2nd Induction Research Articles

PB1733 OUTCOMES WITH CPX‐351 VERSUS 7+3 BY BASELINE BONE MARROW BLAST PERCENTAGE IN OLDER ADULTS WITH NEWLY DIAGNOSED, HIGH‐RISK/SECONDARY AML: EXPLORATORY ANALYSIS OF A PHASE 3 STUDY

Background:CPX‐351 (Vyxeos®; daunorubicin and cytarabine powder for concentrate for solution for infusion), a dual‐drug liposomal encapsulation of cytarabine and daunorubicin at a synergistic ratio, is approved by the EMA and the US FDA for the treatment of adults with newly diagnosed, therapy‐related AML or AML with myelodysplasia‐related changes. In a randomized phase 3 study, induction followed by consolidation with CPX‐351 significantly improved median overall survival (OS) versus conventional 7+3 cytarabine/daunorubicin chemotherapy (9.56 vs 5.95 months; HR = 0.69 [95% CI: 0.52‐0.90; 1‐sided P = 0.003) and had a safety profile comparable to 7+3 in adults aged 60‐75 years with newly diagnosed, high‐risk/secondary AML (Lancet, et al. J Clin Oncol 2018). Some studies suggest a high baseline blast percentage may portend a worse prognosis in AML (DiNardo, et al. Am J Hematol 2016; Hasserjian, et al. Am J Hematol 2014).Aims:This exploratory analysis of the phase 3 study assessed outcomes by baseline bone marrow blast percentage.Methods:A total of 309 patients with AML confirmed by an independent pathologist (per 2008 WHO criteria: ≥20% blasts in either peripheral blood or bone marrow) were randomized 1:1 to receive up to 2 induction cycles of CPX‐351 (100 units/m2 [daunorubicin 44 mg/m2 + cytarabine 100 mg/m2] on Days 1, 3, and 5 [2nd induction: Days 1 and 3]) or 7+3 (cytarabine 100 mg/m2/day continuously for 7 days [2nd induction: 5 days] + daunorubicin 60 mg/m2 on Days 1‐3 [2nd induction: Days 1‐2]). Patients achieving complete remission (CR) or CR with incomplete platelet or neutrophil recovery (CRi) could receive up to 2 consolidation cycles with CPX‐351 (65 units/m2 [daunorubicin 29 mg/m2 + cytarabine 65 mg/m2] on Days 1 and 3) or 5+2 (as for 2nd induction). In this exploratory analysis, outcomes were compared among subgroups of patients categorized by baseline bone marrow blast percentage (<20%, 20%–40%, >40%–60%, or >60%); of note, patients may have had a baseline bone marrow blast percentage <20% with diagnosis of AML confirmed based on other factors.Results:Patients treated with CPX‐351 versus 7+3 had longer median OS across baseline bone marrow blast groups, including patients with <20% blasts (12.62 vs 7.31 months), 20%–40% blasts (11.56 vs 5.95 months), >40%–60% blasts (8.77 vs 4.86 months), or >60% blasts (4.65 vs 2.92 months; Table 1). Patients treated with CPX‐351 also had longer event‐free survival (EFS) and higher rates of CR and CR+CRi than those treated with 7+3, irrespective of baseline bone marrow blast percentage (Table 1). Of note, outcomes were generally worse among patients with higher baseline bone marrow blast percentages for both the CPX‐351 and 7+3 treatment arms. The incidence of grade ≥3 treatment‐emergent adverse events (TEAEs) was >80% for both arms; the most frequently reported grade ≥3 TEAEs in both treatment arms were febrile neutropenia, pneumonia, and hypoxia (Table 2). Few TEAEs leading to discontinuation were reported with CPX‐351 or 7+3 (≤5%). The frequency of TEAEs leading to death increased with baseline bone marrow blast percentage, especially for the 7+3 arm.Summary/Conclusion:Improved survival and remission rates were observed with CPX‐351 versus 7+3 irrespective of baseline bone marrow blast percentage in older adults with newly diagnosed high‐risk/secondary AML.image

PF293 PHASE 3 EXPLORATORY ANALYSIS OF OUTCOMES IN OLDER ADULTS WITH NEWLY DIAGNOSED, HIGH‐RISK/SECONDARY AML WHO ACHIEVED REMISSION WITH CPX‐351 VERSUS 7+3 INDUCTION

Background:CPX‐351 (Vyxeos®; daunorubicin and cytarabine powder for concentrate for solution for infusion), a dual‐drug liposomal encapsulation of cytarabine and daunorubicin at a synergistic ratio, is approved by the EMA and US FDA for the treatment of adults with newly diagnosed, therapy‐related AML or AML with myelodysplasia‐related changes. In a randomized phase 3 study, induction followed by consolidation with CPX‐351 significantly improved median overall survival (OS) versus conventional 7+3 cytarabine/daunorubicin chemotherapy (9.56 vs 5.95 months; HR = 0.69 [95% CI: 0.52–0.90; 1‐sided P = 0.003) and had a safety profile comparable to 7+3 in adults aged 60–75 years with newly diagnosed, high‐risk/secondary AML (Lancet, et al. J Clin Oncol 2018). CPX‐351 was also associated with significantly higher rates versus 7+3 of complete remission (CR) or CR with incomplete platelet or neutrophil recovery (CR+CRi; 73/153 [48%] vs 52/156 [33%]; OR = 1.77 [95% CI: 1.11–2.81]; 2‐sided P = 0.016) and CR (57/153 [37%] vs 40/156 [26%]; OR = 1.69 [95% CI: 1.03–2.78]; 2‐sided P = 0.040).Aims:This exploratory analysis of the phase 3 study evaluated outcomes in the subgroup of patients (pts) who achieved CR+CRi following induction with CPX‐351 versus 7+3.Methods:A total of 309 pts were randomized 1:1 to receive up to 2 induction cycles of CPX‐351 (100 units/m2 [daunorubicin 44 mg/m2 + cytarabine 100 mg/m2] on Days 1, 3, and 5 [2nd induction: Days 1 and 3]) or 7+3 (cytarabine 100 mg/m2/day continuously for 7 days [2nd induction: 5 days] + daunorubicin 60 mg/m2 on Days 1–3 [2nd induction: Days 1–2]). Pts achieving CR+CRi could receive up to 2 consolidation cycles with CPX‐351 (65 units/m2 [daunorubicin 29 mg/m2 + cytarabine 65 mg/m2] on Days 1 and 3) or 5+2 (as for 2nd induction). For this analysis, outcomes were evaluated in the subgroup of pts who achieved CR+CRi following induction.Results:Baseline characteristics of pts who achieved CR+CRi were generally balanced between arms. Median OS was longer with CPX‐351 versus 7+3 in pts who achieved CR+CRi (25.43 vs 10.41 months; HR = 0.49 [95% CI: 0.31–0.77]) or CR (25.43 vs 10.97 months; HR = 0.49 [95% CI: 0.29–0.83]; Figure 1). Of pts who achieved CR+CRi, 40/73 (55%) in the CPX‐351 arm and 24/52 (46%) in the 7+3 arm underwent transplantation (OR = 0.71 [95% CI: 0.35–1.44]; median OS landmarked from the date of transplant was not reached versus 11.65 months, respectively (HR = 0.42 [95% CI: 0.20–0.86]; Figure 2). Serious treatment‐emergent adverse events in ≥5% of pts who achieved CR+CRi were febrile neutropenia (CPX‐351: 15%; 7+3: 12%), acute respiratory failure (7%; 2%), ejection fraction decreased (5%; 4%), sepsis (5%; 4%), pneumonia (3%; 6%), and pulmonary edema (1%; 6%). Four pts with CR+CRi died during the treatment phase (sepsis [CPX‐351]; atrial fibrillation [7+3]; disease progression [7+3]; intracranial hemorrhage [7+3]); no patient experienced early mortality (within 60 days) in either arm. Median time for recovery to neutrophils ≥1,000/μL and platelets ≥100,000/μL, respectively, in pts who achieved CR+CRi was longer with CPX‐351 (37 and 42 days) versus 7+3 (29 and 32 days).Summary/Conclusion:Among pts who achieved CR+CRi in this study, those who received CPX‐351 had longer median OS, a higher rate of transplantation, and longer median OS landmarked from the date of transplant versus 7+3, suggesting potentially deeper responses may be achieved with CPX‐351. The safety profile of CPX‐351 in pts who achieved CR+CRi was consistent with the known profile of 7+3, as well as the overall study population.image

PB1763 CNS INVOLVEMENT AT PRESENTATION IN AML: A RETROSPECTIVE CASE SERIES

Background:Central nervous system involvement at present in Acute Myeloid Leukemia is uncommon. When it occurs, the course is less predictable and prognostication and therapy guidelines are less lucid than with acute lymphoblastic leukemia.Aims:To review the clinical profile, presentation, imaging findings, CSF positivity, management, and outcomes of AML patients with CNS involvement at the time of initial presentation.Methods:We retrospectively collected the clinicopathological profile, management and outcome data of AML patients with CNS involvement over the past 5 years at our Institute. Patients with CNS involvement by CSF positivity or direct CNS or spinal cord involvement were included. It is our policy to perform CNS evaluation at presentation in all Pediatric AML or with symptoms suggestive of CNS involvement e.g. paraparesis, seizures, proptosis.Patients with paraspinal masses causing cord compressions, intra cranial bleed, intraretinal bleed, CNS involvement at relapse, or possible CNS involvement but without either CSF or imaging confirmation were excluded.Results:Eight patients fulfilled our inclusion criteria. Of these 4 were adults and 4 were pediatric patients (<18 years age). Only 1 (12.5%) amongst these was a female. Cytogenetics were t(8:21), t(8:21) +8, t(8:21) +8 +19, AML with t(9:22) in 1 patient each with rest 50% patients having normal cytogenetics.CSF analysis was positive for malignant cells in 3 patients, not done in 1 (because patient was very sick) and negative in the rest. Imaging was not done in 2 patients who were CSF positive with no focal neurological deficits, and was normal in 1 patient with 3rd cranial nerve palsy. Leptomeningeal involvement was present in 2 patients, cavernous sinus and falx cerebri involvement in 1, paravertebral deposits and cord enhancement in 1, and paravertebral and infratemporal deposits in another.All patients were treated with 3+7 induction followed by HIDAC with IT therapy with each cycle and 2 patients received RT as well. Ph positive AML was taken up for transplant after 2nd induction with HIDAC and is currently undergoing the same. 1 patient was not given chemotherapy because she had severe fungal pneumonia and expired.Six out of the 7 treated patients showed near complete resolution of CNS symptoms/imaging findings after chemotherapy. 1 patient with paraplegia had persisting spinal cord lesions despite 2 induction chemotherapies, IT and RT. Four patients relapsed – one CNS relapse, two CNS and BM relapse and 1 patient had BM relapse in the background of persisting CNS disease. Currently only 3 patients are alive, one of whom is undergoing Allogenic HSCT.Summary/Conclusion:CNS involvement in AML is rare at presentation. Presentation can vary from asymptomatic CSF positivity, to isolated cranial nerve involvement to paraplegia and recurrent seizures. Screening and Management protocols are not clearly defined. NCCN recommends screening before first consolidation in patients with monocytic differentiation, Mixed phenotypic acute leukemia, WBC >40000at diagnosis, extra medullary disease or high risk APML. For major neurological signs imaging should be performed. If no signs or symptoms then CSF should be done. Treatment with standard AML chemotherapy with IT/RT seems to have short term effects only. Overall prognosis in this group of patients seems poor with a high rate of relapse and mortality. Larger studies are required to address relevant questions such as high risk patients who should be screened, indications of performing CSF analysis and imaging, and adequate management.image

Outcomes with CPX-351 versus 7+3 by baseline bone marrow (BM) blast percentage in older adults with newly diagnosed high-risk/secondary acute myeloid leukemia (sAML).

7042 Background: CPX-351, a liposomal encapsulation of cytarabine (C) and daunorubicin (D) at a synergistic ratio, is approved as Vyxeos in the US and EU for adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. In a phase 3 study, CPX-351 significantly improved OS and remission rates vs 7+3 in patients (pts) aged 60-75 y with newly diagnosed high-risk/sAML. Some studies suggest a high baseline blast percentage may portend a worse prognosis in AML. This post hoc analysis of phase 3 data assessed outcomes by baseline BM blast percentage. Methods: Pts diagnosed with AML per 2008 WHO criteria (≥20% blasts in peripheral blood or BM) were randomized 1:1 to receive ≤2 inductions of CPX-351 (100 units/m2 [C 100 mg/m2 + D 44 mg/m2] on Days 1, 3, 5 [2nd induction: Days 1, 3]) or 7+3 (C 100 mg/m2/d continuously for 7 d [2nd induction: 5 d] + D 60 mg/m2 on Days 1-3 [2nd induction: Days 1-2]). Pts achieving complete remission (CR) or CR with incomplete platelet or neutrophil recovery (CRi) could receive ≤2 consolidations. Results: CPX-351 had longer median OS and higher remission rates vs 7+3 irrespective of baseline BM blast percentage; median OS was worse in higher blast groups for both treatments (Table). The incidence of grade ≥3 TEAEs was >80% for both arms; febrile neutropenia was the most common. Conclusions: Improved outcomes were observed with CPX-351 vs 7+3 irrespective of baseline BM blast percentage in older adults with newly diagnosed high-risk/sAML. Clinical trial information: NCT01696084. [Table: see text]

The Impact of Hematopoietic Cell Transplantation (HCT) on Survival: An Exploratory Analysis of a Phase 3 Study of CPX-351 Versus 7+3 in Older Patients with Newly Diagnosed, High-Risk/Secondary AML (sAML)

Introduction CPX-351 (Vyxeos®), a dual-drug liposomal encapsulation of cytarabine (C) and daunorubicin (D) at a synergistic ratio, is approved by the FDA and EMA for adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. In a phase 3 study, CPX-351 significantly improved median overall survival (OS; 9.56 vs 5.95 mo; HR = 0.69 [95% CI: 0.52-0.90]; 1-sided P = 0.003) and event-free survival (EFS; 2.53 vs 1.31 mo; HR = 0.74 [95% CI: 0.58-0.96]; 2-sided P = 0.021), and produced a higher rate of complete remission (CR) or CR with incomplete platelet or neutrophil recovery (CR+CRi; 47.7% vs 33.3%; 2-sided P = 0.016) vs 7+3 in patients (pts) aged 60-75 y with newly diagnosed high-risk/sAML. The higher CR+CRi rate may contribute to a higher rate of HCT, which is a potentially curative therapy that can impact long-term survival. Objective This exploratory analysis used a time-dependent proportional hazards model to assess the impact of CPX-351 vs 7+3 on survival independent of HCT status. Methods Pts could receive up to 2 induction cycles of CPX-351 (100 units/m2 [C 100 mg/m2 + D 44 mg/m2] on Days 1, 3, and 5 [2nd induction: Days 1 and 3]) or 7+3 (C 100 mg/m2/d continuously for 7 d [2nd induction: 5 d] + D 60 mg/m2 on Days 1-3 [2nd induction: Days 1-2]). Pts achieving CR or CRi could receive up to 2 consolidation cycles with CPX-351 (65 units/m2 [C 65 mg/m2 + D 29 mg/m2] on Days 1 and 3) or 5+2 (as in 2nd induction). HCT was performed at the physician's discretion. Results Baseline characteristics were balanced between arms. The HCT rate was 34.0% (n = 52) with CPX-351 and 25.0% (n = 39) with 7+3. Median time to HCT was 114.5 d with CPX-351 and 113.0 d with 7+3. Median OS landmarked from the time of HCT was significantly improved with CPX-351 vs 7+3 (not reached vs 10.25 mo; HR = 0.46 [95% CI: 0.24-0.89]). When HCT was treated as a time-dependent covariate, the HRs favored CPX-351 vs 7+3 for OS and EFS (Table), suggesting CPX-351 may be associated with prolonged OS and EFS independent of HCT. The safety profile of CPX-351 was generally consistent with that of 7+3. Early mortality rates with CPX-351 and 7+3, respectively, were 5.9% and 10.6% at Day 30 and 13.7% and 21.2% at Day 60. Conclusions CPX-351 was associated with significantly longer median OS and EFS and higher rates of CR+CRi and HCT vs 7+3 in older pts with newly diagnosed high-risk/sAML. Exploratory analyses suggest CPX-351 prolonged OS and EFS independent of HCT.

Efficacy and Safety of CPX-351 Versus 7+3 in a Subgroup of Older Patients with Newly Diagnosed Acute Myeloid Leukemia with Myelodysplasia-Related Changes (AML-MRC) Enrolled in a Phase 3 Study

Efficacy and Safety of CPX-351 Versus 7+3 in a Subgroup of Older Patients with Newly Diagnosed Acute Myeloid Leukemia with Myelodysplasia-Related Changes (AML-MRC) Enrolled in a Phase 3 Study

The Impact of Hematopoietic Cell Transplantation on Survival: An Exploratory Analysis of a Phase 3 Study of CPX-351 Versus 7+3 in Older Patients with Newly Diagnosed, High-Risk/Secondary AML

The Impact of Hematopoietic Cell Transplantation on Survival: An Exploratory Analysis of a Phase 3 Study of CPX-351 Versus 7+3 in Older Patients with Newly Diagnosed, High-Risk/Secondary AML

The MRD-Negativity Rate Measured By Flow Cytometry after the 1st and the 2nd Induction Course Among CR AML Patients from Different Cytogenetic Subgroups Does Not Differ Though the Morphological CR Achievement Does

Background. The recent ELN recommendations (2017) have introduced new criteria of response in AML - complete remission with MRD-negativity (CR/MRD-neg). It's a well-known fact that AML with different cytogenetics has different chemosensitivity, and so - CR rate in patients with favorable, intermediate or poor cytogenetic markers substantially differs. MRD negativity corresponds to more favorable long-term results in CR patients, but it's not clear whether the MRD-negativity rate is the same in favorable, intermediate or poor risk AML pts. As it is still poorly understood whether the high risk AML patients need classical «7+3» induction, we introduced a new approach for this cohort of patients - prolonged low-dose cytostatic exposure after hypomethylating priming.Aim. To evaluate the MRD-negativity in CR AML patients from different cytogenetic subgroups after the first classical non-intensive induction: «7+3», «Aza+7+3», «Aza-Ida-Ara-C», and the second induction differed by intensity.Materials and patients. 83 AML patients with a median age of 37 y.o. (17-59), m/f 31/52, after achieving CR (69 pts) were included in the MRD study in the National Research Center for Hematology. From March 2016 till Dec 2017, 49 pts disregarding cytogenetic risk were treated with «7+3» as the first induction course (Dauno 60 mg/m2 1-3 days, Ara-C 100 mg/m2 bid 1-7 days). The second induction course for these pts was «7+3» with continuous Ara-C infusion (200 mg/m2 1-7 days). Since Dec 2017 till July 2018 in all patients epigenetic priming with 3 days of Azacitidine (75 mg/m2) was applied additionally in order to obtain the cytogenetic results prior to cytostatic exposure. All patients were tested by molecular markers (FLT3, CEBPa, mNPM1) but this data did not influence the treatment choice. 8 pts from favorable/intermediate cytogenetic risk group after Aza-prephase have got «7+3» (Dauno 60 mg/m2 4-6 days, Ara-C 200 mg/m2 by continuous infusion, 4-10 days), and 13 pts from poor cytogenetic risk group (complex, -7,-5, inv3, monosomy) after Aza-priming received prolonged low-dose schedule (Ida 3 mg/m2 4-10 days, Ara-C 10 mg/m2 bid sc 4-17 days). The second induction course for favorable/intermediate risk group was FLAG-Ida, for poor risk group - the same as the 1st induction. MRD testing was performed by 6-color flow cуtometry with FACS Canto II (BD) machine after 1st and 2nd chemotherapy courses. The rate of MRD-negativity was calculated among CR patients.Results. Totally among 83 patients CR was achieved in 83%, early death was registered in 6% and refractory AML was diagnosed in 11%. The induction and MRD testing results after the 1st and the 2nd induction course according to prognostic group and treatment arm are demonstrated in the Table.1. Morphological CR rate differs substantially in patients from favorable/intermediate and poor risk by any treatment approach (p=0,04). The prolonged low-dose induction with Aza-prephase induced the same numbers of CRs as the classical «7+3»: 69% vs 46% (p=0,42). Epigenetic priming provided identical MRD-negative CRs in all treatment and cytogenetic groups: 75% vs 62% in favorable/intermediate risk group (p=0,29), 67% vs 50% in poor risk (p=0,62). The second intensive induction with Flag-Ida in favorable/intermediate risk group did not increase the portion of MRD-neg CR pts in comparison with «7+3»: 88% vs 71% (р=0,14). Early relapse rate through all groups showed comparable results.Conclusion. Though the morphological CR achievement is highly influenced by cytogenetic subgroup in AML, the MRD-negativity rate among CR pts by flow cytometry after the 1st and the 2nd induction course is similar. The de-intensification of induction for poor risk group did not lead to the deterioration of therapy efficacy and provided the same rate of MRD-negativity. The 2nd intensified induction after «7+3» did not increase the MRD-negativity in CR pts. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Final Safety and Efficacy Results from the CPX-351 Early Access Program (EAP) for Older Patients with High-Risk/Secondary Acute Myeloid Leukemia (sAML)

Background: CPX-351 (Vyxeos®) is a dual-drug liposomal encapsulation of cytarabine and daunorubicin at a synergistic ratio. In a large randomized, open-label, multicenter, phase 3 study of CPX-351 versus conventional cytarabine/daunorubicin chemotherapy (7+3 regimen) in adults aged 60-75 years with newly diagnosed high-risk/sAML, patients treated with CPX-351 had significantly longer survival times and higher remission rates (Lancet JE, et al. J Clin Oncol. 2018). Based on these results, CPX-351 was approved by the US FDA in 2017 for the treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes (AML-MRC). This abstract reports the results of an EAP study that provided expanded access to CPX-351 for older patients who met the eligibility criteria for the phase 3 study and collected additional data on safety and efficacy.Methods: In this phase 4, single-arm, open-label EAP, patients were between 60-75 years of age and had confirmed high-risk/sAML (therapy-related AML [tAML], AML with a history of myelodysplasia [MDS] or chronic myelomonocytic leukemia [CMML], or de novo AML with MDS karyotype). Patients could receive up to 2 cycles of induction with CPX-351 100 units/m2 (cytarabine 100 mg/m2 + daunorubicin 44 mg/m2) on Days 1, 3, and 5 (2nd induction: Days 1 and 3). Patients with complete remission (CR) or CR with incomplete platelet or neutrophil recovery (CRi) could receive up to 4 cycles of consolidation with CPX-351 65 units/m2 (cytarabine 65 mg/m2 + daunorubicin 28.6 mg/m2) on Days 1 and 3. The primary endpoint was safety, and the secondary endpoint was the rate of CR+CRi.Results: Overall, 52 patients received ≥1 dose of CPX-351 and were included in the safety analysis. Among these patients, the median age was 70 years (range: 55-75) and 23% had an Eastern Cooperative Oncology Group score of 2. Median time since diagnosis was 0.30 months (range: 0.03-36.14) months. Patients with AML-MRC accounted for 77% of the safety analysis population, including those with antecedent MDS with prior hypomethylating agent (HMA) treatment (25%), antecedent MDS without prior HMA treatment (21%), antecedent CMML (8%), and de novo AML with MDS karyotype (23%); 23% of patients had tAML. All patients received 1 induction cycle and 25% received 2 induction cycles; 17%, 8%, 4%, and 2% of patients received 1, 2, 3, and 4 consolidation cycles, respectively.CR+CRi was achieved in 23 patients (44% [95% CI: 31%, 59%]), including 15 with CR (29% [95% CI: 17%, 43%]) and 8 with CRi (15% [95% CI: 7%, 28%]; Table). The median time to remission was 37 days (range: 15-72). At the end of the study, 47 (90%) of patients were still alive and 11 (21%) patients received transplant.All patients were alive at Day 30, and the mortality rate at Day 60 was 6%. The safety profile observed in this EAP study was consistent with that of the phase 3, randomized study (Table). Treatment-emergent adverse events (TEAEs) of any grade occurred in 96% of patients, including 44% of patients with an TEAE deemed related to treatment; the only treatment-related AE that occurred in >10% of patients was febrile neutropenia (31%). Only 2 patients (4%) discontinued treatment due to an AE (ejection fraction decrease and intercranial hemorrhage [n = 1 each]). Five patients (10%) had grade 5 AEs during the study, including disease progression, multiple organ dysfunction syndrome, acute respiratory distress syndrome, aspiration, and intracranial hemorrhage (n = 1 each).Conclusions: The data from this EAP study were consistent with results from the randomized, phase 3 study. The safety profile in the EAP study was similar to that observed in the phase 3 study and there was a similar CR+CRi rate (44% vs 48%, respectively) in this high-risk/sAML population. [Display omitted] DisclosuresRoboz:Sandoz: Consultancy; Cellectis: Research Funding; Argenx: Consultancy; Bayer: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Aphivena Therapeutics: Consultancy; Sandoz: Consultancy; AbbVie: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy; Novartis: Consultancy; Celgene Corporation: Consultancy; Celltrion: Consultancy; Jazz Pharmaceuticals: Consultancy; Roche/Genentech: Consultancy; Eisai: Consultancy; Otsuka: Consultancy; Astex Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; Janssen Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy; Eisai: Consultancy; Otsuka: Consultancy; Orsenix: Consultancy; Celltrion: Consultancy; AbbVie: Consultancy; Daiichi Sankyo: Consultancy; Aphivena Therapeutics: Consultancy; Bayer: Consultancy; Argenx: Consultancy; Jazz Pharmaceuticals: Consultancy; Astex Pharmaceuticals: Consultancy; Cellectis: Research Funding; Orsenix: Consultancy; Pfizer: Consultancy. Rubenstein:Alexion: Consultancy, Honoraria, Speakers Bureau; Cyclacel: Other: Travel support; Astex: Other: Travel support. Schiller:Celator/Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding. An:Jazz Pharmaceuticals: Employment. Mancino:Jazz Pharmaceuticals: Employment. Chiarella:Celator/Jazz Pharmaceuticals: Employment, Equity Ownership. Louie:Celator/Jazz Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties. Lin:Jazz Pharmaceuticals: Honoraria.

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

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

Monitoring of FLT3 Phosphorylation and FLT3 Ligand Levels in Patients with FLT3-ITD Mutated Acute Myeloid Leukemia (AML) Treated with Midostaurin within the AMLSG 16-10 Trial of the German-Austrian Study Group

Monitoring of FLT3 Phosphorylation and FLT3 Ligand Levels in Patients with FLT3-ITD Mutated Acute Myeloid Leukemia (AML) Treated with Midostaurin within the AMLSG 16-10 Trial of the German-Austrian Study Group

EFFECT OF AZUMOLENE ON VENTRICULAR REFIBRLLATION IN LANGENDORFF-PERFUSED RABBIT HEARTS

During cardiopulmonary resuscitation, external shock-resistant ventricular fibrillation (VF) and re-fibrillation are common complicating factors. To determine the effects of azumolene, a modulator of ryanodine receptors (RyR), on VF, by studying re-fibrillation vulnerability and calcium transients. Following 15 minutes of global ischemia, normal saline (n=8) or 20μM azumolene (n=8) was infused during reperfusion of Langendorff-perfused rabbit hearts. To induce further stress, we induced long VF (120 seconds) twice in each heart. Those who did not stay in VF for 120 seconds were paced at 50Hz for the same duration. We then tested re-VF inducibility five times in each heart. Left ventricular (LV) epicardial calcium mapping was performed at baseline, after ischemia, after 1st and 2nd VF induction. Calcium dynamics and re-VF inducibility and organization were studied. Azumolene-treated hearts had less successful induction of re-fibrillation episodes compared to controls (32.5% vs. 67.5%, p<0.001). More calcium wavefronts (the surrogate for VF disorganization) were seen in the controls (2.88±0.05 vs. 2.14±0.13 waves per frame, p<0.01; calcium signals appeared more organized visually in azumolene-treated hearts (Panel A). Spontaneous diastolic calcium elevation (SCaE) was significantly increased in controls during post VF compared to baseline (0.117±0.029 vs. 0.052±0.010 AU, p<0.01) and SCaE was abrogated in azumolene-treated hearts (Panel B). RyR modulator, azumolene, reduces re-fibrillation vulnerability and improves calcium dynamics following VF. Dysfunctional RyR is a potential therapeutic target in VF.

Overall survival (OS) with CPX-351 versus 7+3 in older adults with newly diagnosed, therapy-related acute myeloid leukemia (tAML): Subgroup analysis of a phase III study.

7035 Background: tAML may occur as a late complication of cytotoxic therapy and is associated with a poor prognosis. CPX-351 is a liposomal formulation that delivers a synergistic 5:1 molar ratio of cytarabine (C) and daunorubicin (D). In a randomized, open-label, controlled phase III trial in patients (pts) aged 60-75 years with newly diagnosed, secondary AML (tAML or after MDS), CPX-351 significantly improved OS versus 7+3. The current analysis of this phase III study evaluated outcomes in the subgroup of pts with tAML. Methods: Pts were randomized 1:1 to induction with 1-2 cycles of CPX-351 (100 u/m2 [C 100 mg/m2 + D 44 mg/m2] on Days 1, 3, and 5 [2nd induction: Days 1 and 3]) or 7+3 (C 100 mg/m2/day x 7 days [2nd induction: x 5 days] + D 60 mg/m2on Days 1, 2, and 3 [2nd induction: Days 1 and 2]). Pts with complete remission (CR) or CR with incomplete platelet or neutrophil recovery (CRi) could receive up to 2 cycles of consolidation therapy. The study was not powered for this subgroup analysis. Results: 304 pts were enrolled and received study treatment, including 62 (20%) pts with tAML; demographics of tAML pts were similar between study arms. Pts with tAML had typically received prior non-anthracycline chemotherapy alone (25%), radiation alone (25%), or non-anthracycline chemotherapy + radiation (32%). CPX-351 was associated with an OS benefit versus 7+3 in older tAML pts and numerically longer event-free survival (EFS) and remission duration (Table). A greater proportion of tAML pts achieved CR+CRi (47% vs 36%, respectively) and proceeded to stem cell transplantation (37% vs 27%) with CPX-351. The safety profile of CPX-351 was comparable to that of 7+3. Conclusions: CPX-351 is associated with improved outcomes in older pts with newly diagnosed tAML. Outcomes in the tAML subgroup mirrored the overall study population, indicating CPX-351 may represent a new therapeutic option for this difficult to treat population. Clinical trial information: NCT01696084. [Table: see text]

Overall survival (OS) and stem cell transplant (SCT) in patients with FLT3 mutations treated with CPX-351 versus 7+3: Subgroup analysis of a phase III study of older adults with newly diagnosed, high-risk acute myeloid leukemia (AML).

e18507 Background: FLT3+ AML patients (pts; 20%-30% of AML pts) often have rapid post-induction relapse, highlighting the need for therapies that improve the bridge to SCT. CPX-351 is a liposomal formulation that delivers a synergistic 5:1 molar ratio of cytarabine (C) and daunorubicin (D). CPX-351 demonstrated efficacy versus 7+3 in a randomized, open-label, controlled phase III trial in pts aged 60-75 years with newly diagnosed, high-risk AML; our analysis investigated outcomes in the subset of FLT3+ pts. Methods: Pts were randomized 1:1 to induction with 1-2 cycles of CPX-351 (100 u/m2 [C 100 mg/m2 + D 44 mg/m2] on Days 1, 3, and 5 [2nd induction: Days 1 and 3]) or 7+3 (C 100 mg/m2/day x 7 days [2nd induction: x 5 days] + D 60 mg/m2on Days 1, 2, and 3 [2nd induction: Days 1 and 2]). Pts with complete remission (CR) or CR with incomplete platelet or neutrophil recovery (CRi) could receive up to 2 consolidation cycles. Results: Of the pts who had FLT3 mutations assessed and received study treatment, 22/138 (16%) pts in the CPX-351 arm and 20/136 (15%) pts in the 7+3 arm had baseline FLT3 mutations. AML subtypes in FLT3+ pts were: tAML (19%); AML after MDS with (38%) or without (10%) prior hypomethylating agents; AML after CMMoL (12%); and de novo AML with MDS karyotype (21%). In FLT3+ pts, median OS was longer with CPX-351 (10.25 mo) versus 7+3 (4.55 mo; HR = 0.57 [95% CI: 0.24, 1.33]; P= 0.093) and the rate of CR+CRi was higher (68% vs 25%). A greater number of FLT3+ pts treated with CPX-351 were able to undergo SCT (n = 10/22 [45%]; 4 pts were alive as of this analysis, after a median post-SCT follow up of 692 days [range: 96-769]) compared with 7+3 (n = 2/20 [10%]; neither pt still alive). The on-study safety profile of CPX-351 in FLT3+ pts was comparable to 7+3 and consistent with the overall study population. Serious adverse events were experienced by 7 (32%) FLT3+ pts in the CPX-351 arm and 10 (50%) in the 7+3 arm. Conclusions: CPX-351 demonstrated numerical improvement in median OS in older pts with newly diagnosed, FLT3+ high-risk AML and allowed more pts to undergo SCT. The analysis was limited by small number of pts. Clinical trial information: NCT01696084.

Phase II study: Induction chemotherapy &amp; transoral surgery as definitive tx for locally advanced oropharyngeal squamous cell carcinoma (OPSCC)—A novel approach.

6078 Background: The standard of care for OPSCC includes chemoradiation (CRT) or surgery with adjuvant radiation (RT). However, RT is associated with significant life long morbidity. We assessed the efficacy of a two-drug induction regimen, followed by transoral robotic assisted surgery (TORS) &amp; neck dissection for locally advanced OPSCC. Methods: This is an IRB approved single-arm phase II study for untreated stage III or IVA OPSCC patients (pts) with an ECOG &lt; 2 and GFR &gt; 50 cc. Induction chemotherapy consisted of cisplatin 75 mg/m2 and taxotere 75 mg/m2 every 21 days for 3 cycles. Tumor shrinkage was examined after each cycle. If the primary tumor was &gt; 80% smaller, pts underwent TORS and neck dissection(s). At post-op visits, flexible laryngoscopy, blood work, and imaging with PET/CT and/or MRI were done. Short and long term toxicity, progression-free survival (PFS) and overall survival (OS), and quality of life (QOL) were evaluated. Results: Nineteenpts were treated and 14 are available for analysis. Thirteen were male, 12 were Caucasian, 2 were African-American, and 13 were HPV+. Median age at diagnosis was 57. Tumors involved the tonsil (11 pts) and base of tongue (3 pts). Three pts were stage III, and 11 were stage IVA. Tumor size was reduced on average by 58%, 84% and 92% after the 1st, 2nd and 3rd induction cycles respectively. Pathologic complete remission of primary disease occurred in 11 pts and in 7 pts with cervical lymph node disease. Four pts were given dose-reduced chemo and one pt was changed to carboplatin per protocol because of renal dysfunction. In addition, adverse events included three patients with grade I fatigue, neuropathy or nausea. Pre vs post tx QOL scores were not significantly different. At a mean follow-up (f/u) of 13 months (range 2.5 to 19.7), 13 pts are alive and well. Three pts recurred, and were treated with salvage CRT. One pt died of metastatic disease. Conclusions: Cisplatin + Taxotere is an effective induction tx for OPSCC, Induction tx followed by transoral &amp; neck resections without RT is a promising tx model for OPSCC. It appears effective while avoiding adverse effects of RT. Longer f/u is required to assess its true efficacy. Clinical trial information: NCT02760667.

Remissions after Third Induction Chemotherapy for Primary Non-Responders with Acute Myeloid Leukemia (AML) Are Uncommon and Short-Lived

The outcome of adult patients with AML who are primary non-responders to two courses of induction chemotherapy is poor. However, the utility of a 3rd induction for a select subgroup of these patients is uncertain. Here, we evaluated the rates of response and survival after a 3rd course of induction chemotherapy for primary non-responders with AML.We identified 98 patients from the Princess Margaret Cancer Centre between May 1999 and March 2015 who were non-responders to induction and reinduction chemotherapy. No-response to re-induction chemotherapy was defined according to the Revised Recommendations of the International Working Group for AML (JCO, 2003) as patients who survived > 7 days post re-induction and had persistent AML in blood or bone marrow (>5%). Median age was 58.3 years [range: 20-76.6]. 50 (51%) were male. 2% had favorable, 18% normal, 18% intermediate, and 48% adverse cytogenetics. 50% had de novo AML, 23% had AML secondary to MDS or MPN, and 17% had therapy-related AML. Induction chemotherapy consisted of "7+3" (n =88), Nove-HiDAC (n=1), Flag-Ida (n= 2), or similar variants (n=7). Reinduction chemotherapy consisted of Nove-HiDAC (n=70), Flag-Ida (n=7), "7+3" (n=1) or other similar variants (n =20). No patients received the same regimen for both induction and reinduction.Of the 98 primary non-responders, 15 received a 3rd induction regimen, while the others received supportive/palliative care ± low-dose chemotherapy (57 pts), or a non-induction clinical trial (26 pts). Average age was 56.4 (sd: 12.9) for patients who received supportive/palliative care and 47.0 (sd: 17.5) for patients who received a 3rd induction (p=0.008). Other baseline characteristics including gender, cytogenetic risk, marrow blast count post 2nd induction, and time between 1st and 2nd induction, did not differ between patients who did and did not receive a 3rd induction. Time to 3rd induction was a median of 54 days [range:36-126] from the start of the 2nd induction. Of the 15 third inductions, 7 were clinical trials evaluating novel agents in combination with induction chemotherapy, while the other 8 were combinations of standard chemotherapeutics (Flag-Ida n=1), AMSA+HiDAC (n=2), Daunorubicin+ HiDAC (n=1), Nove-HiDAC (n=4).Of the 15 patients who received a 3rd induction, 3 (20%) achieved a CR following Nove-HiDAC and Flag-Ida or AMSA+HiDAC chemotherapy, where the Ara-C was given as continuous infusion. 1 patient underwent allogeneic stem cell transplant (SCT) approximately 3.7 months after 3rd induction and remains alive 4.6 years post CR. 2 patients relapsed 2.3 and 4.7 months post CR without having received alloSCT. None of the 12 other patients responded to the 3rd induction and none had prolonged aplasia. 2 of 15 (13%) died during 3rd induction. Among the 83 patients who did not receive a 3rdinduction, 1 achieved a CR after a phase 1 clinical trial (MDM2 inhibitor) and remains in CR 3.6 years following an alloSCT.For patients who survived the immediate post induction period and were discharged from hospital median overall survival from the start of the 2nd induction did not differ between patients who did and did not receive a 3rd induction (276 days [range: 78-1304] vs 181.5 days [range: 47-1855] respectively p= 0.14). Median duration of hospital stay (including subsequent admissions) was longer for patients receiving a 3rd induction compared to those who did not (94 days following start of the 2nd induction [range: 47-169] vs 57 days [range: 51-181], respectively;(p= 0.003)).In summary, remissions after 3rd inductions for primary non-responders are uncommon, and short-lived, suggesting that 3rd inductions should be considered with caution and only when an SCT strategy is in place. DisclosuresGupta:Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Schuh:Amgen: Membership on an entity's Board of Directors or advisory committees. Yee:Novartis Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding. Schimmer:Novartis: Honoraria.

Importance of Achieving Complete Remission (CR) after Intensive Therapy for Acute Myeloid Leukemia (AML) in Older Adults Age ≥60 Years: Analysis of Risk Factors for Early Mortality and Re-Induction, and Impact of Quality of Response on Overall Survival (OS) in the ECOG-ACRIN E2906 Randomized Trial

Background: The results of the primary endpoint of the E2906 North American Intergroup phase 3 trial - demonstrating significantly inferior OS after single agent clofarabine versus standard intensive daunorubicin & cytarabine induction and consolidation - strongly support the use of intensive therapy for patients age ≥60 years with newly-diagnosed AML who are fit for treatment. This result was achieved despite similar CR rates (including CRi - CR with incomplete blood count recovery) and similar early (30- & 60-day) induction mortality between study arms, raising the question as to the importance of achieving CR as an endpoint. Therefore, we performed a follow-up analysis to address the factors that contribute to early mortality, the necessity for 2nd induction cycle to achieve CR, and to assess the survival impact of the quality of remission.Methods: E2906 design, study population and results for the primary objective were reported previously (ASH 2015, abstr. #217a). We performed this updated analysis to evaluate clinical risk factors for early mortality and re-induction, and to assess the impact of response quality on OS. Univariate comparisons were made with Fisher's exact test (category) and t-test (continuous variable), and logistic regression models were used to examine risk factors associated with early mortality, and with requiring a 2nd cycle of induction therapy. We performed a landmark analysis (beginning Day 60 after initiation of therapy) to determine the impact of response quality (CR/CRi, morphologic leukemia-free-state (MLFS), and treatment failure - i.e. residual/refractory AML) on OS. Survival comparisons were performed with log-rank test.Results: A total of n=727 patients were registered to E2906, the median age is 68 years (range 60-86) and the median follow-up of surviving patients is now 18.3 months. Adjusting for treatment, cytogenetic risk group, FAB subtype, WBC count, and secondary AML, increasing age (p=0.06) and performance status (PS) >1 (p=0.05) were associated with 30-day mortality and only PS >1 (p=0.06) with 60-day mortality. Treatment arm (p=0.003), adverse cytogenetic risk group (p=0.02), increasing age (p=0.03) and baseline WBC <10K (p=0.03) were each independently associated with higher risk of receiving 2nd cycle induction, but there was no difference in CR/CRi (44.2% vs. 42.2%, p=0.58) or in median OS (13.8 versus 12.0 months, p=0.11) for those receiving 1 vs. 2 induction cycles, respectively.We next performed a landmark analysis (day 60, n=608 evaluable patients) to evaluate OS in relation to the quality of response (Table). We observed an advantage in achieving CR and CR/CRi, although the benefit of CRi diminished greatly after 12 months, and OS after MLFS appeared more similar to treatment failure (Figure, p<0.001). The relative adverse impact of CRi and MLFS (vs. CR) was most pronounced for patients treated with clofarabine, where median OS was shorter for those achieving CRi (12.2m vs. 22.6m standard therapy, p=0.007) and MLFS (6.6m vs. 13.4m standard therapy, p=0.15).Conclusion: This follow-up analysis confirms the importance of CR regardless of the number of cycles of induction therapy required to achieve remission, and identifies risk factors associated with early mortality and with requiring re-induction. At longer follow-up the OS after CRi appears to be inferior to true CR, particularly after clofarabine. We hypothesize that this may be due to higher rates of minimal residual disease in CRi, and studies to determine this are being performed. MLFS is not associated with a better overall survival than frank treatment failure (i.e. residual disease) and therefore its value as a response category is uncertain. These results highlight the role of standard intensive remission induction therapy with the intent of achieving CR, which remains the standard of care for fit older adults. [Display omitted] [Display omitted] DisclosuresForan:karyopharm: Honoraria; novartis: Honoraria; medscape: Honoraria; Millennium Pharmaceuticals, Inc.: Research Funding; pfizer: Honoraria; boehringer ingelheim: Research Funding; agios: Research Funding; Cellerant: Research Funding. Melnick:Janssen: Research Funding. Altman:Novartis: Honoraria; BMS: Honoraria; Janssen: Honoraria; Syros: Honoraria. Al-Kali:Novartis: Research Funding; Celgene: Research Funding.

A Phase 1b Study of Vadastuximab Talirine in Combination with 7+3 Induction Therapy for Patients with Newly Diagnosed Acute Myeloid Leukemia (AML)

A Phase 1b Study of Vadastuximab Talirine in Combination with 7+3 Induction Therapy for Patients with Newly Diagnosed Acute Myeloid Leukemia (AML)

Abstract 3203: Phase I results of mitoxantrone in combination with clofarabine in children with refractory/relapsed acute leukemia

Abstract BACKGROUND: Despite excellent outcomes in pediatric ALL, multiply relapsed patients have response rates ∼40%, with &amp;lt;10% OS in CR3.(Gaynon, BJH 2005) The prognosis for relapsed or refractory AML is ∼20% OS.(Wells, JCO 2003) Novel combinations with improved outcomes are needed. Clofarabine and Mitoxantrone have proven efficacy in children with leukemia and offer possible synergistic activity in vivo with less drug resistance.(Chow, Leukemia &amp; Lymphoma 2000) OBJECTIVES: To determine the maximal tolerated dose and overall response rate of clofarabine in combination with mitoxantrone as reinduction therapy for refractory/relapsed acute leukemia. To determine the percent of minimal residual disease (MRD) following reinduction. DESIGN: Prospective, open label, uncontrolled, safety and efficacy study. Patients 0-30.99yr old with ALL, AML or NHL in 1st, 2nd or 3rd relapse OR primary induction failure were given 1 to 3 cycles of clofarabine (escalating doses 20, 30, 35 and 40mg/m2/day) Day 1-5, in combination with mitoxantrone 12mg/m2/day on Day 3-6. Dexrazoxane was given prior to Mitoxantrone. Dose escalation was planned every 3 patients pending dose limiting toxicities. CNS prophylaxis was achieved with intrathecal liposomal cytarabine. Patients were allowed subsequent cycles pending response and anthracycline exposure. RESULTS: To date 17 patients have been enrolled on the Phase I safety portion of this study. Median Age is 13yrs (8months-23yrs); 11 ALL (3 = Induction Failure, 6 = Relapse1, 2 = Relapse2), 5 AML (4 = Induction Failure, 1 = Relapse2), 1 NHL ( = Progressive Disease). There have been 2 prolonged Grade III/IV toxicities at Dose Level 4 (Clofarabine 40mg/m2) (1 hepatic toxicity, 1 prolonged myelosuppression) hence additional patients were enrolled at Dose Level 3 (Clofarabine 35mg/m2). Median time to neutrophil recovery was 24 days. Fourteen of 16 (88%) evaluable leukemia patients achieved a CR after 1 cycle of therapy. Of these patients, 94% achieved MRD negativity (&amp;lt;0.1%). Two patients with relapsed ALL had no response. One patient with relapsed/refractory NHL had progressive disease after 2 cycles. Thirteen of 14 patients achieving CR went on to receive an allogeneic HSCT with continued remission at a median follow up time of 275 days (range 40-634). Overall 1 year survival for leukemia patients is 78.7% (CI95: 47.2-92.5). CONCLUSION: The combination of clofarabine and mitoxantrone reinduction therapy for relapsed or refractory acute leukemia appears to be safe and well tolerated in children, adolescents and young adults with poor risk hematologic malignancies. The Phase I MTD of this combination was found to be 35mg/m2 Clofarabine. Hematopoietic recovery appears to be rapid and complete. Initial data from the first 17 patients enrolled is encouraging with an 88% CR rate in leukemic patients. An extended multicenter Phase II Study is ongoing. Citation Format: Jessica Hochberg, Javier Oesterheld, Olga Militano, Liana Klejmont, Lauren Harrison, Berkley Nickerson, Mitchell S. Cairo. Phase I results of mitoxantrone in combination with clofarabine in children with refractory/relapsed acute leukemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3203.

A Pilot Study of Mitoxantrone in Combination with Clofarabine (MITCL) in Children, Adolescents and Young Adults (CAYA) with Refractory/Relapsed Acute Leukemia

BACKGROUNDDespite excellent outcomes in pediatric ALL, 20-30% of patients relapse or become refractory to frontline therapies with subsequent CR2 rates of only 60%. For multiply relapsed patients, response rates remain around 40%, with <10% overall survival in third complete response.(Gaynon, BJH 2005) In pediatric AML, five-year overall survival remains around 60% among children and adolescents but with a very poor prognosis for relapsed or refractory AML (<20% three-year OS).(Wells, JCO 2003) Clearly, novel combinations with improved complete response rates and long term outcomes are needed for these high risk patients. Several studies have supported the rationale for using either Clofarabine or Mitoxantrone in patients with refractory/relapsed acute leukemia.(Wells, JCO 2003; Jeha, JCO 2009) Mitoxantrone and clofarabine as single agents, have proven effective in children with relapsed/refractory ALL and AML and offer possible synergistic activity in vivo with less drug resistance. (Chow, Leukemia & Lymphoma 2000) OBJECTIVESTo determine the maximal tolerated dose and overall response rate of clofarabine in combination with mitoxantrone as reinduction therapy for refractory/relapsed acute leukemia. To determine the percent of minimal residual disease (MRD) following reinduction with mitoxantrone and clofarabine reinduction therapy.To further characterize the biology of childhood, adolescent and young adult refractory/relapsed acute leukemia. DESIGNProspective, multi-center, treatment-based, non-randomized, open label, uncontrolled, single group assignment, safety and efficacy study (phase I/II). Patients 0-30.99yr old with ALL, AML or NHL in 1st, 2nd or 3rd relapse OR primary induction failure were given 1 to 3 cycles of clofarabine (escalating doses 20, 30, 35 and 40mg/m2/day) Day 1-5, in combination with mitoxantrone 12mg/m2/day on Day 3-6. Dexrazoxane was given prior to Mitoxantrone. Dose escalation was planned every 3 patients pending dose limiting toxicities. CNS prophylaxis was achieved with intrathecal liposomal cytarabine. (Figure 1) Patients were allowed subsequent cycles pending response and anthracycline exposure. RESULTSTo date 15 patients have been enrolled on the safety portion of this study. Median Age is 16yrs (8months-23yrs); 9 ALL (3=Induction Failure, 4=Relapse1, 2=Relapse2), 5 AML (4=Induction Failure, 1=Relapse2), 1 NHL (=Progressive Disease). There have been 2 prolonged Grade III/IV toxicities at Dose Level 4 (Clofarabine 40mg/m2) (1 hepatic toxicity, 1 prolonged myelosuppression) hence we are currently enrolling at Dose Level 3 (Clofarabine 35mg/m2). Median time to neutrophil recovery is 24 days. Twelve of 14 (86%) evaluable leukemia patients achieved a CR after 1 cycle of therapy. Of these patients, 92% achieved MRD negativity (<0.1%). Two patients with relapsed ALL had no response. One patient with relapsed/refractory NHL had progressive disease after 2 cycles. Eleven of 12 patients achieving CR went on to receive an allogeneic HSCT with continued remission at a median follow up time of 224 days (range 31-593). CONCLUSIONThe combination of clofarabine and mitoxantrone reinduction therapy for relapsed or refractory acute leukemia appears to be safe and well tolerated in children, adolescents and young adults with poor risk hematologic malignancies. The MTD or tolerable dose of this combination has yet to be reached. Hematopoietic recovery appears to be rapid and complete. Initial data from the first 15 patients enrolled is encouraging with an 86% CR rate in leukemic patients. Once the MTD or tolerable dose is reached, an extended multicenter Phase II Study will be initiated.Table 1Treatment SchemaDAY1234567821CLOFARABINE●●●●●DEXRAZOXANE●●●●MITOXANTRONE●●●●DEXAMETHASONE●●●●●IT LIPOSOMAL ARAC●FILGASTRIM (…continued until ANC > 1500/mm3 x 2 consecutive days)●→→ DisclosuresNo relevant conflicts of interest to declare.