scholarly journals A Phase 2 Study of Ruxolitinib with Chemotherapy in Children with Philadelphia Chromosome-like Acute Lymphoblastic Leukemia (INCB18424-269/AALL1521): Dose-Finding Results from the Part 1 Safety Phase

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 555-555 ◽  
Author(s):  
Sarah K. Tasian ◽  
Albert Assad ◽  
Deborah S Hunter ◽  
Yining Du ◽  
Mignon L. Loh
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Induction Chemotherapy ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Phase 2 Study ◽  
Multi Agent

Abstract Background: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype occurring in 15-30% of older children and adolescents/young adults (AYAs) with B-ALL. Ph-like ALL is associated with high relapse rates and poor survival despite intensive multi-agent cytotoxic chemotherapy. Development of successful treatment strategies to decrease relapse and improve cure rates in patients with Ph-like ALL remains a major therapeutic gap. Rearrangements of cytokine receptor-like factor 2 (CRLF2-R) with frequent concomitant JAK2 point mutations occur in 50% of Ph-like ALL cases and induce constitutive JAK/STAT and other kinase signaling. An additional 15-20% of Ph-like ALL harbors other JAK pathway alterations, such as JAK2 or EPOR rearrangements, that similarly activate JAK/STAT signaling. Ruxolitinib is a potent, selective JAK1/JAK2 inhibitor with demonstrated activity in preclinical Ph-like ALL models and clinical safety as monotherapy in children with relapsed/refractory cancers. We report the initial safety of ruxolitinib in combination with post-induction chemotherapy in children and AYAs with newly-diagnosed high-risk (HR) Ph-like ALL with CRLF2-R or other JAK pathway alterations treated on the non-randomized, 2-part phase 2 study INCB18424-269 (AALL1521; NCT02723994). Methods: Patients aged 1-21 years at time of diagnosis with HR B-ALL and eligible Ph-like genetic lesions who had completed 4-drug induction chemotherapy as per the Children's Oncology Group (COG) AALL1131 study (NCT02883049) were eligible to participate. Patients were stratified into 4 cohorts by genetic alterations and end-induction flow cytometric minimal residual disease (MRD) status: cohort A = CRLF2-R JAK-mutant, MRD+; B = CRLF2-R JAK-wild-type, MRD+; C = other JAK pathway alterations, MRD+, D = any CRLF2-R or JAK pathway alteration, MRD-. Patients commenced treatment on the INCB18424-269/AALL1521 study at consolidation with ruxolitinib orally twice daily in combination with augmented Berlin-Frankfurt-Münster (aBFM) post-induction chemotherapy as per AALL1131. Five discontinuous dose levels (10-50 mg/m2/dose 14-days-on/14-days-off per cycle [DL-2 to DL2]) and one continuous DL1b (40 mg/m2/dose × 28 days per cycle) of ruxolitinib with aBFM chemotherapy were explored via a standard rolling 6 design. Dose-limiting toxicities (DLTs) were assessed through Day 29 of delayed intensification (DI) and defined as hematologic and non-hematologic toxicity with higher grade or more prolonged duration than observed in children with treated with identical chemotherapy (without ruxolitinib) on other COG HR B-ALL trials. Pharmacokinetic (PK) and pharmacodynamic (PD) analyses were conducted using serial blood samples obtained from patients during consolidation therapy. Results: Forty patients (pts) were enrolled in Part 1 (cohort A, n=10; B, n=9; C, n=5; D, n=16). Four patients discontinued study treatment before the Day 29 DI timepoint, 3 of whom were replaced. Patients had a median age of 14 years, and 67.5% were male. Treatment-emergent adverse events occurred in all patients and included anemia (75%), platelet count decrease and/or thrombocytopenia (65%), febrile neutropenia (72.5%), and AST or ALT increase (57.5%). Thirty-three patients had Grade 3/4 events deemed possibly related to ruxolitinib without identified DLTs. Eleven patients in Part 1 (27.5%) discontinued study therapy for various reasons: CNS relapse (2 pts), end-consolidation MRD+ (4 pts), multi-system organ dysfunction (MSOD; 2 pts), elective MRD- stem cell transplantation (1 pt), psychosocial/compliance issues (2 pts). One patient died of septic shock and MSOD not attributed to ruxolitinib. Preliminary analysis of plasma drug levels at 4 hours post-dose was consistent with the known PK profile of ruxolitinib. PD studies demonstrated dose-dependent inhibition of target phosphoproteins and, importantly, sustained inhibition of phosphorylated STAT5 with continuous ruxolitinib dosing at DL1b. Discussion: These findings demonstrate safety and tolerability of ruxolitinib in combination with intensive multi-agent chemotherapy in children and AYAs with newly-diagnosed HR CRLF2-R/JAK pathway-mutant Ph-like ALL and support continued investigation of treatment efficacy in Part 2 of this trial. Disclosures Tasian: Aleta Biopharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Research Funding; Incyte Corporation: Research Funding. Assad:Incyte Corporation: Employment, Equity Ownership. Hunter:Incyte Corporation: Employment. Du:Incyte Corporation: Employment.

scholarly journals Marqibo®, Vincristine Sulfate Liposome Injection, for the Treatment of Advanced, Relapsed or Refractory Philadelphia Chromosome-Negative (Ph-) Acute Lymphoblastic Leukemia (ALL) in an Adolescent Young Adult (AYA) Population

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1291-1291 ◽  
Author(s):  
Gary J Schiller ◽  
Lloyd E. Damon ◽  
Wendy Stock ◽  
Steven E Coutre ◽  
Pamela Hsu ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Young Adult ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Adult Population ◽  
Philadelphia Chromosome ◽  
Phase 2 ◽  
Vincristine Sulfate ◽  
Phase 2 Study ◽  
The Us

Abstract Background: Patients aged 15 to 39 years old constitute the Adolescent Young Adult (AYA) population. In the US, leukemias represent ~6% of all cancers in this population with the incidence of Acute Lymphoblastic Leukemia (ALL) gradually decreasing with age as the incidence of acute and chronic myeloid leukemias (AML, CML, respectively) increase; ALL occurs at approximately twice the rate of AML in 15- to 19-year olds. Further studies are needed to define the unique features of leukemia in AYA patients, and to better assess and optimize treatment regimens. Marqibo®, vincristine sulfate liposome injection, uses a novel sphingomyelin and cholesterol nanoparticle that facilitates vincristine dose intensification without exacerbation of its toxicity, i.e., it has a wider therapeutic index than standard formulation vincristine. This formulation has also been shown to enhance the penetration and concentration of vincristine into tumors, and prolong plasma circulation time in non-clinical experiments. Marqibo is approved in the US for the treatment of adult patients with Philadelphia chromosome negative (Ph-) ALL in second or greater relapse, whose disease has progressed following two or more previous lines of therapy. We performed a retrospective analysis of data from the Phase 2 RALLY clinical trial (n=65) to examine the effects of Marqibo in the subgroup of the AYA population. The Phase 2 study results of the entire study demonstrated that treatment with single-agent Marqibo resulted in an Overall Response Rate (ORR) of 35%, with 20% of patients achieving a Complete Response (CR) or CR with Incomplete Blood Count Recovery (CRi) (O'Brien, S., 2012 J Clin Oncol). Methods: Data from the RALLY Phase 2 study of Marqibo were analyzed retrospectively to examine only the relapsed or refractory Ph- ALL patients 39 years of age and younger (n=44). In this study, Marqibo (2.25mg/m2) was administered via IV over 60 minutes without dose capping, once per week until response, progression, toxicity or hematopoietic transplant. Results: The median age of the 44 patients was 27 (range: 19-39), 57% were male, 82% had B-cell ALL and 18% had T-cell ALL. 84% had ECOG performance status of 0 or 1. The number of previous treatments ranged from 2-6. 41% had 2 prior lines of treatment, 41% had 3 prior lines of treatment, 16% had 4 prior lines of treatment and 2% had 6 prior lines of treatment. In addition, 59% of patients had previously received a hematopoietic cell transplant. The ORR in the AYA population was 39%, with 25% of patients achieving a CR or CRi. Overall, the safety profile of Marqibo was similar to that in the older adult population, with 35 (79.5%) patients having a treatment-related adverse event, of any grade, on study. The most common treatment-related adverse events, of any grade, in the AYA population were constipation (34%) and peripheral neuropathy (32%). Conclusions: Marqibo (vincristine sulfate liposome injection) was shown to have clinical benefit in AYA patients with relapsed or refractory Ph- ALL with similar safety and efficacy profiles compared to the entire adult population (range: 19-83). Disclosures Schiller: Sunesis: Honoraria, Research Funding. Damon:Atara: Consultancy; Sunesis: Research Funding; McGraw Hill: Other: Chapter Royalties; Sigms Tau: Research Funding. Stock:Gilead: Membership on an entity's Board of Directors or advisory committees. Coutre:Pharmacyclics: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Douer:Gilead: Consultancy.

scholarly journals Pegaspargase Can Safely be Administered in Adults Age 40 and Older with Acute Lymphoblastic Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3816-3816 ◽  
Author(s):  
Ryan J. Daley ◽  
Sridevi Rajeeve ◽  
Charlene C. Kabel ◽  
Jeremy J. Pappacena ◽  
Sarah E. Stump ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Hypersensitivity Reactions ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Frontline Treatment

Introduction: Asparaginase (ASP) has demonstrated a survival benefit in pediatric patients (pts) with acute lymphoblastic leukemia (ALL) and is now part of standard-of-care frontline treatment. As a result, asparaginase preparations have been incorporated into the treatment of adult ALL to improve outcomes. Pegaspargase (PEG-ASP), a modified version of asparaginase with prolonged asparagine depletion, appears to be safe in adults up to age 40 (Stock, et al., Blood, 2019), but is associated with a unique spectrum of toxicities, the risks of which appear to increase with age. Therefore, the safety of PEG-ASP remains a significant concern in older adults w/ ALL. Methods: We conducted a single center retrospective chart review of pts age ≥40 years who received PEG-ASP as part of frontline induction/consolidation or reinduction, between March 2008 and June 2018 at Memorial Sloan Kettering Cancer Center. The primary objective was to evaluate the tolerability and toxicity of PEG-ASP based on the incidence and severity of ASP-related toxicities (hypersensitivity reactions, hypertriglyceridemia, hyperbilirubinemia, transaminitis, pancreatitis, hypofibrinogenemia, etc) according to the Common Terminology Criteria for Adverse Events, version 4.03. Laboratory values recorded were either the peak or the nadir, the more appropriate for toxicity assessment, within a 4-week period following PEG-ASP administration. Secondary objectives were to determine the total number of doses of PEG-ASP administered in comparison to the number of doses intended, and to characterize the rationale for PEG-ASP discontinuation when applicable. Fisher's exact test was used to compare the incidence of PEG-ASP toxicities with respect to pt and treatment characteristics (regimen, age, BMI, gender, Philadelphia chromosome positive (Ph+) vs. Ph-, presence of extramedullary disease, PEG-ASP dose). P values were not adjusted for multiple comparisons. Results: We identified 60 pts with ALL (40 B-ALL and 20 T-ALL) who received at least one dose of PEG-ASP. Nine pts were Ph+. The median pt age at initiation of the treatment was 53, (range, 40 to 80), and 19 pts had a BMI ≥30 kg/m2. Forty-four pts received treatment for newly diagnosed ALL, and 16 pts for relapsed disease. Table 1 lists pt baseline characteristics. Among the 44 pts with newly diagnosed ALL, 27 pts received PEG-ASP as part of pediatric or pediatric-inspired regimens at doses of 2000 - 2500 units/m2, and 1 pt received a modified dose of 1000 units/m2 due to age. The remaining 16 pts received PEG-ASP at doses of 1000 - 2000 units/m2 for consolidation, per established adult regimens (ALL-2 and L-20; Lamanna, et al., Cancer, 2013). Grade 3/4 ASP-related toxicities with a >10% incidence included: hyperbilirubinemia, transaminitis, hypoalbuminemia, hyperglycemia, hypofibrinogenemia, and hypertriglyceridemia. Frontline treatment regimens in which PEG-ASP was used in consolidation cycles only (ALL-2, L-20) were associated w/ a lower incidence of hyperbilirubinemia (p=0.009) and hypertriglyceridemia (p<0.001) compared to those regimens that included PEG-ASP during induction (pediatric/pediatric-inspired regimens) (Table 2). Younger age (40-59 vs. ≥60 years) was associated with a greater risk of hypertriglyceridemia (p<0.001) and higher PEG-ASP dose (≥2000 vs. <2000 units/m2) was associated with a greater risk of hypertriglyceridemia and hypofibrinogenemia (p=0.002 and p=0.025, respectively). Thirty-eight pts (63%) received all intended doses of PEG-ASP. Six pts stopped PEG-ASP to proceed to allogeneic hematopoietic stem cell transplantation (5 in CR1, 1 in CR2), and 7 pts stopped for hypersensitivity reactions. Hepatotoxicity was the only ASP-related toxicity that led to PEG-ASP discontinuation occurring in 5 pts (hyperbilirubinemia, N=4; transaminitis, N=1). The total number of intended doses of PEG-ASP based on regimens used was 186, and 112 were administered. Conclusion: PEG-ASP was incorporated into the treatment of 60 adult ALL pts age ≥40, with manageable toxicity. Seven pts discontinued PEG-ASP due to hypersensitivity reactions and 5 discontinued due to hepatotoxicity, but other reported toxicities did not lead to PEG-ASP discontinuation and the majority of the pts completed all intended doses of PEG-ASP. This study suggests that with careful monitoring, PEG-ASP can safely be administered in adults ≥40 years of age. Disclosures Rajeeve: ASH-HONORS Grant: Research Funding. Tallman:UpToDate: Patents & Royalties; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Biosight: Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees. Geyer:Dava Oncology: Honoraria; Amgen: Research Funding. Park:Takeda: Consultancy; Allogene: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Autolus: Consultancy; GSK: Consultancy; Incyte: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy.

scholarly journals Phase 2 study of pembrolizumab for measurable residual disease in adults with acute lymphoblastic leukemia

2020 ◽  
Vol 4 (14) ◽  
pp. 3239-3245
Author(s):  
Ryan D. Cassaday ◽  
Kelsey-Leigh A. Garcia ◽  
Jonathan R. Fromm ◽  
Mary-Elizabeth M. Percival ◽  
Cameron J. Turtle ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Quantitative Polymerase Chain Reaction ◽  
Philadelphia Chromosome ◽  
Stevens Johnson Syndrome ◽  
Phase 2 ◽  
Phase 2 Study ◽  
Measurable Residual Disease

Abstract The presence of measurable residual disease (MRD) in acute lymphoblastic leukemia (ALL) confers a poor prognosis. CD19-targeted immunotherapy is effective against MRD but is logistically challenging, potentially toxic, and not applicable to T-cell ALL. We thus hypothesized that inhibition of PD-1 with pembrolizumab could also be effective for MRD, but without lineage restriction. The primary objective of this phase 2 study was to evaluate the efficacy of pembrolizumab in patients with ALL and MRD. Key eligibility criteria included adults with B- or T-cell ALL and MRD detectable by multiparameter flow cytometry or quantitative polymerase chain reaction from bone marrow aspirate (BMA) despite chemotherapy (plus ABL kinase inhibitor if Philadelphia chromosome positive). Pembrolizumab 200 mg IV was given every 3 weeks. Response was assessed by BMA using methods that previously detected MRD. The primary end point was complete MRD response rate. We stopped enrollment early; only 1 of 12 (8%) experienced a complete MRD response, which lasted 3 weeks. Interestingly, this patient had previously received hematopoietic cell transplantation and CD19-targeted chimeric antigen receptor–modified T-cell therapy and was the only patient to experience an immune-related adverse event from pembrolizumab (grade 3 Stevens-Johnson syndrome). Median overall survival from enrollment was 12.7 months. In summary, pembrolizumab had minimal activity against MRD but was generally well tolerated. These data can be compared with ongoing anti-PD-1 combination studies in ALL, and they further establish the role of trials specifically for patients with MRD. This trial was registered at www.clinicaltrials.gov as #NCT02767934.

Design of the Hallmarq Trial, a Phase 3 Study of Vincristine Sulfate Liposome Injection (VSLI, Marqibo®) in Adults with Newly Diagnosed, Philadelphia Chromosome Negative Acute Lymphoblastic Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4300-4300
Author(s):  
Steven R. Deitcher ◽  
Jeffrey A. Silverman
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Pharmacokinetic Parameters ◽  
Multiple Time ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Phase 3 ◽  
Childhood All ◽  
Free Survival

Abstract Abstract 4300 Background: Adult acute lymphoblastic leukemia (ALL) is a lethal and fulminant disease and one distinct from childhood ALL. There are approximately 2400 new cases per year in the US; approximately 80% of these will be Philadelphia chromosome (Ph) negative. Despite remarkable success in treatment of childhood and adolescent ALL, adult ALL patients are underserved by existing treatment options as reflected by the poor survival rates and extremely poor outcomes in the relapsed setting. Complete response (CR) rates in the front-line setting range from 90% in patients <30 years old to 57% in patients >60 years old and 3-year disease free survival ranges from 47% to 12% respectively. The unmet medical need in adult ALL is most pronounced in those age 60 and older. VSLI was recently granted accelerated FDA approval as a single-agent for the treatment of adults with advanced, relapsed and refractory Ph-negative ALL and has successfully completed a Phase 2 trial as a component of multi-agent therapy. Trial Design: HALLMARQ (NCT01439347) is a Phase 3, multi-national, randomized study to evaluate the substitution of VSLI for standard vincristine (VCR) in the induction, consolidation, and maintenance phases of combination chemotherapy in the treatment of patients ≥ 60 years old with newly diagnosed Ph-negative ALL. The chemotherapy “backbone” utilized in this trial is modified from the Cancer and Leukemia Group B 8811 protocol. Asparaginase product usage is optional. The total duration of protocol-specified therapy is up to 24 months. VCR is dosed at 1.4 mg/m2 with a per dose cap at 2 mg. VSLI is dosed at 2.25 mg/m2without a dose cap. A protocol-specified dose reduction algorithm applicable to both VSLI and VCR will be used to minimize Grade 3 neurotoxicity while also facilitating continued dosing. Growth factors (e.g., granulocyte colony-stimulating factor) and bowel regimens (e.g., daily stool softener) are recommended and will be prescribed according to investigator preference and institutional guidelines. The primary endpoint is overall survival (OS) and the study is powered for superiority. Secondary endpoints include remission rate, overall response rate, event-free survival, and safety and tolerability. Minimal residual disease (MRD) at multiple time points and pharmacokinetic parameters are being assessed. Conclusion: The HALLMARQ Trial will provide new insights into the frontline treatment of ALL in adults ≥60 years old as well as confirm the clinical benefit of VSLI monotherapy demonstrated in the Phase 2 RALLY Study that supported the initial product approval. HALLMARQ is based on a Special Protocol Assessment with the FDA and is currently enrolling. *On behalf of the HALLMARQ investigators. Disclosures: Deitcher: Talon Therapeutics: Employment, Equity Ownership. Silverman:Talon Therapeutics: Employment.

scholarly journals Ultrasensitive Duplex Sequencing of Pretreatment ABL1 Kinase Domain Mutations in Patients with Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1548-1548 ◽  
Author(s):  
Nicholas J Short ◽  
Hagop M. Kantarjian ◽  
Koji Sasaki ◽  
Farhad Ravandi ◽  
Jorge E. Cortes ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Kinase Domain ◽  
Newly Diagnosed ◽  
Resistance Mutations ◽  
Genetics Research ◽  
Duplex Sequencing ◽  
Philadelphia Chromosome Positive

Abstract Background: Kinase domain (KD) mutations in ABL1 are the dominant mechanism of relapse in patients (pts) with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Previous studies in Ph+ ALL have suggested that some pts harbor subclonal T315I mutations prior to tyrosine kinase inhibitor (TKI) treatment. However, nearly all reports have relied upon inherently error prone RT-PCR to generate template cDNA prior to mutation analysis. We hypothesized that conventional assays might over-estimate the incidence of pre-existing resistance mutations, and that improved sequencing accuracy might yield important information for risk stratification and TKI selection. Methods: Duplex sequencing (DS) is a molecular tagging method that improves the accuracy of conventional next-generation sequencing by more than 10,000-fold, by comparing the nucleotide sequences of each strand of double-stranded molecules. ABL1 DS was performed on genomic DNA from 64 pts with newly diagnosed Ph+ ALL treated with hyper-CVAD plus a TKI. DS of exons 4-10 of ABL1 was performed to an average molecular depth of >10,000x. Among pts who relapsed, using RNA extracted from relapse samples, the KD (codons 221 through 500) of the BCR-ABL1 fusion transcript was sequenced by the Sanger method using a nested PCR approach, with a detection limit of 10-20%. Results: The median age of the cohort was 54 years (range, 20-80 years). The TKI used was imatinib in 5 pts, dasatinib in 38 pts, and ponatinib in 21 pts. All pts achieved complete remission, and 12 pts (19%) underwent allogeneic stem cell transplantation in first remission. A total of 115 pretreatment ABL1 KD mutations were detected among 47 pts (73%). The median number of pretreatment ABL1 KD mutations was 2 (range, 0-6 mutations). The median variant allelic frequency (VAF) of the detected somatic mutations was 0.008% (range, 0.004%-0.649%). Five mutations (4%) and 40 mutations (35%) were present at a VAF ≥0.1% and ≥0.01%, respectively. Eleven mutations known to confer resistance to at least one TKI were detected in 7 pts (11%), and included: F317L in 4 pts, E225K in 2 pts, and E225V, L384M, M244V, Q252H and T315I in 1 pt each. Five mutations were detected in ≥1 pretreatment sample (F317L in 4 pts, M244V in 3 pts, and E255K, E459K and V355V in 2 pts each). Of these 7 pts with pretreatment resistance mutations, 5 pts received a TKI known not to be sensitive to the mutation(s); 2 pts who received ponatinib had mutations at least intermediately sensitive to ponatinib (1 pt with F317L and 1 pt with both E255K and M244V mutations). With a median duration of follow-up of 54 months (range, 1-124 months), 18 pts have relapsed. None of the 7 pts with known pretreatment resistance mutations relapsed. There was no difference in the number of pretreatment mutations between pts who relapsed and those who did not (median mutations: 1 [range, 0-4] and 2 [range, 0-6], respectively; P=0.26). Of the 18 pts who relapsed, 14 underwent Sanger sequencing for ABL1 KD mutations at the time of relapse. Clonal resistance mutations were detected at relapse in 9 pts (64% of sequenced samples): T315I in 6 pts, and F317I, V229L and V338G in 1 pt each (all in pts treated with dasatinib, except V338G in pt on imatinib). Relapse mutations were not observed in pretreatment samples in any of the pts. Conclusions: DS identified very low level pretreatment ABL1 KD mutations in a majority of pts with newly diagnosed Ph+ ALL but these appear inconsequential. Ninety percent of mutations identified have not been described as resistance mutations, suggesting that they may be either synonymous or functionally neutral amino acid changes resulting from normal aging. There was no apparent association of these mutations and risk of relapse, even in the minority of cases in which known resistance mutations were detected at baseline. These data suggest that pretreatment testing for ABL1 KD mutations in Ph+ ALL is unlikely to affect treatment decisions. Disclosures Short: Takeda Oncology: Consultancy. Sasaki:Otsuka Pharmaceutical: Honoraria. Ravandi:Jazz: Honoraria; Orsenix: Honoraria; Orsenix: Honoraria; Seattle Genetics: Research Funding; Sunesis: Honoraria; Xencor: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Abbvie: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Macrogenix: Honoraria, Research Funding; Jazz: Honoraria; Abbvie: Research Funding; Xencor: Research Funding; Macrogenix: Honoraria, Research Funding; Sunesis: Honoraria. Cortes:Pfizer: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Arog: Research Funding. Konopleva:Stemline Therapeutics: Research Funding. Radich:TwinStrand Biosciences: Research Funding. Jabbour:Takeda: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Research Funding; Pfizer: Consultancy, Research Funding; Abbvie: Research Funding.

Nilotinib Combined with Multi-Agent Chemotherapy for Adult Patients with Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Interim Results of Korean Adult ALL Working Party Phase 2 Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1517-1517 ◽  
Author(s):  
Dae-Young Kim ◽  
Young Don Joo ◽  
Je-Hwan Lee ◽  
Jung-Hee Lee ◽  
Dong Hwan Kim ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Dose Intensity ◽  
Rt Pcr ◽  
Free Survival ◽  
Phase 2 Study ◽  
Multi Agent ◽  
Grade 3 ◽  
Philadelphia Chromosome Positive

Abstract Abstract 1517 Background: Incorporation of imatinib into classical cytotoxic chemotherapy has improved the response and survival of patients with Philadelphia chromosome-positive (Ph+) adult acute lymphoblastic leukemia (ALL). Nilotinib (Tasigna, Novartis Pharma, Basel, Switzerland), a second-generation tyrosine kinase inhibitor with enhanced in-vitro inhibition of BCR-ABL kinase, showed faster and deeper responses than imatinib among patients with chronic myeloid leukemia. Moreover, less serious gastrointestinal adverse effects of nilotinib may be beneficial to combination with intensive chemotherapy in Ph+ ALL when compared with imatinib. Herein, we report interim results of a prospective single-arm multicenter phase-2 study evaluating the safety and efficacy of nilotinib-combined multi-agent chemotherapy in Ph+ ALL. Methods: Patients aged over 18 years old were eligible if they had newly diagnosed Ph+ ALL, and adequate hepatic/renal/cardiac function. Diagnosis of Ph+ ALL was dependent upon confirmation of t(9;22) with cytogenetics by conventional GTL-band technique, and/or positive molecular analysis with nested RT PCR for detection of BCR-ABL fusion transcripts. Written informed consent was obtained from all patients. All patients received induction treatment consisting of vincristine, daunorubicin, oral prednisolone, and nilotinib. After achieving complete remission (CR), patients received either 5 courses of consolidation followed by 2-year maintenance with 6-mercaptopurine plus methotrexate, or allogeneic hematopoietic cell transplantation (alloHCT) according to the donor availability and his/her general condition. Nilotinib was administered twice a day with a single dose of 400mg (800mg per day) from day8 of induction until the initiation of alloHCT or the end of maintenance therapy. Quantitative RT-PCR assays were performed at the central lab with Light-Cycler Technology at the time of diagnosis, at CR, and every 3 months thereafter. BCR-ABL quantification was expressed relative to the amount of glucose-6-phosphate dehydrogenase (G6PDH) mRNA. The molecular response was defined as complete (MCR) if the BCR-ABL/G6PDH ratio was less than 1×10−6. Toxicity was graded according to National Cancer Institute Common Toxicity Criteria (version 2.0). For interim analysis, outcome was updated as of July 1, 2011. Results: A total of 50 consecutive patients (male: female = 22: 28) were enrolled onto the study between January 2009 and December 2010. The median age was 44.5 (range 18–71) years old. Type of BCR breakpoint was minor (e1a2) in 66% of patients. The median BCR-ABL/G6PDH ratio was 6.09 (bone marrow) and 3.08 (peripheral blood) at the diagnosis. Except five patients who died in aplasia during induction, 45 (90%) patients achieved hematologic remission (HCR), and MCR rate was 54% at the time of HCR. During the whole treatment periods, administration of nilotinib was interrupted 50 times among 30 patients, and dose was reduced among 6 ones. Of 45 patients who achieved HCR, median dose intensity (DI) of nilotinib between day8 and day of confirmation of HCR was 769.2mg (range 160–800), and MCR rates were not different among two subgroups when dichotomized using the median dose intensity (60.9% vs. 59.1%). During the induction, 20% of patients experienced ≥grade 3 jaundice, which were all reversible, and 2% experienced pancreatitis. Thirty three patients underwent alloHCT, 19 with myeloablative and 14 with non-myeloablative conditioning. Incidences of ≥grade 3 acute graft-versus-host disease (GVHD) and extensive chronic GVHD were 9% and 3%, respectively. With a median follow-up of 17.4 months (range, 6.9–29.1), estimated relapse-free survival (RFS), event-free survival (EFS), and overall survival (OS) at 2 years were 71.1%, 49.4%, and 66.2%, respectively. Of 33 patients who underwent alloHCT, 2-year RFS, EFS, and OS rate were 70.5%, 60.0%, and 83.2%, respectively. Achievement of MCR and DI of nilotinib were not associated with outcome. Conclusion: Nilotinib was tolerable in combination with intensive chemotherapy for adult patients with Ph+ ALL, and the outcomes were comparable to previous results based on imatinib combination. Patient recruitment is ongoing currently based on this interim analysis, and the final results are expected in 2014. Disclosures: Off Label Use: Nilotinib is used as 'off-label drug' for Philadelphia chromosome-positive acute lymphoblastic leukemia in this trial. We have achieved the permission for the use of this drug in this clinical trial from the Korean FDA.

Final Report Of Single-Center Study Of Chemotherapy Plus Dasatinib For The Initial Treatment Of Patients With Philadelphia-Chromosome Positive Acute Lymphoblastic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3914-3914
Author(s):  
Farhad Ravandi ◽  
Susan O'Brien ◽  
Rebecca Garris ◽  
Stefan H. Faderl ◽  
Deborah A. Thomas ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
Research Funding ◽  
Stem Cell Transplant ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Allogeneic Stem Cell Transplant

Abstract Background The dual Src and Abl inhibitor dasatinib has significant in vitro kinase inhibition against wild-type and mutant BCR-ABL, and significant clinical activity in patients with imatinib-resistant lymphoid blast phase CML (CML-LB) and Philadelphia-chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). Aim To determine the long-term efficacy of the combination of the hyperCVAD regimen with dasatinib for treating patients with Ph+ ALL. Methods In this phase II trial, patients with newly diagnosed Ph+ ALL received dasatinib 50 mg po bid (or 100 mg daily) for the first 14 days of each of 8 cycles of alternating hyperCVAD and high dose cytarabine and methotrexate (induction/consolidation cycles). After 42 patients, the protocol was amended to give dasatinib 100 mg daily in the first 14 days of the first cycle and then 70 mg daily continuously from the second cycle. Patients in complete remission (CR) continued to receive maintenance dasatinib 50 mg po bid (or 100 mg daily) and vincristine and prednisone monthly for 2 years followed by dasatinib indefinitely. Patients eligible for allogeneic stem cell transplant proceeded to it in first CR. Results 63 patients with untreated Ph+ ALL and 9 patients with 1 or 2 prior cycles of chemotherapy (before Ph+/BCR-ABL+ status was known) have been enrolled in the study from September 2006 to March 2012. Patients have received a median of 6 cycles (range 1-8) of induction/consolidation. Median age is 55 years (range 21 – 80); 46 patients were older than 50 years, Median WBC at diagnosis was 12 x 109/L (range, 0.4 - 658.1 x 109/L). Ten patients had CNS involvement at presentation. All patients are evaluable for assessment of response to induction; 69 (96%) achieved CR after first cycle or were CR at start. 3 patients died before response assessment from infections. 57 of 69 (83%) evaluable patients achieved cytogenetic (CG) CR after 1 cycle; 5 had a major CG response (4 had 5% and one had 15% Ph+), 2 had insufficient metaphases, and 5 are unknown (no CG exam on day 21 marrow). To date, 45 patients (65%) have achieved complete molecular remission (CMR) and another 19 (28%) have achieved a major (but not complete) molecular response (MMR) at a median of 4 weeks from initiation of treatment (range, 2 – 38 weeks). Minimal residual disease assessment by flow cytometry is negative in 65 (94 %) patients at a median of 3 weeks (range, 2-37 weeks). The median time to neutrophil and platelet recovery for cycle 1 is 18 and 22 days and for subsequent cycles is 15 and 20 days. Grade 3 and 4 adverse events have included bleeding (GI, GU, soft tissue and subdural hematomas), pleural effusions, pericardial effusions, reversible rise in creatinine, deep vein thromboses, pulmonary emboli, as well as diarrhea, infections, hypophosphatemia, hypokalemia, hypocalcemia, hyperglycemia, and elevated transaminases. With a median follow up of 48 months in the surviving patients (range 16.5 - 81.5), 36 patients (50%) are alive and 31 (43%) are in CR. Twelve patients have undergone an allogeneic stem cell transplant. Thirty six patients have died [3 at induction, 16 after relapse, 7 post stem cell transplant performed in CR1, and 10 in CR (6 from infections, 1 from unrelated cardiac event, 1 from unrelated cancer, and 2 from an unknown cause)]. The median disease free survival is 31 months (range, 0.3 to 81) and the median overall survival is 44 months (range, 0.2 to 82). Twenty-one patients have relapsed with a median response duration of 16 months (range, 5 - 62) and 16 of them have died. In 6 patients morphological relapse was preceded by flow and molecular relapse. Six relapsed patients had ABL mutations (4 T315I, 1 F359V, and 1 V299L). Conclusion Combination of chemotherapy with dasatinib is effective in achieving long term remissions in patients with newly diagnosed Ph+ ALL. Disclosures: Ravandi: Bristol Myers Squibb: Honoraria, Research Funding. Off Label Use: Use of dasatinib for the frontline therapy of Ph+ ALL. O'Brien:Pharmacyclics: Research Funding. Jabbour:Bristol Myers Squibb: Consultancy, Honoraria. Cortes:Bristol Myers Squibb: Research Funding. Kantarjian:Bristol Myers Squibb: Research Funding.

Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome–positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study

Blood ◽  
2007 ◽  
Vol 110 (7) ◽  
pp. 2309-2315 ◽  
Author(s):  
Oliver Ottmann ◽  
Hervé Dombret ◽  
Giovanni Martinelli ◽  
Bengt Simonsson ◽  
Francois Guilhot ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Kinase Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Study Drug ◽  
Cytogenetic Response ◽  
Phase 2 ◽  
Effective Treatment Option ◽  
Imatinib Resistance ◽  
Phase 2 Study

Patients with Philadelphia (Ph) chromosome–positive acute lymphoblastic leukemia (ALL) have a rapid disease course and a poor prognosis. Dasatinib, a novel, oral, multitargeted kinase inhibitor of BCR-ABL and SRC family kinases, has previously induced responses in patients with imatinib-resistant or -intolerant Ph-positive ALL. We present the interim results of a phase 2 study designed to further assess the efficacy, safety, and tolerability of dasatinib 140 mg in this patient population (n = 36). With a minimum follow-up of 8 months, treatment with dasatinib resulted in substantial hematologic and cytogenetic response rates. Major hematologic responses were achieved in 42% (15/36) of patients, 67% of whom remained progression-free. Complete cytogenetic responses were attained by 58% (21/36) of patients. The presence of BCR-ABL mutations conferring imatinib resistance did not preclude a response to dasatinib. Dasatinib was also tolerable, with 6% (2/36) of patients discontinuing therapy as a result of study-drug toxicity. Most adverse events (AEs) were grade 1 or 2; febrile neutropenia was the most frequent severe AE, but this and other cytopenias were manageable with dose reduction. Dasatinib represents a safe and effective treatment option and an important therapeutic advance for patients with Ph-positive ALL. This trial was registered at www.clinicaltrials.gov as #CA180015.

scholarly journals Phase II Study of Blinatumomab and Concurrent Oral Tyrosine Kinase Inhibitor Therapy As Consolidation and Maintenance Therapy for Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Following Chemotherapy-Sparing Induction

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 45-45
Author(s):  
Mark B. Geyer ◽  
Amber C. King ◽  
Justin C. O'Brien ◽  
Jae H. Park
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Tyrosine Kinase ◽  
Phase Ii ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Phase Ii Study ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Multi Agent ◽  
Philadelphia Chromosome Positive

Background: Combining oral ABL-targeted tyrosine kinase inhibitors (TKIs) with (w/) multi-agent chemotherapy has improved the long-term disease-free survival of adults w/ Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). However, Ph+ ALL occurs more commonly in older adults, and toxicities of multi-agent chemotherapy, including sequelae of prolonged myelosuppression, are amplified in this population. Others have previously reported rates of morphologic complete response (mCR) approaching 100% among adults w/ Ph+ ALL treated w/ corticosteroids (CS) and dasatinib (DAS) alone as induction therapy, but w/ low rates of minimal residual disease (MRD) negativity by flow cytometry (FACS) and BCR-ABL1 PCR (complete molecular response, CMR) and high rates of relapse in the absence of further consolidation. The bispecific T-cell engager blinatumomab (BLIN) has considerable efficacy in clearing MRD in patients (pts) w/ Ph- B-cell ALL. We have previously reported our institutional experience combining ABL TKIs w/ BLIN in pts w/ Ph+ ALL and MRD, including encouraging safety data and high rates of MRD eradication (King/Geyer et al., Leuk Res, 2019). The ongoing D-ALBA study (GIMEMA LAL2116) is also investigating BLIN + DAS consolidation following 12 weeks of induction (prednisone + DAS followed by DAS), w/out protocol-specified maintenance, and has demonstrated preliminary evidence of efficacy (Chiaretti et al., ASH Meeting, 2019). As such, we designed a phase II study of BLIN as part of a chemotherapy sparing strategy in pts w/ Ph+ ALL (BLISSPHALL), introducing BLIN as early as 6 weeks into treatment for pts in morphologic CR, w/ aim of enhancing early MRD negativity and suppressing resistant clones early in disease course. Study design and methods: Our institution is leading a phase II trial of TKI + BLIN consolidation and maintenance in adults w/ newly-diagnosed Ph+ ALL, w/ potential multicenter expansion (NCT04329325). Pts are eligible if they are ≥18 years-old w/ Ph+ ALL confirmed by cytogenetic or molecular studies, ECOG performance status 0-2, w/out prior therapy for ALL beyond CS, hydroxyurea, or intrathecal chemotherapy, w/out known active extramedullary disease and/or CNS-3 disease, and w/ appropriate organ function. See Figure 1: pts will receive a CS pre-phase (days [d] -6 - 0) followed by modified GIMEMA LAL1205 induction (dexamethasone [DEX] 10 mg/m2 [max 24 mg/d], d1-24, tapered off d25-32) + DAS 140 mg/d (dose adjustments or TKI change permitted per protocol) w/ intrathecal methotrexate (IT MTX) d22, 43 and bone marrow (BM) assessments including FACS and BCR-ABL1 PCR. Pts in mCR on d43 (or optional reassessment ≤ 3 weeks later) will be eligible to proceed to consolidation w/ 3 cycles (C) BLIN 28 mcg/d IVCI, d1-28, concurrent w/ TKI, w/ 14d off BLIN between cycles and BM MRD assessment/IT MTX after each cycle. C1 BLIN + TKI is required to begin inpatient x72 hours. TKI is given continuously including between BLIN cycles. Pts in CMR after consolidation may proceed to maintenance (C4-7 BLIN + TKI, 28d off between cycles). Pts may come off study to proceed to hematopoietic cell transplant (HCT) at any point, though it is recommended such pts receive ≥2C of BLIN + TKI. The primary objective is to determine the proportion of evaluable pts achieving CMR by the end of consolidation (≤ 3C BLIN + TKI). Secondary objectives include safety/toxicity of BLIN + DAS, duration of CMR, incidence of relapse, event-free/overall survival. Exploratory objectives include safety/toxicity of non-DAS TKIs + BLIN, defining patterns/mechanisms of resistance to BLIN+TKI (including ABL kinase mutations), and outcomes among pts not undergoing HCT. The trial utilizes a Simon's minimax two-stage design; 20% CMR rate is considered not promising, a 50% CMR rate is considered promising, and probabilities of type I/II error are set at 0.10/0.10. If ≥ 3 of the first 10 pts achieve CMR we will continue enrollment to max 17 pts. If ≥ 6 pts achieve CMR, then BLIN + TKI will be considered promising for further investigation. The investigators are hopeful this study will add to the currently limited prospective data supporting TKI + BLIN consolidation/maintenance for pts w/ Ph+ ALL and efforts to develop chemotherapy-sparing and immunotherapeutic strategies for older pts w/ ALL. Disclosures Geyer: Amgen: Research Funding. King:Abbvie: Other: advisory board. Park:Novartis: Consultancy; Genentech/Roche: Research Funding; Intellia: Consultancy; Artiva: Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics: Research Funding; Takeda: Consultancy, Research Funding; Servier: Consultancy, Research Funding; AstraZeneca: Consultancy; Allogene: Consultancy; Incyte: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Juno Therapeutics: Research Funding; GSK: Consultancy; Autolus: Consultancy, Research Funding; Minverva: Consultancy; Amgen: Consultancy, Research Funding. OffLabel Disclosure: Blinatumomab is not approved to be given in combination with ABL tyrosine kinase inhibitors for treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia.

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