HD Ara-C Research Articles

Inotuzumab Ozogamicin (InO) Vs Standard of Care (SC) in Patients with Relapsed/Refractory (R/R) Acute Lymphoblastic Leukemia (ALL): Long-Term Results of the Phase 3 INO-VATE Study

Inotuzumab Ozogamicin (InO) Vs Standard of Care (SC) in Patients with Relapsed/Refractory (R/R) Acute Lymphoblastic Leukemia (ALL): Long-Term Results of the Phase 3 INO-VATE Study

Exploration of Potential Relationships between CD22 and Selected Safety Outcomes in the Inotuzumab Ozogamicin Phase 3 INO-VATE Study

Introduction: CD22 is widely expressed on leukemic lymphoblasts in patients with B-cell acute lymphoblastic leukemia (ALL). Inotuzumab ozogamicin (InO), an anti-CD22 monoclonal antibody conjugated to calicheamicin, has shown significantly higher remission rates than standard of care (SC) chemotherapy in relapsed or refractory B-cell (R/R) ALL, independently of CD22 expression level. Here we report safety outcomes by CD22 expression in patients with R/R ALL receiving InO (vs SC) as salvage therapy in the INO-VATE trial (NCT01564784).Methods: Adults with CD22-positive ALL in 1st or 2nd salvage were randomized to InO (n=164; starting dose 1.8 mg/m2/cycle [0.8 mg/m2 on day 1; 0.5 mg/m2 on days 8 and 15 of a 21-28 day cycle for ≤6 cycles]) or SC (n=162; fludarabine/high-dose (HD) cytarabine (Ara-C)/granulocyte colony-stimulating factor, Ara-C plus mitoxantrone, or HD Ara-C).The InO dose was reduced to 1.5 mg/m2 per cycle in patients who achieved complete remission [CR] or CR with incomplete hematologic recover [CRi]. Last patient visit was January 4, 2017. Central flow cytometry was used to assess CD22 expression, which was quantified as % leukemic blasts CD22-positive and as Molecules of Equivalent Soluble Fluorochrome (a quantitative measure of receptor density on leukemic blasts [MESF]). Outcomes were reported in patients by baseline leukemic blast positivity (≥90% vs <90%), and in quartiles of patients (Q1-Q4) defined by CD22 MESF: Q1=lowest CD22 expression, Q4= highest CD22 expression.Results: At baseline, 142 InO patients and 117 SC patients had an evaluable sample for central-lab CD22 analysis. The majority of patients in both arms had high (≥90%) CD22 positivity (InO, 75.4%; SC, 72.6%), with a smaller proportion of patients exhibiting CD22 positivity <90% (InO, 24.6%; SC, 27.4%). The median number of completed cycles in the InO arm for the CD22 expression quartiles was n=2 for Q1, n=3 for Q2, n=2 for Q3, and n=3 for Q4; respective median overall dose was similar across quartiles: 4.2 mg/m2 (range: 1.3-9.2), 4.5 mg/m2 (range: 0.8-9.2), 4.2 mg/m2 (range: 0.8-9.3), and 4.6 mg/m2 (range: 0.8-9.6). In both arms, the most common grade ≥3 treatment-emergent adverse events (TEAEs) were neutropenia (InO, 47% vs SC, 44%), thrombocytopenia (InO, 40% vs SC, 58%), febrile neutropenia (InO, 28% vs SC, 55%), leukopenia (InO, 29% vs SC, 34%), and anemia (InO, 24% vs SC, 44%), with similar rates between CD22 MESF expression quartiles (Table 1). Grade ≥3 hepatotoxicity occurred more frequently in the InO arm (17%) vs SC (8%), occurring with similar rates in the CD22 expression quartiles (Table 1). In the InO arm, more patients with ≥90% CD22 positivity received post-treatment SCT (60 [56%] vs 12 [34%] patients with CD22 <90%); 9 (8%) patients with ≥90% CD22 positivity and 2 (6%) patients with <90% also had a pre-treatment SCT. The rate of post-treatment SCT in the CD22 MESF expression quartiles is shown in Table 2. Among patients who proceeded to SCT in the InO arm, where VOD risk was higher, post-transplant VOD occurred in 16 (27%) patients with ≥90% CD22 positivity vs 2 (17%) patients with <90%. When assessing CD22 expression by MESF, the rate of post-transplant VOD was similar across CD22 MESF quartiles (Table 2).Conclusions: The risk of developing TEAEs, including hepatic adverse events, which were more common in the InO vs SC arm, was not associated with intensity of CD22 expression in either the InO or SC arm. Among InO patients with post-treatment SCT, there was no apparent relationship between CD22 expression and the risk of developing VOD, when analyzing CD22 by % positivity or by MESF. [Display omitted] DisclosuresDeAngelo:BMS: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria; Pfizer Inc: Consultancy, Honoraria; Shire: Honoraria; Takeda: Honoraria; Blueprint Medicines: Honoraria, Research Funding; ARIAD: Consultancy, Research Funding; Amgen: Consultancy; Glycomimetics: Research Funding; Incyte: Consultancy, Honoraria. Advani:Pfizer: Honoraria, Research Funding; Amgen: Research Funding; Novartis: Consultancy; Glycomimetics: Consultancy. O'Brien:Sunesis: Consultancy, Research Funding; Acerta: Research Funding; Pfizer: Consultancy, Research Funding; Aptose Biosciences Inc.: Consultancy; GlaxoSmithKline: Consultancy; Amgen: Consultancy; Gilead: Consultancy, Research Funding; Astellas: Consultancy; Alexion: Consultancy; Abbvie: Consultancy; Kite Pharma: Research Funding; Celgene: Consultancy; Janssen: Consultancy; Vaniam Group LLC: Consultancy; Pharmacyclics: Consultancy, Research Funding; Regeneron: Research Funding; TG Therapeutics: Consultancy, Research Funding. Marks:Novartis: Consultancy; Pfizer: Consultancy; Amgen: Consultancy. Kantarjian:Orsenix: Honoraria; Novartis: Research Funding; Immunogen: Honoraria; BMS: Honoraria, Research Funding; Astex: Research Funding; ARIAD: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Actinium: Honoraria; AbbVie: Honoraria; Pfizer: Honoraria, Research Funding. Wang:Pfizer: Employment, Equity Ownership. Vandendries:Pfizer: Employment, Equity Ownership. Laird:Pfizer: Employment, Equity Ownership. Nick:Pfizer: Employment, Equity Ownership. Stelljes:Amgen: Honoraria; MSD: Consultancy; JAZZ: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Honoraria.

The Outcome of Mantle Cell Lymphoma patients after Treatment Failure and Prognostic value of Secondary Mantle Cell International Prognostic Index (sec MIPI)

▪Background: MCL is a distinct lymphoma entity with improved outcome achieved by the introduction of rituximab, high dose Ara-C and autologous stem cell transplantation (ASCT) into the first line therapy. The outcome of the relapsed patients (pts) remain however poor and there is little data on the outcome after subsequent relapses and there is no information on secondary MIPI prognostic value.Aim: To analyze the outcome of the MCL patients after first line treatment failure and to evaluate the prognostic role of the sec MIPI which is MIPI calculated at the time of relapse/progression.Methods: This analysis is a part of the Lymphoma project in which consecutive lymphoma patients are registered since the year 1999. Altogether 519 newly diagnosed MCL patients were registered in 5 university centers and 9 regional departments between 1999 and 2011. Patients who were treated with rituximab as part of the first line treatment (n=388) were included into the analysis. The diagnoses were confirmed according to WHO classification in the reference pathology centers. The median follow up is 4.5 years.Results: The whole cohort consists of 261 males and 127 females (2.1:1) with median age 65 y (28-87), the majority of pts had advanced disease (CS IV in 81.6% pts), PS ECOG ≥ 2 in 23.6% pts, elevated LDH in 52.5% of pts. The MIPI risk profile was as follows: low risk 21.7%, intermediate risk 27.2% and high risk in 51.1%. All pts received rituximab as part of the induction, 48.7% pts received CHOP, 5.7% alternation of CHOP and HD Ara-C, 26.2% intensive induction with HD Ara-C, 10.3% CVP, 6.4% FC. High dose therapy with ASCT was performed in 23.9% of pts. The ORR was 89.0% with 63.8 CR/CRu, 6.3% had stable disease and 4.9% were primary progressive. The PFS and OS were 2.9 y and 5.5 y with significant impact of MIPI risk (p<0.0001) for both PFS and OS. There were observed 179 relapses/progressions (R/P) and 70 deaths not related to subsequent progression. The cohort of patients with 1st R/P consisted out of 125 males and 54 females (2.3:1) with median age 68 years (38-89). The sed MIPI at the time of 1st R/P was low in 12.7% pts, intermediate in 32.1% and high 59.8% pts. Rituximab was used in 69.5% of patients, DHAP or ESHAP was used in 25.1% cases, FC in 22.8% of cases, CHOP like regimen in 9.4%, HD Ara-C in 11.8%, only 4.7% were treated with targeted therapy temsirolimus or lenalidomide. Altogether 77.2% pts were treated with the polychemotherapy and 22.8 with monotherapy. ASCT and AlloSCT were performed in 5.5% and 8.7% pts resp. During follow up there were observed 74 deaths not related to subsequent progression and 53 2nd R/Ps. The median of 2nd PFS and 2nd OS from the date of 1st R/P was 1.0 and 1.3 years resp. The sec MIPI low vs. intermediate vs. high risk had significant prognostic impact on 2nd PFS: 5.8 vs 1.7 vs 0.9 years (p<0.0001) (fig 1) as well as on OS : 5.8 vs 3.4 vs 1.1 years (p<0.0001) (fig 2). The cohort of 53 pts with 2nd R/P had median age 68 (38-85) yers, male/female ratio was 1.4. Rituximab was used in 45.9% of treated patients and 48.3% of pts were treated with single drug. During follow up 11 pts developed 3rd R/P and other 30 pts died due to current progression, toxicity or in remission. The median of 3rd PFS from the time of 2nd R/P was 6.8 m and OS 7.4 months. Pts who were treated for 3rd R/P recieved rituximab in 50% of cases and the majority (81.2%) were treated with other single drug. The median of 4th PFS from 3rdR/P was 4.9 m and OS 5.5 months .Conclusions: Our analysis of relapsed MCL patients shows that 1: Median PFS from the Dg was 2.9 y but each subsequent relapse resulted in significantly shorter PFS median 12.1, 6.8 and 4.9 months resp. 2: The median OS from Dg was 5.5y but after each relapse it became shorter - 15.7 m, 7.4 m and 5.5 months resp. 3: The sec MIPI at the time of relapse discriminates the groups with significantly different prognosis. DisclosuresNo relevant conflicts of interest to declare.

High Cure Rates of the Short-Term GITIL Chemotherapy Programme for Adult Patients with Burkitt Lymphoma

Abstract Burkitt lymphoma (BL) is a rare disease that account for 2% of all cases of non-Hodgkin lymphoma in adults. Several treatments have been published so far with improving response rates obtained after augmentation with Rituximab of the original protocols. We have previously published the results of a short and intensive chemotherapy regimen translated from the pediatric patients to adults. Here we update and extend our previous results to a cohort of 51 patients with confirmed diagnosis of BL. From December 1991 to January 2014, we enrolled 51 patients with Burkitt lymphoma. The original regimen was applied to the first 22 patients who were treated at the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan. The treatment consisted of and induction phase comprising CTX (500 mg/mq, day 1-2) and VCR (1,4 mg/mq day 1); MTX (150 mg/kg day 8), VP-16 (250 mg/mq q 12 hs, day 14); MTX (250 mg/kg day 21), ADM (50 mg/mq, day 28), VCR (1,4 mg/mq, day 35), and a consolidation phase with HD ARA-C (1000 mg/mq continuos infusion for 4 days with a daily extra dose of 750 mg/mq) plus CDDP (20 mg/mq 4 day continuos infusion). Weekly intratechal chemotherapy for 6 doses was administered. Patients not achieving complete remission (CR) before consolidation, were shifted to sequential high-dose chemotherapy (HDS) comprising HD-CTX and stem cell harvest, HD-ARAC, Dexa-BEAM and BEAM followed by infusion of autologous stem cell transplant (ASCT). Rituximab was included in R-HDS only for in-vivo purging of collected stem cells. An updated version of the protocol was introduced from year 2003 and was applied to a set of 39 patients enrolled by the Gruppo Italiano Terapie Innovative nei Linfomi (GITIL) in four different centers. The new regimen was augmented with rituximab both in the induction (on day 15, day 29, day 36) and after consolidation (two weekly administrations) phases. Also for R-HDS salvage regimen, more rituximab infusions were added to the original schema for a total of 6 administrations. Patients characteristics were as follow: M/F 33/18, median age 46 years (range 18-90 years), stage I-II/III-IV 22/29, IPI H or HI 24 patients, bulky disease 20 patients, CNS involvement in 4 subjects, high LDH levels in 25 patients, ECOG performance status (PS) 0-1 vs 2-3 33/18, BM involvement in 7 subjects. Of 49 patients evaluable for response (2 died of early regimen-related toxicity), CR was obtained after consolidation in 80% of the subjects and was improved to 94% by the R-HDS salvage regimen. In details, of the 4 subjects with PD and the 3 with PR after the induction phase, only one and all three were rescued by R-HDS treatment, respectively. Three patients relapsed after the short-intensive regimen: of them one was saved with R-HDS. With a median follow-up of 1994 days, Kaplan-meier estimates of 5-year OS and PFS were 78% (Figure 1) and 69% respectively, and cumulative incidence of relapse, with Gray test, was 15% (95% CI, 6.5-27; Figure 2). We did not observe any difference in terms OS (p=0.6) and DFS (p=0.7) between patients treated before 2003 by a single center or after 2003 when other hospitals participated to the study. In this study we extended our previous finding and confirmed that the short intensive chemotherapy program achieves high percentages of complete response in patients with BL, while those with primary refractory disease can effectively be saved by the R-HDS regimen. In addition, we demonstrated that our program is easily exportable to other hospitals with reproducible results in a multicenter setting. Figure 1: 5-year OS of patients with Burkitt lymphoma treated with a short-intensive chemotherapy regimen. Figure 1:. 5-year OS of patients with Burkitt lymphoma treated with a short-intensive chemotherapy regimen. Figure 2: 5-year Cumulative Incidence of relapse (with 95% confidential interval) of patients with Burkitt lymphoma treated with a short-intensive chemotherapy regimen Figure 2:. 5-year Cumulative Incidence of relapse (with 95% confidential interval) of patients with Burkitt lymphoma treated with a short-intensive chemotherapy regimen Disclosures No relevant conflicts of interest to declare.

Poor Prognosis With Different Induction Rate Was Observed In Children With Acute Myeloid Leukemia and FLT3-ITD According To The ITD/WT Allelic Ratio: A Result From The Japanese Pediatric Leukemia/Lymphoma Study Group

BackgroundAcute myeloid leukemia harboring internal tandem duplication of fms-like tyrosine kinase 3 (AMLFLT3-ITD) is associated with poor prognosis, but the previous studies have reported that the inferior outcome is only confined to those with high allelic ratio (AR) of ITD/wild type (WT). In our previous AML99 study (2000-2002), AMLFLT3-ITD showed a poor outcome compared to the WT cases (5-year OS; 35% vs. 84%, P<0.0001). We, therefore, assigned all the patients with AMLFLT3-ITD to receive hematopoietic stem cell transplantation (HSCT) in first remission (1CR) in the JPLSG AML-05 study. Patients & MethodsAML-05 study, registered at http://www.umin.ac.jp/ctr/ as UMIN000000511, is a Japanese nation-wide multi-institutional study for children (age<18 years) with de novo AML and enrolled 443 eligible patients from Nov. 2006 to Dec. 2010. Cases with acute promyelocytic leukemia or Down syndrome were excluded. FLT3-ITD was examined centrally for all the patients. After the 2 consecutive induction chemotherapies [(ECM: etoposide, Ara-C, and mitoxantrone) and (HCEI: HD Ara-C, etoposide, and idarubicin)], all the AMLFLT3-ITD patients were allocated to the high risk group and further received intensification therapy including HD Ara-C followed by HSCT in 1CR. All DNA samples were extracted from the first diagnostic bone marrow or peripheral blood and subjected to PCR and direct sequencing. AR of FLT3-ITD/WT was examined by GeneScan, and defined AR >0.4 as high and AR ≤ 0.4 as low as previously reported (Meshinchi S. Blood2006). ResultsWe found 47 patients (10.6%) with AMLFLT3-ITD in this study (30 males, 17 females, and median age of 11 years at diagnosis). The median WBC count was 65,300/ml (3,690 - 522,050/mL). FAB classification included M1 (n=10), M2 (n=9), M4 (n=9), and M5 (n=11), and AML with normal karyotype was dominant (19/47, 40.4%).Of the 29 patients (61.7%) who achieved CR, twenty-seven received HSCT in 1CR and 19 patients survived (19/27, 70.4%). On the other hand, 14/16 non-CR patients received HSCT, but only 4 survived. The only demographic difference between the 29 CR and 16 non-CR cases was the median WBC count at diagnosis (19,000 vs. 124,000/μL, P<0.001), and rapid clearance of bone marrow blasts after single induction course was observed in the CR group (median blast percentage dropped from 73% to 1.1% in the CR group, while that was 85% to 30.6% in the non-CR group). Finally, five-year OS, DFS and EFS for all 47 AMLFLT3-ITD patients were 41.3%, 58.4% and 36.1%, respectively.AR was analyzed in 44 patients with median ratio of 0.68 (range, 0.11 to 4.47). Median AR was not different between CR vs. non-CR cases (0.53 vs. 0.72). There were no difference in 5-year OS (52.8% vs. 42.5%, P=0.302), DFS (54.5% vs. 64.5%, P=0.524), and EFS (50.0% vs. 34.4%, P=0.283) between patients with low (n=12) and high AR (n=32), however, induction rate was significantly higher in the low AR patients (91.7% vs. 53.1%, P=0.018).It was rather surprising that all FLT3-ITDs were found only in JM domain and not in TKI domain in the current trial. In addition, six of 47 (12.8%) AMLFLT3-ITD patients had NPM1mutation simultaneously, and all received HSCT at 1CR and survived. Discussion and ConclusionWe observed a different induction rate between AMLFLT3-ITD patients with low and high AR, but poor final outcomes in both. Regardless of the level of AR, patients with AMLFLT3-ITD, especially who fail to achieve remission, have dismal outcome and effective therapy combined with novel FLT3 inhibitor is urgently needed to overcome the disease. Disclosures:No relevant conflicts of interest to declare.

High-Dose Cytarabine (HD araC) in the Treatment of Leukemias: a Review

Cytarabine (araC) has served as the backbone of acute myeloid leukemia (AML) treatment for nearly forty years. High-dose cytarabine (HD araC) therapy resulted from a theoretical model developed in the 1970s that attempted to maximize the anti-leukemia effect of cytarabine. Since that time, HD araC has been utilized mostly in consolidation therapy for AML and in patients with relapsed or resistant AML. The development of araC and HD araC preceded our current understanding of AML biology-that it is a heterogeneous disease, not a single clinical entity. Thus, the optimal dose, schedule, and clinical setting for the use of cytarabine in hematologic malignancies remain uncertain. Research is now better defining the optimal use of HD araC based on leukemia cell karyotype and molecular signature. Here we review the pharmacodynamics of araC, the landmark studies that established the role of HD araC in AML, and research defining the role of HD araC based on the unique biologic properties of the leukemia cell.

Hematopoietic Stem Cell Transplantation (HSCT) Benefits the Survival of Acute Myeloid Leukemia (AML) Patients with IDH1, NRAS and DNMT3A Mutations

Abstract 1981▪▪This icon denotes a clinically relevant abstract Background:Gene mutations may serve as potential markers to extend the prognostic parameters in acute myeloid leukemia (AML) patients. In this study, we detected distribution of mutations in the nucleophosmin gene (NPM1), C-KIT, the fms-related tyrosine kinase 3 gene (FLT3), Isocitrate dehydrogenase gene 1 and 2 (IDH1, IDH2), the neuroblastoma RAS viral oncogene homolog (NRAS) and DNA methyltransferase 3A gene (DNMT3A) in 442 newly diagnosed AML patients (none-APL). Associations of gene mutations with clinical outcomes in these patients followed HSCT treatment or chemotherapy were further evaluated. Methods:Between February 2005 and December 2011, 442 newly diagnosed AML (none-APL) patients in our centre were retrospectively analyzed. There are 248 males and 194 females, and the median ages were 40 (16–60) years. 393 patients (88.9%) of patients were with single or normal karyotype and 49 patients (11.1%) were with complex abnormal karyotype. In addition to MICM examination, direct sequencing was employed to access the distribution of mutations in of FLT3-ITD (exon14), FLT3-TKD (exon 20), NPM1 (exon12), C-KIT (exon8, 17), IDH2 (exon 4), NRAS (exon1, 2), DNMT3A (exon23) of 445 AML patients. Complete remission (CR) was achieved in 258 patients (58.4%) followed the standard induction therapy, 128 patients received HSCT (Allo-HSCT: 121 vs. Auto-HSCT: 7) therapy after first remission or second remission while 258 patients received consolidation chemotherapy contained 4–6 cycles high dose Ara-C (HD-Ara-C). Overall survival (OS) and Event-free survival (EFS) were measured at last follow-up (censored), and Kaplan-Meier analysis was used to calculate the distribution of OS and EFS. Results:In 442 AML (None-APL) patients, 44 patients (9.7%) had C-KIT mutations, 97 patients (21.9%) had NPM1 mutations, 95 patients (21.5%) had FLT3-ITD mutations, 26 patients (5.9%) had FLT3-TKD mutations, 23 patients (5.2%) had IDH1 mutations, 48 patients (10.9%) had IDH2 mutations, 31 patients (7.0%) had DNMT3A mutations, and 40 patients (9.0%) had NRAS mutations. Using COX regression, we found that mutations in FLT3-ITD (HR:2.113; 95%CI: 1.1420 to 3.144),IDH1 (HR:3.023; 95%CI: 1.055 to 3.879), NRAS (HR:1.881; 95%CI: 1.021 to 2.945), and DNMT3A (HR: 2.394; 95%CI: 1.328 to 4.315) were independent unfavorable prognostic indicators of overall survival of AML patients. We further compared the outcomes of AML patients with such gene mutations followed different therapy (HSCT vs. HD Ara-C), and results shown that patients with mutations in IDH1, NRAS and DNMT3A received HSCT therapy had better survival. The median OS and EFS of patients with FLT3-ITD, IDH1, NRAS and DNMT3A in the two groups (HSCT vs. HD Ara-C) were as follows: IDH1 (OS: 35 months vs. 11 months, p=0.016; EFS: 34 months vs. 8 months, p=0.012), NRAS (OS: 27months vs. 8 months, p=0.008; EFS: 23 months vs. 4 months, p=0.049), DNMT3A (OS: 66 months vs. 19 months, p=0.008; EFS: 54 months vs. 13 months, p=0.002). Conclusions:Taken together, our data proved that mutant FLT3-ITD, IDH1, NRAS, and DNMT3A might serve as poor prognostic markers and hematopoietic stem cell transplantation as first-line treatment could favor the outcome of AML patients carrying IDH1, NRAS, and DNMT3A mutations. Disclosures:No relevant conflicts of interest to declare.

Comparable Toxicity and Outcome of Acute Myeloid Leukemia (AML) Fit Patients Therapy Independently If Daunorubicin or Idarubicin Were Added to Cytarabine/Cladribine Induction Regimens – the Single Centre Study

AbstractAbstract 4337This trial is a continuation of the earlier studies concerning optimalization of induction chemotherapy in acute myeloid (AML) patients using purine analogues (Ho≥owiecki J., Grosicki S., Robak T. et al. Leukemia 2004, Holowiecki J, Grosicki S, Giebel S. et al. J Clin Oncol. 2012).The goal of the study was to evaluate the toxicity and efficacy of combination including idarubicin – IAC (idarubicin 10 mg/m2/d iv, d 1–3; cytarabine 200 mg/m2/d ci, d 1–7, cladribine 5 mg/m2/d d 1–5) in comparison with DAC (daunorubicin 60 mg/m2/d iv d 1–3 in place of idarubicin).The primary endpoints were complete remission rate (CR) and toxicity, the secondary one was overall survival (OS).Patients who achieved CR received two courses of subsequent intensive consolidation: HAM (HD AraC, mitoxantrone) and HD AraC. Reduction of consolidation was accepted in patients treated with early alloBMT. In case of partial remission (PR) after the first induction course the same regimen was repeated. Patients with no remission (NR) or with PR after 2 induction courses were withdrawn from the study.Between 03.2009 and 03.2012, 52 adult untreated patients aged median 57 years (20–72), treated in one center - Department of Hematology of City Hospital in Chorzow/Poland were included to this study; 46% of study participants were male, 54% female and they were evaluated as fit with possibility of intensive chemotherapy including HSCT. PML/RAR alfa positive – FAB M3 cases were excluded.DAC regimen was a standard induction in this group of AML patients. When there was no possibility to apply DAC regimen because of not having access to daunorubicin in our center, the IAC regimen was used.Material and the results are summarized in the table.OutcomeDAC (n = 30)IAC (n = 22)pAge (median)20–72 (55)38–70 (59)NSSex (%)K-53, M-47K-55, M-45NSWBC at dgn. × 103/L median (range)27,7 (2,3–257)11,0 (0,9–210)NSCytogenetic risk (%)Low00NSintermediate5064NSHigh75NSNo data4331NSHSCT (n) auto/allo2/71/5NSCR rate (%)7059NS3-yr OS (%)2623NS2-yr LFS (%)2836NSThe study groups were well balanced with respect to age, sex, WBC and cytogenetics. The entire CR rates in both groups did not differ, and they were similar to previously published results after DAC induction regimen. All patients developed WHO grade IV thrombocytopenia and agranulocytosis. The frequency and severity of infections, mucositis, vomiting, diarrhea, alopecia, polyneuropathy as well as of cardiac, liver or kidney dysfunctions were comparable in particular arms. There were no significant differences in the OS and LFS rates.In conclusion, the results of our study authorize the replacement of daunorubicin to idarubicin in DAC induction regimen without risk of additional toxicity, and with similar outcome. Disclosures:No relevant conflicts of interest to declare.

Central Nervous System (CNS) at First Relapse In APL. A Report on 2 Multicenter Trials.

AbstractAbstract 1084 Background:CNS relapse is rare in APL, and predominates in patients (pts) with increased WBC counts. (De Botton, Leukemia, 2006,20,35; Montesinos, Haematologica,2009,94,1242). We report the incidence, risk factors and outcome of CNS relapse in 2 multicenter clinical trials of the European APL group. Methods:Between 1993 and Feb 2004 (when randomization for AraC in APL 2000 trial ended), 916 APL patients (pts) were included in APL93 (n=576) and APL 2000 (n=340) trials, and 92.2% of them achieved CR (Ades L, Blood 2010, Ades L, JCO 2006). In both trials, induction treatment consisted of ATRA (45 mg/m2/d until CR) and DNR 60mg/m2/d x3 + AraC 200 mg/m2/dx7 followed by a first similar consolidation course and a second course with DNR 45 mg/m2/d x3 and AraC 1g/m2/12hx8 (except in one arm of APL 2000 trial where pts with WBC<10G/L received no AraC for induction and consolidation). A 2 year maintenance treatment, consisting of intermittent ATRA (15d/3 months) and continuous 6MP+ MTX, was administered or not (randomized) in APL 93 trial, and was systematic in APL 2000 trial. In APL 2000 trial, intrathecal CNS prophylaxis with MTX+ AraC (5 injections) was made during consolidation cycles in all pts with baseline WBC > 10G/L. Median follow up was 10 and 5 years, respectively, in APL 93 and APL 2000 trial. Results:6 first relapses involving the CNS were seen (3 in APL 93 and 3 in APL 2000 trial), after 6 to 37 months (median 15 months), representing 3% of the relapses (2% and 6% in APL 93 and 2000, respectively) and 0.7% of the pts who had achieved CR (0.56% and 0.9% in APL 93 and 2000, resp). Of the 6 CNS relapses, 1 was isolated and 5 accompanied by relapse in the bone marrow (haematological in 4 cases, and only molecular in 1 case). Median age was similar (46y) in pts who had or not CNS relapse. Median WBC count was 7.9 G/l in pts with CNS relapse vs 2.5G/l in pts without CNS relapse (p=0.07). 5 of the 6 pts with CNS relapses had WBC> 5G/L, but only 2 had WBC > 10G/l. Among pts who achieved CR, 3 of the 146 (2.05%) pts who received no Ara C had CNS relapse versus 3 of the 699.(0.4%) pts who received AraC (with HD araC in the last consolidation course) (p= 0.06). In pts with WBC > 10G/l, none of 72pts in APL 2000 (who received both HD araC and intrathecal CNS prophylaxis) had CNS relapse, compared 2 of the the 123 (1.6%) pts in APL 93 trial (who received HD araC and no intrathecal CNS prophylaxis). The 6 pts with CNS relapse were all salvaged by intrathecal CT, combined to ATRA and systemic CT in APL 93, and ATO in APL 2000 trial.4 of them were durably salvaged, 3 after auto SCT and 1 after ATO and CT. Conclusion:CNS relapse was very rare in APL in our experience, and only 2 of 6 pts with CNS relapse had baseline WBC > 10G/l. CNS relapse was generally associated to concomitant marrow relapse (sometimes only molecular), and was seen in 0.4% and 2.05% pts treated with and without HD AraC, respectively (p=0.06), suggesting a possible preventive role of HD AraC, although numbers were small to conclude. Interestingly, by comparison, in the Spanish PETHEMA experience where pts received no AraC, 1.6% of the 667 pts who achieved CR had CNS relapse (Montesinos, Haematologica, 2009, 94, 1242). On the other hand, the role of intrathecal CNS prophylaxis was unclear in our experience. Finally, outcome of CNS relapses was better than in our previous report (De Botton, Leukemia, 2006,20,35), possibly due in part to the recent treatment of relapses by ATO, known to penetrate the blood brain barrier (Au et al, Blood, 2008,3587) and which could also play a role in CNS prophylaxis when administered during first line treatment. Disclosures:Fenaux:CELGENE, JANSSEN CILAG, AMGEN, ROCHE, GSK, NOVARTIS, MERCK, CEPHALON: Honoraria, Research Funding.

The Use of Purine Analogues During Induction and Consolidation Therapy of Acute Myeloid Leukemia Does Not Increase the Need for More Frequent Transfusions of Red Blood Cell Concentrates, Platelet Concentrates and Fresh Frozen Plasma

AbstractAbstract 4358 BackgroundAddition of purine analogues to standard induction therapy of acute myeloid leukemia (AML) had previously been demonstrated to increase complete remission rate and does not aggravate infectious complications. The aim of this study was to analyze whether the use of cladribine or fludarabine during induction and consolidation treatment increase the need for more frequent transfusions of red blood cell concentrates, platelet concentrates and fresh frozen plasma. Material and methods118 AML patients, included in two consecutive randomized trials between 1999–2006 in a single centre were analyzed. Induction therapy consisted of daunorubicin + cytarabine (DA-7, n=53) alone or in combination with cladribine or fludarabine (DAC-7 + DAF-7, n=65). Consolidation included one course of high-dose AraC + mitoxantrone and one course of high-dose AraC +/− purine analogues. A median age was 45(17-58) years and 48(20-60) years for patients treated with and without purine analogues, respectively. ResultsDuring induction treatment 7 (1-19) units of red blood cell concentrates (median and range) was transfused in the group with purine analogues compared to 6 (1-23) in the group without purine analogues, p=0,24. Number of transfused platelet concentrates bags was 6 (1-30) in the group of purine analogues and 7 (0-19) in the group without purine analogues, p = 0.49. In the group with purine analogues 0 (0-31) units of fresh frozen plasma was transfused compared to 0 (0-26) in the group without purine analogues, p = 0.91.During HAM consolidation therapy 3 (0-11) units of red blood cell concentrates was transfused in the group with purine analogues compared to 2 (0-9) in the group without purine analogues, p = 0.15. Number of transfused platelet concentrates bags in the group with purine analogues was 2 (0-8) vs. 2 (0-12) in the group without purine analogues, p = 0.25. In the course of HAM consolidation treatment - 0 (0-56) units of fresh frozen plasma was transfused in the group with purine analogues compared to 0 (0-0) in the group without purine analogues, p = 0.027.During HD Ara-C consolidation therapy 3 (0-7) units of red blood cell concentrates was transfused in the group with purine analogues compared to 2 (0-5) in the group without purine analogues, p = 0.03. Number of transfused platelet concentrates bags in the group treated with purine analogues was 3 (1-12) vs. 3 (1-6) in the group without purine analogues, p = 0.61. In the course of HD Ara-C consolidation treatment 0 (0-9) units of fresh frozen plasma was transfused in the group with purine analogues compared to 0 (0-11) in the group without purine analogues, p=0,34. ConclusionsThe vast majority of the obtained results did not reveal any significant differences between the group of AML patients treated with or without purine analogues.During HAM consolidation treatment statistical significance for more fresh frozen plasma units transfused was shown in the patients treated with purine analogues, although the median value was the same in both groups (0). This situation was random and independent of prior use of purine analogues in the induction therapy, because in one of the woman-patient gynecological complications and DIC occurred (bleeding from uterine fibroids). This situation required intensive supportive therapy including fresh frozen plasma transfusions. In one case 56 units of fresh frozen plasma was transfused and in second arm of the study was not applied a plasma transfusions in any patient.Also during second (HD Ara-C) consolidation treatment number of transfused units of RBC's concentrates was significant higher in the group of patients treated with purine analogues, although the median values were similar (3 vs 2). These differences may arise from the fact that in some patients - especially in group of patients treated with purine analogues who obtained the better results of therapy – second HD Ara-C treatment was also more often followed by mobilization and collection of stem cells from peripheral blood for transplantation. In the procedure of stem cells collection a higher hematocrit value is recommended – so frequent decision for RBC's transfusions was made in this group of patients.We conclude that the use of purine analogues in the treatment of AML patients does not increase the need for more frequent transfusions of red blood cell concentrates, platelet concentrates and fresh frozen plasma. Disclosures:No relevant conflicts of interest to declare.

Incidence Rate of Thromboembolic Events (TE) In a Prospectively Evaluated Population of Patients with Lymphoma Enrolled In First Line Treatment Clinical Trials: a Report From the Gruppo Italiano Per Lo Studio Dei Linfomi (GISL)

AbstractAbstract 4208 Introduction:Patients with lymphoma are considered at high risk of thrombosis, due to the disease itself or to the use of chemotherapy. The global risk of thrombosis is around 5%, higher in Non Hodgkin Lymphoma compared to Hodgkin Lymphoma and in advanced stages compared to localized disease. So far few studies have addressed the risk of thrombosis in lymphomas with a prospective approach. In 2007 we started a prospective study on patients with malignant lymphoma (ML) to assess the risk of thromboembolism in such patients and to identify possible risk factors. Methods:from March 1st 2007 all patients enrolled in any of the active clinical trials conducted by the Gruppo Italiano Studio Linfomi for the initial treatment of ML were screened for the occurrence of thromboembolic events (TE) at 3 timepoints: at the time of diagnosis (D), during chemotherapy (C) and during follow-up (F). For each registered TE additional data were required with respect to presence of additional risk factors (drugs, bed stay, comorbidities), concomitant use of anticoagulants, venous catheter implant. A detailed description of TE with treatment and outcome details was also required. Results:as of July 20th 2010, 643 patients have been registered in an active GISL clinical trial. Lymphoma subtype was Follicular Lymphoma (FL) in 70%, Indolent Non Follicular Lymphoma (INFL) in 10%, Hodgkin Lymphoma (HL) in 6%, Mantle Cell Lymphoma (MCL) in 6%, Diffuse Large B Cell Lymphoma (DLBCL) in 7%. Patients had a median age of 57 years (range 16 to 86), the male to female ratio was 1.16: Stage was advanced (III-IV) in 84%. Median follow-up was 18 months.Overall 27 TE have been reported, which corresponds to a proportion of 4.4%. Most events occurred during treatment or follow-up (15 and 6 at C and F timepoints, respectively), while TE proportion at D was low (0.9%). TE rate (×100 person-year) was 3.9 in MCL, followed by other lymphoma subtypes: HL 3.8, FL 2.6, DLBCL 2.4, and INFL 1.8. Interestingly, in MCL all the TE occurred at the C and F timepoints, and these patients were treated with an intense chemotherapy regimen (alternating R-hyperCVAD and HD ARA-C and mtx), while other lymphomas received conventional dose chemotherapy. Overall, the only parameter associated with TE development was PS>2 (RR 6.2, P=0.013), while the RR is 3.8 (P=0.188) if the 21 TE at C+F timepoints are considered.So far, detailed informations concerning TE were received for 20 patients. Of these, only 3 had comorbidities (1 case of diabetes mellitus, 1 case of cardiovascular disease and 1 case of prostatic adenocarcinoma receiving hormonotherapy) and no prior DVT or PE have been described. Two of the 5 cases of bedridden patients stayed in bed for more than 7 days before experiencing TE. Seventeen patients took no thrombogenic drugs as ongoing estroprogestinic therapy or hormonotherapy. Five patients had a venous catheter implant, which was removed only in 1 case due to thromboembolic occurrence. Overall we registered 7 cases of PE and 13 cases of DVT. When looking at the TE event description, 14 patients have been recorded as symptomatic and 4 were already treated with anticoagulants when the TE was diagnosed. The most frequent sites of TE were femoral vein or jugular vein (3 and 3 events, respectively), while the principal diagnostic tool employed for the TE diagnosis was Color Doppler ultrasound. Conclusions:To the best of our knowledge this is the study with the highest number of newly diagnosed patients with ML prospectively considered for the risk of TE. It shows a lower than expected rate of TE, probably because there is a representation of the different histotypes which doesn't replicate the real incidence: Follicular Lymphoma, a subtype with low risk of TE, is certainly over-represented. Our data suggest that therapy is the most important cause for TE. Further analyses on reported events may help to identify additional risk factors. Disclosures:No relevant conflicts of interest to declare.

Pediatric-Type Therapy Including Lineage-Targeted Methotrexate to Improve Early Minimal Residual Disease Response and Survival In Adult Acute Lymphoblastic Leukemia (ALL): Interim Analysis of Northern Italy Leukemia Group Study 10/07

AbstractAbstract 2131 Background.Some studies have shown how the use of pediatric-type therapy (PDT) and minimal residual disease (MRD)-oriented programs could improve outcome of adult ALL. Study Design.We included PDT elements in a pilot trial started January, 2008. Protocol 10/07 consisted of standard induction and late reinduction courses plus 3 PDT blocks (modified after BFM therapy) alternating with 3 lineage-targeted Methotrexate (LTM) blocks (B-precursor: 2.5 g/m2; T-precursor: 5 g/m2; Ph+ or age >55 years: 1.5 g/m2). LTM targeted a Methotrexate plasma concentration of ∼35 and ∼65 micromol/L in B- and T-ALL, respectively, in line with a therapeutic concept developed at St. Jude's Hospital (Memphis, TN, USA) in childhood ALL. The program was integrated by (a) a randomised, radiation-free central nervous system (CNS) prophylaxis study comparing intrathecal Methotrexate, Ara-C, and Prednisone (×12) vs. liposomal Ara-C (DepoCyte 50 mg, ×6 [B-ALL]-8 [T-ALL]); (b) the molecular evaluation of MRD at pre-fixed treatment weeks (w), to optimise risk stratification and indications for allogeneic stem cell transplantation (allo-SCT); and (c) by concurrent imatinib in patients with Ph+ ALL. The whole chemotherapy plus MRD study sequence was as follows: prephase (Prednisone, Cyclophosphamide) → induction (Idarubicin, Vincristine, Asparaginase, Dexamethasone) + w4 MRD → PDT1 (Cyclophosphamide, Vincristine, Idarubicin, Dexamethasone, Ara-C, 6-mercaptopurine) → LTM1 (plus high-dose Ara-C) + w10 MRD → PDT2 → LTM2 (plus Asparaginase) + w16 MRD → PDT3 → LTM3 (plus HD Ara-C) + w22 MRD → reinduction (Idarubicin, Vincristine, Cyclophosphamide, Dexamethasone). CNS prophylaxis was administered only during PDT blocks, with a minimum interval >15 days from/to LTM cycles. Risk classes were standard (SR: pre-B and WBC<30; cortical T and WBC<100; CR at cycle 1) and high (HR: other subsets). Allo-SCT was prescribed as soon as possible to all patients with Ph/t(4;11)+ ALL or other highly adverse cytogenetics; with WBC >100, or CD1a-negative early or mature T phenotype; and to SR/HR patients with MRD >10-4 after LTM1 (w10) or detectable at any level after LTM3 (w22). Autologous SCT followed by maintenance was a suitable alternative when allo-SCT was not feasible. All patients not eligible to frontline allo-SCT and with low positive (<10-4) or negative MRD results were submitted to standard maintenance. Results.Seventy-five of 81 evaluable patients (median age 40 years [range 18–65], 54% male, 23% T-ALL, 60% HR, 20% Ph+) achieved CR (92.5%); 55 of them (73.5%) were alive in CR1 at time of interim analysis (April, 2010). Sixteen patients relapsed (21.5%) and four died in CR of therapy-related complications (one after allo-SCT and 3 aged >55 years after a PDT cycle). With a maximum follow-up slightly >2 years (27.5 mos.), projected overall survival (OS) at 1.5 years is 73% (95% CI 57%-83%), and disease-free survival (DFS) 66% (95% CI 52%-77%). The best results were observed in patients aged 55 years and less (n=65, OS 79%) and those with T-ALL (n=20, OS 86%). These findings correlated well with a favourable early MRD response in Ph-negative subsets: 49% of evaluable cases achieved a major MRD response (<10-4) at end of induction cycle (w4: MRD negative 6/13 T [46%] vs. 7/24 B [29%]; <10-4 2 T and 3 B; overall 61.5% T and 42% B), as did 64% of the patients after LTM1 (w10: MRD negative 11/15 T [73%] and 16/27 B [59%]; <10-4 2 T and 1 B; overall 87% T and 63% B). MRD results were predictive of CR durability. Pooled MRD data from all time-points (w4-22) indicated a probability of CR of 92% in 18 patients with all results <10-4 vs. 60% in 19 patients with at least one MRD value >10-4 (P=0.039). The flexible risk- and MRD-adapted SCT policy resulted in high early transplantability rate in patients with this indication (70% in T-ALL). Finally, the randomised CNS prophylaxis trial preliminarily confirmed the feasibility of intrathecal DepoCyte as planned (total randomised patients = 57). Conclusions.This regimen was highly active, yielding a >90% CR rate in unselected adults aged up to 65 years, with a major early MRD response of 63% in Ph-negative B-ALL and 87% in T-ALL. The toxicity observed after PDT blocks in a first group of patients aged >55 years required a reduction of PDT dose intensity in this age group. LTM therapy proved feasible, up to 5 g/m2 in T-ALL, and remarkable early OS/DFS rates were obtained in T-ALL and in unselected patients aged <55 years. Disclosures:Bassan: Mundipharma: Consultancy, Research Funding. Off Label Use: Study is devoted to assess feasibility/toxicity/value of intrathecal liposome-encapsulated cytarabine (DepoCyte) vs standard intrathecal therapy as prophylaxis of CNS recurrence in adult ALL.

Gemtuzumab-Ozogamicin as Post-Consolidation Therapy In Elderly Patients with Acute Myeloid Leukemia: a Pilot Study

AbstractAbstract 4357The optimal post-remission treatment for elderly patients with acute myeloid leukemia (AML) is presently unknown.We evaluated safety and efficacy of low dose Gemtuzumab-Ozogamicin (GO) as post-remission late consolidation therapy in a cohort of 19 consecutive patients, enrolled in a pilot prospective study. Between June 1999 and February 2010 we observed 152 elderly patients, aged more than 60 years and affected by AML. One hundred and two patients (67%) were considered fit for aggressive therapy and received intensive induction and consolidation therapy including HD Ara-C, Idarubicine and Amifostine. Thirty-nine patients (38%) were over 70 years, 38% had a secondary disease, 35% unfavourable, 45% intermediate and 4 % favourable prognosis Karyotype. Those achieving successful mobilization received autologous transplant while poor mobilizers received a second consolidation with three monthly courses of GO 3 mg/sm i.v. followed by three other courses of GO administered every 3 months.Seventy-two patients achieved CR (69%) after induction: one patiente died in CR, 5 patients had a PS ≥2 and the remaining 66 were elegible for first consolidation. Fifty of these maintained the CR status and received a second consolidation: 19 with GO, 20 with Autologous transplant, and 6 with chemotherapy alone for patient decision. Five patients with a family donor received Allogeneic Transplant and were not included in this analysis.GO was well tolerated: no major adverse events were seen. We overall observed 18 WHO grade III/IV adverse events were all transitory and included hematological toxicity (n = 17), hypertransaminasemia (n = 1).Eight patients (42%) relapsed after GO consolidation and received a GO reinduction: five eventually died after a median follow-up of 13 months while three are still alive with a median follow up of 10 months. Five out of 20 patients died of transplant related toxicity (25%) and 9 relapsed (45%) after autologous transplant. All nine patients died of progressive disease. Five of the 6 patients receiving chemotherapy (83%) relapsed and died.Five years Overall survival was 22% and Disease Free Survival 29.5% in the whole cohort of patients (median follow-up: 50 mouths). The landmark analysis showed a superior outcome in patients receiving GO with a 60% 5 yrs OS and DFS (median follow-up: 60 months) in comparison with patients receiving autologous transplant (28% 5 yrs OS and DFS with median follow-up 70 months) and chemotherapy (17% 5 yrs OS and DFS with a median follow-up of 77 months) (p= 0.009). In conclusion patients receiving GO had a better outcome in comparison with patients receiving autologous transplant and chemothearapy. High percentages of poor mobilizers and transplant related mortality seem to jeopardize autologous transplant feasibility and safety in elderly patients. GO showed to be an alternative and feasible choice in our series, with a low relapse rate, and a low toxicity profile. Disclosures:Leoni:Celgene: Honoraria.

Cladribine in Combination with Standard Daunorubicine and Cytarabine (DAC) as a Remission Induction Treatment Improves the Overall Survival in Untreated Adults with AML Aged < 60 y Contrary to Combination Including Fludarabine (DAF): A Multicenter, Randomized, Phase III PALG AML 1/2004 DAC/DAF/DA Study in 673 Patients-A Final Update.

Abstract 2055Poster Board II-32This trial is a continuation of earlier Polish Adult Leukemia Group (PALG) studies on the use of purine analogues for therapy of AML patients (Leukemia 2004,18:989–97, updated at 7 y: ASH 2006, Abstr.N#2003, Ann Hematol. 2008, 87:361–7).The goal of the present study was to evaluate the efficacy of combination including fludarabine – DAF (daunorubicine 60 mg/m2/d iv, d 1–3; cytarabine (AraC) 200 mg/m2/d ci, d 1–7, and fludarabine 25 mg/m2 iv d 1–5) in untreated adult patients with AML, based on head to head comparison with DAC (DNR, AraC, Cladribine), and standard DA regimens (preliminary results: ASH 2008, abstr.#133).Primary end-points were: complete remission rate (CR) and overall survival (OS); secondary objectives were: toxicity and leukemia-free survival (LFS). Patients achieving CR received two courses of subsequent intensive consolidation: HAM (HD AraC, mitoxantrone) and HD AraC. Reduction of consolidation was accepted in patients treated with early alloBMT. In case of partial remission (PR) after the first induction course the same regimen was repeated. Patients with no remission (NR) or with PR after 2 induction courses were withdrawn from the study.Between 09.2004 and 05.2008, 673 adult untreated AML patients aged 18–60 y, median 47 y, sex: male 49,5%, female 50,5%, treated in 18 co-operating PALG centers were centrally randomized to either DAF (n=225), DAC (n=224) or DA (n=224) arm (1:1:1). PML/RAR alfa positive - FAB M3 cases were excluded. The study groups were well balanced in respect of age, sex, FAB subtype, and WBC. The results are summarized in the table.OutcomeDAC (n = 223)DAF (n = 219)DA (n = 210)P Value (DAC vs DA)P Value (DAC vs DAF)CR685956.013.08CR after 1 cycle625550,5.017163-yr OS46303102.022-yr LFS474039NSNSBoth, the entire CR rate and the CR rate after a single induction course were significantly superior in the DAC arm if compared with DA and DAF subgroups. With a median follow-up of 34 months (the longest observation time 5y) the OS rate equaled 46% for the DAC treated subgroup and was higher in comparison to the standard DA arm and the DAF arm. There were no significant differences in the leukemia free survival rates. The early death rates of 8,5–11%. were similar in the studied treatment subgroups. All patients developed WHO grade IV thrombocytopenia and agranulocytosis. The frequency and severity of infections, mucositis, vomiting, diarrhoea, alopecia, polyneuropathy as well as of cardiac, liver or kidney dysfunctions were comparable in particular arms.In conclusion, this updated results of randomized study prove that the incorporation of cladribine to the standard DA induction regimen (DAC) improves CR rate and the overall survival in adults with AML aged up to 60 y, without additional toxicity. This beneficial effect was not observed in patients treated using the DAF protocol with fludarabine added to the standard “DA 3+7” schedule. Disclosures:Robak:Celgene: Consultancy; Roche: Honoraria, Research Funding; Genmab: Research Funding; Cambridge Antibody Technology: Research Funding; GlaxoSmithKline: Honoraria. Warzocha:BMS: Consultancy, Honoraria; Celgene: Consultancy; Roche: Honoraria; Pfizer: Honoraria; Amgen: Honoraria.

Attempts to Optimise Induction and Consolidation Chemotherapy in Patients with Acute Myeloid Leukaemia: Results of the MRC AML15 Trial.

Abstract 484On behalf of the NCRI AML Working Group, United KingdomThere is a general acceptance that survival in younger patients (<60 years) with AML has improved over the last 20 years, the majority still fail treatment. While the induction rate is satisfactory at >75% relapse remains a problem. Optimisation of induction and defining the schedule and duration of post-induction chemotherapy remains important even as novel approaches such as antibody directed therapy or small molecule therapy are added. The MRC AML15 compared 3 induction chemotherapy schedules and 4 post induction options. In induction patients were randomised to two course of DA or ADE or FLAG-Ida. In each case patients were also eligible to be randomised to receive Gemtuzumab Ozogamicin (GO) or not, which has been separately reported. In consolidation patients were randomised to MRC schedule (MACE/MidAC) or two courses of High Dose Ara-C and for those randomised to Ara-C to a dose of 3g/m2 or 1.5g/m2. Finally patients could be randomised to receive, or not, a 5th course comprising Ara-C.Between October 2002 and January 2009, 1982 patients were randomised between DA (n=994) and ADE (n=988); up to May 2007, patients could also be randomised to FLAG-Ida; the randomised comparison with ADE recruited 1266 patients (FLAG-Ida n=635, ADE n=631). For part of the trial patients could be randomised to GO or not (306 patients in the DA v ADE and 297 in the FLAG-Ida v ADE comparisons were randomised). The median age of patients in the randomised comparisons was 49 years. Overall the ORR was 85% (CR 80%, CRi 5%) and the OS at 5 years is 43%. The randomisations were balanced for age, sex, performance status, de Novo/secondary disease, cytogenetics, white cell count, and GO allocation.Induction outcomesCRCRi30-day mortality5 year relapse5 year RFS5 year OSDA76%7%6%56%38%42%ADE80%6%5%53%35%39%OR/HR, 95% CI1.27 (1.03-1.58)ORR: 1.26 (0.99-1.61)1.00 (0.85-1.18)1.01 (0.88-1.17)1.03 (0.90-1.18)p-value0.030.061.00.80.7FLAG-Ida84%2%6%42%48%46%ADE81%4%6%54%37%41%OR/HR, 95% CI0.84 (0.63-1.13)ORR:0.95 (0.69-1.29)0.69 (0.58-0.84)0.82 (0.69-0.96)0.95 (0.82-1.11)p-value0.30.70.00010.020.5With the exception of a suggestion of greater benefit on ORR with FLAG-Ida among patients given GO, overall outcomes were not affected by GO treatment. In consolidation 1445 patients were randomised between MRC (n=723) and HD Ara-C (n=722). Of the 723 Ara-C patients, 328 were randomised to 3g/m2 and 329 to 1.5g/m2: 227 of the 1619 patients who received 4 courses were randomised for a 5th course with 112 allocated 5 courses.Post-induction outcomes5-year death in CR5 year relapse5 year RFS5 year OSAra-C10%53%42%54%MRC15%51%42%52%OR/HR, 95% CI0.66 (0.44-0.98)1.07 (0.90-1.26)0.99 (0.85-1.16)0.89 (0.74-1.07)p-value0.040.50.90.2Ara-C 1.5g9%58%38%54%Ara-C 3g14%51%43%52%OR/HR, 95% CI0.62 (0.32-1.18)1.17 (0.92-1.49)1.09 (0.87-1.36)0.94 (0.72-1.24)p-value0.140.20.50.75 courses0%58%42%60%4 courses1%53%46%58%OR/HR, 95% CI1.25 (0.02-6.30)1.02 (0.70-1.50)1.00 (0.68-1.47)0.91 (0.56-1.47)p-value1.00.91.00.7 Conclusions:There were no significant differences in the response rate between induction treatments. FLAG-Ida resulted in a reduced relapse rate but this was balanced by increased myelosuppression and deaths in CR resulting in no overall benefit in survival. No survival differences were seen in any of the post induction comparisons, but the MACE/MidAc arm produced more myelosuppression and required more supportive care, and led to increased death in remission. Disclosures:No relevant conflicts of interest to declare.

Therapeutic management of central nervous system lymphomas in a single hematological institute

Primary central nervous system lymphoma is defined as an extranodal lymphoma arising in the central nervous system in the absence of systemic disease. Because of their rare occurrence among lymphomas, optimal treatment could hardly be established. In this retrospective survey we analyzed the result of combined treatment (systemic and intrathecal chemotherapy followed by consolidation radiotherapy) in patients with primary or relapsed central nervous system lymphomas diagnosed and treated in our hematological department between 1998-2009. During this period (mean follow-up of 13.2 months) from 427 patients with newly diagnosed non-Hodgkin's lymphomas, 22 primary central nervous system lymphoma was diagnosed (5.15%, 16 cerebral and 6 spinal cord lymphoma cases). Significant male predominance (14:8) was registered with an age distribution of 34-77 years (mean = 60.7, median = 64 years). No patients were immunocompromised. All central nervous system lymphoma specimens taken with neurosurgical resection or stereotaxic biopsies were confirmed histopathologically. All cerebral lymphoma cases proved to be diffuse large B-cell of origin, while in epidural lymphomas low grade subtypes also occurred. Epidural lymphomas were treated with local radiotherapy (30-40 Gy), except for patients with follicular lymphomas getting rituximab-containing polychemotherapy (R + CHOP regimen) before irradiation. In cerebral lymphoma (every patients had supratentorial localization) the following combined therapy protocol was used: up to three courses of high dose methotrexate (HD MTX 3g/m 2 in a single dose for 4 hours lasting drop-infusion) were given at 4-week intervals, followed by leucovorin-rescue 24 hours after MTX infusion. Intrathecal combination of methotrexate, cytosin-arabinosid and dexamethasone was given three times after HD MTX infusion. In complete response after chemotherapy (evaluated by cranial MRI or CT, PET/CT), whole-brain irradiation was used in a total dose of 30 Gy. In case of partial response, boost irradiation for the tumor bed was also given. In relapse or resistant cases, salvage regimen was applied: HD MTX course combined with high dose cytosin-arabinosid (HD Ara-C) 3g/m 2 /dose b.i.d. over 4 h c.i., repeated in three cycles every four weeks. Complete remission has been achieved in 9 patients with cerebral and in 4 patients with spinal cord lymphoma (13/22; 59.0%), however, one relapsed patient became resistant and later expired, despite salvage therapy. Primarily 9 patients were not evaluable for response: 5 received only one or two HD MTX because of side effects, 4 patients died due to progression of the disease. Mean of the overall survival (OS) in cerebral lymphoma was 19.5 (3-46, median of 10) months, in epidural group 14.1 (2-76, median of 5) months, whilst mean time to progression (TTP) was 4.5 (2-6.5, median of 4 months). The 2-year survival for all patients was 50%. Acute toxicity of chemotherapy was usually hematological, moreover, in 8 patients impaired renal function and sepsis developed. No serious adverse effect of radiotherapy could be detected. In primary central nervous system lymphoma, basic treatment HD methotrexate together with intrathecal combination of methotrexate + cytosin-arabinosid + dexamethasone followed by whole-brain irradiation of at least 30 Gy could produce a medium response rate in our study. In case of relapse or progression, other salvage regimens containing HD Ara-C alternating with HD MTX could reduce the treatment failure, as well. After therapy PET/CT was negative in five patients with prolonged disease-free survival.

High dose ara-C in the treatment of newly diagnosed acute promyelocytic leukemia: long-term results of the German AMLCG

The objective of this study for newly diagnosed acute promyelocytic leukemia (APL) was to evaluate the efficacy of an intensified double induction chemotherapy including high dose ara-C (HD) and all-trans retinoic acid (ATRA) followed by consolidation and 3 years maintenance therapy. In contrast to APL studies stratifying therapy according to pretreatment white blood cell (WBC) count < and > or =10 x 10(9)/l (low/intermediate and high risk according to the Sanz score), our patients received uniform therapy. From 1994 to 2005, 142 patients (age, 16-60 years) were enrolled. In the low/intermediate (n=105) vs high (n=37) WBC group, the rates of complete remission were 95.2 vs 83.8%, of induction death were 4.8 vs 16.2% (P=0.05) and of molecular remission were 87.5 vs 91.3% (P=1). Long-term overall survival was 84.4 vs 73.0% (P=0.12), event free survival was 78.3 vs 67.3% (P=0.11), relapse free survival was 82.1 vs 80.0% (P=0.83) and the cumulative incidence of relapse was 7.4 vs 11.4% (P=0.46). No relapse or death occurred after 4.7 years. ATRA and intensified chemotherapy including HD ara-C followed by prolonged maintenance therapy reduced the relapse risk in high risk patients. Pretreatment WBC count > or =10 x 10(9)/l count was no relevant prognostic factor for relapse.

High Dose (HD-AraC) Vs Standard Dose Cytosine Arabinoside (SDAraC) during Induction and Value of IL-2 during Maintenance in Acute Myelogenous Leukemia (AML): Impact of AraC Dose on Complete Remission Rate and Toxicity (Results on the first 1700 randomized patients of the AML-12 trial of EORTC and GIMEMA Leukemia Groups)

The AML-12 randomized phase III trial of EORTC-LG and GIMEMA assessed the efficacy and toxicity of HD-AraC (3 g/m2/12 hrs for 4 days) combined with daunorubicin (50 mg/sqm for 3 days) and etoposide (50 mg/sqm for 5 days) vs SD-AraC (100 mg/sqm for 10 days) with the same drugs. Patients (pts) in complete remission (CR) received consolidation consisting of AraC (500 mg/sqm/12 hrs for 6 days) and daunorubicin. Subsequently an allogeneic (allo-SCT) or autologous stem cell transplantation (auto-SCT) was planned according to donor availability and age. A 2nd randomization was performed after CR in pts without a donor: auto-SCT followed or not by low dose IL-2. The trial was powered to detect an 8% difference in the 5-yr survival rate; secondary endpoints were response to induction, DFS, toxicity. Randomization was performed centrally; the 1st randomization was stratified for age, performance status, WBC and center. Intent-to-treat analysis was done. From 9/1999 till 1/2008, 2005 previously untreated AML pts (APL excluded), age<61 years, (891 by EORTCLG and 1114 by GIMEMA) were randomized. Currently for 1700 pts (857 in SD-AraC vs 843 in HD-AraC arm) sufficient information on remission induction response is available. The median follow up is 3 years. After 1 or 2 courses of induction, CR was achieved in 631 (73.6%) pts (SD-AraC group) vs 680 (80.7%) pts (HD-AraC group): p=0.001. Partial remission or resistance was documented in 161 (18.8%) vs 114 (13.5%) pts, and death in induction in 65 (7.6%) vs 49 (5.8%). Induction toxicity profile and grade was similar in the 2 arms except for conjunctivitis grade 3: 0.1% (SD-AraC) vs 4.4% (HD-AraC). Currently in 909 pts cytogenetic information is not yet available and in 791 pts cytogenetic information is known. Comparison of SD-AraC vs HD-AraC according to cytogenetic subgroups is shown in the Table.No cytogeneticsGoodIntermediateBadVery badNo pts448 vs 46155 vs 50215 vs 20089 vs 9050 vs 42CR (%)71.2 vs 82.490.9 vs 84.078.6 vs 82.568.5 vs 77.864.0 vs 54.8PR/Resistance (%)20.3 vs 12.60 vs 6.015.3 vs 10.527.0 vs 16.726.0 vs 40.5Induction death (%)8.5 vs 5.09.1 vs 10.06.0 vs 7.04.5 vs 5.610.0 vs 4.8In pts who reached CR, the DFS was similar in the 2 treatment groups: the 3-yr DFS rate was 43.4% (SD-Ara-C) vs 44.6% (HD-Ara-C), hazard ratio (HR)=0.96 (p=0.66). A total of 291 vs 313 DFS-events were reported in the 2 treatment groups: 230 (36.5%) vs 236 (34.7%) relapsed and 61 (9.7%) vs 77 (11.3%) died in CR. Among pts who reached CR, 451 pts had an HLA identical sibling and 860 did not or have not been typed. In the first group, 120/200 (60.0%) SD-AraC vs 134/251 (53.4%) HD-AraC pts underwent an allo-SCT. In the 2nd one, 211/431 (49.0%) SD AraC pts vs 211/429 (49.2%) HD AraC pts underwent an auto-SCT. In pts with a donor, the 3-yr DFS rate was 51.8% (SD-Ara-C) vs 47.6% (HD-Ara-C), HR=1.13, p=0.41, whereas in those without a donor the 3-yr DFS rate was 39.6% (SD-Ara-C) vs 42.9% (HD-Ara-C), HR=0.91, p=0.31. Evaluation of the first 1700 patients of the EORTC-GIMEMA AML-12 trial shows that, with a median follow-up of 3 years, HD-AraC in the induction treatment leads to a significantly higher CR rate than SD-Ara-C without improving the DFS.

Addition of Cladribine to the Standard Daunorubicine - Cytarabine (DA 3+7) Remission Induction Protocol (DAC) Contrary to Adjunct of Fludarabine (DAF) Improves the Overall Survival in Untreated Adults with Acute Myeloid Leukemia Aged up to 60 Y: A Multicenter, Randomized, Phase III PALG AML 1/2004 DAF/DAC/DA Study in 673 Patients

Our previous PALG study in 445 de novo AML patients has demonstrated that addition of cladribine to the standard daunorubicine-cytarabine (DA) remission induction regimen - DAC has a beneficial influence on both the CR rate after one induction cycle (p=0,0008) and on survival in patients older than 40 y (Leukemia 2004, 18:989–97, updated at 7 y: ASH 2006, Abstr.N#2003). The goal of this study was to evaluate the efficacy of original combination including another purine analogue fludarabine – DAF (daunorubicine 60 mg/m2/d iv, d 1–3; cytarabine (AraC) 200 mg/m2/d ci, d 1–7, and fludarabine 25 mg/m2 iv d 1–5) in untreated patients with AML, aged up to 60 y, based on head to head comparison with DAC - (DNR, AraC, Cladribine), and standard DA regimens. We evaluated earlier the DAF protocol in relapsed or refractory AML (PALG pilot study; Ann Hematol. 2008, 87:361–7. Epub 2007 Dec 12); the tolerance was good, CR 44%, LFS 38%. Primary objectives of the presented trial were: complete remission rate (CR) and overall survival (OS); secondary objectives were: toxicity and leukemia-free survival (LFS). Additional analysis was planned for patients submitted to an early bone marrow allotransplantation (alloBMT) after CR. Patients achieving CR received two courses of subsequent intensive consolidation:HAM (HD AraC, mitoxantrone)HD AraC. Reduction of consolidation was accepted in patients treated with early alloBMT.In case of partial remission (PR) after the first induction course the same regimen was repeated. Patients with no remission (NR) or with PR after 2 induction courses were withdrawn from the study. Between 09.2004 and 05.2008, 673 adult untreated AML patients aged 18–60 y, median 47 y, sex: male 49,5%, female 50,5%, treated in 18 co-operating Polish Adult leukemia Group (PALG) centres were centrally randomised to either DAF (n=225), DAC (n=224) or DA (n=224) arm (1:1:1). PML/RAR alfa positive - FAB M3 cases were excluded. The study groups were well balanced in respect of age, sex, FAB subtype, and WBC. After a single induction course the CR rate for patients receiving DAC equalling 63% was significantly higher if compared with DA - 51% (p=0,01), whereas no significant differences were noted between DAC vs. DAF - 55% and DAF vs. DA subgroups. Also the entire CR rate of 68% in the DAC arm was higher in comparison with DA one - 57% (p=0,02). No significant differences were found between DAC vs. DAF - 60%, and DAF vs. DA. At median time of 24 months (longest observation time 3,5y) the OS rate equalled 51% for the DAC treated subgroup and was higher in comparison to the standard DA arm - 39% and the DAF arm - 36% (p=0,03). The leukemia free survival rates (LFS) in DAC, DA and DAF treated cohorts equalled 51%, 32% and 41% respectively (p=NS). The early death rates of 8–10%. were similar in the studied treatment subgroups. All patients developed WHO grade IV thrombocytopenia and agranulocytosis. The frequency and severity of infections, mucositis, vomiting, diarrhoea, alopecia, polyneuropathy as well as of cardiac, liver or kidney dysfunctions were comparable in particular arms. In conclusion, this randomised study proves that the addition of cladribine to the standard DA induction regimen (DAC) improves CR rate and the overall survival in adults with AML aged up to 60 y, without additional toxicity. This beneficial effect was not observed in patients treated using the DAF protocol with fludarabine added to the standard “DA 3+7” schedule

The Reduction of Leukemic Blasts In Bone Marrow Aspirate on Day 6 of Remission Induction Treatment Is Predictive for Complete Remission Rate and Survival in Adult Acute Myeloid Leukemia: The Results of Multicenter, Prospective Polish Adult Leukemia Group Study.

The goal of this study was to pr ove the significance of an early evaluation of leukemic blast reduction based on cytological examination of bone marrow aspirates obtained on day 6 of remission induction treatment.Patients: 152 adult AML patients aged 18–60 (median 47) registered to the PALG prospective trial evaluating the efficacy of 3 remission induction protocols:DAF: daunorubicine (DNR) 60 mg/m2/d iv, d 1–3; cytarabine (AraC) 200 mg/m2/d ci, d 1–7, and fludarabine 25 mg/m2 2h inf. iv d 1–5)DAC (like DAF but cladribin is used at 5 mg/m2 instead of fludarabine) andthe standard DA 3+7 regimen.Patients achieving CR received two courses of subsequent intensive consolidation:HAM (HD AraC, mitoxantrone)HD AraC. In case of partial remission (PR) after the first induction course the same regimen was repeated.Patients with no remission (NR) or with PR after 2 induction courses were withdrawn from the study. Bone marrow aspirates were performed before the treatment and on the 6-th day of the first remission induction course, and the MGG stained marrow smears were evaluated at each centre by two experienced hematologists.Results: Based on the proportion of blasts in bone marrow specimen on day 6 patients were arranged into 2 groups:“responders” with <5 % of blasts (n=59) and“non responders” with >5% of blastic cells in bone marrow (n=31).The complete remission rate (CR) in the “responders” group equaling 86% (82/95) was significantly higher in comparison to that found in the “non responders” group 33%(19/57), p=<0,00001. The probability of overall survival (OS) was also higher in the group of “responders” if compared to “non responders” one; 63% versus 33% respectively, p=0,0009. In multivariate analysis including bone marrow examination, cytogenetic risk group, age, leukocyte count at diagnosis and the induction arm, only the persistence of leukemic blasts >5% in bone marrow specimens on 6-th day of induction was associated with higher risk of not achieving CR (HR = 51,1; p=0,00002), and with shorter OS (HR=2,9; p=0,004).Conclusion: This prospective, multicenter study demonstrates that a simple and commonly accessible evaluation of the leukemic blasts reduction in bone marrow smear on the 6-th day of remission induction treatment is a reliable and independent predictor for achieving CR and for overall survival. This offers a decision point for an early modification of the treatment strategy.