Single Induction Course Research Articles

A Polish Acute Leukemia Group Prospective Multicenter Clinical Trial to Compare the Efficacy of Two Standard Induction Therapies (DA-90 vs DAC) and Two Standard Salvage Regimens (FLAG-IDA vs CLAG-M) in Acute Myeloid Leukemia (AML) Patients ≤ 60 Years Old (PALG-AML1/2016)

Background: AML is the most common acute leukemia in adults. While most adults < 60 years achieve complete remission (CR) with intensive induction chemotherapy, approximately one third have primary refractory disease and, overall, the majority of AML patients still relapse despite having attained initial remission (Dohner et al, 2017). The combination of an anthracycline and cytarabine has been the mainstay of intensive AML induction for more than 50 years. Combined with cytarabine (AraC), high-dose daunorubicin (90 mg/m2) in induction (DA-90) resulted in a higher rate of CR (70.6% vs. 57.3%, P<0.001) and improved overall survival (OS) (median 23.7 vs. 15.7 months; P = 0.003), without increased serious adverse events compared with DA-45 (Fernandez et al, 2009). In two PALG randomized trials, the combination of cladribine with DA (DAC regimen) also resulted in significantly increased CR after a single induction course, compared with the standard two-drug induction (DA-60) (Holowiecki et al, 2012). Both regimens have a recommendation from the National Cancer Comprehensive Network (NCCN) for routine use. For patients with primary refractory disease, the commonly used FLAG-IDA (fludarabine, cytarabine, idarubicin, GCSF) regimen results in a CR rate of 52% (Pastore et al, 2003). Two previous PALG studies confirmed that another standard regimen, CLAG-M (a combination of cladribine, Ara-C, G-CSF and mitoxantrone) is also effective with tolerable toxicity in refractory/relapsed AML patients (Wierzbowska et al, 2008; Jaglal et al, 2014). PALG-AML1/2016 aims to compare the safety and efficacy of two commonly used induction and salvage regimens in AML. This trial is also the first international randomized trial in AML induction to prospectively evaluate the impact of measurable residual disease (MRD) on overall survival, using multi-modality testing (flow-cytometry, next-generation sequencing, and PCR) of serial samples. The study is conducted in accordance with the principles of the "Declaration of Helsinki". Study Design and Methods: PALG-AML1/2016 is a multicenter, randomized, Phase III study which will include 582 patients with newly-diagnosed AML treated at multiple centers across Poland and at Weill Cornell Medicine and The New York Presbyterian Hospital in New York City. This will allow a 10% difference in CR rate between the DAC and DA-90 induction regimens to be confirmed with a power of 80% and level of significance 0.05. Eligible patients must be 18 to 60 years of age with untreated AML, Eastern Cooperative Oncology Group performance status 0-2 and HCT-CI Index of comorbidities, ≤ 3. The trial schema is shown in Figure 1. The trial was initiated in July 2017; 408 patients have been enrolled to date and accrual is ongoing. Preliminary safety and efficacy data were reviewed by the data safety monitoring committee after 194 patients and the recommendation was to proceed without changes. The CR, CRi, CRh after single or double induction were achieved in 63.4%, 16.5% and 0.6% patients, respectively leading to an overall composite CR (cCR) rate 80.5%. Thirty-day mortality, mainly due to infectious complications in aplasia, were observed in 5% and 14.5% did not achieved cCR. Serial samples for MRD are being collected from all patients at multiple time points and analysis is ongoing. ClinicalTrials.gov Identifier: NCT03257241 Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

SAFETY AND EFFICACY OF THE “CARMEN” REGIMEN, A NEW DOSE‐DENSE SHORT‐TERM THERAPY IN PATIENTS WITH AGGRESSIVE B‐CELL LYMPHOMA AND MYC REARRANGEMENT

Introduction: Patients (pts) with aggressive B-cell lymphoma and MYC rearrangement exhibits poor outcome after R-CHOP treatment. In the last decade, these pts were treated with a new dose-dense, short-term therapy termed “CARMEN”, at several Italian Centers. Excellent efficacy and safety profile have been reported in HIV/AIDS pts with high-risk Burkitt lymphoma (BL) [Ferreri et al. BJH 2021], but its efficacy in pts with high-grade B-cell lymphoma with MYC rearrangement (HGBCL) remains to be defined. Herein, we report a retrospective series of consecutive pts with BL or HGBCL treated with CARMEN regimen. Methods: Either HIV-negative and HIV-positive pts aged 18-80 years with BL or HGBCL and MYC rearrangement positive by FISH were treated with CARMEN regimen, which includes a single 36-day induction course of sequential doses of cyclophosphamide, vincristine, rituximab, methotrexate, VP16, and doxorubicin plus intrathecal chemotherapy, followed by consolidation with HD-cytarabine ± cisplatin. Pts who did not achieve complete remission (CR) after induction received BEAM/ASCT after consolidation. Results: 63 pts (22 HGBCL;41 BL) received the CARMEN regimen (Table). Treatment was well tolerated: 56 (89%) pts completed the induction, and 55 (87%) completed the consolidation. G4 hematological toxicity during induction was neutropenia in 48 (76%) pts, thrombocytopenia in 24 (38%) and anemia in 7 (11%), which were recorded after consolidation in 34 (62%), 38 (69%) and 1 (2%) pt, respectively. G4 non hematological toxicity was uncommon: mucositis in 4 (6%) pts and tumor lysis syndrome in 1 (2%) during induction, and heart failure and bleeding in 1 (2%) pt each after consolidation. G4 infections were recorded in 4 (6%) pts during induction and in 2 (3%) after consolidation. Induction and consolidation doses were reduced in 6 (9%) and 4 (7%) pts, respectively. Seven HGBCL and 9 BL pts received ASCT, with expected tolerability. 4 HGBCL and 2 BL pts died of toxicity (sepsis in 4;respiratory failure;COVID-19), with a TRM of 9%. After induction, 18 (82%) HGBCL and 37 (90%) BL pts achieved a response, which was CR in 10 (45%) and 26 (63%) pts, respectively. After the whole treatment, 15 (68%) HGBCL pts and 32 (78%) BL pts achieved a CR, and, at a median follow-up of 54 (2-131) months, 15 (100%) HGBCL and 29 (91%) BL pts remain relapse-free, with a 5-yr PFS of 67% and 70%, respectively. 15 HGBCL and 32 BL pts are alive, with a 5-yr OS of 66% and 77%, respectively. HIV seropositivity did not modify outcome. Age and LDH level were independently associated with OS. Conclusions: With the limitations of a retrospective series, this study shows that CARMEN is a safe and active treatment both in HIVnegative and-positive pts with HGBCL and MYC rearrangement and BL. Survival figures in HGBCL pts compare favorably with results reported with R-CHOP or analogous, and are similar to those achieved in BL pts.

Role of CD19 and specific KIT-D816 on risk stratification refinement in t(8;21) acute myeloid leukemia induced with different cytarabine intensities.

High‐dose cytarabine (Ara‐C) has been reported with increased treatment‐related mortality, whereas few data are available concerning intermediate‐dose Ara‐C for induction of acute myeloid leukemia (AML) with t(8;21) translocation. We retrospectively analyzed factors impacting complete remission (CR), event‐free survival (EFS), cumulative incidence of relapse (CIR), and overall survival (OS) in 197 adults with t(8;21) AML, of whom 107 cases were induced with intermediate‐dose and 90 with standard‐dose Ara‐C (as part of 3 + 7 protocol). After a single induction course, the overall CR rate was 87.6% (170/194), with a significant difference between the standard‐dose (83/105, 79.0%) and intermediate‐dose (87/89, 97.8%) groups (p < 0.001). Rather than general KITmut, the specific KIT‐D816 independently led to a lower probability of achieving CR (HR = 3.29 [1.18–9.24], p = 0.023), worse EFS (HR = 3.53 [1.82–6.84], p < 0.001), and OS (HR = 5.45 [1.77–16.84], p = 0.003) in the standard‐dose group, but not in the intermediate‐dose group. CD19(+) represented the only independent factor predicting lower CIR both in the standard‐dose group (HR = 0.32 [0.10–1.00], p = 0.050) and in the intermediate‐dose group (HR = 0.11 [0.03–0.40], p = 0.001). When combined, KIT(+) plus CD19(−) conferred the most increased relapse risk (3‐year CIR 60%; SE 0.12). Specific KIT‐D816, instead of general KITmut, may be incorporated in prognostication model for t(8;21) AML. Combination of CD19 with KIT provides a more definite risk stratification profile for t(8;21) AML.

A Polish Acute Leukemia Group Prospective Multicenter Clinical Trial to Compare the Efficacy of Two Standard Induction Therapies (DA-90 vs DAC) and Two Standard Salvage Regimens (FLAG-IDA vs CLAG-M) in Acute Myeloid Leukemia (AML) Patients ≤ 60 Years Old (PALG-AML1/2016)

Background: AML is the most common acute leukemia in adults. While most adults &amp;lt; 60 years achieve complete remission (CR) with intensive induction chemotherapy, approximately one third have primary refractory disease and, overall, the majority of AML patients still relapse despite having attained initial remission (Dohner et al, Blood 2017). The combination of an anthracycline and cytarabine has been the mainstay of intensive AML induction for more than 50 years. Combined with cytarabine (AraC), high-dose daunorubicin (90 mg/m2) in induction (DA-90) resulted in a higher rate of CR (70.6% vs. 57.3%, P&amp;lt;0.001) and improved overall survival (OS) (median 23.7 vs. 15.7 months; P = 0.003), without increased serious adverse events compared with DA-45 (Fernandez et al, NEJM, 2009). In two PALG randomized trials, the combination of cladribine with DA (DAC regimen) also resulted in significantly increased CR after a single induction course, compared with the standard two-drug induction (DA-60) (Holowiecki et al, Leukemia, 2004 and JCO 2012). Both regimens have a recommendation from the National Cancer Comprehensive Network (NCCN) for routine use. For patients with primary refractory disease, the commonly used FLAG-IDA (fludarabine, cytarabine, idarubicin, GCSF) regimen results in a CR rate of 52% (Pastore et al, Ann Hem, 2003). Two previous PALG studies confirmed that another standard regimen, CLAG-M (a combination of cladribine, Ara-C, G-CSF and mitoxantrone) is also effective with tolerable toxicity in refractory/relapsed AML patients (Robak et al Leuk Lymph, 2000; Wrzesień-Kuś et al, Eur J Haematol 2003; Wrzesień-Kuś et al, Ann Hematol, 2005; Wierzbowska et al, Eur J Haematol ,2008; Jaglal et al, Leuk Res, 2014). PALG-AML1/2016 aims to compare the safety and efficacy of two commonly used induction and salvage regimens in AML. This trial is also the first international randomized trial in AML induction to prospectively evaluate the impact of measurable residual disease (MRD) on overall survival, using multi-modality testing (flow-cytometry, next-generation sequencing, and PCR) of serial samples. The study is conducted in accordance with the principles of the "Declaration of Helsinki". Study Design and Methods: PALG-AML1/2016 is a multicenter, randomized, Phase III study which will include 582 patients with newly-diagnosed AML treated at multiple centers across Poland and at Weill Cornell Medicine and The New York Presbyterian Hospital in New York City. This will allow a 10% difference in CR rate between the DAC and DA-90 induction regimens to be confirmed with a power of 80% and level of significance 0.05. Eligible patients must be 18 to 60 years of age with untreated AML, Eastern Cooperative Oncology Group performance status 0-2 and HCT-CI Index of comorbidities, ≤ 3. As midostaurin treatment has become approved and available the study was amended with an exclusion of FLT3-mutated patients. The trial schema is shown in Figure 1. The trial was initiated in July 2017 and 279 patients have been enrolled to date and accrual is ongoing. Preliminary safety and efficacy data were reviewed by the data safety monitoring committee after 194 patients and the recommendation was to proceed without changes. Serial samples for MRD are being collected from all patients at multiple time points and analysis is ongoing. ClinicalTrials.gov Identifier: NCT03257241 Figure 1 Disclosures Wierzbowska: Janssen: Honoraria; Celgen/BMS: Honoraria; Novartis: Honoraria; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Research Funding. Pluta:Angelini: Research Funding; Celgene/BMS: Honoraria. Libura:Novartis: Honoraria. Wrobel:Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau. Zaucha:Abbvie: Honoraria; Sandoz: Consultancy, Honoraria; Cellgene: Other: travel, accomodations, expenses; Novartis: Consultancy; BMS: Consultancy; Takeda: Consultancy, Honoraria, Other: travel, accomodations, expenses; Roche: Consultancy, Honoraria, Other: travel, accomodations, expenses. Robak:AstraZeneca: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; GSK: Research Funding; Bristol Meyers Squibb: Research Funding; Novartis: Honoraria, Research Funding; Morphosys: Research Funding; UCB: Honoraria, Research Funding; Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; UTX-TGR: Research Funding; BioGene: Honoraria, Research Funding; Acerta: Research Funding; Momenta: Consultancy; Pfizer: Research Funding; Sandoz: Consultancy, Honoraria; Octapharma: Honoraria; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; Medical University of Lodz: Current Employment; Takeda: Consultancy. Lee:BMS: Consultancy; Helsinn: Other: Member -DSMB; AstraZeneca: Consultancy; Jazz: Consultancy; Roche Molecular Systems: Consultancy. Ritchie:Novartis: Honoraria; Incyte: Speakers Bureau; Sierra Oncology: Honoraria; Abbvie: Honoraria; Pfizer: Honoraria, Research Funding; Jazz pharmaceuticals: Honoraria, Research Funding. Guzman:Cellectis: Research Funding; SeqRx: Honoraria. Roboz:Agios: Consultancy; Amphivena: Consultancy; Astex: Consultancy; Pfizer: Consultancy; Abbvie: Consultancy; Array BioPharma: Consultancy; Bayer: Consultancy; Celltrion: Consultancy; Eisai: Consultancy; Jazz: Consultancy; Roche/Genentech: Consultancy; Sandoz: Consultancy; Actinium: Consultancy; Argenx: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; AstraZeneca: Consultancy; Orsenix: Consultancy; Otsuka: Consultancy; Takeda: Consultancy; Trovagene: Consultancy; Cellectis: Research Funding; Jasper Therapeutics: Consultancy; Epizyme: Consultancy; Helsinn: Consultancy; MEI Pharma: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Novartis: Consultancy. OffLabel Disclosure: cladribine - in induction regimen in AML

Early Assessment of Treatment Response in Acute Myeloid Leukemia Using FLT PET/CT Imaging: A Trial of the ECOG-ACRIN Cancer Research Group (EAI141)

Introduction: Patients with acute myeloid leukemia (AML) are often treated with intensive induction chemotherapy to achieve complete remission (CR). Early response to standard anthracycline plus cytarabine induction (7+3) is assessed by a day 14 nadir bone marrow biopsy. The nadir marrow has limitations, though, including sampling issues and ambiguity as to whether blasts are leukemia cells vs. regenerating marrow. In prior studies, the predictive value for remission of the nadir marrow is only 67-84%. A more accurate predictor of residual disease (RD) would give clinicians an opportunity to modify therapy earlier. Positron emission tomography (PET/CT) with 3'-deoxy-3'-[18F]fluorothymidine (FLT) is a molecular imaging modality that can assess cellular proliferation in the bone marrow compartment. A prior single-institution pilot study showed a significant difference in the marrow FLT uptake between patients with AML who achieved CR and those who had RD after count recovery. Methods: EAI141 was an ECOG-ACRIN-led, prospective, multi-center study designed to assess FLT PET/CT as a predictor of CR after AML induction. The primary objective was to evaluate the predictive value of post-treatment FLT PET/CT imaging for detecting RD, with the secondary objectives of evaluating the predictive value for detecting CR and estimating the sensitivity and specificity. Maximum standardized uptake value (SUVmax) of &amp;gt; 7 g/mL in total bone marrow compartment was chosen prospectively based on data from a pilot study as a marker for presence of leukemia cells at nadir. The predictive values, sensitivity, and specificity of the FLT PET/CT and the nadir bone marrow biopsy were calculated. Eligible subjects were 18 years or older with previously untreated AML who were to receive induction with 7+3. Subjects underwent a nadir marrow biopsy and an FLT PET/CT scan 10-17 days after starting induction, and prior to any re-induction if disease was noted on the nadir marrow. A recovery marrow was performed 28-35 days after initial treatment or re-induction to assess CR or RD. Subjects could undergo an optional pre-treatment scan. Relapse-free survival (RFS) and overall survival (OS) were additional clinical outcomes. Results: 87 subjects from 9 centers were enrolled between 2016-2018, and 61 were considered evaluable. Reasons for being not evaluable included study ineligibility (n=3), no post-treatment scan (n=13), and no remission marrow (n=10). Median age was 58 years (range 21-73); 56% were men and 44% were women. CR was achieved in 56% (34/61). Treatment was a single induction course in 79% (48/61) and re-induction in 21% (13/61). Predictive value based on FLT PET/CT was 60% (9/15, 95% CI 32%-84%) for RD and 61% (28/46, 95% CI 45%-75%) for CR. Of patients who achieved CR, 28/34 had SUVmax ≤ 7 g/mL (sensitivity of 82%) and 9/27 of those who did not had high SUVmax &amp;gt; 7 g/mL (specificity 33%). Predictive value of an aplastic marrow was 59% (26/44) for CR and 56% (9/16) for RD. Of patients who achieved CR, 26/33 had marrow hypoplasia (sensitivity 79%) and 9/27 with RD had disease in the nadir marrow (specificity 33%). Significant heterogeneity of bone marrow compartment post treatment (SUVhetero ranging from 0.24 to 1.07) was observed in FLT-PET/CT scans. Heterogeneity of bone marrow compartment decreased about 50% from pre-treatment to post-treatment FLT PET/CT. OS for all participants, stratified by post-treatment FLT PET/CT response and nadir marrow results, are summarized in the Figure. Conclusions: Although this study did not show significant advantage of FLT PET/CT compared to nadir marrow to predict RD or CR on the average, it did show signal heterogeneity in the study population that may be relevant to disease biology not appreciated by a single sampling site for the nadir or remission marrow. For example, in patients with false negative nadir biopsy, in approximately 20% of patients assessment with FLT PET/CT was correct, likely reflecting bone marrow heterogeneity and limitation of a single point sampling. Similarly, in almost 60% of patients with false positive nadir biopsy, FLT PET/CT assessment was correct. Figure 1 Disclosures Jeraj: AIQ Solutions: Current equity holder in private company. Kostakoglu:F. Hoffmann-La Roche: Consultancy. Strickland:KiTE: Consultancy; Kura: Consultancy; Astellas: Consultancy; Jazz: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Sunesis: Research Funding; ArcherDx: Consultancy; AbbVie: Consultancy. Uy:Daiichi Sankyo: Consultancy; Pfizer: Consultancy; Agios: Consultancy; Genentech: Consultancy; Jazz Pharmaceuticals: Consultancy; Astellas Pharma: Honoraria. Perlman:GE Healthcare: Research Funding; AIQ: Research Funding.

In-silico comparison of two induction regimens (7\u2009+\u20093 vs 7\u2009+\u20093 plus additional bone marrow evaluation) in acute myeloid leukemia treatment

BackgroundClinical integration of systems biology approaches is gaining in importance in the course of digital revolution in modern medicine. We present our results of the analysis of an extended mathematical model describing abnormal human hematopoiesis. The model is able to describe the course of an acute myeloid leukemia including its treatment. In first-line treatment of acute myeloid leukemia, the induction chemotherapy aims for a rapid leukemic cell reduction. We consider combinations of cytarabine and anthracycline-like chemotherapy. Both substances are widely used as standard treatment to achieve first remission. In particular, we compare two scenarios: a single-induction course with 7 days cytarabine and 3 day of anthracycline-like treatment (7 + 3) with a 7 + 3 course and a bone marrow evaluation that leads, in case of insufficient leukemic cell reduction, to the provision of a second chemotherapy course. Three scenarios, based on the leukemias growth kinetics (slow, intermediate, fast), were analyzed. We simulated different intensity combinations for both therapy schemata (7 + 3 and 7 + 3 + evaluation).ResultsOur model shows that within the 7 + 3 regimen a wider range of intensity combinations result in a complete remission (CR), compared to 7 + 3 + evaluation (fast: 64.3% vs 46.4%; intermediate: 63.7% vs 46.7%; slow: 0% vs 0%). Additionally, the number of simulations resulting in a prolonged CR was higher within the standard regimen (fast: 59.8% vs 40.1%; intermediate: 48.6% vs 31.0%; slow: 0% vs 0%). On the contrary, the 7 + 3 + evaluation regimen allows CR and prolonged CR by lower chemotherapy intensities compared to 7 + 3. Leukemic pace has a strong impact on treatment response and especially on specific effective doses. As a result, faster leukemias are characterized by superior treatment outcomes and can be treated effectively with lower treatment intensities.ConclusionsWe could show that 7 + 3 treatment has considerable more chemotherapy combinations leading to a first CR. However, the 7 + 3 + evaluation regimen leads to CR for lower therapy intensity and presumably less side effects. An additional evaluation can be considered beneficial to control therapy success, especially in low dose settings. The treatment success is dependent on leukemia growth dynamics. The determination of leukemic pace should be a relevant part of a personalized medicine.

Efficacy and Toxicity of Induction Therapy with Cladribine, Idarubicin, and Cytarabine (IAC) for Acute Myeloid Leukemia.

We report our single-center experience with cytarabine and idarubicin for induction therapy for acute myeloid leukemia (AML) with an additional 5 days of cladribine (IAC therapy). From July 2012 to September 2014, 38 patients completed a full course of IAC induction. Median patient age was 61 years, 61% of patients were ≥60 years old, and 71% were male. The complete remission (CR) rate was 63% following a single induction course, three patients (8%) required a second induction course to achieve CR, for an overall response rate of 71%. The median duration of severe neutropenia was 30.5 days. Thirty-two percent of patients developed mucositis, 76% experienced diarrhea, and 61% developed a rash. Incidence of CR following IAC induction therapy for AML was comparable to historical data, but with frequent diarrhea, rash, and fungal infections. This study found IAC efficacy and toxicity was similar irrespective of age.

Cladribine, Cytarabine and Mitoxantrone As Treatment Intensification for Patients with Acute Myeloid Leukemia with the Excess of Bone Marrow Blasts on Day 14 of the First Induction. Prospective, Multicenter Study By the Polish Adult Leukemia Group (PALG)

ObjectivesThe treatment results of acute myeloid leukemia (AML) patients (pts) younger than 60yo are still unsatisfactory. The strategy of double induction in AMLis based on two courses of chemotherapy depends on percentage of bone marrow (BM) blast at 7-14 days of treatment. This therapy intensification may induce higher response rate but toxicity appeared as early death (ED) rates still a medical dilemma. The advantage from addition of cladribine (2CdA) to standard induction and reinduction treatment was previously confirmed in PALG's trials.AimThe aim of this study was an estimation of efficacy and toxicity of treatment intensification based on BM blast at 14 day (D14) by second early induction, CLAM (2CdA + cytarabine + mitoxantron)MethodsWe performed multicenter, prospective, non-randomized trial where pts received DAC induction treatment with subsequent second early induction according as D14 BM biopsy results. When BM examination revealed >10% of blast without hypocellular marrowand pts met all criteria to intensive chemotherapy, second intensive induction with CLAM protocol (2CdA 5mg/m2 iv days 1-5, Cytarabine 2g/m2 iv days 1-5, Mitoxantron 10mg/m2 iv days 1-3) from day 16 was applied. The pts were allocated to risk-adjusted postremission treatment with high-dose cytarabine (HD-AraC) for low-risk group according to European Leukemia Net (ELN) classification and allogeneic stem cell transplantation (allo-SCT) recommended for intermediate and high-risk group.ResultsOne hundred seventy one newly diagnosed AML pts from 8 PALG's centers were enrolled to the study. The median age was 47 yo (range19-60). According to WHO 2008 classification, our group consisted of 9% AML with recurrent genetic abnormalities, 19% AML related to myelodysplasia, 3% therapy-related AML and 69% AML not otherwise classified. Analysis of cytogenetic-molecular risk factors based on ELN classification revealed favorable, intermediate-1, intermediate-2, poor-risk groups in 17%, 44%, 18% and 21% AML pts, respectively. Twenty-six (15%) out of 171 pts had elevated BM infiltration of blasts at D14, with the median 44% (range 11-100%). Overall, 22 of 26 pts were judged as eligible to receive second induction, reasons for exclusion being in all cases active infection.Response evaluation was available in 150 pts, 21 pts were still ongoing in the protocol. Complete remission (CR) rate after single DAC induction course was 71% (n=106), partial remission (PR), non-remission (NR) and ED was 8% (n=12), 18% (n=28) and 3% (n=4), respectively. Response after double induction was evaluated in 21 out of 22 cases; one patient still has not reached time of measurement. CR was observed in 14/21 pts (67%), NR in 5% (n=1), ED 28% (n=6). The CR rate after inductiontreatment applied to first hospitalization (DAC or DAC+ CLAM) was 81% (n=120). Twelve pts who had <10% of blasts at day 14 and achieved PR after first induction were allocated to second DAC induction. Six out of them achieved CR leading to the overall CR rate 85%.In 27 pts who achieved CR allo-SCT was performed till June 2016, however there are pts who are still awaiting allo-SCT.The median duration of hospital stay was 31 (11-73) and 66 (52-76) days respectively for the DAC and the DAC + CLAM induction. During the single DAC induction the median number of days with neutropenia <0.5 G/l was 24 (12-101), and with thrombocytopenia <20 G/l was 12 (0-51). The median number of transfused packed red blood cell (PRBC) was 9 (0-32) and the number of platelet concentrate units was 15 (2-124). During DAC+CLAM double induction the median number of days of the neutropenia <0.5 G/l was 53 (17-73) and thrombocytopenia <20 G/l was 19 (4-57). The median number of PRBC was 18 (10-44) and the number of platelet concentrate units was 30 (5-153).With the median time of follow-up 16 months the median overall survival (OS) was not reached. The probability of 1-year OS was 59% and the probability of 1-year disease free survival was 83% (Figure 1, Panel A and B).ConclusionThe preliminary results of our study suggest that early second induction CLAM is a feasible and effective treatment option in younger AML patients which further improves the CR rate and do not compromise the feasibility of allo-SCT. [Display omitted] DisclosuresGrzybowska-Izydorczyk:BMS: Honoraria; Novartis: Honoraria. Warzocha:BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Robak:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Wierzbowska:Novartis: Consultancy, Honoraria; Janssen Cilag: Consultancy.

Improved Overall Survival with Gemtuzumab Ozogamicin (GO) Compared with Best Supportive Care (BSC) in Elderly Patients with Untreated Acute Myeloid Leukemia (AML) Not Considered Fit for Intensive Chemotherapy: Final Results from the Randomized Phase III Study (AML-19) of the EORTC and Gimema Leukemia Groups

▪Background: An unmet medical need persists for elderly patients (pts) with AML who are deemed not to be fit for intensive chemotherapy. Such pts are usually treated with BSC and hydroxyurea or low-dose cytarabine, but outcomes are dismal. The immunoconjugate GO has shown single agent efficacy and tolerability in older pts with relapsed AML. The AML-19 study was designed as a sequential phase II/III trial comparing GO monotherapy to BSC (including hydroxyurea if clinically indicated) in pts age ≥ 61 yrs with previously untreated AML who were considered unfit for intensive chemotherapy (or refused it). Of the two induction schedules of GO (total dose 9 mg/m2 delivered in 2 or 3 fractions over one week) under comparison in the phase II part of the study, the 2-fraction regimen was found to have the best efficacy profile to warrant phase III comparison with BSC (BJH 2010; 149:376). We herein report the final results of the phase III part of the study.Methods: Untreated pts with de novo or secondary AML, adequate renal and hepatic function, and WBC count <30x109/L at baseline (a short course of hydroxyurea permitted) were centrally randomized 1:1 (stratified by age, WHO PS, CD33 expression on marrow blasts, WBC at diagnosis, and center) to receive either a single induction course of GO (6 mg/m2 day 1 and 3 mg/m2 day 8) or BSC. Pts with no evidence of disease progression following GO induction could receive up to 8 monthly infusions of the drug at 2 mg/m2. The primary objective of the study was to compare overall survival (OS) in the two groups. A total of 210 deaths was required in order to detect a hazard ratio (HR) of 0.63 for OS, with 90% power and 2-sided alpha=5%.Results: Between 11/2004 and 03/2013, 237 pts were randomized from 35 European sites. The intention-to-treat population comprised 118 pts in the GO arm and 119 in the BSC arm. The median age was 77 years (range 62-88) with 64% of pts over 75 years. Baseline characteristics were well balanced between arms. At the final analysis (05/2014 cutoff), 228 deaths occurred: 113/118 (95.8%) in the GO arm, and 115/119 (96.6%) in the BSC arm. GO significantly improved OS (median 4.9 vs 3.6 months; 45.9% vs 29% alive at 6 months; 24.3% vs 9.7% alive at 1 year; 10.3% vs 6.9% alive at 1.5 year; HR, 0.69; 95% CI, 0.53-0.90; P=0.005) compared with BSC. Subgroup analyses based on stratification factors and other baseline characteristics showed that the OS benefit was generally consistent among subgroups, with a greater effect seen in pts with good/intermediate cytogenetics (median 7.3 vs 3.8 months; HR, 0.48; 99% CI, 0.31-0.75), in those with high CD33 expression (≥81% positive blasts; median 5.5 vs 3.8 months; HR, 0.47; 99% CI, 0.30-0.74), as well as in those with secondary AML (median 7 vs 4 months; HR, 0.55; 99% CI, 0.33-0.91). Among 111 pts who received at least the first dose of GO, the overall complete response rate was 27% (CR 15.3%, CRi 11.7%), and the overall disease control rate (including PR in 5.4% and stable disease for >30 days in 24.3%) was 56.7%. Of the 30 pts who achieved CR/CRi, 28 later relapsed or died in remission (1 infection, 2 general physical deterioration, 2 unknown cause), and the median disease-free survival (DFS) was 5.3 months with a 1-year DFS of 20%. CR/CRi pts had a median survival from remission of 8.2 months, with 40% alive at 1 year. The 30-day all-cause mortality from randomization was comparable in the GO (10.8%) and BSC (13.5%) arms. Most frequent grade 3+ non-hematologic adverse events (AEs) for GO vs BSC were infection (35.1% vs 34.3%), febrile neutropenia (18% vs 23.7%), bleeding (12.6% vs 12.3%), fatigue (11.7% vs 21%), and cardiac toxicity (6.3% vs 14%). Severe liver dysfunction occurred infrequently (2.7% vs 1.8% for GO vs BSC), and no episodes of VOD were reported. Overall, AEs led to GO discontinuation or death in 27 pts (24.3%).Conclusions: Compared with BSC including hydroxyurea as necessary, single agent GO in the dose/schedule chosen significantly improved OS in elderly AML pts not considered fit for intensive chemotherapy, with an acceptable safety profile. Of note, estimates of the benefit of GO were greater in pts presenting with better-risk cytogenetics, high CD33 expression on blast cells, or secondary disease. DisclosuresOff Label Use: Gemtuzumab Ozogamicin in AML.

Long-term follow-up of patients who received repeat-dose rituximab as maintenance therapy for ANCA-associated vasculitis.

ANCA-associated vasculitis (AAV) is characterized by a chronic relapsing course. Rituximab (RTX) is an effective maintenance treatment; however, the long-term outcomes after its discontinuation are unclear. The aim of this study was to explore the long-term outcomes of AAV patients treated with repeat-dose RTX maintenance therapy. AAV patients receiving a RTX treatment protocol consisting of an induction and maintenance phase were included. For initial remission induction, RTX was dosed at 1 g every 2 weeks or 375 mg/m(2) weekly for 4 consecutive weeks and for remission maintenance at 1 g every 6 months for 24 months. At the first RTX administration, ongoing immunosuppressives were withdrawn. Sixty-nine patients were identified, 67 of whom were failing other therapies. Nine relapsed during the RTX treatment protocol; however, all 69 were in remission at the end of the maintenance phase on a median prednisolone dose of 2.5 mg/day and 9% were receiving additional immunosuppression. During subsequent observation, 28 patients relapsed a median of 34.4 months after the last RTX infusion. Risk factors for relapse were PR3-associated disease (P = 0.039), B cell return within 12 months of the last RTX infusion (P = 0.0038) and switch from ANCA negativity to positivity (P = 0.0046). Two patients died and two developed severe hypogammaglobulinaemia. This study supports the efficacy and safety of a fixed-interval RTX maintenance regimen in relapsing/refractory AAV. Relapses after discontinuation of maintenance therapy did occur, but at a lower rate than after a single RTX induction course. PR3-associated disease, the switch from ANCA negative to positive and the return of B cells within 12 months of the last RTX administration were risk factors for further relapse.

The predictive value of GSTT1 polymorphisms in predicting the early response to induction BCG therapy in patients with non–muscle invasive bladder cancer

IntroductionWe evaluated the predictive value of glutathione S transferase mu (GSTM1) and theta (GSTT1) polymorphisms in early response to bacillus Calmette-Guérin (BCG) induction therapy in patients with primary non–muscle invasive bladder cancer. MethodsGSTM1 and GSTT1 polymorphisms were analyzed by multiplex polymerase chain reaction using blood genomic DNA from 135 patients with primary non–muscle invasive bladder cancer who were being treated with a single induction course of BCG. BCG nonresponsiveness (early BCG failure) was defined as a tumor recurrence or progression within 12 months after BCG induction therapy. The predictive value of GST polymorphisms was evaluated by Kaplan-Meier analysis and multivariate logistic regression models. ResultsPatients carrying a GSTT1-positive genotype demonstrated a higher likelihood of early BCG failure regardless of cigarette smoking. After stratification based on the tumor stage and grade, the high-risk group (T1G3) with a GSTT1-positive genotype showed a 14-fold higher risk of early BCG failure compared with those with a GSTT1-null genotype. In a combined analysis of 2 genes, the GSTT1-positive/GSTM1-null genotype had a higher risk of BCG nonresponsiveness compared with the GSTT1-null/GSTM1-null genotype (odds ratio = 4.17, 95% CI: 1.54–11.26). By multivariate logistic regression analysis, the GSTT1-positive genotype was an independent predictor of early BCG failure (odds ratio = 3.67, 95% CI: 1.61–8.38). Kaplan-Meier estimates revealed a significant difference in disease-free survival depending on the GSTT1 genotype (log rank test, P = 0.038). ConclusionsThe results of this study suggest that the GSTT1-positive genotype is an independent predictor of early BCG failure. These results can help determine whether patients would benefit from adjuvant BCG treatment or may require more aggressive alternative therapies.

Early Bone Marrow Examination, On The Fifth Day Of Induction For AML, Is Highly Predictive Of Response

▪Rapid eradication of blasts from peripheral blood during induction therapy in AML is associated with remission and overall survival. We prospectively evaluated the value of a bone marrow (BM) examination on day 5 of induction therapy in unselected newly diagnosed AML patients assigned for intensive induction. Seventy nine patients were enrolled during a 29-months period in six medical centers in Israel. BM blasts were evaluated by two independent observers and in most cases with the support of FACS analysis. Induction protocols administrated were 3+7 with daunorubicin 60 or 90 mg/m2 or clofarabine 40mg/m2 for five days [58 (73%), 10(13%) and 11(14%) patients, respectively]. Patients' median age was 59 (range 22-78) years. Among surviving patients the actual follow-up time was longer than 9 months in 25(48%) patients and longer than 12 months in 16 (30%) patients. Cytogenetic results are available for 70 patients [2(3%), 47(67) and 21(30%) with standard, intermediate and poor risk, respectively]. Flt3ITD mutation was present in 11(13.9%) patients and NPM1 mutation, in 12 who presented with normal karyotype and were negative for FLT3-ITD.Treatment protocol was not altered on the basis of day 5 BM examination which was repeated on day 12-14. Residual disease (>10% blasts) was detected and a re-induction protocol (repeat 3+7 at doses of 60 or 45mg/m2 at day 14 or clofarabine 30mg/m2 on day 21) was administered in 20(25%) patients. Overall, 50(72%) patients achieved remission (CR1). Post-remission therapies varied according to patient age and risk factors. Overall, 29(37%) patients underwent allogeneic stem cell transplantation. During the study period, 27(34.2%) patients succumbed, 5(6.3%) during induction, 8(10%) while in remission and 12(15%) following relapse.Day 5 blast counts higher than 10% of all BM nucleated cells predicted for the identification of residual leukemia on day 14 regardless of BM cellularity. Moreover, day 5 counts lower than 10% of all BM nucleated cells predicted for the achievement of CR1 with a single induction course. The 10% cutoff for BM day 5 blast count accurately identified these patients with a sensitivity of 80% and specificity of 74%. Kaplan Meir analysis demonstrated superior overall survival (OS) and lower relapse rate (figure 1a&b) of rapid responders than those with more than 10% blasts in day 5 BM. The 2-year anticipated OS is 80% and 35% (p=0.05), respectively. For the 50 patients who achieved CR1, the predicted 2-year relapse rate was as low as 8% for patients with a low day 5 BM blast count and 82% in the group of higher day 5 BM blasts (p=0.004). [Display omitted] Bone marrow day 5 aspiration was not always informative and in seven cases where biopsy was not available the blast content couldn't be assessed. Of the 72 patients with a valid day 5 blasts count, 24 (33%) were rapid responders in whom blasts were less than 10% of BM nucleated cells. On day 14, a lower than 10%, blast count was recognized in 54% of patients. However, 11/16 (69%) of patients who despite high blast counts at day 5 had a low count at day 14, either failed to achieve remission or relapsed. Only 5 patients presented with a low blast count at day 5 had a day 14 blasts count higher than 10%. Rapid response on day 5 was not associated with age or molecular status; yet, there was a trend (p=0.08) towards lower frequency of poor cytogenetics among these patients. Surprisingly, mean presenting WBC was higher among rapid responders. ConclusionBone marrow blast count on the fifth day of induction during chemotherapy is a powerful predictor of AML prognosis, irrespective of other pre-treatment risk factors. Larger studies, with longer follow up are required to determine its role in clinical management. 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.

Abstract 4700: Clinical outcome of T-acute lymphoblastic leukemia/lymphoma (T-ALL/T-LBL): the Bologna experience.

Abstract Background. Precursor T cell ALL/LBL occurs most frequently in late childhood, adolescence, and young adulthood, with a 2:1 male predominance; it comprises 15 and 25 percent of childhood and adult ALL, respectively, and 2 percent of adult non-Hodgkin lymphoma. In adult patients prognosis is poor, due to the high incidence of relapse even after allogenic stem cell transplantation. Design and Methods. We retrospectively analysed and currently report clinical outcome results about 52 newly diagnosed and younger than 60 years T-ALL patients (median age 30 years, range 14-73 years) treated, from 2006 to 2012 according to standard chemotherapy regimen, including adapted pediatric-like schedule, BFM protocol, and adult schedules. After induction, all the patients underwent consolidation for at least one course. All the patients shared the same strategy for intensification, that consisted, when available, in allogenic or autologous stem cell transplantation. Detailed data about cytogenetics and molecular biology will be provided on site. Durations of complete remission (CR) and overall survival (OS) were estimated according to the Kaplan-Meier method. The CR duration was calculated from start of CR to first evidence of disease recurrence. Results. Informed consent was obtained; after a single induction course 41/52 patients obtained a CR (78.8%) and 2 patients a partial remission (PR) (3.8%) for an overall response rate (ORR) of 82.6%. Seven patients (13.4%) had resistant disease, and 2 (3.8%) died during induction. After a median follow-up of 22.7 months, 19 patients (36.5%) are still in CR. The median CR duration and OS were 12.3 and 23.15 months, respectively. The most common grade 3 adverse events included gastro-intestinal toxicities (i.e. nausea, vomiting, mucositis and diarrhoea) and liver dysfunction. Conclusion. Our analysis confirms, in line with literature data, that, despite intensive chemotherapeutic treatments and stem cell transplantation, T-ALL and T-LBL adult patients still show a bad prognosis. The relatively satisfying induction remission rate is followed, in most cases, by a high relapse rate. Therefore, a molecular stratification approach, based on gene-expression profile analysis (Ferrando et al, Cancer Cell 2002) should be routinely performed, in order to identify new targets, to optimize therapy, to reduce toxicity and to improve clinical outcome. Acknowledgments. Work supported by European LeukemiaNet, AIRC, AIL, PRIN, University of Bologna and BolognAIL. Citation Format: Mariachiara Abbenante, Cristina Papayannidis, Ilaria Iacobucci, Chiara Sartor, Stefania Paolini, Emanuela Ottaviani, Sarah Parisi, Anna Ferrari, Claudia Venturi, Viviana Guadagnuolo, Nicoletta Testoni, Michele Cavo, Giovanni Martinelli. Clinical outcome of T-acute lymphoblastic leukemia/lymphoma (T-ALL/T-LBL): the Bologna experience. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4700. doi:10.1158/1538-7445.AM2013-4700

Abstract 1179: Nelarabine front-line therapy for adult T-lymphoblastic leukemia/lymphoma (T-LBL/ALL): preliminary results of a single center experience.

Abstract Background. Precursor T cell LBL/ALL occurs most frequently in late childhood, adolescence, and young adulthood, with a 2:1 male predominance; it comprises 15 and 25 percent of childhood and adult ALL, respectively, and 2 percent of adult non-Hodgkin lymphoma. Nelarabine is an anticancer prodrug of arabinofuranosylguanine (ara-G); it inhibits DNA synthesis and leads to high molecular weight DNA fragmentation and cell death. Nelarabine has showed relevant efficacy in phase II clinical trials, both in pediatric and in adult LBL/ALLpopulations. Design and Methods. We report clinical outcome results of 9 newly diagnosed and younger than 60 years T-ALL patients (median age 29 years, range 22-45 years, 3/6 M/F, 8 T-ALL, 1 T-LBL) treated according to pediatric-like adapted schedule. Cytogentics data and molecular biologic features will be provided on site. Induction cycle included Vincristine, daunoblastine, L-asparaginase and Prednisone. After induction, all the patients received consolidation therapy with cyclophosphamyde, L-asparaginase, Cytarabine and 6-Mercaptopurine. Subsequently all the patients receveid Nelarabine 1500 mg/sqm (days 1-3-5 every 21) for two cycles. All the patients shared the same strategy for intensification, which consisted in allogenic stem cell transplantation, if available, or additional courses of consolidation chemotherapy. Durations of complete remission (CR) and overall survival (OS) were estimated according to the Kaplan-Meier method. The CR duration was dated from start of CR to first evidence of disease recurrence. Results. After a single induction course, 9/9 patients obtained a CR (100%). Eight patients underwent an allogenic bone marrow transplantation. After a median follow-up of 24 months, 7/9 patients (78%) are alive in CR. The median CR duration and OS were 13.4 and 24.4 months, respectively. Neurological toxicity of grade 3 has not been reported. We did not observe grade 3-4 haematological toxicity. Conclusion. Nelarabine is a promising drug, which induces a remarkable complete remission rate at the expense of a very low and manageable toxicity. Acknowledgments. Work supported by European LeukemiaNet, AIRC, AIL, PRIN, University of Bologna and BolognAIL. Citation Format: Chiara Sartor, Mariachiara Abbenante, Cristina Papayannidis, Ilaria Iacobucci, Stefania Paolini, Emanuela Ottaviani, Annalisa Lonetti, Sarah Parisi, Anna Ferrari, Viviana Guadagnuolo, Sandro Grilli, Nicoletta Testoni, Michele Cavo, Giovanni Martinelli. Nelarabine front-line therapy for adult T-lymphoblastic leukemia/lymphoma (T-LBL/ALL): preliminary results of a single center experience. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1179. doi:10.1158/1538-7445.AM2013-1179

Idarubicin Appears Equivalent to Dose-Intense daunorubicin for AML Induction

AbstractAbstract ▪3581▪This icon denotes a clinically relevant abstractWorldwide cancer drug shortages have recently required the substitution of daunorubicin, the “gold standard” anthracycline for idarubicin for induction therapy in acute myeloid leukemia(AML). Previously published randomized trials have shown idarubicin (12/m2) to be equal to, or better than daunorubicin (45–50mg/m2) for achieving complete remission(Blood. 1991 Apr 15;77(8):1666–74). It is currently unknown whether these results can be extrapolated when compared to intensified doses of daunorubicin(90mg/m2), shown to improve the CR rate when compared to 45 mg/m2 (N Engl J Med. 2009 Sep 24;361(13):1249–59). We therefore conducted an observational study to compare CR rates in AML patients who received either daunorubicin 90mg/m2 or idarubicin 12mg/m2 for the treatment of newly diagnosed AML. Methods:Medical records were used to identify newly diagnosed patients with AML who received daunorubicin 90mg/m2(Dau-90) or idarubicin 12mg/m2(Ida-12) between 1/2007 and 6/2012. Patients with APL were excluded. MDS patients who evolved to AML were included. AML was diagnosed by WHO criteria. Patients received daunorubin 90mg/m2 IV bolus or idarubicin 12mg/m2 IV bolus on days 1–3. Cytarabine 100mg/m2 by continuous infusion was given concomitantly on day 1–7 to both groups. All patients underwent marrow biopsy on day 14 after initiation of therapy. If residual disease was found, patients were considered treatment failure. Patients without residual disease were re-biopsied around the time of WBC recovery to assess CR. CR rates are reported after a single induction course. Results:28 Ida-12 and 37 Dau-90 patients were identified. Table 1 shows patient demographics and outcomes. There was no significant baseline difference between the 2 study arms for gender, age, weight, maximum WBC prior to therapy, cytogenetic risk group, percent of patients with FLT-3 ITD or NPM mutations, or combined risk factors. A non-significant trend was observed in the percent of marrow blasts prior to therapy and in the number of patients>60years(but not for age >55) within the Ida-12 study arm. Overall CR was similar between the Ida-12 and Dau- 90 treatment groups(p<0.1072) Subset analysis shows CR rates were significantly higher in Ida-12 treated patients who had an unfavorable karyotype(p<0.0359) or unfavorable combined cytogenetic risk(0.0388) or for age > 55 years(p<.0063). Overall morbidity and mortality was similar between groups. Conclusion:Ida-12 appears to be as effective as Dau-90 for achieving CR after a single induction course. Thus, Thus, substitution of Ida-12 for Dau-90 during times of drug shortages appears acceptable. Ida-12 may potentially be superior for patients >55 years or for those with unfavorable cytogenetics. These results warrant validation from a randomized clinical trial.CharacteristicIda12Dau-90p-valueNumber2837Male13180.8592Age/median (range)56 (24–73)48 (21–72)0.1508Age >601060.0708Age>5514120.31Weight/kg (range)84.8 (51–124)82.8 (48–130)0.6831BSA1.92 (1.45–2.30)1.93 (1.47–2.43)0.9233Percent blasts prior to therapy63.8 (15–100)50.3 (20–95)0.0575Maximum WBC prior to therapy25.7 (0.2–137)35.3 (0–252)0.4365NPM positive (%)7/22 (32)6/25 (25)0.5499FLT-3 ITD (%)6/23 (26)4/32 (12.5)0.2902Karyotype (Cytogenetics)Good, %3/28 (11)8/35 (23)0.3187Intermediate8/28 (29)12/35 (34)0.7864Unfavorable17/28 (61)15/35 (43)0.2074Unknown0/28 (0)2/37 (5)0.5019Combined risk factors (Cyto+Molecular)Good, %3/28 (11)8/36 (22)0.3217Intermediate8/28 (29)9/36 (25)0.7818Unfavorable17/28 (61)19/36 (53)0.6149ResultsComplete remission (%)17/28 (61)15/37 (41)0.1072Karyotype (Cytogenetics)17/28 (61)13/35 (37)0.2937Good2/3 (67)5/8 (63)0.99Intermediate5/8 (63)5/12 (42)0.649Unfavorable10/17 (65)3/15 (20)0.0359Combined risk factors (Cyto+Molecular)17/28 (61)14/36 (39)0.1072Good2/3 (67)5/8 (63)0.99Intermediate5/8 (63)5/9 (56)0.99Unfavorable10/17 (65)4/19 (2)0.0388Age> 608/10 (80)1/6 (17)0.035Age <609/18 (50)14/31 (45)0.7746Age>557/14 (50)2/13 (15)0.0063CTC grade 3–4 toxicity (excluding cytopenias)7/27 (26)5/37 (14)0.3311Non-relapse mortality5/27 (19)2/37 (5)0.1222 Disclosures:No relevant conflicts of interest to declare.

1666 SWOG S0353 PHASE II TRIAL OF INTRAVESICAL GEMCITABINE IN PATIENTS WITH NON-MUSCLE INVASIVE BLADDER CANCER WHO RECURRED FOLLOWING AT LEAST TWO PRIOR COURSES OF BCG

INTRODUCTION AND OBJECTIVES: The optimal treatment for patients with intermediate and high-risk non-muscle-invasive bladder cancer (NMIBC) who have recurred following intravesical BCG therapy is unclear. Gemcitabine has good activity against urothelial cancer when used systemically, and prior Phase I & II studies have shown it to be active and well tolerated when used intravesically. However, durable responses following a single 6-week induction course have been observed in 30% of high-risk patients. SWOG performed a multi-institutional phase II study to evaluate the potential role of gemcitabine induction plus maintenance therapy in this setting. METHODS: Eligible patients had recurrent NMIBC, stage Tis, T1, Ta high-grade (HG), or Ta low-grade (LG) with 2 lesions, following a minimum of 2 prior courses of intravesical BCG therapy (6 6 weeks or 6 3 weeks, with or without maintenance). Prior single dose peri-operative chemotherapy and up to 1 course of weekly intravesical chemotherapy within the prior year were allowed. All visible lesions were resected and patients were treated with 2gm gemcitabine in 100cc NS weekly x6 and then monthly to 12 months. Patients had bladder biopsy at the initial 3-month evaluation following induction, and then were followed with cystoscopy and cytology every 3 months with further biopsies as clinically indicated. Initial response required negative cystoscopy, cytology and biopsy at 3 months. RESULTS: 58 patients were enrolled; 9 were ineligible and 2 received no treatment. Of 47 evaluable patients, 41 (87%) had high-risk disease, with HGTa in 11 (23%), HGT1 in 2 (4%), and Tis in 28 (8 with and 20 without associated papillary lesions). All patients have been followed a minimum of 12 months. Thirty patients had G1-2 toxicity, mostly dysuria and urinary frequency, while 3 had G3 toxicity (dysuria, frequency and neutropenia). At the initial 3-month evaluation, 21 (45%) patients were free of disease while 13 patients were continuously disease free at 12 months (28% of evaluable patients and 62% of the initial responders). CONCLUSIONS: Intravesical gemcitabine has activity in high risk BCG refractory NMIBC. However, only a minority of patients with intermediate to high-risk disease who have recurred after 2 prior courses of intravesical BCG will attain a durable response to this treatment, even with the addition of monthly maintenance treatments.

Phase 2 randomized study of p53 antisense oligonucleotide (cenersen) plus idarubicin with or without cytarabine in refractory and relapsed acute myeloid leukemia

The p53 antisense oligonucleotide cenersen has been shown to sensitize acute myeloid leukemia (AML) stem cells to DNA damaging agents. To determine whether cenersen merits testing in larger efficacy studies, an exploratory study of cenersen in combination with idarubicin either alone or with 1 of 2 doses of cytarabine was performed in first-salvage AML patients. Patients who either had failed to respond to a single induction course or had responded to induction but relapsed within 12 months were enrolled. Stopping rules based on an expected 14% complete response (CR) rate were applied to each treatment arm. Fifty-three patients were treated, and none of the arms was terminated for lack of activity. Nearly all patients received a single course unless they responded. Ten of the 53 (19%) patients responded (8 CR and 2 CR with incomplete platelet recovery). There was a positive trend for a better response rate with increasing intensity of chemotherapy in the patients refractory to front-line treatment compared with those who had relapsed previously. One-third (17/53) of the patients received cenersen inhibitors (acetaminophen and/or high dose antioxidants) during treatment, and none of these responded to treatment. No unique toxicity was attributed to cenersen. The results of this study suggested that the combination of cenersen with chemotherapy may have clinical efficacy, and additional studies are warranted to explore its full potential.

Abstract 2236: Fludarabine, Cytarabine, Idarubicin and Etoposide (FLAIE) schedule is safe and active for young patients with newly diagnosed acute myeloid leukemia (AML): Results of a multicentric phase III Italian study

Abstract Background. Fludarabine plus Cytarabine and Idarubicine (FLAI) was proved to be an effective and well tollerated induction regimen for treatment of acute myeloid leukaemia (AML). The trial objective was to assess the efficacy of Etoposide when used in combination with FLAI schedule. Design and Methods. We retrospectively report clinical outcome results of 101 newly diagnosed and younger than 60 years AML patients (median age 46 years, range 18-60 years) treated in a Phase III clinical trial, with FLAIE induction chemotherapy, including Etoposide to the FLAI schedule. Induction consisted of Fludarabine 25mg/m2/day on days 1-5, Idarubicin 6 mg/m2/day on days 1, 3 and 5, Cytarabine 2 g/m2 infused in 4 h, daily on days1-5 and Etoposide 100 mg/m2/day on day 1-5. After induction, all the patients underwent consolidation with Cytarabine (2 g [[Unsupported Character – /]]sqm i.v. infusion on days 1-5) and Idarubicin (12 mg[[Unsupported Character – /]] sqm i.v. infusion on days 1, 3 and 5). All the patients shared the same strategy for intensification, that was allogenic or autologous stem cell transplantation. After consolidation, maintenance treatment with Cytarabine was given to patients who obtained a complete remission but who could not undergo allogenic or autologous stem cell transplantation. More than half of the patients had abnormal karyotypes. Molecular analysis at diagnosis for the more frequent abnormalities was performed. Duration of CR and overall survival was estimated according to the Kaplan-Meier method. The CR duration was dated from start of CR to first evidence of recurrence. Results. After a single induction course of FLAIE, 73 pts obtained a CR (72.2%) and 8 pts a CRp (7.9%) for an overall response rate of 80.2%. Fifteen patients (14.9%) had resistant disease, and 5 (4.9%) died during induction. After a median follow-up of 33 months, 75 patients (76%) are in continuous CR. The median CR duration and OS were 45 and 55 months, respectively. 11 pts underwent ABMT and 44 a BMT. Relapses were more frequent in patients who were not submitted to allogenic stem cell transplantation. Of the 55 transplanted patients, 28 (51.9%; 1 with chromosome 7 abnormality), were alive in CR after a median follow up of 10 months (range, 2 to 45 months) after transplantation, 14 (25.9%) relapsed (median DFS 4 months), and 13 (24%) died in CR or CRp of transplant related complications. The most common grade 3 adverse events included gastro-intestinal toxicities(i.e. nausea, vomiting, mucositis and diarrhoea), liver dysfunction, and skin rash. Conclusion. The combination of etoposide to FLAI is safe and active. Further studies exploring different dosing and scheduling are warranted, particularly in patients with poor-risk AML. Supported by: European LeukemiaNet, FIRB 2006, AIRC, AIL, PRIN, University of Bologna. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2236. doi:10.1158/1538-7445.AM2011-2236

Schedule- and dose-dependency of CPX-351, a synergistic fixed ratio cytarabine:daunorubicin formulation, in consolidation treatment against human leukemia xenografts

CPX-351, a liposomal formulation co-encapsulating cytarabine (Cyt) and daunorubicin (Daun), has been developed, which delivers synergistic Cyt:Daun molar ratios to bone marrow. CPX-351 has demonstrated markedly superior anti-leukemic activity over free Cyt:Daun drug cocktails in preclinical models. Given the prolonged plasma lifetime of CPX-351, we examined the relationship between therapeutic efficacy and the frequency of treatment in the consolidation setting using a bone marrow-engrafting human leukemia xenograft model. Adding a day 1,3,5 consolidation treatment course for CPX-351 therapy improved the increase in lifespan (ILS) from 116% and no cures for a single induction course, to 268% plus a 33% cure rate for an induction plus consolidation course. In contrast, free Cyt:Daun cocktail treatment provided much lower ILS values with no cures. Administering CPX-351 as consolidation therapy starting on day 42 using a day 1,3, day 1,5, or day 1,7 schedule yielded ILS values of 154%, 185%, and 108%, respectively. The increased efficacy observed for the day 1,3 and day 1,5 consolidation schedules was associated with elevated bone marrow drug accumulation for the second doses. The enhanced efficacy obtained for intermediate dosing frequency in the consolidation setting suggests that the anti-leukemic activity of synergistic drug ratios is dependent on both duration of exposure and maintenance above a therapeutic threshold.