Courses Of High-dose Cytarabine Research Articles

Updated Results on a Multicenter Phase II Study of a Dose Intensified Pediatric Regimen in Adults with Acute Lymphoblastic Leukemia: The 06-254 DFCI ALL Consortium Trial

Background: Adolescent and young adult (AYA) patients (pts) with acute lymphoblastic leukemia (ALL) have good outcomes when treated with pediatric regimens (DeAngelo Leukemia 2014; Stock Blood 2019). Here we update our multi-center Phase II study (06-254) applying the DFCI pediatric regimen to young adults, as well as our post-trial experience. The 06-254 protocol is based on the very high-risk arm of the DFCI Pediatric Protocol 05-001. This report focuses on Philadelphia negative (Ph-) pts. Methods: Pts between 18-50 years (yrs) with de novo ALL were eligible. The primary objective was to determine the feasibility of a single dose of pegylated-asparaginase (PEG-ASP) during induction followed by a 30 week PEG-ASP consolidation. Induction chemotherapy included doxorubicin, prednisone, vincristine, PEG-ASP, and intra-thecal chemotherapy (IT). Consolidation I consisted of high-dose methotrexate (A), followed by a BFM-like intensification (B), and a course of high-dose cytarabine, etoposide and dexamethasone (C). Central nervous system prophylaxis included intrathecal therapy and cranial radiation. Intensification therapy consisted of eight 3-week courses of doxorubicin, vincristine, dexamethasone, 6-MP and 30 weeks of PEG-ASP. Dosing of PEG-ASP was initially 2500 IU/m2 every 2 weeks but due to toxicity was reduced to 2000 IU/m2 every 3 weeks and given concomitantly with consolidation. Body surface area was capped at 2.3m2 for PEG-ASP dosing. Continuation therapy consisted of 3 week courses of vincristine, dexamethasone, methotrexate, and 6-MP until 2 yrs from complete remission (CR). Additional consecutive Ph- pts treated “as per” 06-254 (2009-2021) were identified; these pts received treatment following 06-254 including PEG-ASP 2000 IU/m2 every 3 weeks in consolidation. Median follow-up was calculated with the reverse Kaplan Meier indicator. The chi square test was used to compare categorical characteristics. Overall survival (OS) and event free survival (EFS) among groups were compared with the log rank test. Results: A total of 152 Ph- pts were treated from 2007 to 2021 (89 pts on protocol and 63 “as per”). Median follow up was 3.5 yrs for pts treated on protocol and 3.8 yrs for pts treated “as per.” Characteristics at diagnosis: Median age 27.9 yrs (82, 54% < 30 yrs); 39.5% female; 31.6% T-lineage; 53.3% overweight/obese BMI per CDC criteria. Older pts (30-50 yrs) were more likely to be overweight/obese than younger (18-29y) pts (71.4% vs. 37.8%, p < 0.001) and were more frequently allografted in CR1 (21.4% vs. 9.8%, p = 0.045). CR was achieved by 142 (92.1%) pts. Among 81 (53.3%) pts with known end-induction measurable residual disease (MRD) status, 68 (84.0%) were MRD negative. In total, 88 (57.9%) pts completed all protocol treatment, 9 (5.9%) had induction failure, 3 (2.0%) died during treatment, 13 (8.6%) relapsed during treatment, 16 (10.5%) exited the protocol for other reasons, and 22 (15.1%) were consolidated with bone marrow transplant (BMT) in CR1. Among the 95 patients who remained on protocol for at least 1 year, 73 (76.8%) had ≥ 26 wks of asparagine depletion. Regarding toxicity: 21 pts (13.8%) had clinical pancreatitis, 98 (64.5%) experienced grade 3-4 laboratory hepatotoxicity, and 20 (13.1%) had allergic reactions to ASP. OS of the entire cohort was 84.4% (95% CI 77.4-89.3) at 3 yrs and 75.8% (95% CI 67.0-82.6) at 5 yrs. Pts aged 18-29 yrs had superior 5-yr OS to those aged 30-50 yrs (82.4% [95% CI 69.4-90.2] vs. 67.1% [95% CI 53.3-77.7], p = 0.004), and pts with a BMI < 25 at diagnosis had superior 5-yr OS than those with BMI ≥ 25 (87.1% [95% CI 73.5-94.0] vs. 66.5% [95% CI 53.9-76.5], p = 0.002). Patients with negative MRD at end of induction had a 5-yr OS of 80.7% (95% CI 66.7-89.3) and those with positive MRD 59.1% (95% CI 21.8-83.4) (p = 0.16). Pts treated “as per” had superior 5-yr OS to those treated on protocol (86.0% [95% CI 71.3-93.5] vs. 68.7% [95% CI 56.5-78.1], p = 0.012). EFS was 77.1% (95% CI 69.0-83.3) at 3 yrs and 70.6% (95% CI 61.4-78.0) at 5 yrs. Pts aged 18-29 yrs had superior 5-yr EFS compared to those aged 30-50 yrs (76.3% [95% CI 63.0-85.3] vs. 62.8% [95% CI 48.8-74.0], p = 0.033). Treatment on trial (compared to “as per”), BMI, and MRD status were not statistically associated with EFS. Conclusions: The administration of a pediatric regimen with dose intensified PEG-ASP to population between 18-50 is feasible and results in a high remission rate with 5-yr OS 75.8%.

Prognostic Value of Interleukin-17 A Gene Polymorphism and Serum IL-17 Levels in Adult Acute Myeloid Leukaemia Patients

Background: T helper 17 (Th17) cells play a role in the pathogenesis and prognosis of acute myeloid leukemia (AML). Th17 cells produce interleukin (IL)-17A and IL-17F, that share strong surface expression and homology of the IL-23 receptor (IL-23R). Objective: To evaluate the expression of IL-17A gene polymorphism and IL-17 serum level in adult AML patients and to clarify its prognostic significance. Patients and methods: In this prospective study, 48 patients with de novo AML and 48 healthy matched controls were enrolled. Cases were diagnosed at clinical pathology and managed in Medical Oncology Departments. We evaluated both serum IL-17 levels, measured by ELISA, and IL-17A (rs2275913) gene polymorphism was assessed using realtime polymerase chain reaction (PCR) in all patients and control. All patients received “3+7” as induction, responders received 3-4 courses of high dose cytarabine as consolidation, while non-responders received salvage therapy. Results: Serum levels of IL-17 were higher in AML patients (median 27 pg/ml) vs 17 pg/ml in the control group (P < 0.001). Also, serum IL 17 level was higher in non-responders with median 37.5 (pg/ml) vs 23 (pg/ml) in responders (P < 0.001). while IL-17A mutant genotypes and alleles showed no significant relation between expression of IL-17 A gene polymorphism and response to treatment or outcome of studied AML cases. Conclusion: Serum IL-17 levels can be considered a useful diagnostic and prognostic factor in AML patients, unlike IL-17 A gene polymorphisms.

Prognostic Value of Interleukin-17 A Gene Polymorphism and Serum IL-17 Levels in Adult Acute Myeloid Leukaemia Patients

Background: T helper 17 (Th17) cells play a role in the pathogenesis and prognosis of acute myeloid leukemia (AML). Th17 cells produce interleukin (IL)-17A and IL-17F, that share strong surface expression and homology of the IL-23 receptor (IL-23R). Objective: To evaluate the expression of IL-17A gene polymorphism and IL-17 serum level in adult AML patients and to clarify its prognostic significance. Patients and methods: In this prospective study, 48 patients with de novo AML and 48 healthy matched controls were enrolled. Cases were diagnosed at clinical pathology and managed in Medical Oncology Departments. We evaluated both serum IL-17 levels, measured by ELISA, and IL-17A (rs2275913) gene polymorphism was assessed using realtime polymerase chain reaction (PCR) in all patients and control. All patients received “3+7” as induction, responders received 3-4 courses of high dose cytarabine as consolidation, while non-responders received salvage therapy. Results: Serum levels of IL-17 were higher in AML patients (median 27 pg/ml) vs 17 pg/ml in the control group (P < 0.001). Also, serum IL 17 level was higher in non-responders with median 37.5 (pg/ml) vs 23 (pg/ml) in responders (P < 0.001). while IL-17A mutant genotypes and alleles showed no significant relation between expression of IL-17 A gene polymorphism and response to treatment or outcome of studied AML cases. Conclusion: Serum IL-17 levels can be considered a useful diagnostic and prognostic factor in AML patients, unlike IL-17 A gene polymorphisms.

Postremission therapy with repeated courses of high-dose cytarabine, idarubicin, and limited autologous stem cell support achieves a very good long-term outcome in European leukemia net favorable and intermediate-risk acute myeloid leukemia.

Consolidation treatment in acute myeloid leukemia (AML) patients achieving complete remission (CR) is warranted. High-dose cytarabine (HDAC) is considered first choice in favorable risk and an option in intermediate-risk AML. However, its optimal dose and schedule, as well as the benefit of additional chemotherapy agents remain controversial. Herein, we report on the long-term outcome of consecutive unselected AML patients treated with repeated courses of HDAC, with the addition of idarubicin, followed by autologous peripheral blood stem cell (PBSC) support, in order to limit toxicity, according to Northern Italy Leukemia Group (NILG) AML-01/00 study (EUDRACT number 00400673). Among 338 patients consecutively diagnosed from 2001 to 2017 at our center, 148 with high-risk AML (adverse cytogenetic, isolated FLT3-internal tandem duplication mutation, refractory to first induction) were addressed to allogeneic stem cell transplant. All other cases, 186 patients (55%), median age 53 (range 19-75), were considered standard-risk and received the NILG AML-01/00 program. After achieving CR, patients were mobilized with cytarabine 8 g/sqm to collect autologous CD34+-PBSC and received three consolidation cycles with HDAC (20 g/sqm) plus idarubicin (20 mg/sqm) per cycle, followed by reinfusion of limited doses of CD34+ PBSC (1-2x106/kg). The program was completed by 160 (86%) patients. Toxicity was acceptable. Neutrophils recovered a median of 10 days. Treatment-related mortality was 3/160 (1.8%). After a median follow-up of 66.4 months, overall survival (OS) and relapse-free survival (RFS) at 5-years were 61.4% and 52.4%, respectively. Twenty-eight selected patients aged >65 had similar outcomes. According to European leukemia net-2010 classification, the OS and RFS at 5-years were 76.4% and 65% in favorable risk, without differences between molecular subgroups, 52.3% and 47.2% in Intermediate-I, 45.2% and 36.5% in Intermediate-II risk patients, respectively. In conclusion, consolidation including repeated courses of high dose cytarabine and idarubicin, with limited PBSC support, proved feasible and very effective in nonhigh risk patients. The incorporation of novel agents in its backbone may be tested to further improve patient's prognosis.

Randomized Trial of Intermediate-dose Cytarabine in Induction and Consolidation Therapy in Adults with Acute Myeloid Leukemia.

Cytarabine, 100-200 mg/mE+2/day, is commonly used in induction therapy of acute myelogenous leukemia (AML). Whether a higher dose of cytarabine would be more effective is unknown. Also, there is controversy whether high-dose cytarabine is better than an intermediate-dose combined with other drugs for post-remission therapy. In this open-label, randomized controlled, parallel group study, roles of intermediate-dose cytarabine were investigated. Subjects with AML age 15-55 years were randomized to receive daunorubicin, omacetaxine mepesuccinate, and conventional- or intermediate-dose cytarabine. Subjects achieving complete remission were randomized to receive 3 courses of high-dose cytarabine or 2 courses of intermediate-dose cytarabine with daunorubicin in the 1st and mitoxantrone in the 2nd course. The primary endpoint was disease-free survival (DFS). 591 subjects were randomized to intermediate- (N = 295) or conventional-dose (N = 296) cytarabine group. Three-year DFSs were 67% [95% confidence interval (CI), 61-73] in the intermediate-dose cohort compared with 54% (95% CI, 48-61) in the conventional-dose cohort [Hazard Ratio (HR), 0.67; 95%CI, 0.51-0.89; P = 0.005). Three-year survivals were 68% (95%CI, 63-74) and 59% (95%CI, 53-65; HR, 0.720; 95%CI, 0.56-0.94; P = 0.014). Two courses of intermediate-dose cytarabine with daunorubicin or mitoxantrone resulted in similar DFS and survival as three courses of high-dose cytarabine when used for post-remission therapy. Induction therapy with intermediate-dose cytarabine with daunorubicin and omacetaxine mepesuccinate increases DFS and survival in persons with AML ages 15-55 years compared with conventional-dose cytarabine.See related commentary by Watts and Bradley, p. 3073.

Patients with high-risk DLBCL benefit from dose-dense immunochemotherapy combined with early systemic CNS prophylaxis

AbstractSurvival of patients with high-risk diffuse large B-cell lymphoma (DLBCL) is suboptimal, and the risk of central nervous system (CNS) progression is relatively high. We conducted a phase 2 trial in 139 patients aged 18 to 64 years who had primary DLBCL with an age-adjusted International Prognostic Index (aaIPI) score of 2 to 3 or site-specific risk factors for CNS recurrence. The goal was to assess whether a dose-dense immunochemotherapy with early systemic CNS prophylaxis improves the outcome and reduces the incidence of CNS events. Treatment consisted of 2 courses of high-dose methotrexate in combination with biweekly rituximab (R), cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP-14), followed by 4 courses of R-CHOP-14 with etoposide (R-CHOEP) and 1 course of high-dose cytarabine with R. In addition, liposomal cytarabine was administered intrathecally at courses 1, 3, and 5. Coprimary endpoints were failure-free survival and CNS progression rates. Thirty-six (26%) patients experienced treatment failure. Progression occurred in 23 (16%) patients, including three (2.2%) CNS events. At 5 years of median follow-up, failure-free survival, overall survival, and CNS progression rates were 74%, 83%, and 2.3%, respectively. Treatment reduced the risk of progression compared with our previous trial, in which systemic CNS prophylaxis was given after 6 courses of biweekly R-CHOEP (hazard ratio, 0.49; 95% CI, 0.31-0.77; P = .002) and overcame the adverse impact of an aaIPI score of 3 on survival. In addition, outcome of the patients with BCL2/MYC double-hit lymphomas was comparable to the patients without the rearrangements. The results are encouraging, with a low toxic death rate, low number of CNS events, and favorable survival rates. This trial was registered at www.clinicaltrials.gov as #NCT01325194.

High Risk of Relapse with Intermediate Dose Cytarabine for Consolidation in Young Favorable Risk AML Patients Following Induction with 7+3

Introduction CALGB study in 1994 reported improved leukemia free survival (LFS) with sequential courses of high dose cytarabine (HIDAC- 3 gm/m2, q12h on days 1, 3 and 5) compared to lower doses of 100 mg/m2 and 400 mg/m2 per day. Following this study, HIDAC has been commonly used for chemotherapy consolidation in AML patients 60 years or younger. More recently, several groups investigated the role of intermediate dose cytarabine (IDAC-1.5 gm/m2 q12h D 1, 3 and 5 or D 1-3) in this population and reported equivalent outcomes for IDAC compared to HIDAC (Table 1). ELN guidelines published in January 2017 recommend IDAC for consolidation therapy in young (&amp;lt;60 years) favorable risk AML patients. Following these studies and ELN publication, consolidation protocols for AML patients 60 years or younger were changed from HIDAC to IDAC at Singapore General Hospital (SGH) in 2011 and at University of Minnesota Medical Center (UMMC) in February 2017. NCCN continues to recommend HIDAC as category 1 recommendation for consolidation of patients in this setting. We performed a combined analysis of outcomes in young favorable risk AML patients to assess impact of this change in practice on outcomes at our institutions as a quality initiative. Methods Patients 60 years or younger with ELN favorable risk AML between 2004 and 2015 at SGH and between September 2015 and March 2018 at UMMC, who underwent induction therapy with 7+3 regimen (idarubicin 12 mg/m2 D1-3 or daunorubicin 60 - 90 mg/m2 and cytarabine 100 mg/m2 continuous infusion from D1-7) and consolidation with cytarabine monotherapy were identified. These dates were chosen to allow reasonably equal time distribution before and after change in our practice. We extracted relevant outcomes data using chart review. We used Chi-square testing and applied Kaplan-Meier survival analysis to detect differences in relapse and survival outcomes. Results Of 67 ELN favorable risk patients 60 years or younger, 42 received HIDAC and 25 received IDAC. Median age was 39 years (range 16-59). 64 patients received 1 induction cycle and 3 patients received 2 induction cycles to achieve complete remission. Median LFS and overall survival (OS) with HIDAC vs IDAC were not-reached (NR, median time for follow up = 6.9 years) vs 1.35 years (p=0.004) and NR vs 2.27 years (p=0.001) respectively (Figure 1). Cumulative incidence of relapse at 2 years was 23.8% for HIDAC and 60% for IDAC groups (p=0.003). 3-year LFS and OS for HIDAC vs IDAC groups were 71% vs 36% (p=0.06) and 90% vs 48% (p=0.002). Discussion Historical data suggests chemotherapy consolidation with 3-4 cycles of HIDAC achieves long-term LFS of 60 - 70 % in young favorable risk AML patients. While the outcomes in HIDAC group in this study are comparable to historical data with good outcomes, a significantly larger proportion of patients in the IDAC group had early relapse (60%) and death. A major difference between the patients in this study and the other studies which showed similar outcomes with HIDAC and IDAC is the mode of induction. Data from large randomized studies in AML (Table 1) that suggest similar efficacy of IDAC compared to HIDAC used higher intensity induction regimens (frequently double induction therapy) compared to 7+3 and/or used other agents in combination with Ara-C for consolidation. These data are not broadly applicable in patients who receive a single cycle of 7+3 for induction, when selecting dose of Ara-C as monotherapy for consolidation. Furthermore, studies that used 7+3 for induction therapy showed benefit for HIDAC compared with multi-agent chemotherapy that included IDAC (Table 1). Conclusion Using single agent IDAC for post remission therapy is associated with higher rates of relapse and poor overall survival compared to HIDAC among young, ELN favorable risk AML patients who achieve complete remission following 7+3. The large randomized studies that suggested equivalency of IDAC to HIDAC for post remission therapy in AML patients, either used more than one cycle of intensive induction regimen and/or used cytarabine in combination with an anthracycline for consolidation. Hence, ELN guidelines should be cautiously interpreted given the above limitations in generalizability. Our study suggests that HIDAC, rather than IDAC, is the preferred chemotherapy consolidation regimen in young, favorable risk AML patients following standard 7+3 induction. Foot note: BK &amp; NAAH contributed equally. FH &amp; ZL contributed equally. Disclosures Kolla: Amgen: Equity Ownership. Weisdorf:Pharmacyclics: Consultancy; Incyte: Research Funding; Fate Therapeutics: Consultancy.

The Clinical Association and Prognostic Impact of IL1RAP Expression in Patients with De Novo Acute Myeloid Leukemia

Introduction One of the contributing factors to the relapse of acute myeloid leukemia (AML) is the presence of leukemia stem cells (LSCs). Interleukin 1 receptor accessory protein (IL1RAP) was reported to be one of the LSC markers. Most studies regarding clinical implications of IL1RAP expression in AML focused on small and selected patient groups. Besides, its correlation with other molecular alterations has not been reported yet in literature. In this study, we aimed to elucidate the relationship between bone marrow IL1RAP expression level and clinical and biological features in patients with de novo non-M3 AML. Furthermore, we would like to explore its prognostic impact and potential underlying mechanism. Method We enrolled 275 newly diagnosed de novo non-M3 AML patients. Among them, 187 (68%) patients received standard induction chemotherapy and 2-4 courses of high-dose cytarabine based post-remission therapy. Analyses of 54 gene mutations were performed by next generation sequencing. The global gene expressions were profiled with the Affymetrix GeneChip Human Transcriptome Array 2.0. Result We used the median as the cut-off value to define the higher and lower IL1RAP expression groups. The patients with higher IL1RAP expression had significantly higher white blood cell counts at diagnosis, higher peripheral blast counts, and higher lactate dehydrogenase levels. Higher IL1RAP expression was closely associated with t(8;21), favorable-risk cytogenetics based on the refined MRC classification, but inversely with unfavorable-risk cytogenetics. Compared with low-expression patients, the high-expression patients had significantly more FLT3/ITD and KIT mutations, but less mutations in U2AF1, TP53, or CEBPA. Among the 187 patients receiving standard intensive chemotherapy, those with lower IL1RAP expression had significantly longer overall survival (OS) than those with higher expression (P=0.047) after a median follow-up time of 91.1 months, but disease-free survival (DFS) was not significantly different between the two groups (P=0.311). Among the 77 patients who relapsed after first complete remission (CR), the second CR rate was similar between the two groups (P=0.649), but the second DFS was significantly longer in the low-expression patients than the high-expression patients (P=0.028) which was also reflected in a significantly longer survival after first relapse in the former group than the latter group (P=0.014). The prognostic impact of IL1RAP expression on OS could be externally validated in the TCGA cohort (P=0.038). Its prognostic implication remained significant in the subgroup of our cohort with intermediate-risk cytogenetics (P=0.006) and those with normal karyotype (P=0.025). In multivariate analysis incorporating age, transplantation status, 2017 ELN risk-stratification and IL1RAP expression as covariates, the higher IL1RAP expression was an independent poor prognostic factor for OS (HR=1.555, P=0.025). The Gene Set Enrichment Analysis revealed significant up-regulation of LSC related genes in the higher IL1RAP expressed patients (Figure 1 and 2). We further profiled genome-wide RNA expression with 70,523 probes to survey the potential molecular mechanisms underlying the IL1RAP expression signature. Totally, 313 differentially expressed genes were identified (&gt;1.5-fold change and Student t-test P&lt;0.0001, Figure 3). We used Ingenuity Pathway Analysis (Qiagen) to analyze the possible underlying mechanism and found that the top upstream regulators were transcription factors, such as GATA1/GATA2 (P=1.39*10-11 and 1.61*10-10, respectively), and ABCB6 (P=3.84*10-8), one of the ATP-Binding Cassette transporter superfamily. The hub genes in the regulation network included ELAVL1 and NFκB, in addition to GATA1 and GATA2. Conclusion Higher IL1RAP expression is associated with distinct clinical and genetic alterations. It is an independent prognostic factor for OS irrespective of the risk category based on the ELN classification. Transcription factors, such as GATA1 and GATA2, ABCB6, ELAVL1 and NFκB might be involved in the underlying mechanism. Further prospective large cohort is warrant to validate our findings. Disclosures Tien: Novartis: Other: Travel Grant. Hou:Celgene: Research Funding; Abbvie, Astellas, BMS, Celgene, Chugai, Daiichi Sankyo, IQVIA, Johnson &amp; Johnson, Kirin, Merck Sharp &amp; Dohme, Novartis, Pfizer, PharmaEssential, Roche, Takeda: Honoraria. Tien:Daiichi Sankyo: Honoraria; Roche: Honoraria; Abbvie: Honoraria; Alexion: Honoraria; Celgene: Honoraria; Johnson &amp;Johnson: Honoraria; Novartis: Honoraria; Celgene: Research Funding; BMS: Honoraria; Pfizer: Honoraria; Roche: Research Funding.

Autologous Stem Cell Transplantation in Mantle Cell Lymphoma - Selection Mechanisms and Survival By Age Group

Purpose The second Nordic lymphoma group protocol for mantle cell lymphoma (NLG-MCL 2) includes three courses of maxi-CHOP alternating with three courses of high-dose cytarabine, and followed by consolidation with high-dose therapy and autologous stem-cell transplantation (ASCT). This has been the standard of care for younger MCL patients in Sweden since year 2000. Since 2008, rituximab has been added. On a population level, it is not well described how many patients' complete treatment and undergo consolidation with ASCT and which reasons that govern this decision. Our aim was to describe selection mechanisms to ASCT, and further describe outcome for ASCT transplanted versus non-transplanted patients in different age groups. Methods We investigated 670 MCL patients aged 22-70 years and diagnosed 2000-2014 (among whom 416 were 22-65 years) using data from the Swedish population-based lymphoma register. Clinical, demographical, and comorbidity data was linked to the patient cohort through nationwide health care registers. Severity of comorbidity was defined according to the Charlson comorbidity index (CCI; 0,1 and 2+). Selection mechanisms were analysed by estimating odds ratios (ORs) with 95% confidence intervals (CIs) for being transplanted using univariable and multivariable logistic regression models. Patients that did not reach complete remission during induction chemotherapy and therefore not transplanted were identified and excluded when analyzing other selection mechanisms. Demographic determinants were specifically considered, including marital status (married, not married, divorced and widower) and educational level (up to 9 years, 10-12, and more than 12 years of schooling). Survival functions, by ASCT and age at diagnosis (&lt;50, 50-59, 60-65, 66-70) were estimated using the Kaplan-Meier method. Moreover, hazard ratios (HRs) with 95% confidence intervals (CI) comparing all-cause mortality by ASCT and age were estimated using Cox regression (adjusted for calendar year of diagnosis, age at diagnosis, sex and country of birth). Results Among patients aged up to 70 years, 355 (54%) were not selected for ASCT whereas 299 (46%) were given ASCT in first remission. Among patients up to 65 years, 158/416 (38%) were not selected for ASCT. Sixteen patients did not reach complete remission after induction chemotherapy and were thus not transplanted and not further included. Being a widow, having lower educational level, older age at diagnosis, higher comorbidity burden, diagnosed during an earlier calendar period, stage I disease and a lower mantle cell lymphoma prognostic index (MIPI) (Table 1) was in univariable analyses, associated with a reduced chance of receiving ASCT, while this was not seen for different sex, county, hospital and country of birth. In adjusted analyses of sociodemographic characteristics, being unmarried (compared to married) significantly decreased the odds of receiving ASCT (adj. OR=0.56, 95% CI: 0.34-0.94). Also, patients with any comorbidity, CCI 1 (adj. OR=0.51, 95% CI: 0.29-0.90) and severe comorbidity, CCI 2+ (adj. OR=0.41, 95% CI: 0.25-0.68) had lower chance of receiving ASCT. For patients younger than 60 years at diagnosis MIPI and stage were generally lower in the non-transplanted group and here selection to ASCT was not associated with inferior OS (Figure 1). For patients aged 60-65 who were not selected to transplantation, overall survival was inferior compared to patients who underwent ASCT (p-value from log rank test=0.01, Figure 1). However, this association was attenuated when adjusting for potential confounders in a Cox regression (HR: 0.66, 95% CI 0.42-1.03). Conclusion A surprisingly high proportion of patients (more than 50%) were not treated with ASCT as part of primary treatment. Reasons for not being selected to ASCT included both medical and socioeconomic factors. Patients who were unmarried were less often transplanted. Among younger patients (&lt;60 years), omission of ASCT seemed over-represented for "indolent" cases and no prognostic difference was seen, while for patients 60-65 years of age, omission of transplantation was associated with inferior OS. Improvements in both supportive functions, awareness for clinicians about their decisions and development of alternative, more tolerable, treatment concepts are needed for a large fraction of MCL patients and would likely improve survival. Disclosures Glimelius: Janssen Pharmaceuticals: Honoraria. Smedby:Janssen Pharmaceuticals: Other: This project was partly funded through a private-public collaboration between KI and Janssen pharmaceuticals.; Takeda: Research Funding; Celgene: Honoraria. Albertsson-Lindblad:Janssen Pharmaceuticals: Other: This study was partly funded via the public-private real world evidence collaboration between Karolinska Institutet and Janssen Pharmaceuticals (contract: 5-63/2015). Eloranta:Janssen Pharmaceuticals.: Other: project coordinator for a public-private real world evidence; Karolinska Institutet: Other: coordinator for a public-private real world evidence. Jerkeman:Janssen: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Acerta: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding.

Randomized phase-II trial evaluating induction therapy with idarubicin and etoposide plus sequential or concurrent azacitidine and maintenance therapy with azacitidine

The aim of this randomized phase-II study was to evaluate the effect of substituting cytarabine by azacitidine in intensive induction therapy of patients with acute myeloid leukemia (AML). Patients were randomized to four induction schedules for two cycles: STANDARD (idarubicin, cytarabine, etoposide); and azacitidine given prior (PRIOR), concurrently (CONCURRENT), or after (AFTER) therapy with idarubicin and etoposide. Consolidation therapy consisted of allogeneic hematopoietic-cell transplantation or three courses of high-dose cytarabine followed by 2-year maintenance therapy with azacitidine in the azacitidine-arms. AML with CBFB-MYH11, RUNX1-RUNX1T1, mutated NPM1, and FLT3-ITD were excluded and accrued to genotype-specific trials. The primary end point was response to induction therapy. The statistical design was based on an optimal two-stage design applied for each arm separately. During the first stage, 104 patients (median age 62.6, range 18–82 years) were randomized; the study arms PRIOR and CONCURRENT were terminated early due to inefficacy. After randomization of 268 patients, all azacitidine-containing arms showed inferior response rates compared to STANDARD. Event-free and overall survival were significantly inferior in the azacitidine-containing arms compared to the standard arm (p < 0.001 and p = 0.03, respectively). The data from this trial do not support the substitution of cytarabine by azacitidine in intensive induction therapy.

Pilot Prospective Phase II Study of Nilotinib Combined with Chemotherapy for Myeloid Blastic Phase of Chronic Myeloid Leukemia or Acute Myeloid Leukemia with BCR/ABL1

Various chemotherapy regimens attempted however have been evaluated these treatment e not effective in chronic myeloid leukemia myeloid blastic phase (CML-MBP). Imatinib treatment in this subset of patients were also not very promising due to low response rates, short response duration, and transformation to BC. Some studies showed that nilotinib or dasatinib were superior to imatinib in terms of rapid time to response?? and higher molecular response in newly diagnosed CML patients . It can be translated to CML-MBP. We evaluated 2nd generation TKI, nilotinib and high-dose daunorubicin induction chemotherapy combination if to attempt an improvement in the response rate and survival in patients with CML-MBP or acute myeloid leukemia with BCR/ABL1 (AML-BCR/ABL1).The primary end point of the study was complete remission (CR) rate after induction chemotherapy (IC). Patients received cytarabine 200 mg/m2/day by continuous IV infusion over 24 hours daily for 7 days (D 1-7) along with daunorubicin 90 mg/m2/day IV daily for 3 days (D 1-3). Nilotinib 400mg bid PO was added without interruption from D8 of induction chemotherapy until allogeneic hematopoietic cell transplantation (alloHCT) or during 2 years. Re-induction chemotherapy was given as cytarabine 200 mg/m2/day by continuous iv infusion over 24 hours daily for 5 days (D 1-5) plus daunorubicin 45 mg/m2/day iv daily for 2 days (D 1-2) when D14 bone marrow blasts exceeded 5%. Four courses of high-dose cytarabine (Cytarabine 3 g/m2) were administered in 3-hour IV infusion every 12 hours on days 1, 3, and 5 (a total of six doses per course). This prospective phase II study was early terminated due to slow enrollment.A total of 10 (6 male & 4 female) patients were enrolled. Six patients were diagnosed as CML-MBP and 4 patients as AML-BCR/ABL1 (all these patients will be presented as CML-MBP). Median age CML-MBP patients was 50.9 (22.5-63.0) years. Five patients had received prior therapies (low-dose cytarabine in 1, imatinib in 2 and dasatinib in 2 patients). Median time from CML-MBP diagnosis to induction chemotherapy was 3.12 (0-3.12) months. All patients received IC. Nilotinib was interrupted temporarily during IC in 5 patients (hyperbilirubin emia in 2 pts?, cytopenia in 1, rash in 1 and poor general condition in 1 patient). Nine patients showed bone marrow (BM) blast<5% in early evaluation. CR was achieved in all (CR in 9 patients and CRi in 1) patients. One patient who had achieved CRi died of pneumonia without full hematological recovery during IC. Molecular response (MRIS) at the time of CR was not-evaluable in 1, MR1.0 in 3, MR2.0 in 2, MR3.0 in 2 and MR4.5 in 2 patients. Eight patients received 1 or 2 cycles of consolidation and 1 patients died during consolidation therapy. Five patients proceeded to alloHCT after consolidation. Two more (1 by relapse after alloHCT and 1 by graft-versus-host disease) patients died after alloHCT. Two patients died after alloHCT (1 by relapse and 1 after stopping nilotinib by toxicities). Median overall survival was 5.0 (95% CI, 1.5-8.4) months. Four patients are still alive (3 patients after alloHCT and 1 patient without alloHCT; 6.4+, 12.2+, 29.4+ and 43.6 months).In conclusion, nilotinib combined with IC is feasible and can be a good bridging therapy for these extremely rare CML-MBP or AML-BCR/ABL1 if they are IC-eligible although this conclusion is very limited and should be confirmed by large scale studies because of the small sample size of this study. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Outcomes of Intensive Treatment of Adult Acute Myeloid Leukemia Patients: A Retrospective Study From a Single Centre.

Acute Myeloid Leukemia (AML) is a very aggressive cancer with difficult treatment and poor outcomes. The treatment of these patients is quite challenging due to various reasons including the need for extensive supportive care, and high cost of therapy. Reports on outcomes from India are few. We analyzed 93 adult patients (≥ 18years) with AML who were treated with curative intent between 2007 and 2014. Patients received daunorubicin at dose of 60-90mg/m2 and cytarabine 100mg/m2 during induction and consolidation with 3 courses of high dose cytarabine (1.5-3g/m2per dose for 6 doses per cycle). Only 4 patients underwent consolidation allogenic stem cell transplantation in first remission (CR1). The median age was 37 (18-66) years; males: 52%. Conventional cytogenetics (N = 63) showed 23% (N = 15), 56% (N = 35), 27% (N = 13) in good, intermediate risk and poor riskcategory respectively. FLT3-ITD was positive in 12/33 (36%) and NPM mutation in7/23 (30%). Daunorubicin dose was 60mg/m2 in 75% (N = 70) and 90mg/m2 in 25% (N = 23) patients. Induction mortality was 17% (16/93) [60mg/m2:19% (13/70), and 90mg/m2:13% (3/23); p = 0.39)]. Complete remission was achieved by 60% (56/93) [60mg/m2:53% (37/70), and 90mg/m2:83% (19/23); p = 0.09)]. The median overall survival was 9.2months and the actuarial survival at 2years was 30%. By univariate analysis, FLT3-ITD positivity, white cell counts higher than 100,000/mm3 at presentation, and use of lower dose of daunorubicin in induction were associated with poorer outcomes. Outcomes in adult AML are generally poor. Many patients with high risk disease don't receive allogenic transplantation in CR1. Increased availability of allogenic stem cell transplantation may help to improve outcomes.

Four versus five chemotherapy courses in patients with low risk acute myeloid leukemia: A Children’s Oncology Group report.

10515 Background: For pediatric patients with low risk (LR) acute myeloid leukemia (AML), the Children’s Oncology Group (COG) trial AAML1031 used a 4-course chemotherapy backbone consisting of two induction courses of cytarabine/daunorubicin/etoposide, a third course of cytarabine/etoposide and a fourth course of cytarabine/mitoxantrone. The prior COG trial, AAML0531, included the same four courses plus a fifth course of high dose cytarabine. Removal of course 5 from AAML1031 was based in part on prior studies that suggested no benefit from a fifth course. Methods: We compared overall survival (OS), disease free survival (DFS), and relapse risk (RR) for LR patients receiving four versus five chemotherapy courses in a pooled analysis of comparable patients treated on AAML0531 and AAML1031. LR was defined as the presence of inv(16)/t(16;16) or t(8;21) cytogenetic features, NPM1 or CEBPA mutations, or MRD &lt; 0.1% post-Induction I in those with no high risk features. AAML0531 patients assigned to gemotuzumab were excluded. Follow-up for outcomes began at the start of course 4. Cox (OS and EFS) and risk (RR) regressions were used to estimate unadjusted hazard ratios (HR) comparing outcomes for patients who received only four versus five chemotherapy courses. Start of a fifth chemotherapy course was assessed as a time-varying exposure in all analyses to avoid exposure misclassification. Results: A total of 921 LR patients (225 from AAML0531, 696 from AAML1031) were included; 191 (21%) received a fifth course. There were no significant differences in distributions of sex, age, race, or ethnicity between patients treated with four or five courses. Median times to absolute neutrophil count and platelet count recovery after course 4 were also comparable. Patients who received only four courses had significantly lower OS (HR = 1.83, 95% CI: 1.22-2.74, p = 0.003), DSF (HR = 1.49, 95% CI: 1.13-1.97, p = 0.005), and higher RR (HR = 1.42, 95% CI: 1.08-1.88, p = 0.013) compared to those who received five courses. Conclusions: Removal of a fifth cytarabine-containing course appears to result in worse OS, DFS, and RR in pediatric patients with LR AML. Multivariable analyses to further refine the estimates are ongoing.

Phase I/II Study on Cytarabine and Idarubicin Combined with Escalating Doses of Clofarabine in Untreated Patients with Acute Myeloid Leukemia and High Risk for Induction Failure (AMLSG 17-10 CIARA)

Background: Clofarabine is a second-generation purine nucleoside analogue, which has shown synergistic activity with cytarabine. We determined the maximum tolerated dose (MTD, primary endpoint), safety and efficacy (secondary endpoints) of clofarabine in combination with cytarabine and idarubicin in newly diagnosed acute myeloid leukemia (AML) patients with high-risk for induction failure stratified in two age groups (< 60 years and ≥ 60 years).Methods: In this prospective, open-label, multicenter phase I/II study (EudraCT 2010-021719-18, CIARA trial), newly diagnosed AML patients with high risk of induction failure (NPM1 wildtype, FLT3-ITD negative), who were eligible for intensive chemotherapy, received two induction courses (cytarabine 750 mg/m2 d1-5, idarubicin 7.5 mg/m2 in patients <60 years or 6 mg/m2 in patients ≥60 years d1+3) with increasing doses of clofarabine (20-35 mg/m2 d1-5) following a 3+3 design with extension cohorts. Consolidation consisted of up to 3 courses of high-dose cytarabine or allogeneic hematopoietic cell transplantation (HCT).Results: Forty-two patients with de novo (n=32) or secondary (n=10) AML were included. Median age was 58.5 years (range 28-73, 24 patients < 60 years, 18 patients ≥ 60 years). Intermediate/adverse risk cytogenetics were found in 22 and 12 patients, respectively (karyotype missing in 8 patients). All patients received induction 1, 27 (64%) received induction 2; 4 (10%) patients died during induction courses 1 or 2. Eight patients developed a dose-limiting toxicity (6 patients with grade 3/4 non-hematologic toxicity and 3 patients with grade 4/5 hematologic toxicity) and the MTD was determined at 30 mg/m2 clofarabine for both age cohorts (younger patients: 2 of 6 patients with DLT at 35 mg/m2, no DLT at 30 mg/m2 (n=9); older patients: 4 of 6 patients with DLT at 35 mg/m2 in the extension phase, no DLT at 30 mg/m2 (n=3). The most frequent grade 3-5 non-hematologic adverse events were febrile neutropenia, sepsis, increased liver enzymes, pneumonia, decreased appetite and diarrhea occurring in 55, 24, 21, 21, 10 and 10% of patients. The median time to neutrophils ≥0.5/nl and platelets ≥50/nl after induction 1 was 25 and 24 days, respectively. Sixteen patients (38%) proceeded to allogeneic HCT in first CR and 8 (19%) received at least one course of high-dose cytarabine consolidation.Complete remission (CR) or CR with incomplete recovery (CRi) was achieved in 67%. After a median follow up of 2.2 years the 2-year overall survival (OS) was 56% and the 2-year event-free survival was 38% (median EFS 11.4 months). Compared to a matched historical control of 197 younger AML patients (SHG 0199 trial, Schlenk et al. NEJM 2008), the CR rate was 79% in the 24 younger CIARA patients compared to 66% in the control cohort (P=.18), and 2-year OS was higher for CIARA than for control patients (74% vs 49%, P=.021, Figure A). The allogeneic HCT rate in first CR (CR1) was higher in younger CIARA compared to younger control patients (58% vs 27%, P=.002). The CR rate in older CIARA patients was 50% compared to 36% in a historical control of 191 older patients, who were selected using the same genetic inclusion criteria as for CIARA patients (HD98B trial, Schlenk et al. Haematologica 2009, P=.23). Two-year OS in older patients was similar between CIARA and control patients (33% vs 17%, P=.31, Figure B). The allogeneic HCT rate in CR1 was 11% vs 2% in CIARA vs control patients (P=.029).Conclusion: Clofarabine can be safely administered at 30 mg/m2 in combination with cytarabine and idarubicin in younger and older newly diagnosed AML patients. Allogeneic HCT in CR1 was feasible in a high proportion of younger AML patients and likely contributed to the favorable outcome compared to historical control patients. [Display omitted] DisclosuresKrauter:Genzyme: Research Funding. Schlenk:Amgen: Research Funding; Pfizer: Honoraria, Research Funding. Paschka:Novartis: Consultancy; Medupdate GmbH: Honoraria; Bristol-Myers Squibb: Honoraria; Pfizer Pharma GmbH: Honoraria; Celgene: Honoraria; ASTEX Pharmaceuticals: Consultancy. Lübbert:Ratiopharm: Other: Study drug valproic acid; Celgene: Other: Travel Funding; Janssen-Cilag: Other: Travel Funding, Research Funding. Janning:Teva: Honoraria. Becker:BMS: Honoraria; Novartis: Honoraria. Heuser:Tetralogic: Research Funding; Novartis: Consultancy, Research Funding; Celgene: Honoraria; Pfizer: Research Funding; Bayer Pharma AG: Research Funding; BerGenBio: Research Funding; Karyopharm Therapeutics Inc: Research Funding.

A Comparison of 1 or 2 Courses of High Dose Cytarabine As Consolidation in Younger Patients with AML: First Results of the UK NCRI AML17 Trial

On behalf of the UK NCRI AML Working PartyIntroductionOutcomes in younger patients with AML have steadily improved over the last 4 decades. However, the question of the optimal chemotherapy schedule remains open. As outcomes improve attention turns from survival to survivorship: can similar - or better - outcomes be obtained with less cost to the patient. We have previously shown in our MRC AML12,15 trials that a fifth course of chemotherapy did not improve outcomes in these younger patients. A retrospective analysis of patients who received 3 or 4 courses of treatment showed that, while patients with poor risk disease had better outcomes with four courses, any effect of a fourth course was much less clear for patients with good or standard risk disease.MethodsThe UK NCRI AML17 trial (ISRCTN: 55675535) was designed for patients with AML or high risk MDS up to the age of 60. Following their first course of treatment, patients were allocated a risk group based upon a validated score (comprising cytogenetics, WBC, age, secondary disease and blast response to course 1)[1]; additionally, patients who failed to achieve at least a 50% reduction in blasts were considered poor risk. A protocol amendment included patients who were otherwise standard risk, but were FLT-3 ITD mutant/NPM1c wild type in the poor risk group. Remaining adults who were either good or standard risk could be randomised after 2 courses of treatment (DA or ADE, with or without GO at 3/6 mg/m2) to receive 1 or 2 courses of consolidation (3 or 4 courses in total). Before mid-2010 patients were randomised between MACE/MidAC vs MACE; based on the results of AML15 [2], a protocol amendment changed consolidation to 1 or 2 courses of Ara-C 3g/m2/d for 5 days. Follow-up is complete to 1st March 2015, with median follow-up of 28.8 months (range 0.1-68.2).ResultsFrom July 2009 to June 2015, 1017 patients were randomised. Median age was 48 (range 16-72); 45% were male; 24% had core binding factor leukaemia; 76% intermediate risk disease; 1% had secondary disease, and 3% high risk MDS; WHO PS was 2+ in 4% of patients. Overall survival at 5 years was 57%. An additional course of consolidation reduced relapse (CIR 53% vs 57%; HR 0.81 (0.67-0.99) p=0.04), with no difference in death in remission (7% vs 6%; HR1.10 (0.61-2.00) p=0.8), leading to some evidence of improved relapse free survival (41% vs 37%, HR 0.84 (0.70-1.01) p=0.06). Survival however, did not differ significantly between the arms (58% vs 55%, HR 0.90 (0.71=1.14) p=0.4), reflecting the effect of salvage: 3 year survival from relapse was 32% vs 31% (HR 0.97 (0.75-1.26) p=0.8). In stratified analyses, there was no difference in the effect of the extra course by cytogenetics (p-values for interaction between cytogenetics and treatment p=1.0 for survival); while relapse was reduced more in CBF leukaemias (HR 0.63 (0.40-1.00), p=0.05) than in others (HR 0.91 (0.73-1.13) p=0.4), the test for interaction was not significant (p=0.16). Information on minimal residual disease (by immunophenotype to a sensitivity of up to 1 in 104) was available for 353 patients post course 1 and 265 patients post course 2. There was no evidence of a differential effect of an extra course of consolidation by MRD status after either course (p=1.0 for survival post course 1; p=0.3 for survival post course 2). In stratified analyses, there was no interaction between treatment and age, sex, performance status or diagnosis. However, there was a significant benefit for FLT3-ITD WT patients (OS: 63% vs 54%, HR 0.75 (0.57-0.99) p=0.04), which was not present for ITD mutant patients (41% vs 58%; HR 1.38 (0.84-2.26) p=0.2; p=0.04 for interaction), and evidence of greater benefit for 4 courses in patients with lower WBC at diagnosis (p=0.04 for trend). There was no heterogeneity by induction therapy (p=0.7), in particular the use of gemtuzumab ozogamicin or not (p=0.2).ConclusionsThese data in good and standard risk patients (as defined comprising 63% of patients diagnosed) suggests no overall survival benefit of a 4th course of chemotherapy in younger patients with AML, although relapse was significantly reduced. With respect to subgroups, there was a suggestion that 4 courses of treatment was beneficial for FLT3 wild type patients. Attention now turns to whether the use of more intensive induction regimens such as FLAG-Ida can improve outcomes while delivering fewer courses.[1] Burnett et al. Blood 2006:108 (11): Abstract 18[2] Burnett et al. JCO 2013: 31(27);3360-8 DisclosuresRussell:Therakos: Other: shares. Cavenagh:Celgene: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau.

A Multicenter Phase II Study Using a Dose Intensified Pegylated-Asparaginase Pediatric Regimen in Adults with Untreated Acute Lymphoblastic Leukemia: A DFCI ALL Consortium Trial

▪Background: Current chemotherapy regimens in children with ALL produce disease-free survival (DFS) rates of greater than 80%. In contrast, adults with ALL have a much poorer prognosis, with DFS rates of 30-40%. Recent prospective studies suggest that young adults may have superior outcomes when treated with intensive pediatric regimens. We recently reported a 4-yr DFS and overall survival (OS) of 69% (n=78 who achieved CR) and 67% (n=92), respectively (DeAngelo et al. Leukemia 2015) using a native E. coliasparaginase based regimen. This phase II successor trial was performed to determine if a pediatric regimen using pegylated-asparaginase (peg-asp) could be feasibly administered to adults.Methods: Patients (pts) between 18-50 yrs with de novo ALL were eligible. The primary objective of this study was to determine the feasibility of a single dose of peg-asp during induction and of delivering peg-asp every 2 wks during a 30 wk consolidation period. The therapeutic backbone of this protocol was based on the very high-risk arm of the DFCI Childhood ALL Consortium Protocol 05-01. Pts received induction chemotherapy, which included doxorubicin, prednisone, vincristine, pegylated-asparaginase (peg-asp), and triple intrathecal therapy. Consolidation I consisted of a course of high-dose methotrexate, followed by a BFM-like intensification and a course of high-dose cytarabine, etoposide and dexamethasone. CNS prophylaxis included triple intrathecal therapy and cranial radiation. Intensification therapy consisted of eight 3-wk courses of doxorubicin, vincristine, dexamethasone, 6-mercaptopurine and 30 wks of IV peg-asp initially dosed at 2500 IU/m2every 2 wks. Continuation therapy consisted of 3 wk courses of vincristine, dexamethasone, methotrexate and 6-mercaptopurine for a total of 2 yrs from complete remission (CR). Imatinib at 600 mg/d was administered to those pts who were Philadelphia chromosome (Ph) positive.Results: Of 112 pts enrolled, 110 were eligible. The first 65 pts were treated with the initial study design of IV peg-asp during induction and peg-asp every two wks for 15 doses during consolidation. However, due to the high frequency of asparaginase toxicities mainly hyperbilirubinemia, peg-asp was replaced with native E. coli asp at a dose of 25,000 IU/m2 IM during induction and the dose and frequency peg-asp was decreased to 2000 IU/m2 every 3 wks during the consolidation phase in the subsequent 45 pts. The median age was 32 yrs, (range, 18-50), 61% were male, 82% had B-lineage phenotype, and 21 were Ph positive. The CR rate after 4 wks was 89%. 70 pts had the opportunity to receive peg-asp intensification therapy (42 at the 2500 IU/m2 every 2 wks schedule and 28 on the 2000 IU/m2 every 3 wk schedule). Of the 42, 18 pts (43%; 80% CI, 32-54%) on the 2 wk schedule completed at least 13 of 15 doses of peg-asp (26 wks) and 22 of 28 pts (79%; 80% CI, 65-88%) on the 3 wk schedule completed at least 8 of 10 doses of peg-asp, which met the feasibility endpoint (lower bound CI > 60%). The median asp levels post the induction dose of peg-asp were 0.025, 0.78, 0.28, 0.10, at baseline, 7, 11 and 25 days and >0.20 for each consolidation time point for both the 2 and 3 wk cohorts. Two deaths occurred during induction therapy (sepsis; CNS hemorrhage). Post-induction four pts developed pancreatitis, 14 pts had an allergic reaction to the asp, 12 pts developed osteonecrosis, 2 had a bone fracture, 13 pts had thrombosis/embolism and 32 pts had a grade 3-4 neutropenic infection. With a median follow-up time of 39 mos, the estimated 3-yr DFS is 73% for those who achieved a CR (n=90) and the estimated 3-yr OS is 75%.Conclusions: The administration of a dose intensified pediatric regimen with peg-asp to adults with ALL is feasible. However, the dose and schedule of peg-asp that is well-tolerated in adults is lower and less frequent as compared to that of pediatric pts. Although the DFS and OS are high for an adult cohort, longer follow up is needed. Pediatric-like therapies, including those using intensive peg-asp, are tolerable in young adults with ALL and represent a major therapeutic advance.Table 1Outcome Summaryn3-yr % OS [95% CI]n3-yr % DFS [95% CI]All Pts./CR Pts.11075 [66-82]9073 [62-81]ImmunophenotypeB cell9074 [64-82]7270 [58-80]T cell2078 [52-91]1883 [57-94]Ph-8980 [70-87]7875 [63-84] [Display omitted] DisclosuresDeAngelo:Pfizer: Consultancy; Amgen: Consultancy; Incyte: Consultancy; Bristol Myers Squibb: Consultancy; Agios: Consultancy; Ariad: Consultancy; Novartis: Consultancy; Celgene: Consultancy. Storring:Celgene Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees. Steensma:Celgene: Consultancy; Amgen: Consultancy; Incyte: Consultancy; Onconova: Consultancy. Stone:Pfizer: Consultancy; Juno: Consultancy; AROG: Consultancy; Amgen: Consultancy; Agios: Consultancy; Celator: Consultancy; Novartis: Research Funding; Sunesis: Consultancy, Other: DSMB for clinical trial; Abbvie: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; Merck: Consultancy; Roche/Genetech: Consultancy.

Long-term outcomes for patients with acute myeloid leukemia: a single-center experience from AIIMS, India.

To analyze clinicopathological characteristics of acute myeloid leukemia (AML) patients and to evaluate long-term outcome of these patients presented to single tertiary care center in India. We evaluated outcomes of 480 patients (age 8-60 years), classified into good, intermediate and poor risk according to cytogenetic results. Standard "3 + 7" induction therapy with dose of daunorubicin ranging from 45 to 90 mg/m(2) followed by two to three courses of high-dose cytarabine (12-18 g/m(2) ) as consolidation therapy was given to majority. The complete remission rate of the treated population (407 patients) was 70% with 84.8% in good risk, 67.9% in intermediate risk and 54.2% in poor risk (P = 0.0001). Induction mortality was 18.4%. One hundred twenty-nine patients relapsed with median treatment free interval of 10.4 months. At a median follow-up of 34.5 months, the median overall survival (OS) was 20.6 months with an estimated 5-year survival rate of 35.5%. No difference was found in OS between the three risk groups; however, patients with intermediate risk had a better leukemia-free survival (LFS) in comparison to good risk. Multivariate analysis showed age, performance status, treatment completion and hematopoietic stem cell transplant affecting OS, while only treatment completion affected LFS. This is one of the largest single-center studies reflecting more accurately the outcome of AML in India. These results are likely due to uniform treatment protocols, intensification of induction and post-remission treatments with comprehensive supportive care.

Plasma Affinity Proteomic Immunoprofiling As a Novel Prognostic Tool in High Risk Diffuse Large B-Cell Lymphoma Patients: A Nordic Lymphoma Group Study

▪BackgroundDespite recent advances in molecular profiling of diffuse large B-cell lymphoma (DLBCL), only a few biomarkers currently have an impact on treatment. In a previous study we could observe the heterogeneity of DLBCL in the plasma immunoprofile from DLBCL patients, by use of recombinant antibody microarrays. By unsupervised hierarchical clustering, an immunoprofile of 23 plasma proteins could divide patients into two subgroups with significantly different overall survival (OS). In this study we aimed to expand the immunoprofiling with longitudinal plasma samples from high risk DLBCL patients, to search for novel prognostic and potentially predictive markers.Material and MethodsPlasma samples from 126 high risk DLBCL patients included in a phase II clinical trial of the Nordic Lymphoma Group (CRY04) were collected at diagnosis, during and after treatment, and in the event of progression or relapse. Inclusion criteria were age 18-65 years, primary diffuse large B-cell lymphoma without CNS involvement, age-adjusted International Prognostic Index (aaIPI) 2-3 and WHO performance score 0-3. Six courses of R-CHOEP-14 were given followed by systemic CNS prophylaxis with one course of high-dose cytarabine and one course of high-dose methotrexate. Additionally, age and sex matched controls (n = 40) were included. Two hundred and eighty-three recombinant scFv antibody fragments directed against 97 known serum antigens, mainly immunoregulatory proteins, were selected from phage display libraries to be used in the antibody microarrays.ResultsImmunoprofiles distinguishing DLBCL patients from healthy controls were identified. Furthermore, a different protein expression was found in patients with aaIPI 3 versus 2 as well as in patients with shorter versus longer progression free survival (PFS). The kinases CDK-2 and BTK were upregulated both in patients with higher aaIPI score and in patients with shorter PFS. Comparing the patients who developed disease progression with those who did not, seven differentially deregulated proteins were identified including the phosphatase PTP-1B, the chemokine MCP-1, and the cytokines IL-4, IL-6 and IL-12, all previously implicated in B-cell lymphoma pathogenesis. In addition, results showed that subdivision of patients according to immunoprofile as defined in our previous study, could be performed also in the present patient cohort. The immunoprofile comprises T-helper (TH)1 cytokines, TH2 cytokines, complement proteins, chemokines, enzymes, and membrane proteins. The 23 included proteins are β-galactosidase, C1 esterase inhibitor, C4, C5, Cystatin C, Eotaxin, GLP-1 R, GM-CSF, HLA-DR/DP, IgM, IL-1ra, IL- 2, IL- 3, IL- 6, IL- 10, IL- 12, Leptin, MCP-1, MCP-3, Mucin-1, PSA, TNF-α, and TNF-β. Although not significant, a potential association to PFS and OS could be observed between the two generated subgroups. Finally, expression of IL-10 was shown to improve the prognostic value of aaIPI regarding both PFS and OS.ConclusionProtein expression profiling of plasma from high risk DLBCL patients provided novel insights into the biology of DLBCL. New candidate prognostic markers were identified which could potentially guide us in the prediction of outcome and in the choice of treatment for DLBCL patients. However, as this study was aimed for discovery, the findings must be validated in future studies with independent patient cohorts. DisclosuresNo relevant conflicts of interest to declare.

Achieving Early Remission By Induction Therapy Predicts a Favorable Outcome in Patients with Acute Myeloid Leukemia and an Intermediate Risk Karyotype Undergoing Allogeneic Stem Cell Transplantation in First Complete Remission

Purpose: Acute myeloid leukemia (AML) is a highly heterogeneous disease. In addition to patient-related factors (co-morbidities, age, physical performance) and disease-specific variables (genetic risk profile) response to treatment is an important prognostic factor. In particular, the rapid achievement of hematologic remission by induction therapy was shown to predict overall outcome irrespective of the type of post-remission therapy employed. Here, we specifically investigated the impact of achieving early remission (ER), i.e. absence of leukemic blasts in the bone marrow at the end of the first course of induction therapy, as compared to delayed remission (DR) on the outcome of patients with AML who underwent allogeneic stem cell transplantation (alloSCT) in first complete remission (CR1) at our center.Patients and Methods: We retrospectively analyzed 132 consecutive patients (ER: N=79, DR: N=53) with AML and an intermediate risk karyotype transplanted at our center between 1994 and 2013. Median age at alloSCT was 48 years. Before referral to transplantation, all patients were treated in a German multicenter AML trial. Patients aged <60 years were treated according to a double induction strategy, which consisted of one course of “7+3” followed by one course of high-dose cytarabine (HD-AraC) (3000 mg/m²). Patients aged ≥60 years were treated with a single course of “7+3”. In case of residual leukemic blasts, i.e. 5% or more in the bone marrow on day +16, first induction was followed by either one additional course of the same regimen or one course of HD-AraC (1000 mg/m2). Depending on the timing of alloSCT, one (N=78) or two (N=7) additional courses HD-AraC consolidation were given. For transplantation, myeloablative conditioning (MAC) (N=58) consisted of 12 Gy total body irradiation (TBI) and 120 mg/m2 cyclophosphamide (CY). Reduced-intensity conditioning (RIC) (N=74) consisted of fludarabine (FLU) 150 mg/m2, oral busulfan (BU) 8 mg/kg and anti-thymocyte globulin (ATG)(Fresenius®) 40 mg/kg. Transplants were from related (N=60) or unrelated (N=72) donors and were HLA-matched (10/10 antigens) (N=119) or HLA-mismatched (N=13) according to high-resolution molecular typing. Immunosuppression consisted of short course methotrexate (MTX) and cyclosporine in patients treated with MAC or cyclosporine and mycophenolate mofetil (MMF) in patients treated with RIC prior to alloSCT.Results: After a median follow-up of 56 (4-220) months for the surviving patients, 87 patients (66%) are alive and in CR. 26 patients (20%) relapsed after a median interval of 8 (1-133) months, whereas 19 patients (14%) died from NRM. Projected overall survival (OS) of the entire cohort after 1, 3, 5 and 10 years was 81%, 68%, 65%, and 61%. At the same time points the cumulative incidence of relapse (CI-R) or non-relapse mortality (CI-NRM) was 12%, 19%, 22%, and 22% or 13%, 13%, 13%, and 17%. In contrast to patients showing DR, patients achieving ER had a significantly higher 3-year OS and disease-free survival (DFS) of 76% versus 54% (p=0.03) and 76% versus 53% (p=0.03). Likewise, 3 years after alloSCT the CI-R was significantly lower in the ER subgroup as compared to patients achieving DR, i.e. 10% versus 35% (p=0.004). In contrast, NRM did not differ significantly between the ER and the DR subgroup. Multivariate analysis identified DR as an independent prognosticator for an inferior DFS (HR 3.37, p=0.002) and a higher CI-R (HR 3.55, p=0.002). Notably, there was no significant difference in OS, DFS, or CI-R between patients treated with MAC versus RIC in the ER or the DR subgroup.Conclusions: Taken together, these data indicate that rapid achievement of remission may predict a favorable outcome in patients with intermediate risk AML undergoing alloSCT in CR1. In turn, the adverse effect of DR may not be necessarily overcome by alloSCT. DisclosuresNo relevant conflicts of interest to declare.

Tacrolimus-induced left ventricular apical hypertrophy in a patient with post-allogeneic hematopoietic stem cell transplantation

We report a case of tacrolimus-induced left ventricular apical hypertrophy in a 28-year-old Japanese man with post-allogeneic hematopoietic stem cell transplantation. He was diagnosed with acute myelomonocytic leukemia (FAB AML-M4) in July 2012. He failed to achieve complete remission after two courses of induction chemotherapies (one course of cytarabine plus idarubicin and one course of high-dose cytarabine plus mitoxantrone). Therefore, he underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) after conditioning with 12-Gy total body irradiation, high-dose cytarabine and high-dose cyclophosphamide in November 2012.