the impact of Tx decisions (starting Tx at BR vs delaying Tx until clinR). We present the updated preliminary results of this study. Methods: MM pts in (or prior to) first or second BR who had achieved ≥ PR since their last Tx were included. Bi-monthly evaluations were performed. Forty-one Spanish sites are participating after approval from their independent ethics committees, with 410 pts expected to be included. The main objective was to assess time to progression (TTP) from BR in both groups (pts who started Tx at the onset of asymptomatic BR vs pts who started Tx at clinR). Secondary objectives included demographic, clinical, and Tx characteristics; median time from BR to clinR; and response rates. Here we present the results of 138 pts with baseline data (48.4%) of a total of 285 registered. Results: In the cohort evaluated (n = 138), mean age was 67.9 years, and 50.7% were male. MM types were IgG Κ (43.5%), IgG λ (22.1%), IgA Κ (16%), and IgA λ (7.6%). Prognostic stage at diagnosis according to the International Staging System (ISS) was II (32.6%) followed by I and III (22.7% each) and data not available (22%). Pts' cytogenetic risk included standard risk (20.8%), high risk (8.5%), and no cytogenetic alterations (32.3%). More than half of pts (51.5%) had received autologous stem cell transplant, 13.2% consolidation and 21.1% maintenance. After first-line Tx, pts had achieved sCR (16.0%), CR (33.6%), VGPR (28.8%), or PR (21.6%). Pts with BR had a median time from diagnosis to BR of 2.66 years. Tx was delayed until clinR in 51.2% of pts, and 48.8% had started Tx at BR (73.3% of whom had significant paraprotein relapse; Figure); there were no relevant differences in demographic and clinical characteristics between the 2 groups. Median time to BR was 31.97 months. Median time from BR to clinR was 105.0 days. Among pts who started Tx at BR, most pts received lenalidomide-based Tx (75% at first relapse and 70.6% at second relapse). At the time of the analysis, only 3 pts had disease progression (1 in each group). In pts who started Tx at BR, first-line Tx after diagnosis was mainly bortezomib-based (73.3%). sCR was achieved in 20.0% of pts, CR in 33.3%, PR in 26.7%, and VGPR in 20.0%. Since the beginning of the study, Tx was prescribed in 54 pts (39.1%). Since only 3 pts had progressed, further follow-up data, particularly in terms of TTP and survival, are needed to identify differences between these 2 strategies. Conclusions: To our knowledge, this is the first prospective study in MM that evaluates the effects of starting Tx at BR vs starting Tx at clinR. In this updated cohort, we find that almost half of pts started Tx at BR (48.8%). We also found that a higher percentage of pts started Tx at BR with significant paraprotein relapse (73.3%), which seems to be a clear factor guiding Tx decision for the physician. Further follow-up and a complete study are needed to identify the differences between these 2 strategies and to define patients who could benefit from early Tx. Figure 1. Percentage of pts who started Tx at clinR, BR, or significant paraprotein relapse (n = 138). Figure 1. Percentage of pts who started Tx at clinR, BR, or significant paraprotein relapse (n = 138). Disclosures Gironella: Celgene Corporation: Consultancy, Honoraria. Fernández de Larrea:Celgene Corporation: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Lahuerta:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cabañas:Amgen: Membership on an entity's Board of Directors or advisory committees. Lostaunau:Celgene SLU: Employment. Vilanova:Celgene SLU: Employment. Alegre:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.

Background: We have overcome the limitations of 40 years of ex vivo testing. The aim of this study is to determine the ability of Vivia's novel test to predict the complete remission (CR) rates after induction chemotherapy with cytarabine (Ara-C) and idarubicin (Ida) in 1st line AML. Material and Methods: Bone marrow samples from adult patients diagnosed with de novo AML in Spanish centers from the PETHEMA group were included. Whole marrow samples maintaining their Native Environment were incubated for 48h in well plates containing Ara-C, Ida, or their combination. Pharmacological responses are calculated using population models. Induction response was assessed according to the Cheson criteria (2003). Patients attaining a CR/CRi were classified as responders and the remaining as resistant. Results: 390 patient samples were used to calculate the dose response (DR) curves for Ara-C alone, Ida alone, and their synergism. For clinical correlation we used 142 patients with median 56 years. The strongest clinical predictor was the Area Under the Curve (AUC) of the DR of Ara-C, and the AUC of IDA. The GAM models revealed a significant relationship between the AUC of the concentration-effect curves of both, idarubicin and, particularly, Ara-C, with greater values associated to higher probabilities of post-induction resistance. The fitted Generalized Additive Method predictions of expected values for each patient were in turn related to overall survival when a discrimination value to define positive and negative test results that prioritized specificity over sensitivity was chosen based on equaling positive and negative predictive values (Fig 1A). Prioritizing specificity over sensitivity reflects the higher cost of false positive over false negative decisions: only in very rare instances, an effective treatment would be erroneously negated to a sensitive patient at the expense of overlooking a number of resistant patients. However, the later patients could take their chances on re-induction therapy. While for diagnostics sensitivity and specificity should both be optimized, for Personalized Medicine the positive and negative predictive values should be optimized preferentially because they define the patient response correlation. Fig 1B shows a table illustrating the correlation between clinical outcome (columns) and the test predictions (lines). From a diagnostic criteria (columns), clinically resistant patients (1st column) are not well predicted with a Sensitivity of 51%, while clinically sensitive patients (2nd column) are very well predicted with a Specificity of 94%. From a Precision Medicine criteria (Lines), patients predicted resistant (1st line) and well predicted with 80% positive predictive value, similar to patients predicted sensitive (2nd line) well predicted with 79% Negative Predictive Value. The test does not properly identify 23/142 that are clinically resistant and the test predicts as sensitive (bottom left quadrant right panel). This mismatched subgroup mimics the problems from molecular markers where a resistant clone present in a minority of leukemic cells cannot be detected yet drives the patient response. However, this group mismatch does not prevent a good correlation with the test predicted outcomes. Flow cytometry identified 2 clones in 75% of these 23 samples, and we revised all samples analyzing each of 2 clones separately whenever they were present. Results did not change by this clonal analysis, suggesting flow cytometry may not identify resistant clones. Future improvements of the test adding 16 concentrations to the dose response curves may be able to detect the presence and parameters of these resistant clones driving patient response. Conclusions: This novel test is able to predict the clinical response to Ida + Ara-C induction with overall correlation and predictive values of 80%, higher than ever achieved. It is significantly higher than the current clinical response rate of 66.7%. Thus this novel test may be valuable information to guide 1st line patient therapy. Figure 1. ROC curve and clinical correlation Figure 1. ROC curve and clinical correlation Disclosures Ballesteros: Vivia Biotech: Employment. Cordoba:Celgene: Research Funding. Ramos:GlaxoSmithKline: Honoraria; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria. Gaspar:Vivia Biotech: Employment. Gorrochategui:Vivia Biotech: Employment. Rojas:Vivia Biotech: Employment. Gomez:Vivia Biotech: Employment. Hernández:Vivia Biotech: Employment. Robles:Vivia Biotech: Employment.

Introduction: Relapses after front-line therapy for Burkitt lymphoma/leukemia (BL) are unfrequent, and there is scarce information about the best rescue strategy for these patients. The objective of this study was to evaluate the incidence of relapse, salvage treatment and prognosis after relapse in patients with BL treated with two consecutive Spanish protocols. Patients and methods: Retrospective study of patients diagnosed with BL in 40 Spanish hospitals betwen January 1997 and October 2014 treated with first line chemotherapy according to protocols PETHEMA LAL-3/97 (specific chemotherapy without rituximab) and BURKIMAB (rituximab plus specific chemotherapy). The demographic, clinical and biological characteristics were collected at the time of diagnosis and at relapse, as well as the salvage treatment and outcomes. Results: 233 patients were diagnosed with Burkitt lymphoma (n=150) or leukemia (n=83) and received first-line therapy according to PETHEMA LAL-3/97 (n=53) and BURKIMAB (n=180) protocols. Baseline characteristics at diagnosis are described in Table 1. A total of 26 patients relapsed, 11 (28%) treated with PETHEMA LAL-3/97 protocol and 15 (10%) with BURKIMAB protocol (p=0.009). The cumulative incidence of relapse at 10 years was 27% (95% CI, 12%-42%) in PETHEMA LAL-3/97 protocol vs.16% (95% CI, 4%-28%) in BURKIMAB protocol (p= 0.013) (Figure 1). Time to relapse was shorter in PETHEMA LAL-3/97 protocol (median of 3.7 months) vs. BURKIMAB protocol (6.3 months), but it was not significant (p=0.506). No differences were observed in relapse incidence between Burkitt leukemia and Burkitt lymphoma in PETHEMA LAL-3/97 protocol (6/31 vs. 5/22, p=1) and BURKIMAB protocol (7/41 vs. 8/107, p=0.124). Out of 15 patients in whom rescue treatment strategy was evaluable, 12 received chemotherapy with high-dose methotrexate and/or cytarabine (4 of the them followed response, CR in 2, followed by SCT in the 2 patients achieving PR [autologous in one and allogeneic SCT in the other]), and the remaining 3 patients received DA-EPOCH-R (n=1, achieving CR), R-ICE (n=1, no response) and paliative care (n=1). At the time of the analysis, only 3 patients are alive. Median overall survival after relapse was 3 months (95% CI, 0.9-5.1) for PETHEMA LAL-3/97 relapsed group and 3.6 months (95% CI, 0.1-7.1) for BURKIMAB relapsed patients group. Conclusions: Patients with Burkitt leukemia/lymphoma treated with specific immunochemotherapy have lower probability of relapse compared with those treated with specific chemotherapy without rituximab. In our series, the most frequent regimens administered for the treatment of relapsed patients were based in high-dose methotrexate and/or cytarabine. The prognosis of relapsed Burkitt leukemia/lymphoma is poor, independently of the type of rescue therapy. Supported by grants RD12/0036/0029 (RTICC, FEDER), Instituto Carlos III, Spain. Disclosures No relevant conflicts of interest to declare.

The expression of CD56 antigen in acute promyelocytic leukemia (APL) blasts has been associated with short remission duration and extramedullary relapse. We investigated the clinical significance of CD56 expression in a large series of patients with APL treated with all-trans retinoic acid and anthracycline-based regimens. Between 1996 and 2009, 651 APL patients with available data on CD56 expression were included in 3 subsequent trials (PETHEMA LPA96 and LPA99 and PETHEMA/HOVON LPA2005). Seventy-two patients (11%) were CD56+ (expression of CD56 in ≥ 20% leukemic promyelocytes). CD56+ APL was significantly associated with high white blood cell counts; low albumin levels; BCR3 isoform; and the coexpression of CD2, CD34, CD7, HLA-DR, CD15, and CD117 antigens. For CD56+ APL, the 5-year relapse rate was 22%, compared with a 10% relapse rate for CD56− APL (P = .006). In the multivariate analysis, CD56 expression retained the statistical significance together with the relapse-risk score. CD56+ APL also showed a greater risk of extramedullary relapse (P < .001). In summary, CD56 expression is associated with the coexpression of immaturity-associated and T-cell antigens and is an independent adverse prognostic factor for relapse in patients with APL treated with all-trans-retinoic acid plus idarubicin–derived regimens. This marker may be considered for implementing risk-adapted therapeutic strategies in APL. The LPA2005 trial is registered at http://www.clinicaltrials.gov as NCT00408278.

Comparative Study; Journal Article; Multicenter Study; Research Support, Non-U.S. Gov't; BACKGROUND About one half of adults with acute lymphoblastic leukemia are not cured of the disease and ultimately die. The objective of this study was to explore the factors influencing the outcome of adult patients with relapsed acute lymphoblastic leukemia. DESIGN AND METHODS. We analyzed the characteristics, the outcome and the prognostic factors for survival after first relapse in a series of 263 adult patients with acute lymphoblastic leukemia (excluding those with mature B-cell acute lymphoblastic leukemia) prospectively enrolled in four consecutive risk-adapted PETHEMA trials. RESULTS. The median overall survival after relapse was 4.5 months (95% CI, 4-5 months) with a 5-year overall survival of 10% (95% CI, 8%-12%); 45% of patients receiving intensive second-line treatment achieved a second complete remission and 22% (95% CI, 14%-30%) of them remained disease free at 5 years. Factors predicting a good outcome after rescue therapy were age less than 30 years (2-year overall survival of 21% versus 10% for those over 30 years old; P

Background The prevalence of and risk factors for central nervous system recurrence in patients with acute promyelocytic leukemia are not well established and remain a controversial matter. Design and Methods Between 1996 and 2005, 739 patients with newly diagnosed acute promyelocytic leukemia enrolled in two consecutive trials (PETHEMA LPA96 and LPA99) received induction therapy-with all-trans retinoic acid and idarubicin. Consolidation therapy comprised three courses of anthracycline monochemotherapy (LPA96), with all-trans retinoic acid and reinforced doses of idarubicin in patients with an intermediate or high risk of relapse (LPA99). Central nervous system prophylaxis was not given. Results Central nervous system relapse was documented in 11 patients. The 5-year cumulative incidence of central nervous system relapse was 1.7% (LPA96 3.2% and LPA99 1.2%; p=0.09). The cumulative incidence was 0%, 0.8%, and 5.5% in low-, intermediate-, and high-risk patients, respectively. Relapse risk score (p=0.0001) and the occurrence of central nervous system hemorrhage during induction (5-year cumulative incidence 18.7%, p=0.006) were independent risk factors for central nervous system relapse. Conclusions This study shows a low incidence of central nervous system relapse in patients with acute promyelocytic leukemia following therapy with all-trans retinoic acid and anthracycline without specific central nervous system prophylaxis. Central nervous system relapse was significantly associated with high white blood cell counts and prior central nervous system hemorrhage, which emerged as independent prognostic factors.

All-trans retinoic acid (ATRA) plus anthracycline chemotherapy is the reference treatment of newly diagnosed acute promyelocytic leukemia (APL), whereas the role of cytosine arabinoside (AraC) remains disputed. We performed a joint analysis of patients younger than 65 years included in Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA) LPA 99 trial, where patients received no AraC in addition to ATRA, high cumulative dose idarubicin, and mitoxantrone, and APL 2000 trial, where patients received AraC in addition to ATRA and lower cumulative dose daunorubicin. In patients with white blood cell (WBC) count less than 10 × 109/L, complete remission (CR) rates were similar, but 3-year cumulative incidence of relapse (CIR) was significantly lower in LPA 99 trial: 4.2% versus 14.3% (P = .03), although 3-year survival was similar in both trials. This suggested that AraC is not required in APL with WBC count less than 10 × 109/L, at least in trials with high-dose anthracycline and maintenance treatment. In patients with WBC of 10 × 109/L or more, however, the CR rate (95.1% vs 83.6% P = .018) and 3-year survival (91.5% vs 80.8%, P = .026) were significantly higher in APL 2000 trial, and there was a trend for lower 3-year CIR (9.9% vs 18.5%, P = .12), suggesting a beneficial role for AraC in those patients.

Background Adverse karyotype and age are associated with poor prognosis in older AML patients (pts). Although complete remission (CR) can be achieved with intensive chemotherapy (IC) in pts with adverse cytogenetics, overall survival (OS) and leukemia free-survival (LFS) are poor (Knipp S, et al. Cancer 2007). In addition, low doses of ARA-C (LDAC) did not offer survival benefit in older pts with poor cytogenetics as compared to hydroxyurea and best supportive care (BSC) (Burnett A, et al. Cancer 2007). Azacitidine has shown a survival advantage in older pts with newly diagnosed AML in a recent phase 3 trial, as compared to conventional care regimens (BSC/LDAC/IC)(Dombret H, et al. EHA 2014). Aim To evaluate the role of azacitidine and factors associated with OS in pts with newly diagnosed AML and adverse karyotype from the ALMA study (Ramos F, et al. Blood 2012;120:abstract 3593). Methods Retrospective, multicenter study, of pts with newly diagnosed AML and adverse karyotype who received front-line azacitidine in Spain. Response to azacitidine was evaluated by ELN-2010 criteria. Overall survival was evaluated by Kaplan-Meier method and log-rank test. Results Thirty-nine pts were identified. Median age: 71y (52-83). Baseline characteristics are shown in table 1. All pts received azacitidine (75 mg/m2 sc x7 days) as first line treatment. Median time from AML diagnosis to therapy was 16 days (1-88). 56% of pts had bone marrow (BM) blasts >30% at diagnosis (median: 32%; range: 20-90). Five out of 39 (13%) pts had leucocyte count (WBC) >15x109/L and 20/39 (51%) had ECOG performance status >1. Complex karyotype (CK) and monosomal karyotype (MK) was present in 18/39 pts each (46%). Within the subset showing CK, 14/18 (78%) had MK. Complete remission (CR) and CRi was 23.1% and 5.1% respectively (ORR=28.2%). Median courses of therapy to best response: 3 (1-11). After 17m median follow-up, median OS (95% CI) was 7m (3.1-8.8). Estimated 1-year survival was 29.8%. There were no differences in median OS in pts with MK vs. rest of pts with CK (median OS 9m [95% CI: 5.3-12.6] vs. 6.5m [3.1-8.8], respectively; p=0.854). Monosomal karyotype, CK with >5 abnormalities, BM blasts >30% and ECOG status >1 did not achieve statistically significance in multivariate analysis. Only WBC at baseline (>10x109/L or >15x109/L; threshold not relevant) had an impact on OS in both univariate (3m [95% CI: 4.9-13] vs. 9m [4.9-13] if WBC 10x109/L3.341.17-9.580.025BM blast >30%1.080.46-2.540.855MK0.950.33-2.740.919CK1.610.58-4.510.361ECOG >11.840.81-4.170.144 Conclusion Albeit retrospective and non-comparative, azacitidine seems to improve median and 1y survival as compared to historic AML data in pts with adverse cytogenetics. An elevated WBC >10x109/L at diagnosis was the only parameter associated to adverse outcome in this set of pts.Table 1Baseline characteristicsAge, median (range)71 (52-83)ECOG performance status 0-1 2-319 (48.7%) 20 (51.3%)WBC (x109/L), median (range) WBC >10x109/L, N (%)2.2 (0.9-89.2) 5 (12.8%)BM blasts, median; (range) BM blasts >30%, N (%)32 (20-90) 22(56.4%)Complex karyotype (CK), N (%)18 (46.2)Monosomal karyotype (MK), N (%)18 (46.2%)Both CK and MK, N (%)14/18 (77.8%)Prior MDS, N (%)11 (28.2%)Karyotype, N (%) Complex >3 Complex >5 Chrom 7 abn Chrom 3 abn -7 only Chrom 5 and 7 abn Chrom 5 abn Other6 (15.4%) 11 (28.2%) 4 (10.3%) 4 (10.3%) 8 (20.5%) 2 (5.1%) 2 (5.1%) 2 (5.1%)*Excludes pts with chromosome 5 and 7 abnormality Disclosures Falantes: Celgene: Consultancy. Off Label Use: Use of azacitidine in AML with blast count >30% This paper deals with both on-label and off-label use of azacitidine in AML. Xicoy:Celgene: Honoraria. Ramos:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Introduction: Despite the great medical advances associated with the introduction of thalidomide, bortezomib (BORT), and lenalidomide (LEN) for the treatment of multiple myeloma (MM), it remains an incurable disease. Most patients (pts) show disease progression, consistent with the clinical evolution of MM, and only a low percentage achieve long-term responses and extended progression-free survival (PFS). The heterogeneous nature of MM in both the clinical and biological setting is reflected in the heterogeneity of MM relapses. The International Myeloma Workshop Consensus Panel (Rajkumar, Blood 2011) states that treatment (Tx) shall begin either at clinical relapse with symptoms (clinR), or in the event of asymptomatic relapse with significant paraprotein relapse, biological relapse (BR). The purpose of this Spanish registry is to describe MM relapse patterns comparing the impact of Tx decisions in pts who meet the criteria for biological relapse (BR) according to IMWG criteria with those in whom Tx was delayed until clinical relapse (clinR). Here, the preliminary results of this study are presented. Methods: MM pts in (or previous to) first or second BR who have achieved ≥ PR since their last Tx are eligible for inclusion in this observational prospective registry at the time BR is detected. Evaluations performed at least bi-monthly are mandatory. A total of 41 Spanish sites participated in the registry following approval from their independent ethics committees, with 410 pts expected to be included, without physician’s decision of prescribing Tx affecting the inclusion. The main objective of the registry is to assess the time to progression (TTP) from the start of anti-MM Tx at the onset of asymptomatic BR vs. the start of Tx at the time of clinR. Secondary objectives are to describe demographics of BR; to assess the median time elapsing from BR to clinR; to assess overall response rate (ORR), event-free survival (EFS), PFS, overall survival (OS) at BR and at clinR (if appropriate); to asses safety and quality of life (QoL) using 2 validated questionnaires (European Organisation for Research and Treatment of Cancer [EORTC] QLQ-C30 and QLQ-MY24); to document the tolerability profile of the Tx; and to describe the use of associated resources. Here, we summarize baseline characteristics and preliminary results from 83 pts (out of 126 registered pts) who had basal data in the registry at the time of this report. Results: Overall, 79% of pts presented with a BR and 21% were in a bi-monthly watchful waiting follow up. The mean age of pts was 67 years, 53% were female, 57% were in first relapse, 43% and 27% had an ECOG performance status (PS) of 0 and 1, respectively, while the ECOG PS was unknown in 30% of pts at the time of this report. In total, 30% of pts had ISS stage I, 26% had ISS stage II, and 22% had ISS stage III, while ISS stage data were not available or unknown for 12% and 10% of pts, respectively. MM types were IgG Κ (37% of pts), IgG λ (23%), IgA Κ (13%), IgA λ (9%), and type was unknown in 17% of pts. 28% of IgG/IgA MM types were Bence-Jones. Cytogenetic risk assessments were available in 66% of pts. Among those pts with a BR, 51% received active Tx without waiting for a ClinR. First-line Tx was BORT-based in 70% of pts. Overall, 55% of pts had undergone autologous stem cell transplantation, 15% had received consolidation Tx and 34% had received maintenance Tx. After first-line Tx, 17% of pts achieved a stringent complete response (sCR), 31% achieved a CR, 24% achieved a very good partial response (VGPR), and 10% achieved a PR. The median time to BR was 24.53 months. Most (63%) pts who registered after second relapse received LEN-based Tx. Conclusions: To our knowledge, this is the first prospective study in MM to evaluate BR as well as the effects of Tx based on the decision to start Tx at BR vs. clinR. In this preliminary cohort, the physicians’ decision to start active Tx at BR, before the onset of clinR in 50% of cases, was noteworthy. Further follow-up is needed to identify the differences between these two strategies. Updated clinical results will be presented at the meeting. MM-BR Study, Spanish Myeloma Group-GEM/PETHEMA Bibliography Alegre A, et al. Haematologica. 2002;87:609-14. Brioli A, et al. Blood. 2014;123:3414-9. Fernández de Larrea C, et al. Bone Marrow Transplant. 2014;49:223-7. Lenhoff S, et al. Haematologica. 2006;91:1228-33. Rajkumar SV, et al. Blood. 2011;117:4691-5. Zamarin D, et al. Bone Marrow Transplant. 2013;48:419-24. Disclosures Alegre: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lahuerta:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ruiz:Celgene: Celgene Stock options as part of the employee's compensation plan Other, Employment. Vilanova:Celgene: Contracted by Celgene Other.