Gemtuzumab-Ozogamicin in Combination with Fludarabine, Cytarabine, Idarubicin (FLAI-GO) as Induction Therapy in CD33-Positive AML patients Younger Than 65 Years. Report of a Multicentric Trial

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3998-3998
Author(s):  
Anna Candoni ◽  
Giovanni Martinelli ◽  
Cristina Papayannidis ◽  
Erica Simeone ◽  
Eleonora Toffoletti ◽  
...  
Keyword(s):  
Adverse Events ◽  
Safety Profile ◽  
Response Rate ◽  
Residual Disease ◽  
Target Therapy ◽  
Prospective Trial ◽  
Gemtuzumab Ozogamicin ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Induction Regimen

Abstract INTRODUCTION. The addition of Gemtuzumab-ozogamicin (GO) to an induction regimen including synergistic drugs, such as intermediate dose of cytarabine (Ara-C), idarubicin and fludarabine (FLAI), could reduce treatment failure in AML patients. Nevertheless, the role and safety of this antibody target-therapy in first-line chemotherapy in patients younger than 65 years has not yet been defined. PATIENTS and METHODS. The primary goal of this multicenter prospective trial (EUDRACT Number 2007-005248-26) was to evaluate the efficacy and the safety profile of FLAI plus GO as induction regimen. Sixty-eight consecutive AML patients were included from five Italian hematological centres. All patients were younger than 65 with a median age of 48 years and CD33 expression exceeded 20% in all cases. The M/F ratio was 37/31, and 54/68 (79%) of patients were poor-risk at diagnosis. The induction regimen (FLAI-GO) included fludarabine (30 mg/sqm) and Ara-C (2 g/sqm) on days 1–5, idarubicin (10 mg/sqm) on days 1, 3, and 5 and GO (3 mg/sqm) on day 6. Hematopoietic stem cell transplant (HSCT) was planned for all high risk AML patients in first complete remission (CR) after consolidation with intermediate doses of Ara-C and idarubicin (IDAC-IDA). Cytogenetic, multidrug-resistance phenotype, FLT3 mutation status, and WT1 quantitative expression analyses were performed at diagnosis in all patients. WT1 expression and cytogenetic (in positive cases) analyses were performed after induction to detect and follow Minimal Residual Disease. RESULTS. Patients were evaluated for response rate, treatment-related adverse events, overall survival and relapse free survival. After induction with FLAI-GO, CR rate was 86% (54 of 63 evaluable pts); one patient achieved partial remission and eight were resistant. There were only two cases of death during induction (DDI). After FLAI-GO, the mean value of WT1 dropped from 4540±2342 copies/104ABL to 180±277 copies/104ABL. The toxicity of FLAI-GO was acceptable; 58% of patients experienced transient and reversible GO infusion-related adverse events (especially fever and chills), but no cases of veno-occlusive disease occurred during CHT or after HSCT. After a median follow-up of 9 months (range 1–32), 60/68 (88%) patients are alive (57/60 in CR). The probability of 12 and 18 mths OS a was 91% and 78%, respectively. The probability of 12 and 18 mths RFS was 87 % and 78%, respectively. Allogeneic and autologus HSCT was performed in 30 (44%) and 8 (12%) patients. CONCLUSIONS. The preliminary results of this multicentric trial confirm that FLAI-GO is an effective and well tolerated induction regimen for CD33 positive AML patients younger than 65 years, with a high complete response rate, favourable safety profile and low DDI.

scholarly journals Blinatumomab In pediatric relapsed/refractory B-cell acute lymphoblastic leukemia: RIALTO expanded access study final analysis

2022 ◽  
Author(s):  
Franco Locatelli ◽  
Gerhard Zugmaier ◽  
Noemi Mergen ◽  
Peter Bader ◽  
Sima Jeha ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Adverse Events ◽  
B Cell ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Cell Transplant ◽  
Open Label ◽  
Hematopoietic Stem ◽  
Expanded Access ◽  
Molecular Abnormalities

The safety and efficacy of blinatumomab, a CD3/CD19-directed bispecific T-cell engager molecule, for treatment of pediatric relapsed/refractory B-cell precursor acute lymphoblastic leukemia (R/R B-ALL) were examined in an open-label, single-arm, expanded access study (RIALTO). Children (>28 days, <18 years) with CD19+ R/R B-ALL received up to five cycles of blinatumomab by continuous infusion (cycle: 4 weeks on/2 weeks off). The primary endpoint was incidence of adverse events. Secondary endpoints included complete response (CR) and measurable residual disease (MRD) response within the first two cycles, relapse-free survival (RFS), overall survival (OS) and allogeneic hematopoietic stem cell transplant (alloHSCT) after treatment. At final data cutoff (1/10/20), 110 patients were enrolled (median age, 8.5 years; 88% ≥5% blasts at baseline). Blinatumomab treatment resulted in a low incidence of grade 3-4 cytokine release syndrome (n=2 [1.8%]) and neurologic events (n=4 [3.6%]). No blinatumomab-related fatal adverse events were reported. The probability of response was not affected by the presence of cytogenetic/molecular abnormalities. Median OS was 14.6 months (95%CI: 11.0─not estimable) and was significantly greater for MRD responders versus MRD non-responders (not estimable vs 9.3; HR 0.18, 95%CI: 0.08─0.39). One-year OS probability was higher for patients who received alloHSCT versus without alloHSCT post-blinatumomab (87% versus 29%). Median RFS for MRD responders (n=57) was 8.0 months (95%CI:3.4─10.1) versus 2.8 months (95%CI: 0.3─9.2) for MRD non-responders (n=10). Of patients achieving CR after 2 cycles, 73.5% (95%CI: 61.4%-83.5%) proceeded to alloHSCT. These findings support the use of blinatumomab as a safe and efficacious treatment for pediatric R/R B-ALL. (ClinicalTrials.gov identifier NCT02187354)

scholarly journals Bispecific T-cell engaging antibodies in B-cell precursor acute lymphoblastic leukemias: focus on blinatumomab

2020 ◽  
Vol 11 ◽  
pp. 204062072091963
Author(s):  
Jose-Maria Ribera ◽  
Eulalia Genescà ◽  
Jordi Ribera
Keyword(s):  
T Cell ◽  
B Cell ◽  
De Novo ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Development Program ◽  
Cell Transplant ◽  
Cell Precursor ◽  
Hematopoietic Stem ◽  
Clinical Development Program

Bispecific T-cell engaging antibodies are constructs engineered to bind to two different antigens, one to a tumor-specific target and the other to CD3-positive T cells or natural killer (NK) cells. Blinatumomab engages CD19 and CD3, performing effective serial lysis. The clinical development program in acute lymphoblastic leukemia (ALL) includes clinical trials in relapsed or refractory (R/R) patients and in B-cell precursor (BCP) ALL patients with measurable residual disease. Several trials are currently being conducted in de novo BCP-ALL, either in induction, consolidation, or before or after hematopoietic stem cell transplant. Combination with other targeted therapies or with other immunotherapeutic approaches are also underway. Several strategies are aimed to optimize the use of blinatumomab either by overcoming the mechanisms of resistance (e.g. inhibition of PD-1/PD-L1) or by improvements in the route of application, among others.

Autologous Transplantation for Aggressive Non-Hodgkin’s Lymphoma: Results of a Randomized Trial Evaluating Graft Source and Minimal Residual Disease

2002 ◽  
Vol 20 (9) ◽  
pp. 2344-2352 ◽  
Author(s):  
Julie M. Vose ◽  
Graham Sharp ◽  
Wing C. Chan ◽  
Craig Nichols ◽  
Kevin Loh ◽  
...  
Keyword(s):  
Stem Cell ◽  
Median Time ◽  
Response Rate ◽  
Complete Response Rate ◽  
Residual Disease ◽  
Complete Response ◽  
Hematopoietic Stem ◽  
Transfusion Independence ◽  
Rbc Transfusion ◽  
Minimal Residual

PURPOSE: To determine whether the source of autologous hematopoietic stem cells altered the clinical outcomes of patients undergoing high-dose chemotherapy and hematopoietic stem-cell transplantation (HSCT) for aggressive non-Hodgkin’s lymphoma (NHL). PATIENTS AND METHODS: Of 105 high-risk, persistent, or relapsed NHL patients slated for an autologous HSCT entered onto this trial, 93 eligible patients were randomized to receive cytokine-naive autologous bone marrow transplantation (ABMT) (n = 46) or mobilized peripheral-blood stem-cell transplantation (PBSCT) (n = 47). All patients received carmustine, etoposide, cytarabine, and cyclophosphamide as the conditioning regimen. PBSCT patients also received identical mobilization with granulocyte colony-stimulating factor (G-CSF) 10 μg/kg/d, and both groups received G-CSF 5 μg/kg/d after the infusion of the stem-cell product until neutrophil engraftment. RESULTS: PBSCT patients had significantly faster engraftment of all cell lineages: median time to absolute neutrophil count ≥ 500/μL, 10 days versus 13 days on the ABMT arm; median time to platelet count greater than 20,000/μL untransfused, 11 days versus 15 days on the ABMT arm; and median time to RBC transfusion independence, 8 days versus 16 days on the ABMT arm. The complete response rate was 72% for PBSCT and 54% for ABMT. The death rate before posttransplant day 100 was 2% on the ABMT arm and 6% on PBSCT arm. Event-free survival was 37% for PBSCT and 37% for ABMT. However, overall survival for PBSCT was 61% compared with 43% for ABMT. CONCLUSION: Patients with aggressive NHL receiving HSCT randomized to PBSCT demonstrated improved neutrophil engraftment and platelet and RBC transfusion independence. The complete response rate and EFS were not statistically different by randomization arm. Patients whose harvests were positive for minimal residual disease by molecular analysis had poorer EFS.

scholarly journals Concordant acute myeloblastic leukemia in identical twins treated with allogeneic transplantation from a younger HLA-identical sibling following a single apheresis procedure

2020 ◽  
Author(s):  
Yajaira Valentine Jimenez-Antolinez ◽  
Elias Eugenio Gonzalez-Lopez ◽  
Ileana Yazmín Velasco Ruiz ◽  
Marcela Cantu-Moreno ◽  
David Gomez-Almaguer ◽  
...  
Keyword(s):  
Complete Remission ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Monozygotic Twins ◽  
Human Leukocyte ◽  
Allogeneic Transplantation ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Leukocyte Antigen ◽  
Similar Genetic Background

A concordant leukemia is that which occurs in a pair of monozygotic twins; a similar genetic background suggests an in utero monoclonal origin. We present the case of a pair of monozygotic infants with concordant acute myeloid leukemia who underwent a peripheral blood hematopoietic stem-cell transplant (HSCT) from a single, younger human leukocyte antigen-identical sibling donor, using a fractioned graft collected during only one apheresis procedure. Twin A relapsed at +456 and received a second haploidentical HSCT from his father, twin B has been in complete remission since the first HSCT. Both children are in complete remission and with negative minimal residual disease at +900 (after second transplant) and +1488, respectively.

An Active Hemovigilance Program Characterizing the Safety Profile of 7,437 Platelet Transfusions Prepared with Photochemical Treatment (INTERCEPT™).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2894-2894 ◽  
Author(s):  
J.C. Osselaer ◽  
J.P. Cazenave ◽  
C. Waller ◽  
M. Lambermont ◽  
O. Garraud ◽  
...  
Keyword(s):  
Adverse Events ◽  
Causal Relationship ◽  
Safety Profile ◽  
Vital Signs ◽  
Primary Diagnosis ◽  
Buffy Coat ◽  
Cell Transplant ◽  
Wide Range ◽  
Uva Light ◽  
Clinical Description

Abstract Background. Inactivation of pathogens and leukocytes in platelet components using amotosalen and UVA light (INTERCEPT) is in routine use in some European blood centers. An active hemovigilance program was implemented to characterize the safety profile of INTERCEPT platelets (PLT) in a broad patient population. The results of the first 5,106 transfusions (txn) have been reported (HV1: Vox Sang2006;91(s3): 181). Here we report the results of an additional 7,437 txn. Methods. Apheresis or buffy coat PLT were leukoreduced, suspended in ∼35% plasma and 65% Intersol™, treated with the INTERCEPT system and stored for up to 7 days. INTERCEPT treatment replaced bacterial screening and gamma irradiation. Blood centers using INTERCEPT PLT were requested to complete a data form after txn. The focus of the study was on response to txn occurring within the first 24 hr of txn. Investigators recorded: patient (pt) demographics, primary diagnosis and therapy, and type of PLT product. For adverse events, the following data were collected: time of event following txn, clinical description, objective clinical parameters (vital signs), results from clinical and laboratory tests (radiographs, bacterial cultures), event severity (grade 0–4), serious or non-serious nature, and causal relationship to txn (unrelated, probably unrelated, possibly related, probably related, or related). Results. A total of 7,437 PLT txn were administered to 1,400 pts. The mean age of pts was 60 (range <1–96) years. 53.4% of the pts had hematologic diseases and required conventional chemotherapy(44.8%) and stem cell transplant(8.6%). PLT txn associated with “related” (possibly related, probably related, or related) adverse events following INTERCEPT PLT txn were infrequent (n=55, 0.7%) and most reactions were of grade 1 (absence of immediate or long-term life-threatening medical conditions). 45 pts(3.2%) experienced at least one event following one or more INTERCEPT txn. Adverse events classified as “related” to the INTERCEPT PLT txn occurred only in 39(2.8%) of the 45 pts. The events were generally representative of the events expected with PLT txn. The most frequently reported signs/symptoms were chills, fever, urticaria, dyspnea, nausea, and vomiting. Only 5 events were considered as severe (≥grade 2), however, no causal relationship to INTERCEPT PLT txn was found. Repeated exposure to INTERCEPT PLT did not increase the likelihood of a txn reaction. No cases of Txn Related Acute Lung Injury and no deaths due to an INTERCEPT txn were reported. Conclusions. In this cohort study, 99.3% of INTERCEPT PLT txn were without reported txn reactions. Only 2.8% of pts with reported adverse reactions had a possible, probable or related attribution to PLT txn. These results are consistent with those reported in the HV1 study and further suggest that routine txn of INTERCEPT PLT is well tolerated in a wide range of pts. Adverse events following INTERCEPT PLT txn classified as related to txn were infrequent and most were of mild severity.

A Phase II Study of Sepantronium Bromide (YM155) Plus Rituximab in Previously Treated Subjects with Aggressive CD20-Positive B Cell Non-Hodgkin's Lymphoma Who Are Ineligible for or Have Previously Received an Autologous Stem Cell Transplant - Stage I Results.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2731-2731 ◽  
Author(s):  
Kyriakos P Papadopoulos ◽  
Scott E. Smith ◽  
Joyce Steinberg ◽  
Renelle Papa ◽  
Javier Lopez-Jimenez ◽  
...  
Keyword(s):  
Stem Cell ◽  
Adverse Events ◽  
B Cell ◽  
Overall Response Rate ◽  
Stem Cell Transplant ◽  
Response Rate ◽  
Median Number ◽  
Autologous Stem Cell Transplant ◽  
Stage I ◽  
Cell Transplant

Abstract Abstract 2731 Background: Survivin is responsible for preservation of cell viability and regulation of mitosis in tumor cells. Survivin is overexpressed in the majority of aggressive B-cell lymphomas and thus is an attractive target in subjects with relapsed lymphoma. YM155 is a survivin suppressant that in vitro, when combined with rituximab, synergistically enhances the induction of apoptosis in lymphoma cells. In human DLBCL xenograft models, this combination significantly inhibits tumor growth and prolongs survival. Based on these preclinical combination data and single agent clinical data, a Phase 2 study utilizing YM155 rituximab was initiated. Methods: The study employs a two-stage group sequential method, designed to enroll a total of 40 subjects with an interim futility assessment (Stage I). Eligible patients have histologically confirmed relapsed CD20-positive primary or transformed diffuse large B cell lymphoma (DLBCL) or grade 3 follicular lymphoma (FL) and are either not candidates or previously had an autologous stem cell transplant (ASCT). Subjects had received ≥ 1 prior anthracycline containing regimen with a documented response to the last regimen prior to study entry. Induction, ASCT and maintenance therapy were considered as one regimen. The dosing regimen was YM155 5 mg/m2/day as a 168 hour (7-day) continuous infusion in a 14 day cycle and rituximab 375 mg/m22 Days 1 and 8 cycles 1 – 4 and then repeated every 10 cycles. The primary endpoint of the study is objective response rate (ORR) per modified IWG 2007. Imaging studies are performed every 8 weeks (4 cycles) after initiation of therapy. In order to continue enrolling in the study, an overall response rate of 4/16 (25%) must be achieved. Results from the completed Stage I are reported here. Results: Sixteen subjects, the majority of whom were male 13/16 (81%), were enrolled in Stage I. The median age was 62.9 (range: 32 – 78) with a majority of subjects 15/16 (93.8%) with DLBCL. IPI/FLIPI scores were intermediate in 10 subjects (62.5%) and high in 3 subjects (18.8%). The median number of prior therapies was 2 (range: 1 – 5), 16/16 (100%) of patients received rituximab in 1st or subsequent lines of therapy. Seven patients (43.7%) had prior ASCT. The median number of cycles of YM155 administered was 11 (1–37). The overall response rate was 9/16 (56.3%) with 2/16 (12.5%) CR, 7/16 (43.8%) PR and 4/16 (25%) SD. The median time to response was 53 days (range: 52 – 109). Median duration of response and median PFS has not been achieved. Clinical benefit rate was 13/16 (81.3%). The most common adverse events reported, regardless of relationship, were pyrexia 8/16 (50%), cough 7/16 (43.8%), asthenia 5/16 (31%) and fatigue, back pain, vomiting, neutropenia and thrombocytopenia each 4/16 (25%). Five subjects (31.3%) experience Grade 4 adverse events and 2 (12.5%) had Grade 5 adverse events (disease progression and respiratory failure), neither of which was considered related to therapy. The most common Grade 4 event was neutropenia 4/16 (25%), with all other Grade 4 events occurring in only 1 subject (febrile neutropenia, thrombocytopenia, general physical health deterioration, infusion site extravasation, central line infection, infective thrombosis, mediastinitis, dyspnoea, pleural effusion). Conclusion: In subjects with relapsed aggressive NHL receiving combination YM155 and rituximab, the ORR for Stage I was 56.3%, which exceeds the requirement to continue to Stage II. Overall the combination regimen was well tolerated with limited hematologic toxicities. Stage II enrollment is ongoing. Disclosures: Papadopoulos: Astellas: Consultancy, Research Funding. Steinberg:Astellas Pharma: Employment. Papa:Astellas Pharma: Employment. Keating:Astellas Pharma: Employment.

A Multicenter, Phase IV Observational Study Of Ofatumumab In Chronic Lymphocytic Leukemia (CLL): A European Research Initiative On CLL (ERIC) Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1645-1645 ◽  
Author(s):  
Carol Moreno ◽  
Marco Montillo ◽  
Panayiotidis Panayiotis ◽  
Adrian Bloor ◽  
Jehan Dupuis ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Board Of Directors ◽  
Safety Profile ◽  
Research Funding ◽  
Response Rate ◽  
Lymphocytic Leukemia ◽  
Hematologic Toxicity ◽  
Phase Ii Trials ◽  
Advisory Committees

Abstract Background Ofatumumab was given a conditional approval in the EU on April 2010 for the treatment of CLL refractory to fludarabine (F-ref) and alemtuzumab (A-ref), encouraging the retrieval of further data in patients treated in a “daily life” setting and to investigate treatment safety. Aims The main objective of this study was to obtain information on the safety profile of ofatumumab given outside clinical trials in patients with previously treated CLL. The secondary endpoints were efficacy, progression-free-survival (PFS), and overall survival (OS). Methods This was an observational, retrospective study. Patients were eligible regardless of prior treatments or disease status and provided they had not been included in ofatumumab clinical trials. Data on patients’ characteristics at diagnosis, prior treatment, adverse events response rate, PFS and OS were recorded. Results One-hundred and twenty patients were screened of which 103 from 25 centers in 10 European countries were eventually eligible for the study. There were 71 males; median age at initiation of ofatumumab was 64 years (range, 38-84); 66% patients were in advanced clinical stage (Rai III-IV/Binet C) and 33 patients presented bulky lymphadenopathy. Number of prior lines of therapy was 4 (range, 1-13). 94% had received prior F-based therapy, 54% received A-based therapy and 51% received both. Eighty-one percent had been previously exposed to rituximab-combination regimens. Fifty-four percent were F-ref, 70% A-ref and 41% were both F- and A-refractory. Cytogenetics within 3 months prior therapy was available in 52 patients of which 34 presented abnormalities (11 patients: 17p-; 9 patients: 11q-; 2 patients: 13q-; 1 patient: trisomy 12; 11 patients: two or more abnormalities including 17p- or 11q-). Forty-two of 50 patients showed unmutated IGHV genes. The median number of cycles of ofatumumab given was 9 (range, 0-16) and the median percentage of given/planned cycles was 83.3% (range, 0-133). In most patients the treatment dose and schedule were as follows: 300 mg 1st infusion followed by 2000 mg for subsequent infusions (8 weekly followed by 4 doses monthly). One hundred and sixty-one adverse events were reported in 68 patients, with 28 (17%) of them being considered as ofatumumab-related. Infusion related-reactions occurred in 19 (28%) patients (III-IV: 6%). Neutropenia was reported in 26% (III-IV: 19%), thrombocytopenia in 15% (III-IV: 12%) and anemia in 15% (III-IV: 7%). The non-hematological adverse events, included infection 44% (III-IV: 36%), fatigue 10% (III-IV: 4%), fever 10% (III-IV: 6%), rash 10% (III-IV: 3%), cough 7% (III-IV: 1%), diarrhea 6% (grade III-IV: 0%) and nausea 1% (III-IV: 0%). Hematologic toxicity correlated with the number of prior lines of therapy. Autoimmune hemolytic anemia and Richter syndrome were reported in one patient each. Two heavily pre-treated patients (5 and 6 prior lines of therapy, respectively) developed progressive multifocal leukoencephalopathy. The overall response rate (ORR) was 23% and the median PFS and OS were 5 and 12 months, respectively. The main causes of death were disease progression (61%) and infection (28%). Conclusions The safety profile of ofatumumab given outside clinical trials to patients with poor-prognosis and heavily pre-treated CLL was consistent with that observed in clinical trials. Although not unexpectedly the ORR was lower in this study, PFS and OS were in line with those reported in phase II trials. Disclosures: Montillo: Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Mundipharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Bloor:GSK: Consultancy, Honoraria, Paid speaker Other. Schuh:GSK: Honoraria; Celgene: Honoraria; Mundipharma: Honoraria. Geisler:Roche: Consultancy; GSK: Consultancy. Hillmen:GlaxoSmithKline: Honoraria, Research Funding. Stilgenbauer:GSK: Honoraria, support Other. Smolej:GSK: Consultancy, Honoraria, travel grants Other. Jaeger:GSK: Honoraria, Research Funding. Leblond:Roche : Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Mundipharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Kimby:Roche: Consultancy, Honoraria, Research Funding; celgene: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria, Research Funding; Emergent BioSolutions: Consultancy, Honoraria, Research Funding; Gilead Sciences: Consultancy, Honoraria, Research Funding; Jansen: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding.

The Mitochondrial Metabolism Inhibitor Cpi-613 in Combination with High Dose Ara-C (HDAC) and Mitoxantrone Is Highly Active in Poor Risk Relapsed or Refractory Acute Myeloid Leukemia (AML)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2556-2556
Author(s):  
Timothy Pardee ◽  
Kristin Pladna ◽  
Scott Isom ◽  
Leslie Renee Ellis ◽  
Dmitriy Berenzon ◽  
...  
Keyword(s):  
Stem Cell ◽  
Median Survival ◽  
Response Rate ◽  
Residual Disease ◽  
Single Agent ◽  
High Dose ◽  
Cell Transplant ◽  
Historical Cohort ◽  
Poor Risk ◽  
Equity Ownership

Abstract Background: CPI-613 is a first in class agent that inhibits pyruvate dehydrogenase (PDH) and α-ketogluterate dehydrogenase. As a single agent CPI-613 was found to be well tolerated with possible activity in several patients with myeloid malignancies.This trial determined the maximum tolerated dose (MTD), safety, and efficacy of CPI-613 in combination with HDAC and mitoxantrone in patients with relapsed or refractory AML. Methods: CPI-613 was given daily on days 1 through 5 starting at a dose of 500 mg/m2. Beginning on day 3, HDAC at 3,000 mg/m2 (or 1,500 mg/m2 for age ≥60) is administered every 12 hours for 5 total doses and mitoxantrone at 6 mg/m2 is given daily for 3 doses. If residual disease is present on day 14 re-induction with the same or a three day abbreviated course could be given. Patients who achieved a complete remission with or without complete count recovery (CR or CRi) could receive up to a total of two additional consolidation cycles with the goal to get responders to stem cell transplant whenever possible. Results: A total of 67 patients have been enrolled and 65 are evaluable. The median age is 60 (range 21-79). Nineteen patients had refractory disease and 14 received at least 1 previous line of salvage therapy. In patients with relapsed disease the median duration of CR1 was 5 months. Cytogenetics were poor risk in 30 patients, intermediate in 30 and good in 6. One patient had CML in myeloid blast crisis. The overall intention to treat response rate was 48% (26CR+5CRi) with a median survival of 6.4 months. In patients ≥60 years old the CR/CRi rate was 42% (15/36). Surprisingly, the response rate for patients with poor risk cytogenetics was 47% (11CR+3CRi) with a median survival of 5.2 months. In a historical cohort treated with HDAC, mitoxantrone and asparaginase at our institution, only 19% (3/16) of patients with poor risk cytogenetics responded with a median survival of 2.8 months. The MTD of CPI-613 in combination with HDAC and mitoxantrone is 2,500 mg/m2. The dose limiting toxicities were diarrhea and nausea. Nine patients (13%) died on or before day 30. The most common toxicities attributed to CPI-613 were diarrhea and nausea, mainly grade 1 or 2. At the time of this submission thirteen patients have gone on to allogeneic stem cell transplantation. Several patients with circulating blasts had blood samples taken before and after CPI-613 infusion. Three of these patients had increased phosphorylation of PDH consistent with its inhibition. Additionally, two patients demonstrated a robust phosphorylation of adenosine monophosphate-activated protein kinase consistent with depletion of ATP. To explore if loss of p53 function (common in poor risk cytogenetics) affected response we tested CPI-613 alone or with an anthracycline against an AML cell line with and without p53 knockdown. Suppression of p53 function resulted in significant resistance to the anthracycline but no change in response to CPI-613; the combination enhanced cell kill over either agent alone. Conclusions: CPI-613 in combination with HDAC and mitoxantrone is a promising salvage regimen, especially in patients with poor risk cytogenetics. Disclosures Pardee: Novartis: Speakers Bureau; Celgene: Speakers Bureau. Off Label Use: CPI-613 is a novel anticancer agent not currently approved by the FDA. Ellis:Alexion: Speakers Bureau. Manuel:Novartis: Speakers Bureau. Hurd:Merck: Equity Ownership; Pfizer: Equity Ownership; Medtronic: Equity Ownership; Procter and Gamble: Equity Ownership; Bristol Myers Squib: Equity Ownership. Powell:Celgene: Speakers Bureau; Cornerstone Pharmaceuticals: Consultancy.

Hematopoietic stem cell transplant (HSCT) versus intensive chemotherapy in infant acute lymphoblastic leukemia (ALL)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 9514-9514 ◽  
Author(s):  
Z. E. Dreyer ◽  
P. Dinndorf ◽  
H. Sather ◽  
J. M. Hilden ◽  
M. Devidas ◽  
...  
Keyword(s):  
Lymphoblastic Leukemia ◽  
Prospective Trial ◽  
Control Group ◽  
P Value ◽  
Cell Transplant ◽  
Statistical Regression ◽  
Hematopoietic Stem ◽  
Dismal Prognosis ◽  
Preparative Regimen ◽  
Intensified Chemotherapy

9514 Background: Infants (<366 days) with ALL and an MLL rearrangement (MLL-R), have a dismal prognosis. Early relapse is common and event free survival (EFS) is poor. The Children's Oncology Group (COG) parallel pilot trials, 1953 and 9407, were designed to prospectively compare early HSCT to intensified chemotherapy in infants with MLL-R ALL. This is the largest prospective trial investigating the role of HSCT in such patients (pts) in first remission (CR-1). Methods: From 1997–2000, 186 pts were registered (132 MLL-R). Both trials were identical through Induction, Induction Intensification and Re-Induction (Re-I), then diverged. Pts with MLL-R ALL with matched/one antigen mismatched - related/unrelated donors were to undergo HSCT (mandated on 1953/optional on 9407) at completion of Re-I. The HSCT regimen was ara-c, cyclophosphamide, steroid and total body irradiation; graft vs. host prophylaxis was cyclosporine. Results: Compliance with protocol mandated conditioning for HSCT was poor and 28/53 HSCT pts received non-protocol preparative regimens. By life table comparisons, the 5 year HSCT EFS was 50.9% (SE=9.9%, RHR 1.13) vs. 48.7% (SE=10.1%) p=0.68 in 47 control pts (chemotherapy-treated, MLL-R), who survived 143 days (median time to HSCT = 143 days). By statistical regression analysis the RHR for HSCT was 1.454 (90% CI 0.911, 2.318), p-value = 0.19, showing a trend in favor of chemotherapy alone. Neither donor source nor preparative regimen affected HSCT outcome. Chemotherapy outcomes were similar on 1953 and 9407. Events for HSCT pts were most common in the first 6 months: 20 events (11 HSCT related deaths/9 relapses). In the control group, 7/9 events in this time period were due to relapse. Conclusion: These results show no advantage for HSCT in CR1 in infants with MLL-R ALL. These data do not support the routine use of HSCT in CR1 in MLL-R infants. No significant financial relationships to disclose.

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