ALBERT

Description: Purpose In patients with relapsed acute myeloid leukemia (AML) 〉 60 years of age we analyzed age at relapse, interval from first complete remission (CR1) to relapse, cytogenetic risk at initial diagnosis, prior allogeneic stem cell transplantation (alloSCT) and FLT3/NPM1 mutational status as possible prognostic factors for overall survival (OS). Introduction After achieving CR1 more than 50% of elderly AML patients eventually relapse. Prognostic factors for OS are poorly defined in this patient population. For younger patients with relapsed AML a risk score has been described including age at relapse, interval from CR1 to relapse, cytogenetic risk at initial diagnosis and prior stem cell transplantation (SCT) as prognostic factors. We sought to investigate whether these are also prognostic factors in elderly patients with relapsed AML. In addition, we assessed the prognostic impact of FLT3- and NPM1 mutational status (wild-type (wt) or mutated (mut)) at diagnosis. Patients and methods In the ongoing multicenter OSHO trial #69 for AML patients 〉 60 years we evaluated data of all relapsed patients. Overall survival was calculated from the day of first relapse until the day of death using the Kaplan Meier method. Univariate analysis was performed to test for the influence of age at relapse, interval from CR1 to relapse, cytogenetic risk at initial diagnosis, prior alloSCT and FLT3/NPM1 mutational status. Subsequently, independent prognostic factors were defined in a multivariate analysis with age at relapse, time from CR1 to relapse, cytogenetic risk at initial diagnosis and prior alloSCT as covariates. Results From April 2005 until April 2013 904 patients were registered. 733 of these received intensive induction chemotherapy which resulted in CR1 in 447 (61%) pts. In this patient group 260 relapses were observed after a median interval, calculated from the day of CR1, for living patients of 2.7 years (range 0.1 to 7.5). Median age at relapse was 69 years (range 60 – 85) with 129 (49.6%) pts. being 60 to 68 years old, 102 (39.2%) pts. being 69 to 74 years old and 29 (11.1%) pts. being 75 to 85 years old. Median interval from CR1 to relapse was 0.58 years (0.07 – 6.28). 114 (43.8%) relapses occurred up to 6 months after CR1, 119 (45.8%) between 7 and 18 months after CR1 and 27 (10.4%) later than 18 months after CR1. Only five (1.9%) relapsed pts. showed good risk cytogenetics at diagnosis, whereas it was of intermediate risk in 159 (61.1%) pts., of poor risk in 68 (26.2%) pts. and unknown in 28 (10.8%) pts. Forty-one (15.8%) pts. had received prior alloSCT in CR1. Information on FLT3- and NPM1 mutational status at diagnosis was available in 194 (74.6%) pts. 110 (42.3%) pts. had FLT3/NPM1 wt/wt, 48 (18.5%) pts. had FLT3/NPM1 wt/mut, 23 (8.8%) pts. had FLT3/NPM1 mut/wt and 13 (5.0%) pts. had FLT3/NPM1 mut/mut. OS rate at 2 years of all relapsed pts. was 13 ± 2%. For patients younger than 69 years and for those 69 years of age or older OS rate at 2 years was 17 ± 4% and 9 ± 3%, respectively (p=0.03). The interval between CR1 and first relapse also affected 2 year-OS with 7 ± 3%, 15 ± 4% and 36 ± 12% for pts. with relapse up to 6 months, 7 to 18 months and later than 18 months after CR1, respectively ( 18 months: p=0.009). OS rate at 2 years was also influenced by cytogenetic risk at initial diagnosis with 17 ± 3% for pts. having good or intermediate risk cytogenetics and 3 ± 2% for those with poor risk cytogenetics (p〈 0.0005). Prior alloSCT had a negative influence on OS. Two-year OS rate was 10 ± 5 and 13 ± 3% (p= .015) for patients with prior alloSCT vs. those without prior alloSCT, respectively. FLT3/NPM1 mutational status at diagnosis had no impact on OS. In univariate analysis age at relapse (p

Description: Background Although invasive fungal infection (IFI), especially invasive aspergillosis (IA) is a frequent and lethal complication in severely immunocompromised hematologic patients (pts) such as allogeneic stem cell recipients, diagnosis still remains difficult and conventional diagnostic tools lack sensitivity. Examining tissue or effusion samples might help to identify the causative pathogen of the underlying infection. However, culture-based methods for IFI detection only yield results in a minority of patients. The addition of a specific polymerase chain reaction (PCR) directly in these clinical specimens might therefore improve the detection of IA. Thus the performance of an established Aspergillus-specific nested PCR in fresh tissue and effusion samples of immunocompromised pts was evaluated. Methods By means of an established Aspergillus-specific PCR protocol, we investigated 98 fresh tissue and effusion specimens from 74 immunocompromised, predominantly hematologic patients. The diagnosis of IFI was suspected due to underlying immunosuppression and radiologic abnormalities. Of these patients 23/74 (31%) had proven (n=17) or probable (n=6) IFI using the 2008 EORTC/MSG criteria. The remaining 51 (69%) pts were classified as having either possible (n=27) or having no IFI (n=24) due to lack of host criteria or missing specific radiologic features. IA was identified as the underlying IFI in 18/23 proven/probable patients. Results PCR positivity in tissue and effusion samples was observed in 16/18 proven/probable IA and 6 possible IA patients, while patients with no IA according to EORTC/MSG did not show positive PCR signals. In 5 patients with proven IFI, non-Aspergillus moulds (2 Mucorales spp. and 3 Rhizopus spp.) were found while Aspergillus PCR remained negative. Thus, Aspergillus PCR analysis for diagnosing IA yielded sensitivity/specificity values of 0.89 (95%CI 0.67-0.97) / 1.0 (95%CI 0.86-1.0) respectively, as well as a positive likelihood ratio of 〉200 and a negative likelihood ratio of 0.1 leading to a diagnostic odds ratio of 〉200. Conclusions In our multicenter analysis of samples from predominantly hematologic pts with suspected IFI, we observed a good diagnostic performance of the PCR assay for detection of IA directly in fresh tissue and effusion samples. Thus, PCR testing of these samples represents a sensitive and complementary tool for identification of the underlying infection: A positive tissue/effusion PCR result makes the presence of IA highly likely whereas IA is unlikely in case of a negative result, however this could indicate non-Aspergillus IFI. For the clinician, the additional PCR testing of these specimens in pts with suspected IFI improves the diagnostic armamentarium and might help in identifying the causative pathogen. Disclosures: Lehrnbecher: Gilead: Honoraria; MSD: Honoraria; Pfizer: Honoraria; Astellas: Honoraria.

Description: Purpose: To define prognostic factors for overall survival in adult patients (pts) with relapsed acute myeloid leukemia (AML). Introduction: Prognostic factors for overall survival after AML relapse are poorly defined. Here, we investigate patient and disease related factors in terms of their impact on prognosis after AML relapse in a cohort of 495 adult AML relapse patients treated in two prospective AML trials of the East German Society of Hematology and Oncology (OSHO). Patients and methods: We retrospectively evaluated all consecutive relapsed AML pts treated in two OSHO trials (OSHO #61 (pts 〈 60 years) and OSHO #69 (pts 〉 60 years)). Age, cytogenetic risk at initial diagnosis, FLT3/NPM1 mutational status, type of AML (de novo versus secondary to myelodysplastic syndrome or myeloproliferative neoplasia (MDS/MPN) versus therapy related), time interval from first complete remission (CR1) to relapse and allogeneic stem cell transplantation (alloSCT) as consolidation in CR1 were evaluated in univariate and multivariate analysis. Results: Between March 2002 and July 2014, a total of 862 and 968 patients (pts) were enrolled in the OSHO #61 and #69 trial, respectively. Five hundred and thirty two of 690 (77%) documented pts achieved first complete remission in the #61 and 501 of 813 (62%) pts in the #69 trial. Of these, 495 pts (252 male, 243 female) experienced AML relapse, 207(39%) pts in #61 and 288(57%) pts in #69. Median age at relapse was 63 years (range 18 to 86 years). Initial diagnoses were de novo AML, secondary AML to MDS/MPN and therapy related AML in 332(67%) pts, 129 (25.9%) pts and 30 (6%) pts, respectively. Time from CR1 to relapse was 〈 = 6 months in 198 (40%) pts, 7 to 18 months in 226 (45.7%) pts and 〉 18 months in 71 (14.3%) pts. Initial karyotpe was available for 449 pts (90.7 %). It was favorable, intermediate and poor in 20 (4.5%) pts, 301(67%) pts and 128(28.5%) pts, respectively. Sixty two (13.9%) relapsed pts had a monosomal karyotype at initial diagnosis. NPM1/FLT3 mutational status at initial diagnosis was available in 354 (78.8%) pts, 378 (71%) pts in #61 and 370 (74%) pts in #69. One hundred and three (20.8%) had allogeneic stem cell transplantation as consolidation in CR1 (56 pts) in #61 and (47 pts) in #69. Relapse therapy was documented in 450 (91%) pts. Six pts that had immunosuppression withdrawn as the only therapy and nine pts that had received a tyrosine kinase inhibitor as monotherapy were excluded from further analysis due to small numbers. All other treatments were as follows: intensive chemotherapy (INT) n=225, alloSCT with or without prior INT n=50, donor lymphocyte infusions (DLi) with or without prior chemotherapy n=22, palliative mild cytoreductive chemotherapy (mCT) n=66, azacitidine (Aza) n=52, best supportive care (BSC) n=20. With these, CR was achieved in 78 (36%), 34 (68%), 8 (36%), 6 (9%), 1 (2%), 0 (0%), respectively. Median overall survival probability (OS) for all 495 relapsed patients was 6 months. It was 11.3 months, 5.7 months, 4.5 months and 4.6 months for patients aged 18 to 50 years, 51 to 60 years, 61 to 70 years and 71 to 86 years, respectively (p

Description: Abstract 128 The treatment of elderly patients (pts) with AML remains challenging. High treatment associated mortality using protocols developed for younger patients and high relapse rates for pts reaching CR are frequent causes of failure, while many pts are assessed as ineligible for intensive chemotherapy. Patient registration at diagnosis to check for patient allocation or the use of age-adjusted induction protocols to reduce treatment related mortality may improve the management of these pts. In a prospective German Intergroup Study for patients ≥ 60 years, comparable to a completed study for patients 〈 60 years (Büchner JCO 2012 in press), the outcomes from two study groups using specific induction and consolidation protocols were compared to a common standard arm (CSA). By October 2011, 1041 pts had been randomized to the study-specific regimens or CSA in a 9:1 ratio. Eighty four patients (8%) were excluded due to incorrect diagnosis, secondary neoplasias or other reasons. Treatment in the CSA consisted of araC [100 mg/m2 continuous infusion (c.i.) d1-7] and daunorubicin (60 mg/m2 i.v. on d3- 5). A second induction was given if marrow blasts ≥5% on d15. Pts in CR received two consolidations with araC (1 g/m2 i.v. bid on d1, 3 und 5). The OSHO study group (group A) investigated araC (1 g/m2 i.v. bid d1, 3, 5) plus mitoxantrone (10 mg/m2 d1-3) for induction and araC (0.5 g/m2 i.v. bid d1, 3, 5) plus mitoxantrone (10 mg/m2 d1-2) for consolidation, while the AMLCG (group B) analyzed TAD (ara-C 100 mg/m2 c.i. d1,2; ara-C 100 mg/m2 bid i.v. d3-8)-HAM (ara-C 1g/m2bid i.v. d1-3) vs HAM-HAM ± G-CSF in pts with ≥5% blasts and TAD as consolidation followed by maintenance. Of 957 eligible pts, the median age was 69 (range: 60–87) years (68, 70 and 67 years for A, B and CSA, respectively; p

Description: Introduction: Primary central nervous system lymphoma (PCNSL) relapses in up to 60% after conventional chemotherapy. The prognosis of refractory or recurrent PCNSL is very poor with a median survival of up to 5 months. Whole brain radiotherapy may improve survival up to 10 months, but is associated with significant neurotoxicity. High-dose chemotherapy (HDT) and autologous stem-cell transplantation (ASCT) have demonstrated high efficacy in the treatment of newly-diagnosed primary CNS lymphoma (PCNSL) in younger patients (pts.). To evaluate the efficacy of this approach, we initiated a prospective multicenter phase II study with HDT and ASCT for relapsed PCNSL. This trial is registered at ClinicalTrials.gov (NCT 00647049) Patients and Methods: Thirty eight pts.

Description: Background In multiple myeloma (MM), the introduction of novel compounds into first-line intensive treatment pathways has clearly improved patients’ prognosis. Very recently however, specific molecular cytogenetic abnormalities, lactate dehydrogenase elevation and International Staging System 3 disease were identified to be associated with dismal prognosis despite upfront autologous (auto) stem cell transplant (SCT). Consolidative allogeneic (allo) following initial auto SCT was shown to extend progression-free survival (PFS) as well as overall survival (OS) in some prospective studies on newly diagnosed MM patients (pts). Relatively little is known on the impact of cytogenetic features other than chromosome 13q deletion (del13q) on the outcomes of pts undergoing upfront auto followed by allo (auto/allo) SCT. Patients and methods When the DSMM V treatment program was designed del13q detected by fluorescence in situ hybridisation (FISH) was accepted as one of the distinct risk factors in MM. We therefore used FISH del13q to define the study’s “high-risk” group and aimed to compare tandem high-dose melphalan 200 mg/m² (Mel) with one cycle of Mel followed by reduced-intensity conditioning (RIC) allo SCT. Allocation to either transplant regimen was by availability of an HLA-matched (at least 9/10 matches) related (MRD) or unrelated donor (MUD). Initially, all pts underwent non-novel compound cytoreduction and chemomobilization of peripheral blood stem cells (PBSC). RIC allo SCT was prepared by fludarabine and melphalan (plus ATG in MUD cases). PFS was the primary endpoint. The study was powered to detect an improvement of 2-year PFS from 20% (tandem Mel) to 40.3% (HR, 1.769). Results 199 out of 225 del13q pts with a median age of 53 (range, 30 – 60) yrs who had been enrolled between 10/2001 and 03/2007, were included in the intent-to treat population. Allo SCT was performed in 126/199 pts (63%), 74 of whom (59%) received MUD allografts. At a median follow-up of 49.2 months (mo), 2-year PFS (calculated from day 1 of second SCT) was 59% with auto/allo SCT versus 47% with tandem Mel. Median PFS with auto/allo SCT was 34.5 mo versus 21.8 mo, respectively (p=.005). Two-year non-relapse mortality (NRM) associated with auto/allo SCT was 11.9%. As of yet, there is no difference in OS between the groups, with the median not yet reached for either transplant modality. PFS/OS in auto/allo SCT were independent of donor source (MRD vs MUD). As definitions of cytogenetic risk have evolved over time, we analyzed further FISH abnormalities in pts’ baseline samples: in addition to uniform del13q, 13.6% of pts displayed del17p. Median PFS for del13q/del17p pts after HD Mel was 6 mo versus not reached with auto/allo SCT, respectively (p=.0002). Median OS in del13q/del17p after HD Mel was 23.4 mo versus not reached, respectively (p=.011). In translocation (4;14)/del13q pts (20.7%), median PFS with tandem Mel was 19.3 mo versus 19.1 with auto/allo SCT, respectively (p=.251). Conclusions This prospective trial shows auto/allo SCT to significantly extend PFS when compared to tandem HD Mel in a large cohort of del13q MM pts. It is the first study to demonstrate allo SCT in MM can be safely performed from matched unrelated donors at a reasonable rate of NRM. Utilizing a comprehensive set of FISH cytogenetics, our data for the first time demonstrate allo SCT to specifically benefit patients with high-risk features (del13q/del17p). Incremental gain of PFS when compared to tandem Mel was more than 20 months. Extended OS data on the whole study will be presented. Disclosures No relevant conflicts of interest to declare.

Description: The incidence of acute myeloid leukemia (AML) is age-dependent with the majority of patients (pts) being older than 60 years at diagnosis. Treatment of these pts needs to be well balanced between sufficient efficacy and tolerable toxicity. Here, we report long term follow-up of the OSHO AML97 study. Pts with AML older than 60 years were registered after informed consent and received age-adapted intensive chemotherapy treatment (curative arm; induction therapy with AraC 2 g/m2 iv day 1, 3, 5, 7 and mitoxantrone 10 mg/m2 iv day 1 to 3 to induce complete remission (CR), followed by 2 consolidation courses with AraC 240 mg/m2 iv day 1 to 5 and mitoxantrone 10 mg/m2 iv day 1 to 2), low dose chemotherapy (palliative arm; idarubicin 10 mg po day 1 and either thioguanine 40 mg po day 1-5, or AraC 80 mg sc day 1-5 or etoposide 100mg po day 1-5) or supportive therapy (best supportive care including transfusions). A total of 618 pts were enrolled (curative arm n=471, palliative treatment n=115 and supportive therapy n=32 pts). In the curative arm, CR was obtained in 66.8% of pts. Treatment related mortality (TRM) was 11.2% after induction and 4.5% after consolidation I, respectively. Median overall survival for all pts in the curative arm was 12 months, event free survival (EFS) at 12 years was 0.11±0.02%. In multivariate analysis, cytogenetics at diagnosis was the most important prognostic factor for CR (p=0.001). With a median follow up of 10 years (range 0.1 - 11.8) probability of overall survival (OS) at 5 years was 0.48±0.11; 0.13±0.03; 0.10±0.04 and 0.08±0.03 for pts with favorable, normal, other and unfavorable cytogenetics. Median survival for pts treated with palliative chemotherapy was 54 days. In conclusion treatment of older AML pts with an intense dose of AraC in the induction therapy is feasible and able to induce high rates of CR. Nevertheless, despite the high CR rate in this setting OS and EFS are still low. However, importantly, this does not apply for patients with favorable cytogenetics. This result also confirms the need for cytogenetic analysis to be performed in all pts older than 60 years potentially eligible for intensive induction therapy. The treatment results with palliative chemotherapy are disappointing. These results reported here need to be set in relation with the new therapeutic modalities for AML including epigenetic and molecular therapies. Disclosures Al-Ali: Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Wolf:Bayer: Honoraria; Geo Pharma: Honoraria.

Description: Treatment of elderly patients with AML remains challenging. While increasing doses of induction and consolidation chemotherapy have failed to improve outcome, efforts to decrease relapse rates using the graft-versus-leukemia effect have shown promising results in phase II studies. In the present analysis of the prospective OSHO 2004 study we evaluated the effect of post-induction hematopoietic cell transplantation (HCT) in comparison to conventional consolidation chemotherapy (CT) on outcome in elderly patients with AML. The OSHO 2004 study is part of the German intergroup study. Upon achieving complete remission (CR) after induction, patients were assigned to CT or HCT depending on the availability of a matched related or unrelated donor. Unrelated, single antigen mismatched donors were accepted in high risk situations. By April 2014 from 817 eligible patients, 505 entered CR (62%) after one or two induction therapies. From the 452 patients who received consolidation in CR 1, 31 patients (7%) relapsed and 10 (2%) died of complications during consolidation. No further therapy for medical reasons was given to 73 patients, 206 patients received second consolidation with cytarabine (0.5 g/m2 i.v. bid d1, 3, 5) plus mitoxantrone (10 mg/m² d1-2) and 132 patients underwent HCT. Most frequent conditioning regimens for HCT were low dose TBI (83%) and treosulfan/fludarabine (12%). Most of the patients received HCT from unrelated (80%) donors and the majority received grafts from HLA-identical (78%) donors. Our analysis was restricted to the 315 patients

Description: The optimal consolidation chemotherapy in AML patients 〉60 years has yet to be defined in detail. Although age-adjusted induction chemotherapy results in CR rates comparable to those in younger patients, relapse remains the major hurdle to successful treatment. While the role of stem cell transplantation (HSCT) in elderly patients is currently being evaluated in randomized studies, we focus here on the intensity of consolidation chemotherapy. Patients data from the elderly AML trials OSHO 1997 (n=410) and OSHO 2004 (n=733) were pooled and analyzed. These protocols have identical inclusion/exclusion criteria and induction chemotherapy, but differ in the intensity of consolidation therapy. In the OSHO 1997 trial, Ara-C 120 mg/m2 bid was given from day 1-5 and mitoxantrone 10 mg/m2 from day 1-2 as consolidation. In the OSHO 2004 an intensified consolidation using Ara-C 500 mg/m2 bid on day 1/3/5 was applied together with mitoxantrone as used in the OSHO 1997 study. Of the 1143 patients, 689 entered CR (60% in the OSHO 1997 and 61% in the OSHO 2004) and 536 (OSHO 1997, n=242, OSHO 2004, n=294) did not receive HSCT as consolidation. The analysis concentrated on the dose of AraC used in the consolidation for this elderly population and on the cycles of consolidation applied. Patient characteristics were compared using chi-square test for categorical data and Wilcoxon rank sum test for continuous data. OS was analyzed using the Kaplan-Meier method, and univariate comparisons were made by means of the log-rank test. Cox regression was used to find any association between consolidation chemotherapy considered as a time-dependent covariate on Overall Survival (OS) or Relapse Incidence (RI). RI and Non Relapse Mortality (NRM) were calculated using the competing risk method, and the Gray test was applied to compare differences. Multivariate modeling was performed by Cox regression analyses with a forward selection method. Median ages in the AML studies were 66 (60-81) years and 69 (60-85) years for the OSHO 1997 and OSHO 2004, respectively. Patients characteristics were balanced except for age and Karnofsky score (p〈 .0005) and a trend towards more intermediate and high risk karyotypes, more female and less WBC in the OSHO 2004 compared to the OSHO 1997 study (p=0.06). OS at 15 years was 14±2% in all patients with no difference between the two consolidations, but strong dependence on cytogenetic risk factors. In multivariate analyses risk factors for survival were high/intermediate risk karyotypes, male gender, non de-novo AML and less than two consolidations. Patients with two consolidations had better OS than patients with one or no consolidations in the pooled group and in each of the two protocols with no difference between OSHO 1997 and OSHO 2004. Relapse incidence amounted to 79±2% and NRM 10±04% at 15 years with no difference between the two protocols. Relapse incidence was dependent upon cytogenetic risk and the number of consolidations applied in a multivariate model. There were no risk factors predicting TRM in multivariate analysis. Our analysis of patient characteristics according to the number of consolidations showed the distribution of consolidation therapies to be 15.2%, 28.0%, 56.6% and 14.2%, 32.3% and 53.4% for 0, 1 and 2 consolidations in the OSHO 1997 and OSHO 2004 respectively (n.s.). Higher age, higher risk cytogenetics, non-de novo AML type, less CR after one induction cycle and lower WBC count at diagnosis were characteristic of patients receiving none or one as compared to two consolidation therapies. The multivariate analysis revealed cytogenetics and gender as independent risk factors, but not the application of one as opposed to two consolidation treatments. The increase of AraC dose in the OSHO 2004 was unable to either increase survival or improve relapse incidence in the cohort of elderly patients. TRM was not different between the OSHO 1997 and 2004 studies. However, the application of one or two consolidation cycles had a significant impact on survival that was not due to decreased relapse incidence after normalization for risk factors. Interestingly, just above 50% of patients received 2 consolidations as proposed in the protocol with no statistically significant difference between OSHO 1997 and OSHO 2004. Patients receiving fewer consolidation therapy cycles are older, have more non-de novo AML and lower WBC count. Disclosures: Hochhaus: Novartis: Consultancy, Honoraria, Research Funding, Travel Other; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Ariad: Consultancy, Honoraria.

Description: Abstract 302 Background: Primary central nervous system lymphoma (PCNSL) is an aggressive non-Hodgkin′s lymphoma with poor prognosis. Addition of methotrexate (MTX) to whole brain radiotherapy (WBRT) has improved the prognosis of patients (pts) with PCNSL, but a significant proportion are still not cured. Preliminary reports suggested that dose-intensified chemotherapy (HDT) and autologous stem-cell transplantation (ASCT) are highly effective in the treatment of newly-diagnosed PCNSL in younger pts. To strengthen the evidence of this approach, we initiated a prospective multicenter phase II study with early HDT and ASCT to investigate efficacy, safety and survival. This trial is registered at ClinicalTrials.gov (NCT 00647049). Methods: Immunocompetent pts