Death In CR Research Articles

Phase 2 Trial of Mini-Hyper-CVD Plus Inotuzumab Ozogamicin, with or without Blinatumomab, in Older Patients with Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia

Background The introduction of inotuzumab ozogamicin (InO) and blinatumomab (blina) has drastically improved the overall survival (OS) of patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). Older patients with B-ALL have worse outcomes compared with younger patients due to the poor-risk biology of their disease and their inability to tolerate intensive chemotherapy. We aim to study the incorporation of InO and blina with low intensity chemotherapy in older patients with newly diagnosed (ND) B-ALL. Methods Adults ≥60 years with ND Philadelphia chromosome (Ph)-negative B-ALL who were untreated or had received up to two cycles of previous therapy were eligible. Other inclusion criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of ≤3 and adequate organ function. Patients with central nervous system (CNS) disease were eligible. Patients received mini-Hyper-CVD (mHCVD, cyclophosphamide 150mg/m 2 q12h D1-3, dexamethasone 20mg daily D1-4, 11-14, and vincristine 2mg D1, 8 alternating with methotrexate (MTX) 250mg/m 2 D1 & cytarabine 500mg/m 2 q12h D2, 3) for up to 8 cycles. Eight doses of intrathecal (IT) MTX /cytarabine were given for CNS prophylaxis; patients with CNS disease had IT hydrocortisone, MTX, and cytarabine twice weekly till CNS clearance, then weekly x4. Eight doses of rituximab 375mg/m 2 were given on D1, 8 of C1-4 if CD20 was ≥20% by flow cytometry. Initially, InO was given at 1.3-1.8mg/m 2 on D3 of C1 and 1.0-1.3mg/m 2 on D3 in C2-4. The protocol was amended from patient 50 such that InO was given in fractionated doses with a maximum cumulative dose of 2.7mg/m 2 (0.6 mg/m 2 on D2 of C1, 0.3 mg/m 2 on D8 of C1, then 0.3 mg/m 2 on D2 and D8 of C2-4). Ursodeoxycholic acid was given to all patients. Four cycles of blina 28µg/day replaced C5-8 of mHCVD + InO. Maintenance was initially with vincristine 2mg D1, prednisolone 50mg daily D1-5, 6-mercaptopurine 50mg BID & MTX 10mg/m 2 weekly (POMP) for three years. After the protocol amendment, this was reduced to 12 cycles of POMP, with one cycle of blina given after every three POMP cycles (total four blina cycles). Results 83 patients with a median age of 68y (range, 60 - 87; ≥70y, 34%) were enrolled (Table 1). Several patients had high-risk features: 25 (39%) harbored TP53 mutations, 9 (18%) had a Ph-like signature, and 19 (23%) had high-risk cytogenetics (12 low hypodiploidy/near triploidy, 3 tetraploidy, 3 complex and 1 t(4;11)). 77 patients were not in CR at enrollment and evaluable for response. 76 (99%) responded, with 69 (90%) attaining CR. Among responders, 60 (79%) and 71 (94%) patients had no detectable minimal residual disease (MRD) by flow cytometry after C1 and overall, respectively. No early deaths were observed. After a median follow-up of 88 months (IQR, 41-120), the median overall survival (OS) was 56 months (95%CI, 28-85), and the median progression-free survival (PFS) was 47 months (95% CI, 21-72). The 5-year continuous remission duration (CRD) and OS rates were 78% and 49%, respectively. The 5-year OS for patients aged 60-69 without adverse cytogenetics (n=40), age 60-69 with adverse cytogenetics (n=15), age ≥70 without adverse cytogenetics (n=24) and age ≥70 with adverse cytogenetics (n=4) were 73%, 27%, 39% and 0%, respectively. Five (6%) patients underwent allogeneic stem cell transplantation (ASCT) in first CR, 12 (15%) relapsed, 33 (40%) remain in ongoing continuous remission without ASCT, and 33 (40%) died in remission. Of the 12 relapsing patients, 5 had extramedullary disease, all with CNS involvement. 12 (14%) patients died due to progressive disease at a median of 23 (range 2 - 78) months; these patients had a median age of 64 (range 60 - 79) years. Of the 33 who died in remission, nine were due to secondary myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). The median age of these patients was 71 years (range, 64 - 87), with a median time to MDS/AML of 34 months (range, 7 - 75). Fourteen deaths in CR were due to treatment-related complications (9 sepsis, 3 veno-occlusive disease (VOD), 2 ASCT). Six (7%) patients developed veno-occlusive disease, 4/49 (8%) in the pre-amendment group and 2/34 (6%) in the post-amendment group. Conclusion Older patients with ND Ph-negative ALL treated with mHCVD plus InO, with or without blina had excellent response rates and deep remissions. However, further adjustment of the regimen is needed, especially in patients ≥70 years.

Activation of the PI3K/AKT/mTOR Pathway in Cajal–Retzius Cells Leads to Their Survival and Increases Susceptibility to Kainate-Induced Seizures

Cajal-Retzius cells (CRs) are a class of transient neurons in the mammalian cortex that play a critical role in cortical development. Neocortical CRs undergo almost complete elimination in the first two postnatal weeks in rodents and the persistence of CRs during postnatal life has been detected in pathological conditions related to epilepsy. However, it is unclear whether their persistence is a cause or consequence of these diseases. To decipher the molecular mechanisms involved in CR death, we investigated the contribution of the PI3K/AKT/mTOR pathway as it plays a critical role in cell survival. We first showed that this pathway is less active in CRs after birth before massive cell death. We also explored the spatio-temporal activation of both AKT and mTOR pathways and reveal area-specific differences along both the rostro-caudal and medio-lateral axes. Next, using genetic approaches to maintain an active pathway in CRs, we found that the removal of either PTEN or TSC1, two negative regulators of the pathway, lead to differential CR survivals, with a stronger effect in the Pten model. Persistent cells in this latter mutant are still active. They express more Reelin and their persistence is associated with an increase in the duration of kainate-induced seizures in females. Altogether, we show that the decrease in PI3K/AKT/mTOR activity in CRs primes these cells to death by possibly repressing a survival pathway, with the mTORC1 branch contributing less to the phenotype.

Fractionated Inotuzumab Ozogamicin Combined with Low-Intensity Chemotherapy in Older Patients with Newly Diagnosed CD22+ Philadelphia Chromosome (Ph)-Negative B-Cell Precursor (BCP) Acute Lymphoblastic Leukemia (ALL): Results of the EWALL-INO Study

Introduction. We report here the results of the EWALL-INO Phase 2 study (ClinicalTrials.gov: NCT03249870) evaluating the activity and safety of frontline inotuzumab ozogamicin (INO), an anti-CD22 antibody conjugated to calicheamicin, combined to low-intensity chemotherapy in 131 older patients with CD22+ Ph-negative BCP-ALL. Methods. This single arm prospective study has been conducted in several European centers from the European Working group on adult ALL (EWALL). Eligibility criteria were patients aged ≥55 years, with an ECOG performance status ≤2, newly diagnosed with CD22+ (20% or more of positive blast cells) Ph-negative BCP-ALL without central nervous system (CNS) involvement. After a prephase including 5 days (D) of dexamethasone (DEX) 10mg per D and intrathecal (IT) methotrexate (MTX), the induction regimen was delivered in 2 parts. Induction part I (Ind1) consisted of one triple IT, vincristine (VCR) 2 mg (1 mg over 70 years of age) D1 D8 D15 D22 and DEX 20 mg D1D2 D8D9 D15D16 D22D23 combined with 3 injections of INO (0.8 mg/m² D1, 0.5 mg/m² D8 and D15). Induction part II (Ind2) was offered to patients in CR or CRp (CR with platelets <100 x 109/L) after Ind1 or as salvage therapy. Ind2 consisted of DEX 20mg D1D8, cyclophosphamide (CY) 300 mg/m² D1 to D3, one triple IT D2 and 2 injections of INO (0.5 mg/m² D1 and D8). Patients in CR/CRp were programmed to receive 6 blocks of consolidation (Ara-C 1.5g/m²/12h adapted to renal clearance D1D2 and DEX 10mg/12h D1D2, cycles 1 and 4; MTX 1.5 g/m² over 24h D1, VCR 1 or 2 mg D1, one triple IT D2 and 6-mercaptopurin (6-MP) D1 to D7, cycles 2 and 5; CY 500 mg/m² D1D2, VP16 75 mg/m² D1D2, one triple IT D2 and MTX 25 mg/m² D1, cycles 3 and 6) followed by a POMP maintenance (VCR, 6-MP, MTX, DEX) during 18 months. Allogeneic hematopoietic stem cell transplant (HSCT) was allowed after at least 3 blocks of consolidation at the discretion of the investigator. The primary endpoint of the study was overall survival (OS) with an expected 1-year OS rate of 70%. The evaluable population consisted of patients who received at least 1 dose of INO. Minimal residual disease (MRD) was assessed on bone marrow aspirates after Ind1 and Ind2 using quantification of clonal molecular rearrangements. The study was planned to recruit up to 130 patients. All patients provided informed consent. Results. Between 12/2017 and 03/2022, 6 screen failures occurred (including one Ph+ ALL) and 131 patients were enrolled and received at least one dose of INO. These 131 patients were considered for the intent-to-treat analysis. However, among them, 5 patients had CD22 expression <20% and 3 had CNS involvement. Patient characteristics are shown on Table 1. After Ind1, the CR/CRp rate was 88.5% (116/131, 9 CRp) and 4/131 (3%) patients had died. MRD <10-4 was achieved in 56 of 97 (56.6%) CR/CRp tested patients. A total of 120 patients received Ind2 (115 CR/CRp patients, as 1 death in CR occurred between Ind1 and Ind2 and 5 patients received Ind2 after failure of Ind1) and 118 patients eventually achieved CR/CRp (112 CR, including 3 late CR after Ind2; 6 CRp) resulting in a CR/CRp rate of 90% (118/131) after Ind1 + Ind2. No patient died during Ind2. MRD <10-4 was achieved in 80 of 99 CR/CRp tested patients (80.8%) after Ind2. Overall, the full planned INO dosing was administered to 108 patients (82.5%). With a median follow-up of 15 months (range 3-42), 29 patients relapsed and 50 patients died, including 29 deaths after relapse. Only 11/118 CR/CRp patients received an HSCT (9.4%). With a 1-year OS of 72.5% (95% CI, 64-81), the primary endpoint was reached. At 2 years, OS was 53.6% (95% CI, 44-64). Leukemia- free survival was 64.9% (95% CI, 56-74) at 1 year and 49.8% (95% CI, 40-61) at 2 years. (Figure 1) A grade 3-4 liver toxicity was observed in 21 patients (16%), including 3 patients (2.2%) with transient sinusoidal obstruction syndrome (SOS), 2 during Ind1 and 1 after HSCT. Conclusion. These results confirm that fractionated INO combined to low-intensity chemotherapy is a very active and well tolerated frontline therapy for older patients with CD22+ Ph-neg BCP-ALL, as previously reported in the MDACC INO/mini-HCVD study (Jabbour et al. Cancer 2019). An updated analysis will be provided at ASH meeting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Frontline Combination of Hyper-CVAD with Ponatinib for Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia-6-Year Follow-up Results

Background: The combination of cytotoxic chemotherapy with a BCR::ABL1 tyrosine kinase inhibitor (TKI) has historically been standard of care for patients (pts) with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Ponatinib is 3rd generation TKI with more potent BCR::ABL1 inhibition than earlier-generation TKIs. Ponatinib also suppresses T315I clones, which are responsible for most relapses with other TKIs. Here we present the 6-year follow-up results of hyper-CVAD plus ponatinib for patients with newly diagnosed Ph+ ALL. Methods: This was a phase 2, single-arm study to evaluate the efficacy and safety of hyper-CVAD with ponatinib in adults with newly diagnosed Ph+ ALL. Pts age 18 years or older with previously untreated Ph+ ALL were eligible; pts who had received 1 to 2 courses of prior chemotherapy, with or without a TKI, were also eligible. Pts were required to have an ECOG performance status of 2 or less, bilirubin <3mg/dl, creatinine <3mg/dl, and normal cardiac function. Pts received hyper-CVAD alternating with high-dose methotrexate and cytarabine for 8 cycles. Initially, ponatinib was given at a dose of 45 mg daily. Due to 2 deaths due to cardiovascular events related to ponatinib, beginning with pt #37, the protocol was amended. After the amendment, ponatinib was administered at a dose of 45 mg for 14 days in cycle 1, then 30mg daily once patients achieved CR and 15mg daily once a complete molecular response (CMR) was achieved. Maintenance therapy was given for 2 years, vincristine, prednisone and ponatinib. Pts received 12 doses of intrathecal chemotherapy with alternating doses of cytarabine and methotrexate. Results: 86 pts were treated. Pts characteristics are summarized in Table 1. The median age was 46 years (range 21-80). Sixty-six pts (77%) had received no prior ALL-directed therapy, and 20 pts (23%) had received 1-2 courses of therapy prior to enrollment. Among these 20 pts, 18 were in CR and 2 had persistent disease at the time of enrollment. Sixty three pts (73%) had a p190 transcript, and 21 (24%) had a p210 transcript. Among 68 pts with active disease at enrollment, all pts achieved CR. Among 54 pts evaluable for cytogenetic response, all pts achieved complete cytogenetic response, including 50 pts (93%) after 1 cycle. Among 85 pts evaluable for molecular response, 83 pts (98%) achieved at least a major molecular response and 73 pts (86%) achieved a CMR. No pts died in the first 4 weeks of therapy. After a median follow up of 75 months (range, 16-123+ months), the 5-year overall survival (OS) and relapse-free survival rates were 75% and 68%, respectively (Figure 1). Twenty pts (23%) underwent stem cell transplantation (SCT) in first remission (5 of whom relapsed post SCT and 1 of whom died from post-SCT complications), 10 pts (12%) died in CR, 13 pts (19%) relapsed without SCT, and 43 pts (50%) are in ongoing remission without SCT. Of the relapsed pts, 5 were on ponatinib at the time of relapse, 2 of whom acquired an E255K kinase domain mutation at relapse; and 5 were on imatinib or dasatinib at the time of relapse, 3 of whom acquired a T315I kinase domain mutation. Among the 10 deaths in CR, 2 were treatment-related (both due to myocardial infarction before the amendment to implement lower doses of ponatinib). In a 8-month landmark analysis, the 5-year OS for pts without ASCT and with ASCT were 87% and 70%, respectively (p =0.09). Among the pts who are in ongoing remission without ASCT, 3 received subsequent therapy for MRD-positive disease. The most common grade ≥3 AE was infections and/or febrile neutropenia, seen in 82 pts (95%). Other grade ≥3 AEs including elevated transaminases in 25 pts (29%), increased amylase and/or lipase in 15 (17%), hyperbilirubinemia in 13 pts (15%), and clinical pancreatitis in 13 pts (15%). Five pts (6%) had a grade ≥3 venous thrombotic event, and 5 pts (6%) had a grade ≥3 arterial cardiovascular event. Two patients died from ponatinib-related cardiovascular complications, both from MI during cycle 2. Conclusion: The combination of hyper-CVAD and ponatinib results deep and durable remissions in pts with newly diagnosed Ph+ ALL. The overall CMR rate was 86% and the 5-year OS was 75%, which compares favorably with regimens using first- or second-generation TKIs in this population. The combination was safe; the use of lower doses of ponatinib maintained efficacy and mitigated the risk of ponatinib-related toxicity. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Interim Results of Russian Acute Lymphoblastic Leukemia (RALL-2016) Study with Centralized MRD-Monitoring and Randomization for Autologous HSCT with Non-Myeloablative Conditioning in Adult Ph-Negative ALL Patients

Introduction. MRD-tailored therapy based on pediatric-inspired intensification is a back-bone of the majority of the European study groups in adult ALL. Taking in consideration the major pitfalls of the first Russian acute lymphoblastic leukemia study group trial RALL-2009 (NCT01193933) - high CR death rate, early CNS relapses in T-ALL, selection bias in auto-HSCT vs chemotherapy comparison, absence of MRD monitoring - a new RALL-2016 protocol (NCT03462095) was introduced based on the same principles as the first one - non-intensive but non-interruptive approach with low numbers of allo-HSCT, but with further deintensification of consolidation phase, centralized MRD-monitoring and randomization for autologous HSCT with non-myeloablative conditioning (CEAM). AIM. To analyze the 2,5 years efficacy and to determine significance of MRD status after induction in the new Russian ongoing prospective multicenter study RALL-2016. Materials and patients. RALL-2016 was based on the previous RALL-2009 protocol , but one day high-dose MTX and high-dose ARA-C blocks were eliminated and substituted by 2 months of non-interruptive therapy, L-asparaginase was scheduled for 1 year of treatment instead of 2,5 y, 15 intrathecal injections were increased up to 21 mostly while consolidation phase, CR T-ALL patients were brought to randomization after the informed consent: auto-HSCT vs no auto-HSCT, - with the similar further maintenance. All primary bone samples are collected and tested for cytogenetics and molecular markers, all included patients are monitored by flow cytometry by aberrant immunophenotype in a centralized lab. Results and discussion. From Dec 2016 till Jul 2019 148 Ph-negative ALL pts from 10 centers were included: median age 33 y (18-54) (BCP-ALL-80 (54%) pts, T-ALL- 64 (44%), biphenotypic- 4 (2%)). CR was achieved in 84% pts. The induction death before CR was 8% (n=12), refractory ALL was registered in 12 pts (8%). Death in CR occurred in 4%. After CR achievement 52 T-ALL patients were randomized either to chemotherapy (n=25) or to autoHSCT(n= 27). 15 of 27 T-ALL pts were transplanted at a median time of 6 months from CR (1 of 27 received alloHSCT - Neimegen Syndrom, 2 of 27 died in CR before HSCT, one pt refused the autotransplant ). OS and DFS at 2-years constituted 70,7% and 80%. 2-y OS was 65,8% for BCP-ALL, 80% for T-ALL and 66,7% for MPAL (p=0,5). 2-y DFS was 78,7% for BCP-ALL, 83,4% for T-ALL and 100% for MPAL (p=0,88). AlloHSCT in 1st CR have received only 3 (2%) pts. We have registered the differences in OS in pts who were treated in Federal Center (51 pts) or in Regional centers (97pts): 82% vs 64,6%, respectively (p=0,02). But there were no differences in DFS: 87,7% vs 77,3%, respectively (p=0,66) (Pic1). We have detected very high death rate in induction and in CR in the regional Centers despite the fact that the main pts characteristics were similar (median age, hyperleukocytosis, high risk group). MRD persistence after induction (70th day of protocol) became a significant factor of poor prognosis: 2-yeasr OS and DFS in MRD-negative (59 pts) and MRD-positive (33pts) were 91,8% vs 56,4% (p=0,017) and 88,7% vs 64,3% (p=0,16), respectively (Pic 2). Median of relapse was 7 month. Conclusion. The new RALL-2016 study pitifully continues to demonstrate high induction and CR death rate in regional centers despite of de-intensification of chemotherapy. We've observed significant differences in OS in Federal Center vs Regionals Centers, but not in DFS. MRD monitoring by FCM in ALL patients revealed that the persistence of MRD after induction (day+70) was an independent factor of poor prognosis and high relapse rate suggesting the introduction of new treatment approaches within a very short time after induction (maximum 3 months) in MRD positive patients. Figure Disclosures No relevant conflicts of interest to declare.

Smoking Confers Poor Survival in Patients (Pts) with Newly Diagnosed Philadelphia Chromosome Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) Treated with the Combination of Intensive Therapy with Tyrosine Kinase Inhibitor (TKI)

Smoking Confers Poor Survival in Patients (Pts) with Newly Diagnosed Philadelphia Chromosome Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) Treated with the Combination of Intensive Therapy with Tyrosine Kinase Inhibitor (TKI)

MRD Status Did Not Correspond to the Relapse Incidence within One Year of Follow-up By Non-Intensive but Non-Interruptive Approach: The First Interim Results of the Russian Prospective Multicenter RALL-2016 Trial for Ph-Negative Adult ALL

IntroductionRALL-2009 study (NCT01193933) has demonstrated that non-intensive but non-interruptive treatment with fewer allo-HSCT is rather effective in adult Ph-negative ALL pts aged 18-55 yy, producing more than 50% OS at 8-years [Parovichnikova, EHA E836, 2017]. In this study we have shown that only age, initial WBC >30*109/l and t(4;11) became the factors of poor prognosis for BCP-ALL and none of the factors - for T-ALL. MRD was not measured in this study. Since Dec 2016 we started a new RALL-2016 (NCT03462095) protocol based on the same principle but modified according to the conclusions drawn from RALL-2009.Aim.To evaluate the first interim results of MRD monitoring and 1-year probability of relapse regarding MRD status in Ph-negative ALL treated by RALL-2016 protocol.Materials and patients.Taking in consideration the major pitfalls of RALL-2009 (high CR rate, early CNS relapses in T-ALL, selection bias for autologous HSCT in T-cell ALL, absence of MRD testing) a new study was developed. One day high-dose MTX block and one-day high-dose ARA-C block are eliminated and substituted by 2 months of non-intensive and non-interruptive treatment, L-asparaginase is scheduled for 1 year of treatment instead of 2,5 y, 15 intrathecal injections are increased up to 21 during consolidation phase, CR T-ALL patients are brought to randomization after the informed consent: auto-HSCT vs no auto-HSCT, - with further similar maintenance. All primary bone marrow samples are collected and tested for cytogenetic and molecular markers, all included pts are MRD monitored by flow cytometry in a centralized lab at 3-time points (days +70,+133,+190).Since Dec2016 till July 2018, 86 adult Ph-negative ALL pts from 11 centers (10 regions of Russia) were included in theRALL-2016 protocol: median age 33 y (18-54), m/f 54/32, BCP-ALL was diagnosed in 48 (56%), T-ALL/LBL - in 35 (40,5%), biphenotypic ALL -3 (3,5%).Results.CR rate in 76 available for the analysis patients was 80% (n=61), induction death occurred in 12% (n=9) and refractory ALL was registered in 8% (n=6). There were no deaths in CR so far. 2 allo-HSCT were performed (1 MUD and 1 haplo) for BCP-ALL with MRD persistence and T-ALL associated with Nijmegen breakage syndrome, respectively. 26 T-ALL patients after CR achievement were randomized for chemo (n=13) or for auto-HSCT (n=13). Up to now 7 of randomized T-ALL patients were transplanted at a median of 6 mo of CR. OS for the whole cohort constituted 68% at 18 months, relapse probability - 8,7%.MRD at the 1st time point (+70 day) was measured in 54 pts, at the 2nd time point (+133 day) - in 43 pts and at the 3rd time point (+190 day) - in 36 pts. MRD-positivity was detected in 15 pts (28%) at day+70 (BCP-ALL=11 out of 32 pts, T-ALL=4 out of 22), at day +133 - in 8 pts (19%) (BCP-ALL=7 out of 30 pts, T-ALL=1 out of 13), at day +190 - in 2 pts (5%) (both BCP-ALL). MRD clearance was much better in T-ALL patients, as it was demonstrated by other studies earlier [Bruggemen, Goekbuget]. But we have to mention that regardless our non-intensive approach, the portion of MRD-positive patients was similar at the same time points as in the other studies applying highly intensive protocol.We did not reveal any differences in early (within 1-year) relapse probability according to MRD status, though we have to assume that the study is small and the period of follow is too short.ConclusionOur data demonstrate that non-intensive but non-interruptive approach is as effective as more intensive protocols providing very similar MRD clearance in Ph-negative ALL. MRD is declining better in T-ALL patients comparing to BCP-ALL. And no correspondence was noticed between the MRD-positivity and relapse probability at the 18 mo of follow-up. DisclosuresKulikov:Russian Foundation for Basic Research grant 18-015-00399 A: Research Funding.

Is Arsenic Trioxide (ATO) Required in the Treatment of High Risk Newly Diagnosed APL? Analysis of a Randomized Trial (APL2006) By the French Belgian Swiss APL Group

▪Background:In standard risk APL, ATRA+ATO combinations (without CT) are at least as effective as classical ATRA + anthracycline based chemotherapy (CT) while being less myelosuppressive (Lo Coco, NEJM 2014, Burnett, Lancet Oncol, 2015). In high risk APL (WBC> 10G/l), it is still unclear if CT can be avoided or greatly reduced, but addition of ATO to ATRA + CT reduces relapses (Powell, Blood 2010). In a randomized trial (APL2006 trial) in high-risk APL patients (pts) who received ATRA + CT induction treatment, we evaluated the addition of ATO to CT during consolidation.Methods: Between 2006 and 2015, newly diagnosed APL pts <70 years with WBC> 10 G/L, after an induction of ATRA 45mg/m2/d until CR with Idarubicin (Ida) 12 mg/m2/dx3 and AraC 200mg/m2/dx7, were randomized for consolidation between CT and CT+ATO. The CT group (standard group) received a first consolidation with Ida 12 mg/m2/dx3 and AraC 200mg/m2/dx7, a second consolidation with Ida 9 mg/m2/dx3 and AraC 1g/m2/12h x4d, and 2-year maintenance with intermittent ATRA and continuous 6 MP + MTX. The CT+ATO group received the same treatment except that ATO 0.15 mg/Kg/d d1 -25 was added during both consolidation courses. After a first interim analysis in Sept 2010, based on 81 pts, AraC was deleted from consolidation cycles of the CT+ ATO group. The primary endpoint was EFS from CR achievement.Results: 211 pts <70 years with WBC> 10 G/L were included (after the exclusion of 8 diagnostic errors) in 58 centers. 95.7% achieved CR, 3.3% had early death and 1% resistant leukemia. 193 pts were randomized for consolidation, 97 in the CT and 96 the CT+ ATO groups. Pre-treatment characteristics were well balanced between the 2 groups. 7 pts (3 CT vs 4 CT+ATO) had relapsed (5-year cumulative incidence of relapse (CIR) of 2.5% vs 3.9%; p= 0.39) and 9 pts had died in CR :7 (7.8%), 2 (5.1%), 0 (0%) in the CT, CT (with AraC) + ATO, CT (without AraC) + ATO groups respectively (p=0.04). Causes of death in CR were bleeding (n=5), infection (n=2), previous cancer relapse (n=2). One patient in the CT+ATO arm developed AML/MDS.5-year OS was 93% vs 94% (p=0.56) and 5-year EFS was 89% vs 93% (p=0.47) in the CT and CT+ATO groups, respectively. Omission of AraC (after the amendment) in the CT+ATO group did not increase CIR (5 year CIR 5.3% with and 3.3% without AraC, p=0.57). In the CT, CT (with AraC) + ATO, CT (without AraC) + ATO groups respectively, median time to ANC>1 G/L after consolidation 2 was 22, 25 and 19 days (p<0.0001), and median time to platelets>50G/l was 24, 26 and 20 days (p<0.0001). Similarly, median duration of hospitalization after the first and the second consolidation courses were 33, 34, 29 d (p<0.0001) and 31, 32, 28 d (p=0.0005), respectively.Conclusion: Very high CR rates and very few relapses are now obtained in high risk APL on a large multicenter basis using classical ATRA and CT (including AraC) for induction and consolidation, and maintenance treatment, but at the expense of 5 to 7% deaths in CR. Addition of ATO to this regimen did not further reduce relapses, and added some myelosuppression if CT contained AraC. However, if ATO was added and AraC omitted from consolidation cycles, relapses were not increased, while myelosuppression and deaths in CR were reduced. ATO therefore appears useful in high risk APL. We are currently comparing, in the international APOLLO trial, the "classical" ATRA-CT approach and a prolonged ATO-ATRA regimen with only 2 days of Ida during induction treatment, hoping to further reduce myelosuppression and possibly relapses. DisclosuresAdes:Celgene, Takeda, Novartis, Astex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Recher:Celgene, Sunesis, Amgen, Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene, Sunesis, Amgen, Novartis, Chugai: Research Funding. Pigneux:Agios: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria. Fenaux:Celgene, Novartis, Teva: Honoraria; Celgene, Janssen, Novartis, Astex, Teva: Research Funding.

Arsenic Trioxide (ATO) and ATRA with Limited Chemotherapy (CT) in Newly Diagnosed Standard Risk APL in the Elderly. a Report By the French Belgian Swiss APL Group (APL 2006 trial)

▪Background.Treatment of APL in the elderly with conventional ATRA-anthracycline based CT regimens is associated, like in younger patients, with very few relapses, but high death rates (CR rate of 87.3%, 10-year CIR of 9.3%, 21.7% deaths in CR, and a 10-year OS of 58% in patients aged> 65 years in our previous APL trials ;Blood 2010 115:1690). Recent results have shown that, in standard risk APL, ATRA+ATO combinations (without CT) are at least as effective as classical ATRA + CT regimens while being less myelosuppressive (Lo Coco, NEJM 2014; Burnett, Lancet Oncol, 2015) thus constituting a very appealing approach for elderly patients. However, when our APL 2006 trial started, the feasibility of treatment of APL without CT was unknown. Furthermore, access to ATO still remains limited for frontline treatment of APL in most countries. We present results of APL 2006 trial, where we combined ATO to ATRA and reduced CT in patients aged older than 70 with standard risk APL (baseline WBC <10G/L).Methods. Between 2006 and 2015, newly diagnosed APL patients (pts)>70 years with WBC <10 G/L received induction treatment with ATRA 45mg/m2/d until CR and Idarubicin (Ida) 9 mg/m2/d on days 3, 5 and 7, a first consolidation course with Ida 9 mg/m2/dx3 combined with ATO 0.1 mg/kg/d during 25 days, a second consolidation course with ATO (same schedule)and ATRA during 15 days, followed by maintenance during 2 years with intermittent ATRA continuous 6 MP + MTX, plus 15 days ATO cycles every 3 months during the first maintenance year. In Sept 2010, after inclusion of 55 patients, because mortality in CR was still high (10/51 CR pts) while no relapse was observed, consolidation CT was reduced to one day of Ida during the first consolidation cycle. The primary endpoint was event-free survival (EFS) from CR achievement. We present here results at the reference date of Jan, 1, 2016. Results. Median age of the 123 pts included (after excluding one diagnosis error) was 73.6 years (range 70-88.4), with 56 % males. 113 (92%) pts achieved CR, 4 (3%) had resistant leukemia, and 6 (5%) had early death from sepsis (n=3), and multiorgan failure (n=3). Of the 113 CR pts, 3 relapsed (5-year cumulative incidence of relapse of 2.9%), with no significant difference across periods (p= 0.10, Gray’s test). 14 (12%) patients died in CR, including 4/62 (4%) accrued after vs 10/51 (20%) before the amendment (p= 0.045, Fisher’s test). Causes of death in CR were sepsis (n=4 before and 2 after amendment), bleeding (n=5 before and 1 after), general deterioration (n=1 before) and prostate cancer (n=1 after). 5-year OS was 80% (95%CI, 73-88%) and 5-year EFS was 80% (95%CI, 73-88%), with no difference according to period (p=0.71 and p=0.80 by the log-rank test, respectively). Mean time to ANC>1 G/L and platelets> 50G/l after the first consolidation course was 16.2 and 11.9 days in the original vs 5.6 and 4.0 days in the amended protocol (p<0.0001 and p<0.0001), while the second consolidation course was not associated with myelosuppression.Conclusion. In this very old patient population (>70 years) with standard risk APL, addition of ATO, that allowed reduction of the amount of CT administered, was associated with high CR rates, without any increase (and a possible reduction) in the relapse rate compared to our previous experience with ATRA-CT regimens. However, reduction of mortality in CR with this regimen was only seen when consolidation CT was reduced to one single day of Ida. This is further evidence of the role of ATO in a patient population in whom myelosuppression must be avoided. DisclosuresAdes:Celgene, Takeda, Novartis, Astex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Thomas:Pfizer: Consultancy. Pigneux:Agios: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria. Fenaux:Celgene, Novartis, Teva: Honoraria; Celgene, Janssen, Novartis, Astex, Teva: Research Funding.

Postremission Therapy with Repeated Courses of HD-Arac, Idarubicin and Limited Autologous Stem Cell Support Achieves a Very Good Long-Term Outcome in ELN Favourable and Intermediate-Risk AML Except in NPM-Mutated Patients Where Relapse May Occur Even after Five Years

Introduction: Postremission treatment in adult acute myeloid leukemia (AML) is mandatory to improve long-term remission duration. Allogeneic stem-cell transplantation (allo-SCT) is considered gold standard in younger patients (pts) with higher risk of relapse, whereas in pts categorized as standard-risk (SR) AML the optimal treatment remains an open issue. High-dose cytarabine (HD-ARAC) is considered the backbone of postremission treatment in SR AML. The optimal dose and schedule, and the clinical benefit of additional chemotherapeutic agents remain controversial (Schaich, 2011- Lowenberg, 2011- Lowenberg, 2013) as well as the relative efficacy of HD-ARAC in the different cytogenetic and molecular subgroups of SR AML. We analyzed the very long term outcome of consecutive unselected AML pts treated according to AML 00 NILG protocol (Bassan, Blood, 2003: 102; 11) with three repetitive HD-ARAC-based cycles, associated with idarubicin, followed by limited peripheral blood stem cell (PBSC) support, in order to reduce toxicities.Methods: We evaluated 263 consecutive AML pts, diagnosed at our Institution, from January 2001 to March 2016 (median age 52 years - range 15-65). The treatment plan included induction with ICE (Idarubicin-Cytarabine-Etoposide) followed by IC consolidation or HD-ARAC/HD-idarubicin (SPLIT therapy) in refractory cases. ARAC 1g/mq bd for 4 days (A8) was given to CR pts, to collect 3-6x10^6 CD34/kg in 3 aliquots. Patients with ELN favorable or intermediate risk AML, considered SR AML, received 3 cycles of HD-ARAC (2g/mq bd for 5 days) plus idarubicin (8mg/mq for 2 days) with PBSC reinfusion (1-2x10^6 CD34/Kg) (A20). The pts with insufficient CD34 cells yield, received 2 courses HD-ARAC (1g/mq bd for 5 days) plus idarubicin (10mg/mq day 1) (A10). The cumulative dose of ARAC and idarubicin given according to A20 protocol were 69,4 g/mq and 162 mg/mq, respectively.Results: Among 263 pts, 142 (54%) pts were considered SR and 116 (44.1%) HR. Only 5 pts were lacking molecular or cytogenetic information (1.9%) to allow ELN risk classification. Accordingly, 65 pts (25.2%) were favorable [35.4% core binding factor (CBF) positive, 9.2% CEPBA mutated and 55.4% NPM mutated], 87 (33.7%) Intermediate-I, 45 (17.4%) Intermediate II and 61 (23.7%) adverse risk. CR rate after ICE treatment was 77.6% (204/263), 95.8% in SR and 56% in HR pts and after ICE+SPLIT it was 88.2% (232/263); early or aplastic death was 6%. A8 course was administered in 218 pts, of whom 179 were successfully mobilized (82.1%). Among 136 SR pts, 127 were received HD-ARAC (A20 or A10), 4 allo-SCT for early relapse, 3 pts did not proceed to A20 because of prolonged cytopenia and 2 are ongoing. Hematological toxicity was acceptable. ANC recovered at a median of 10 days after CD34+ cells reinfusion. Two death in CR occurred within 100 days after A20 therapy (1.6%). After a median follow-up of 53.3 months (range 1-172), the median survival of SR AML patients was 118.9 months, the DFS and OS at 5 y were 51+/-4.8% and 56.5+/-4.7%, and at 10 y 43.3+/-5.9% and 49.6+/-5.7%, respectively. According to ELN risk, the OS at 5 y and 10 y was 78.3+/-6% and 68+/-8.7% in favorable (median OS not reached), 52.3+/-8% and 46+/-9.4% in Intermediate-I (median OS 118.8 months), and 42+10% and 33.6+/-10.9% in Intermediate-II (median OS 33.1 months) (p0.0034) (Figure1). According to molecular characteristics, the OS at 5-y was 100% in CEBPA-mutated, 77+/-9% (+/-SE) in CBF-mutated and 71+/-11% in NPM-mutated subgroups, respectively (Figure 2). In NPM-mutated pts it was 56+/-14% if FLT3 was mutated and 75+/-10% if not. At 8-y OS was not evaluable in CEBPA-mutated, it remained 77+/-9% in CBF mutated but dropped to 47+/-15% in NPM-mutated pts due to late relapses (28%), which occurred in pts without FLT3. The median time to relapse in NPM pts was 17 m, the latest relapse occurred after 97 months.Conclusion: A postremission program with repeated courses of HD-ARAC associated to idarubicin and limited autologous CD34+ cells support was feasible, well tolerated and very effective, also long-term, in pts with ELN favourable or intermediate risk AML. The late relapse tendency of NPM-mutated AML is puzzling and should be considered by innovative programs aimed at improving these results. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Is Arsenic Trioxide (ATO) Required in the Treatment of Standard Risk Newly Diagnosed APL? Analysis of a Randomized Trial (APL 2006) By the French Belgian Swiss APL Group

57th Annual Meeting of the American-Society-of-Hematology Location: Orlando, FL Date: DEC 05-08, 2015

Excellent Outcome in Pediatric AML with Response Guided Chemotherapy without Allogeneic HSCT in First Complete Remission: Results from Protocol DB-AML01

Background: Contemporary treatment schedules for pediatric acute myeloid leukemia (AML) have improved 5 year-overall survival rates up to 70% . These schedules usually consist of 4 to 5 intensive courses mainly based on cytarabine (AraC) and anthracyclines, with allo-HSCT upfront in a subset of patients . Long-term side effects such as late cardiotoxicity caused by high cumulative anthracycline dosages are a major concern. Therefore, the DCOG/BSPHO collaboration adapted the NOPHO 2004 protocol to DB-AML01 to reduce cumulative anthracyclines from 420-450 mg/m² to 300-330 mg/m² and to omit HSCT in CR1.Material: The treatment consisted of 5 chemotherapy courses: first induction course AIET (AraC conventional dose and Idarubicin (Ida) 36 mg/m2); second induction course AM (AraC conventional dose and Mitoxantrone (Mitox) 30 mg/m2) when blasts at day 15 < 5% or FLA-DNX (high dose AraC and Daunoxome (DNX) 180 mg/m2) when blasts > 5% at day 15 or t(8;21) AML; 3 consolidation courses (high dose AraC with Etoposide as course 3 and 5 and in between high dose AraC alone). Cumulative dose of AraC is 43,4 gr/m2 and of anthracyclines 300 mg/m² for patients receiving AIET+AM or 330 mg/m² for patients receiving AIET/FLA-DNX.Results: From 2010 to 2014 a total of 113 children with AML, median age 6.0 yrs (range 0-16), gender 56 males, were included. Second induction course was AM in n=75 and FLA-DNX in n= 33. Death in induction occurred in 4 patients, CR rate was 102/113 (90.3%) and 7 patients were refractory after induction. The later events were death in CR (n=2), relapse in CR (n=40), and secondary malignancies (n=0). HSCT was given to 3 patients in CR1 (physician's decision). Median follow up time is 2.6 years (range (range 1-5). Probability of EFS at 2 years was 60% (95% CI 49-69%) and 2-yr OS was 76 (95% CI 66-83%)77.9%. Especially inv 16 (n=10) and t(8;21) AML (n=16) had an excellent outcome (inv 16:2-yr EFS: 70% (95% CI 32-89%) and 2-yr OS 91% (95% CI 51-99%) resp t(8;21):2-yr EFS: 87% (95% CI 57-97%) and OS: 94% (95% CI 63-99%)), EFS nor OS in other genetic subgroups such as FLT3-ITD and MLL rearrangements were significantly different from the total group. Children with an older age (> 10 years) (n=34) or high WBC count (>50.109/l) (n=41) had the poorest 2-yr EFS: 51 (95% CI 33-67%) resp EFS: 40% (95% CI 24-56%), whereas OS was not significantly worse. For the patients with a relapse, 32 achieved a second CR and 4 a partial remission (90%) . In second CR 34 patients received an allo-HSCT. Until now 26 of the 40 patients are still in second CR.Conclusion: The DB-AML01 outcome data suggest that the choice of high cumulative doses of AraC with moderate cumulative doses of anthracyclines up to 300-330 mgr/m² results in a favorable overall survival for particularly those children with t(8;21), inv (16) AML, young age or lower WBC counts. Children with relapsed AML could be rescued with second line treatment and allo-HSCT. These results underscore the relevance of identification of subgroups of pediatric AML patients, based on age, WBC count and t(8;21) or inv 16, curable with "lower risk" treatment arms without allo-HSCT in CR1. DisclosuresKaspers:Janssen-Cilag: Research Funding.

First Results of the Multicenter Total Therapy Gimema LAL 1509 Protocol for De Novo Adult Philadelphia Chromosome Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) Patients

▪Introduction: Ph+ ALL management has changed since the introduction of tyrosine kinase inhibitors (TKI). In the GIMEMA LAL 1509 protocol for adult Ph+ ALL, Dasatinib was administered in combination with steroids as induction treatment, and chemotherapy and/or allogeneic transplantation (HSCT) was given if patients did not reach a sustained complete molecular response (CMR) after induction.Methods: Steroids were administered from day -6 to day 31. Dasatinib (140 mg/day) was given between days 1 and 84. Patients reaching a confirmed CMR (i.e. BCR/ABL to ABL ratio=0) at the end of induction (day +85), continued Dasatinib for 6 additional months. Patients in complete hematologic remission (CHR), but not in CMR, were stratified according to HSCT eligibility: those with a promptly available donor underwent directly a HSCT; if the donor was not readily available, a consolidation cycle with clofarabine and cyclophosphamide was administered. HSCT non-eligible patients received two cycles of clofarabine and cyclophosphamide of 5 and 3 days, respectively. Dasatinib was administered until disease progression. Molecular testing was used to identify the presence of a BCR/ABL transcript, define the fusion protein and quantify BCR/ABL levels at baseline and at follow-up. Mutational screening was performed in relapsed cases.Results: Sixty of the 64 enrolled patients were eligible. Median age was 41.9 years (range: 18.7-59.1), 34 were males and 26 females; the median WBC count was 12.5 x 109/l (range 1.4-178.0); the p190 fusion product was detected in 33 patients, p210 in 18 and p190/p210 in 9. Median follow-up is 17.6 months (range 4.1-31.6). After the steroid pre-phase, 38 patients (63%) had a blast reduction ≥75%. At day 85, 58 patients achieved a CHR (97%) and 2 were non-responders (1 hematologic relapse and 1 disease progression): notably, both had a p210 fusion transcript. A CMR was obtained in 11 patients (18.6%): of these, 72% had a p190 fusion transcript. Overall, 24% of p190+ patients and 11% of p210+ or p190/210+ cases obtained a CMR. As previously reported in other GIMEMA trials, no deaths in induction occurred. Among the CMR patients, only 1 experienced a hematologic relapse and harbored a T315I mutation. Among the 46 non-CMR cases, 17/27 eligible patients underwent a HSCT, while 9 did not; 5 relapses occurred in the non-transplanted group, while 1 was observed in the HSCT group. Of the 19 HSCT non-eligible patients, 14 received the planned therapy: in this group, 2 relapses occurred. At 24 months, the overall survival (OS) is 69.1% (95%CI: 55.3-86.3), with a disease-free survival (DFS) at 18 months of 61.6% (95%CI: 47.6.0-79.8). A better DFS was observed in patients who obtained a CMR at day +85. Dasatinib exerted a rapid blast clearance, that was highly significant (p<0.0001) between the onset and day +22, and between day +22 and +45; a significantly more rapid clearance (p=0.0005, p=0.0013 and p=0.001 at days +22, +45 and +57, respectively) was observed in patients who achieved a CMR at day +85, underlining the heterogeneous sensitivity of Ph+ ALL blasts to TKI. Importantly, a significantly greater clearance was observed in p190 (n=33) vs p190/210 and p210 (n=27) cases (p=0.0008, p=0.0032, p=0.0031, p=0.0016, p=0.007 at diagnosis, days +22, +45, +57, and +85, respectively). Mutational screening was performed in 6/12 patients who relapsed and mutations were detected in 5: 3 T315I and 2 V299L, of which 1 with a concomitant F317L. Overall, 12 relapses (5 in the p190 and 7 in the p210 subgroup) and 7 deaths in CR occurred, 5 of which in allografted patients. The median time to relapse was 6.7 months (range 0.3-22.5).Conclusions: We confirm that a chemo-free induction approach for adult Ph+ ALL patients results in a very high CHR rate (97%), with no deaths in induction. In this Dasatinib-based protocol, a sustained CMR is achieved after induction in >18% of cases, suggesting that a subset of patients may be spared further intensive treatment. We witnessed an increase in p190/p210-p210+ cases compared to earlier studies; these patients showed a worse prognosis as underlined by a lower susceptibility to TKI, lower blast clearance and greater incidence of relapses (58%). At this first analysis, OS and DFS are at least comparable to those obtained in previous GIMEMA studies, despite the higher incidence of p210+ patients – which accounted for 45% of cases in this cohort – and which may require an intensified approach. DisclosuresMartinelli:Pfizer: Consultancy; BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; ARIAD: Consultancy.

Conventional 7+3 Consolidation Is Equal in Long-Term Outcome to High Dose ARA-C in Case of the High Total Doses of Different Anthracyclines/Anthracenedione in Induction/Consolidation - the Interim Results of Russian Randomized Multicenter AML-10 Trial

Introduction.The vast majority of AML clinical trials incorporate high-dose ARA-C (HDARA-C) as a basic approach. Though it was recently proved by a controlled prospective comparison that different treatment strategies in patients with AML did not show clinically relevant outcome differences (Th.Buchner, JCO, 2012), the RALSG initiated a randomized multicenter AML-10 trial (ClinicalTrials.gov Identifier: NCT01587430) aiming to evaluate the necessity of HDARA-C in consolidation in the context of high total dose of different anthracyclines/anthracenedione (660-720 mg/m2).Materials and methods.The patients aged 16-60 yy with de novo AML (except APL) were randomized before treatment start to different types of consolidation after two induction 7+3 with daunorubicin 60 mg/m2x3 and ARA-C 100 mg/m2 bid iv (1-7d) in the 1st course and 200 mg/m2/d (1-7d) continuous infusion in the 2nd course: (1st arm) two courses of 7+3 with Idarubicin (Ida) 12 mg/m2x3 and with Mitoxantrone (Mito) 10 mg/m2x3, in both ARA-C 100 mg/m2 bid iv (1-7d); (2nd arm) two courses of HDARA-C 1g/m2 bid iv 1-3 days with Ida 8 mg/m2 3-5 days and Mito10 mg/m2 3-5 days. After consolidation all pts proceeded to the maintenance 5+5 courses (ARA-C 100 mg/m2 bid iv 1-5 days with 6-mercaptopurine 50 mg/m2 1-5 days). Allogeneic HSCT was indicated to patients from intermediate and poor cytogenetic risk groups, late CR, WBC > 100*109/l.Results.From Jan 2010 till Jan 2014, 250 AML patients from 20 centers were randomized: (1st arm) 125 pts (m.age 45 y, 17-59 yy; 73f / 52m; LDH=674 IU (128-6653); cytogenetics favorable - 17,3%, intermediate - 66,7%, poor - 16%) and (2nd arm) 125 pts (m.age 43y, 16-60yy; 69f/56m; LDH=704 IU (123-8159); cytogenetics favorable - 20%, intermediate - 58,6%, poor - 21,4%). No molecular testing in cytogenetically normal pts was done. The analysis was performed in May 2014. The follow-up data were available in 199 pts.CR was achieved in 72,9% (n=145), early death was registered in 12,7% (n=25) and refractory disease - in 12,4% (n=24). Death in CR did not differed in a randomized groups (1st) 13,9% and (2nd) 13,7%. 17% of CR pts (n=20) were withdrawn from the protocol due to refusals (3,5%), infectious complications (13,5%). No relevant cardiotoxicity was registered on both arms. 12% (8 pts on the 1st arm, 9 - on the 2nd) were transplanted in 1st CR from HLA-identical donors.3-years OS and DFS by intent-to-treat analysis were identical on both arms: (1st arm) 43% and 62%, (2nd arm) - 38% and 51%, respectively. For those patients in whom consolidation was fulfilled the comparison of DFS in different cytogenetic groups demonstrated equal efficacy of each consolidation arm: favorable - 85% (1st) and 85% (2nd), intermediate -65% (1st) and 57% (2nd), poor - 20% (1st) and 22% (2nd). In a multivariate analysis only cytogenetic group (HR=3,01, p=0,005) and CR achievement after the 2nd induction course (HR=2,83, p=0,0007) adversely influenced DFS. As the land-mark (5 mo of CR) analysis have shown, the bad prognosis of late CR could be modified by allo-HSCT in 1st CR: DFS of transplanted patients = 86%, non-transplanted=27% (p=0,03).Conclusion.Our interim analysis has demonstrated that conventional 7+3 consolidation is equal in long-term outcome to high dose ARA-C in case of the high total doses of different anthracyclines/ anthracenedione in induction/consolidation. CR after the 2nd induction became independent adverse prognostic factor (even inside cytogenetic risk groups) defining patients who should be transplanted in 1st CR. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

FLT3-ITD Internal Tandem Duplication Confers Poor Prognosis In Patients With Acute Promyelocytic Leukemia Treated With The AIDA Protocols. Long-Term Follow-Up Analysis

Although previous studies in APL have revealed that the FlT3-ITD mutation is associated with an elevated presenting WBC count, hypogranular variant (M3v) morphology and the short (bcr3) isoform of PML-RARA, the prognostic significance of FlT3 mutations in APL has not been firmly established. We report an update of these patients with a median follow-up of 9 years in which we observed that the presence at baseline of the FlT3-ITD mutation confers a very poor overall survival (OS). One hundred and forty-seven patients with newly diagnosed APL were observed and treated with the AIDA (73 patients) and AIDA2000 protocols (74 patients) at the Sapienza University of Rome during the period April 1993-October 2010. Diagnosis was initially established morphologically and subsequently confirmed in all cases by RT-PCR. The following clinical characteristics at diagnosis were analyzed according to the FlT3 status: age, sex, FAB classification, peripheral WBC and platelet count, hemoglobin, karyotype, PML/RAR isoform and relapse risk. For statistical analysis, the Wilcoxon-Mann-Whitney test was used to compare non-parametric series and the Fisher's exact test to compare categories. OS was estimated using the Kaplan-Meier method, whereas relapse-free considered as events relapse and death in CR. Thirty-three patients were identified as FlT3+, 19 were males (57%) and 14 were females; 27% had a variant type according to the FAB classification and 36% were classified as high-risk. Twenty-one FlT3+ patients (63%) presented the bcr3 transcript compared to 37/114 (32%) FlT3- patients (p=0.002). Eight FlT3+ patients (24%) experienced a differentiation syndrome compared to 14 (12%) in the negative cohort (p=0.02). After a median follow-up of 9 years (range 5-19), we could document a significant worse long-term outcome for FlT3+ patients: OS was 96% in the FlT3- cohort compared to 39% in the FlT3+ cohort (p=0.0001), relapse-free survival (RFS) 90% in FlT3- patients vs 30% in the FlT3+ ones (p=0.017), CIR at 9 years was 4% (95% CI, 1,279-6,238) for the FLT3-negative cohort and 60% (95% CI,22.632-81.236) for the FLT3-positive subset (p=0.0001). While this study confirms that there is no difference in response to induction with the AIDA schedule in FlT3+ APL patients, the longest follow-up so fare reported has allowed to demonstrate the significantly worse long-term outcome for this subset of APL, in terms of OS, RFS and DFS. Further studies aimed at investigating whether other clonal mutations may play a role in this unfavorable subset of patients are needed. Disclosures:No relevant conflicts of interest to declare.

Arsenic Trioxide (ATO) Or ATRA For Consolidation Treatment Of Standard Risk Non Elderly Newly Diagnosed APL– Second Interim Analysis Of a Randomized Trial (APL 2006) By The French Belgian Swiss APL Group

▪ BackgroundATRA combined to anthracycline-based chemotherapy (CT) remains the classical treatment of newly diagnosed APL, but it is myelosuppressive and may be associated with long-term cardiac toxicity. Both ATO (Powell, Blood 2010) and ATRA (Sanz , Blood 2004) may allow to reduce the amount of CT and further diminish the relapse risk. In a randomized trial (APL 2006 trial), we compared for consolidation treatment ATO, ATRA and Ara C in standard risk APL ( ie with baseline WBC < 10G/L). MethodsIn this trial (started in Nov, 2006) newly diagnosed APL patients (pts) < 70 years with WBC < 10 G/L were randomized for consolidation between AraC, ATO and ATRA. The AraC group (standard group) received for induction: ATRA 45mg/m2/d until CR with Idarubicin (Ida) 12 mg/m2/dx3 and AraC 200mg/m2/dx7 started on day 3; first consolidation with the same CT course, second consolidation with Ida 9 mg/m2/dx3 and AraC 1g/m2/12h x4d ; maintenance during two years with intermittent ATRA 15d/ 3 months and continuous 6 MP + MTX,). The ATO and ATRA groups received the same treatment as the AraC group , but AraC was replaced respectively by ATO 0.15 mg/Kg/d d1 to 25 and ATRA 45 mg/m2/d d1 to 15 for both consolidation courses. We present here results of the second interim analysis, made at the reference date of 1st Jan 2012, in 349 pts aged < 70 years included in 78 centers before 2012. The primary endpoint was event free survival (EFS) at 2 years from CR achievement. Relapse, survival, side effects of the treatment and duration of hospitalization were secondary endpoints. ResultsPre-treatment characteristics were well balanced between the 3 consolidation groups. 347 pts (99.4 %) achieved CR, and 2 (0.5%) had early death. Overall, 3, 0, and 4 pts had relapsed and 5, 2, and 2 pts had died in CR in the AraC, ATO and ATRA consolidation groups, respectively. Two year EFS was 95%, 97.4% and 96.8% (p=NS) and 2 year OS was 96.6%, 97.4% and 99% (p=NS), in the AraC, ATO and ATRA consolidation groups, respectively. Median time to ANC >1 G/L and platelets > 50G/L after the first consolidation course was 24 and 25 days, 24 and 23 days, 17 and 20 days in the AraC, ATO and ATRA group, respectively (p<0.01). Similarly, time to ANC >1 G/L and platelets > 50G/L after the second consolidation course was 23 and 27 days, 19 and 18 days, 13 and 19 days in the AraC, ATO and ATRA group (p<0.01). The overall duration of hospitalization was 60.9, 63.1 and 33 days in in the AraC, ATO and ATRA groups, respectively (p<0.01). ConclusionVery high CR rates (close to 98-99%) are now obtained in standard risk APL on a very large multicenter basis using classical ATRA and anthracycline based CT combinations, with very few relapses. ATO or ATRA can replace AraC during consolidation cycles without increasing the relapse risk, and can possibly reduce the rate of deaths in CR (2 and 2 patients versus 5 patients, although the difference was NS). However Ida and ATO, when used concomitantly for consolidation cycles, proved as myelosuppressive as Ida-AraC cycles, while myelosuppression was reduced with Ida-ATRA consolidation courses. Disclosures:Off Label Use: ATO in the treatment of 1st Line APL.

The Long-Term Outcome Of Adult Patients With Acute Myeloid Leukemia NPM+ and FLT3/ITD- Is Not Significantly Improved By The Application Of An Allogeneic Stem Cell Transplantation

▪ IntroductionThe discovery of the NPM mutation in acute myeloid leukemia (AML) allowed to identify a distinct entity with intermediate-good prognosis particularly when the FLT3/ITD mutation is absent. The most appropriate consolidation treatment of these patients upon the achievement of the first complete remission has not been established yet and the role of allogeneic stem cell transplantation (SCT) is still debated. Aimto assess long-term outcome of adult patients with NPM positive acute myeloid leukemia according to type and intensity of consolidation therapy. Patients and methodsBetween May 2000 and February 2012, 1155 patients were enrolled into two consecutive, prospective Northern Italy Leukemia Group (NILG) trials (00/01 and 02/06). Six-hundred sixty nine were studied for NPM mutation and 218 (33%) proved positive (by immunohistochemistry or by molecular analysis) (Falini et al, Haematologica. 2007 Apr;92(4):519-32). Median age of NPM+ patients was 50 years (range 16-72) and 134 (61%) were female. Median WBC was 33.3 x 10^9/L (range 0.9-313.9), 71 (33%) had myelomonocytic leukemia (FAB M4), and 211 (96%) had de novo AML. According to the European Leukemia Net (ELN) classification, cytogenetic risk groups were: normal 178 (82%), intermediate 26 (12%), unfavorable 2 (1%) and unknown 12 (5%). Eighty-two (38%) patients had a concurrent FLT3/ITD mutation and 31 (14%) a FLT3/TKD mutation. According to cytogenetics and additional risk factors (late response, WBC count >50x10^9/L, FAB class M0/6/7, hepato/splenomegaly, MDS-related/secondary AML, FLT3/ITD mutation), patients were stratified in standard (SR) and high (HR) risk groups.In both studies the remission induction was based on combination of cytarabine with idarubicin. Post-remission therapy was allogeneic SCT in HR while high-dose cytarabine or busulfan/cyclophosphamide with autologous SCT was given to SR patients. The molecular evaluation of minimal residual disease (MRD) was planned after induction, before the post-remission consolidation and the follow-up. ResultsComplete remission (CR) was achieved in 196/218 (90%) NPM+ patients. One hundred sixty-eight out of 196 remitters (86%) received post-remission consolidation therapy: allogeneic SCT 72 (37%), high dose Ara-C 74 (38%), autologous SCT 14 (7%), other therapy 8 (4%); 28 patients did not receive consolidation due to early relapse (n=24), CR death (n=3), and loss to follow-up (n=1). With a median follow-up of 1.8 years (range 0.008-12.66), 99 CR patients (50.5%) were alive in 1st CR, 13 (6.5%) died of complications, and 84 (43%) had recurrent AML. In a cumulative analysis, 5-year overall and disease-free survival were 46% (OS) and 43% (DFS), respectively. In univariate analysis FLT3/ITD mutation (n=82) affected negatively 5-year OS (29% vs. 49%, P < .0001) and DFS (27% vs. 46%, P < .0001), whereas FLT3/TDK mutation did not. In patients with FLT3/ITD mutation able to receive consolidation therapy (n=49), the application of allogeneic SCT improved DFS significantly (55% vs. 18%, P = .03) and reduced the cumulative incidence of relapse (CIR) (39% vs. 81%, P = .026). In patients with NPM+ and FLT3/ITD- AML, the risk of relapse after high dose cytarabine or autologous SCT (n=68) was more than doubled compared to that observed after allogeneic SCT (n=42) (50% vs. 23%, P= .08) (Figure). However, DFS (48% vs. 69.5%, p= .17), and OS (60% vs. 72%, p= .80) were not significantly different since allogeneic SCT was associated with higher treatment related mortality, albeit effective in the salvage of some relapsed patients. In multivariate analysis, FLT3/ITD mutation was the most powerful factor that unfavorably affected OS, DFS and CIR, while age > 55 years negatively affected OS and DFS. No other clinical factor was predictive for relapse in FLT3- patients. The relationship between MRD and clinical outcome is currently being studied and will be presented. ConclusionsOur data indicate that allogeneic SCT is the most active post-remission treatment for NPM+ AML, but its benefit over chemotherapy may be limited in patients without FLT3/ITD. For this reason the evaluation of MRD could help identify the patients for whom an allogeneic SCT should be preferable. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Outcomes Continue to Be Favorable for De Novo Philadelphia Chromosome Negative B-Lymphoblastic Leukemia (ALL) After Therapy with Hyper-CVAD (with or without Rituximab) Regimen

AbstractAbstract ▪3572▪This icon denotes a clinically relevant abstractThe hyper-CVAD regimen [Kantarjian, JCO 18: 547, 2000; Kantarjian, Cancer 101: 2788, 2004] includes intensive cycles of hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone) alternating with high dose methotrexate (MTX) and cytarabine every 21 days for 8 courses, followed by maintenance therapy with POMP (6-mercaptopurine, MTX, VCR, prednisone) interrupted by early and late intensifications. The regimen was modified in 1999 to include use of laminar air flow rooms during the induction phase for patients (pts) aged 60 years or older. Therapeutic modifications included rituximab 375 mg/m2 (Days 1 & 11 of hyper-CVAD, Days 1 & 8 of MTX-cytarabine for 8 total doses) for CD20 expression > 20% to counteract increased propensity for relapse [Thomas D, Blood 113: 6330, 2009], early anthracycline intensification with liposomal daunorubicin-cytarabine from 1999–2000 only [omitted thereafter owing to lack of benefit, Thomas D, Cancer 116: 4580, 2010], augmentation of CNS prophylaxis, and extension of maintenance POMP therapy from 24 to 30 months with additional early and late intensifications [details in Thomas D, JCO 28: 3830, 2010]. Overall, 216 pts with Ph negative B-lymphoblastic leukemia have been treated with the modified hyper-CVAD regimens. Median age was 46 years (range, 16–84). For the CD20 positive B-lymphoblastic subset treated with hyper-CVAD and rituximab 3-yr rates of CR duration (CRD) and survival (OS) were 66% and 57%. In the younger (age < 60 years) CD20-positive subset, rates of CRD and OS were superior compared with standard hyper-CVAD (69% v 38%; P <.001% and 71% v 47%, P =.003). Historical experience in 37 adolescent and young adult (AYA) subset aged 15 – 30 yrs with CD20 positive B-lymphoblastic leukemia (prior to shift to augmented BFM regimen as first line therapy) showed that the addition of rituximab improved 3-yr CRD rates from 26% to 60% (P =.001) and 3-yr OS rates from 47% to 70% (P =.05) compared with standard hyper-CVAD without rituximab. There were no significant differences in outcome for this AYA subset by regimen (standard or modified) for the CD20 negative groups (all 3-yr rates > 70%). Elderly pts aged 60 year or older with CD20 positive B-lymphoblastic leukemia treated with hyper-CVAD and rituximab, in contrast to the Burkitt experience, had outcomes which were similar to the historical experience with standard hyper-CVAD (rates of CRD 59% v 50%, P = NS and OS 23% v 32%, P = NS, respectively), despite high rates of negativity for minimal residual disease (MRD) by multiparameter flow cytometry (MFC) at CR, related mainly to deaths in CR during consolidation. MRD positivity by MFC after induction therapy with hyper-CVAD and rituximab was associated with a higher relapse rate and lower 3-yr CR duration rates compared with MRD negative status at the time of CR. Additional doses of rituximab were added to consolidation (Day 1 of cycles 5 – 8) and maintenance chemotherapy in order to potentially improve outcomes for the MRD positive subset. Upfront dose reductions of cyclophosphamide, doxorubicin, vincristine, dexamethasone and methotrexate have been implemented for all cycles of induction-consolidation phase for older age and/or poor performance status with reduction in rate of deaths in CR noted. Incorporation of pegylated asparginase (one dose of 2000 Units/m2 with capping per cycle, 1000 Units/m2 if older or poor performance status) during the induction-consolidation phase (“augmented hyper-CVAD”) was piloted as first line therapy in 19 pts aged 30 – 59 years of age, then omitted owing to excessive toxicity. Incorporation of rituximab into first line intensive chemotherapy such as the hyper-CVAD regimen appears beneficial for younger pts, prompting investigation of second generation anti-CD20 monoclonal antibodies such as ofatumumab and hyper-CVAD (regardless of CD20 expression owing to data showing upregulation of CD20 expression) for the younger subsets and inotuzumab (with or without rituximab) and “mini-hyper-CVAD” for the elderly group. Multivariate analysis of outcomes by risk groups (age/MRD status/CD20 expression) and the impact of the early/late intensifications during maintenance chemotherapy will be presented. Disclosures:O'Brien:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Absence of Chromosomal Abnormalities Corresponds to Better Survival in Adult Ph-Negative ACUTE Lymphoblastic Leukemia – Results of the Russian ACUTE Lymphoblastic Leukemia (RALL) Study Group.

AbstractAbstract 2572Adult ALL regardless recent advantages in adolescents and young adults is still considered to be a therapeutical problem. So called “a pediatric-like approach” applied in adult ALL is reported to be more reasonable even in the older adults (up to 55 y).RALL has initiated a prospective multicenter trial for adult Ph-neg ALL based on: 1) evaluation of b/m blast clearance after 7 days of Prednisolone (PRD) prephase and its substitution by Dexamethasone (DEXA) if b/m blast count was >25%; 2) continuous 2,5 years treatment schedule with prolonged L-asparaginase (Σ=590.000 IU); 3) evaluation of the impact of the late intensification (2 courses of HD of methotrexate and ARA-C) on MRD clearance. The study is registered on the ClinicalTrials.gov public site; NCT01193933.From Nov, 2008, till June, 2012, 24 centers enrolled 173 pts: median age 28 y (15–55), 71f/101m, 112 (64,7%) = B-lin, 54 (31,2%) = T-lin, 1 pt -undifferentiated AL (0,6%), 6 - uknown phenotype (3,5%), median LDH=848 ME (72–13061), median L=13,5 (0,6–556*109/l). Cytogenetics was evaluable in 58,3% of pts (n=101) and 46,5% of them (n=47) had normal karyotype (NK). Initial risk group was evaluated in 154 pts among whom 46 patients (29,9%) were in the standard risk (SR) group (WBC <30 for B-Lin, <100 for T-Lin, EGIL BII-III, T-III; LDH < 2N, No late CR, t(4;11)-negative), 109 (60,1%) - in the high risk (HR) group (WBC >30 for B-Lin, >100 for T-Lin, EGIL BI, T-I-II-IV; LDH > 2N, No late CR, t(4;11)-positive). 19/173 pts (11%) were not qualified. The analysis was performed in June, 2012. +8 day b/m blast count was reported in 149 pts and b/m blasts less than 25% were detected in 36,2% of pts. The portion of PRD non-responders was statistically different in SR and HR groups: 24/45 (53,3%) and 68/101 (67,3%) (p=0,01), confirming the initial risk groups identification.Induction results were obtained in 150 pts, and CR rate was identical in both risk groups (SR=86,9%; HR=84,1%) with total 12 induction deaths (8,0%) and 6 resistant leukemias (4,0%). With a median follow-up of 12 mo (1–36 mo) death in CR was reported in 9/132 (6,8%) pts. OS at 36 mo was 58,6%, DFS-68,3%.MRD analysis for clonal IgH and TCR rearrangements was carried out in 25 pts. And as in our previous studies (ASH 2006, abstr 2294) the clearance was slow with only 41,6% pts negative for MRD at day +133 (4mo) of the protocol. Two late intensification courses (day +157 = 5 mo) increased MRD negativity only up to 50%. Such slow MRD clearance did not correspond to higher relapse rate so far.Age, WBC, immunophenotype, LDH, risk group, +8 day b/m blast count, time to CR, time without treatment (<>8days), L-asparaginase cessation did not influence survival. OS and DFS differed in pts with NK vs all other abnormalities: 87,4% vs 57,9% (p=0,002) and 88,9% vs 66,5%, respectively (p=0,02).So, our data demonstrated that ALL-2009 protocol provided 58% 3-years overall survival and 68,3% DFS. In adult Ph-neg ALL normal karyotype predicts better survival. The MRD clearance is very slow while on this protocol. Disclosures:No relevant conflicts of interest to declare.

ATRA and Arsenic Trioxide (ATO) Versus ATRA and Idarubicin (AIDA) for Newly Diagnosed, Non High-Risk Acute Promyelocytic Leukemia (APL): Results of the Phase III, Prospective, Randomized, Intergroup APL0406 Study by the Italian-German Cooperative Groups Gimema-SAL-AMLSG

AbstractAbstract 6 BackgroundSimultaneous ATRA and chemotherapy (CHT) is the current gold standard for newly diagnosed APL resulting in ∼80% cure rates, while arsenic trioxide (ATO) is the treatment of choice for relapsed patients. ATO in variable combinations including ± ATRA ± CHT has also been tested as front-line therapy yielding encouraging results in several pilot studies as well as in two phase III studies conducted in China and the US. So far, no randomised studies have compared front-line CHT-free ATO+ATRA combination against the standard ATRA+CHT approach. Patients and MethodsThe phase III, randomised, prospective APL0406 trial was started in October 2007 by the Italian GIMEMA group and joined in November 2008 by the German SAL and AMLSG multicenter groups. Eligible patients were adults aged 18-<71 years with newly diagnosed, genetically confirmed, non-high-risk (WBC≤10×109/L) APL. Patients were randomized to receive the ATO+ATRA combination originally reported by the MD Anderson group (Estey et al. Blood 2006, arm A), or the Italian AIDA2000 risk-adapted protocol for non high-risk disease (arm B). Patients in arm A received ATO 0.15/kg plus ATRA 45 mg/m2 daily until CR, then ATO 5 days/week, 4 weeks on 4 weeks off, for a total of 4 courses and ATRA 2 weeks on and 2 weeks off for a total of 7 courses. Patients in arm B received the standard AIDA (ATRA+Idarubicin) induction followed by 3 cycles of anthracycline-based plus ATRA consolidation and low dose CHT and ATRA for maintenance as reported (Lo-Coco et al., Blood 2011). The primary study objective was EFS at 2 years. The study was designed to show that the rate of patients alive event-free at two years in the experimental treatment arm is at least 80%. Secondary objectives included OS, DFS, CIR rates, molecular response and toxicity profile. ResultsFrom October 2007 to September 2010, the required sample size of 162 enrolled patients was completed. Median age was 45.3 years (18.7–70.2 years) and median WBC 1.50 × 109/L. As to the Sanz’s risk score, 61.8% and 38.2% of patients were in the intermediate- and low-risk categories, respectively. The two treatment arms were well balanced for main baseline characteristics including age, sex, median WBC and Sanz’s score. Eight patients were not evaluable for induction due to ineligibility or protocol violation. Of 154 patients evaluable for response to induction, CR was achieved in 150 (97.4%): 75/75 (100%) in arm A vs 75/79 (95%) in arm B (P=0.12). After a median follow-up of 31 months (range 0.07–50.4) the 2 year EFS (primary objective) was 97% (C.I.95%: 93.1–100) and 86.7% (C.I.95%: 80.3–93.6) in arms A and B respectively (P=0.03). There were 1 death in CR and 2 relapses in arm A, and 7 deaths (4 in induction, 3 in CR) and 4 relapses in arm B. As to secondary objectives, OS, DFS, and CIR rates were 98.7% vs. 91.1% (P=0.03), 97% vs. 91.6% (P=0.19) and 1.6% vs. 4.3% (P=0.41) in arm A and B, respectively. Fever episodes, prolonged (>15 d) grade ≥ 3 neutropenia and thrombocytopenia were significantly more frequent in patients in arm B as compared to those in arm A (P <.001 for all comparisons). Other side effects including differentiation syndrome and increase of liver enzymes were recorded with similar frequency in the two study arms. Two patients in arm A had QTc prolongation requiring ATO discontinuation with final withdrawal in one case. PCR analysis of PML/RARA (sensitivity 10−4) was centrally performed in Rome (F. Lo-Coco) and Dresden (C. Thiede) and showed molecular CR in 141/142 (99%) of evaluable patients after completion of 3rd consolidation. One patient in arm B who tested PCR-positive at this time point was considered resistant and taken off protocol as per study design. ConclusionsFor patients with newly diagnosed non-high-risk APL, as compared to the standard AIDA regimen, the front-line CHT-free ATO+ATRA combination is at least not inferior for 2 year EFS. [Display omitted] [Display omitted] Disclosures:Lo-Coco:Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Cephalon: Speakers Bureau. Off Label Use: Arsenic Trioxide (ATO) is currently approved for therapy of relapsed APL in the US and Europe. In this study the role of ATO in front-line therapy of APL is explored. Fiedler:Pfizer Inc.: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Breccia:Celgene: Honoraria; Novartis: Honoraria; BMS: Honoraria. Platzbecker:GlaxoSmithKline: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Amgen: Consultancy.