Potent Efficacy of Combined PI3K/mTOR and JAK or SRC/ABL Inhibition in Philadelphia Chromosome-like Acute Lymphoblastic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 798-798 ◽  
Author(s):  
Sarah K Tasian ◽  
Yong Li ◽  
Feng Shen ◽  
Theresa Ryan ◽  
Tiffaney L Vincent ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Acute Lymphoblastic Leukemia ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Pi3k Pathway ◽  
Vehicle Treatment ◽  
Pathway Inhibition ◽  
Pdx Models ◽  
Phosphoflow Cytometry

Abstract Background. Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is associated with genomic alterations that activate JAK/STAT and PI3K/Akt/mTOR signal transduction and with poor clinical outcomes. Therapeutic disruption of PI3K pathway signaling in Ph-like ALL has been minimally investigated to date, however. We hypothesized that PI3K isoform-selective or dual PI3K pathway protein inhibition would robustly inhibit Ph-like ALL proliferation in vivoand abrogate aberrant signaling. Methods. NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice were engrafted with primary CRLF2/JAK-mutant or ABL/PDGFR-mutant Ph-like ALL specimens (Table 1) and treated with inhibitors of PI3K? (BYL719), PI3K? (idelalisib), PI3K/mTOR (gedatolisib), TORC1/TORC2 (AZD2014) or with vehicle. Treated patient-derived xenograft (PDX) models were assessed for pharmacodynamic inhibition of signal transduction phosphoproteins at 72 hours by phosphoflow cytometry and for residual ALL in murine spleens after 3-4 weeks of inhibitor or vehicle treatment by quantitative flow cytometry. Subsequent studies tested the efficacy of gedatolisib with the JAK1/2 inhibitor ruxolitinib (CRLF2/JAK-mutant models) or gedatolisib with the SRC/ABL inhibitor dasatinib (ABL/PDGFR-mutant models). Table 1. Genomic characteristics of Ph-like ALL specimens utilized for PDX studies. USI Disease status CRLF2/JAK alterations ABL/PDGFR alterations PALTWS D IGH@-CRLF2* PAMDKS D IGH@-CRLF2, JAK2R683G PAMDRM D IGH@-CRLF2,JAK2GPinsR683 ALL121 R IGH@-CRLF2, JAK2R683G ALL4364 R P2RY8-CRLF2, JAK2R683G PAKMVD D JAK1 S646F PAKYEP D BCR-JAK2 PAKKCA D EBF1-PDGFRB PAKVKK D NUP214-ABL1 PANSFD D ETV6-ABL1 USI = unique specimen identifier. D = de novo, R = relapse. * non-Ph-like by prediction analysis of microarrays. Results. All tested PDX models demonstrated inhibition of leukemia proliferation and abrogation of activated signaling with PI3K pathway inhibition. Gedatolisib treatment resulted in near-eradication of leukemia in CRLF2/JAK-mutant models (n=7) with mean 92.2% (range 86.0-99.4%) leukemia reduction vs vehicle treatment (p<0.0001), as well as prolonged animal survival (p<0.005). Gedatolisib also inhibited leukemia proliferation in ABL/PDGFR-mutant models (n=3) with mean 66.9 (range 42.0-87.6) leukemia reduction vs vehicle controls (p<0.0001). BYL719, idelalisib, and AZD2014 monotherapy decreased ALL burden in JAK-mutant models with mean 52.7% (range 27.5-72.9%), 41.6% (range 22.6-53.1%), and 56.3% (range 20.1-88.7%) reduction, respectively. These three inhibitors had variable potency in ABL/PDGFR-mutant models with 39.1% (range 11.4-71.2%) ALL reduction with BYL719, 0.4% (range -25.2-13.9%) reduction with idelalisib, and 14.5% (range -15.5-30.7%) reduction with AZD2014 treatment vs vehicle controls. Leukemias with greatest basal signaling activation measured by phosphoflow cytometry demonstrated greatest leukemia reduction with PI3K pathway inhibition in the treatment studies, suggesting that basal phosphoprotein levels may be predictive biomarkers of response. Given the recently reported efficacy of JAK inhibition in CRLF2/JAK-mutant and SRC/ABL inhibition in ABL/PDGFR-mutant Ph-like ALL PDX models, we hypothesized that dual pathway inhibition would be more effective than monotherapy. Indeed, simultaneous treatment with gedatolisib and ruxolitinib additively or synergistically reduced ALL burden in all tested CRLF2/JAK-mutant models vs gedatolisib or ruxolitinib monotherapy (p<0.001). Similarly, combined gedatolisib and dasatinib treatment induced markedly greater anti-leukemia efficacy in ABL/PDGFR-mutant models vs. either inhibitor alone (p<0.001). Conclusions. PI3K pathway inhibition is a biochemically relevant therapeutic approach for Ph-like ALL. Dual PI3K/mTOR inhibition with gedatolisib monotherapy potently inhibited leukemia proliferation and demonstrated additive or synergistic activity in combination with JAK or SRC/ABL inhibition in JAK-mutant or ABL/PDGFR-mutant Ph-like ALL, respectively. These data provide compelling rationale for testing combinations of signal transduction inhibitors without or with cytotoxic chemotherapy in children and adults with Ph-like ALL. Disclosures Off Label Use:preclinical testing of signal transaction inhibitors in Ph-like ALL models. Teachey:Novartis:Research Funding. Maude:Novartis:Consultancy, Research Funding. Perl:Actinium Pharmaceuticals:Consultancy; Asana Biosciences:Consultancy; Arog Pharmaceuticals:Consultancy; Ambit/Daichi Sankyo:Consultancy; Astellas US Pharma Inc.:Consultancy. Hunger:Sigma Tau:Consultancy; Jazz Pharmaceuticals:Consultancy; Spectrum Pharmaceuticals:Consultancy; Merck:Equity Ownership. Grupp:Novartis:Consultancy, Research Funding.

In Vivo Efficacy of PI3K Pathway Signaling Inhibition for Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2672-2672 ◽  
Author(s):  
Sarah K. Tasian ◽  
Yong Li ◽  
Theresa Ryan ◽  
Tiffaney Vincent ◽  
David T. Teachey ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Mtor Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Pi3k Pathway ◽  
Mtor Inhibition ◽  
Therapeutic Trials

Abstract The Philadelphia chromosome (Ph)-like subtype of B-precursor acute lymphoblastic leukemia (ALL) comprises approximately 15% of high-risk ALL, has a kinase-activated gene expression profile similar to that of BCR-ABL1-rearranged ALL, and is associated with a variety of mutations and gene fusions known or predicted to activate oncogenic signal transduction. Children and adults with Ph-like ALL have a very high risk of relapse and poor survival when treated with conventional chemotherapy. Others and we have previously observed constitutive activation of cytokine receptor signaling in Ph-like ALL, particularly of the JAK/STAT and PI3K/Akt/mTOR pathways (Tasian et al., Blood 2012). Preclinical and early clinical studies of JAK inhibition in childhood ALL are in progress. However, the functional role of aberrant PI3K pathway signaling has not been previously investigated in Ph-like ALL. The clinical efficacy of the mTOR inhibitor rapamycin and its analogues has proven suboptimal in various solid and hematologic malignancies, at least in part due to upregulation of Akt signaling, a known sequela of signal transduction inhibitor (STI) monotherapy and a common resistance mechanism. We hypothesized that newer-generation STIs that target multiple PI3K pathway signaling proteins or that selectively inhibit PI3K isoforms may result in superior inhibition of leukemia proliferation and minimize upregulation of alternate signaling pathways. We used patient-derived xenotransplantation models to determine the effects of PI3K pathway STIs upon NOD-SCID-γ-null (NSG) mice well-engrafted with de novo (n = 3) or relapsed (n = 1) childhood Ph-like ALL specimens with JAK2 mutations and/or CRLF2 alterations (Maude et al., Blood 2012). Specifically, we tested the PI3Kα inhibitor BYL719 (30 mg/kg/day), the PI3Kδ inhibitor CAL101 (idelalisib; 30 mg/kg/day), the PI3K/mTOR inhibitor PKI587 (10 mg/kg/day), and the TORC1/TORC2 inhibitor AZD2014 (20 mg/kg/day) to identify the most efficacious PI3K pathway inhibitor(s). Initial pharmacodynamic studies demonstrated that mice treated with each of the four STIs for 72 hours demonstrated potent in vivo inhibition of relevant phosphoproteins in comparison to vehicle-treated mice as measured by phosphoflow cytometric analyses of gated human ALL cells within murine spleens. In particular, both BYL719 and CAL101 treatments resulted in marked inhibition of phosphorylated (p) PI3K, mTOR, S6, and AktS473 via comparison of median fluorescent intensities for STI- vs. vehicle-treated groups with the Mann-Whitney test (p <0.01 for all phosphoproteins). Increased phosphorylation of other measured proteins was not observed, suggesting that proximal inhibition effectively abrogated aberrant PI3K pathway signal transduction with minimal compensatory signaling upregulation. PKI587 treatment robustly inhibited pS6 and p4EBP1 in comparison to vehicle-treated mice (p = 0.001 and 0.003, respectively), but, surprisingly, had minimal effects upon upstream phosphoproteins. AZD2014 inhibited pS6, p4EBP1, and pAktS473, as well as pERK (p < 0.05 for all phosphoproteins). In longer-term therapeutic trials, TORC1/TORC2 inhibition induced stable disease in xenografted mice treated for 4 weeks in comparison to vehicle controls (p < 0.005), while PI3K/mTOR inhibition robustly decreased leukemic burden below pre-treatment levels in blood, bone marrow, and spleen versus vehicle-treated mice (p < 0.001). These studies demonstrate that PI3K pathway inhibition is an effective and biochemically relevant therapeutic strategy for Ph-like ALL. Pharmacodynamic studies and therapeutic trials of the four PI3K pathway STIs are currently ongoing in additional xenograft models of ALLs expressing various defined genetic lesions to delineate the potential therapeutic range of these compounds. Results from these studies will help to improve our understanding of the critical biologic mechanisms involved in Ph-like ALL and to inform our development of clinical trials to test STI-based therapies in patients with these high-risk leukemias. Disclosures: No relevant conflicts of interest to declare.

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 Pediatric-Inspired Chemotherapy Incorporating Pegaspargase Is Safe and Results in High Rates of MRD Negativity in Adults Ages 18-60 with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4013-4013 ◽  
Author(s):  
Mark Blaine Geyer ◽  
Ellen K. Ritchie ◽  
Arati V. Rao ◽  
M. Isabella Cazacu ◽  
Shreya Vemuri ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Advisory Board ◽  
Lymphoblastic Lymphoma ◽  
Advisory Committees ◽  
Grade 3

Abstract Introduction: Among adolescents and young adults with (w/) acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL), treatment using a pediatric (vs. adult) regimen appears to achieve superior event-free (EFS) and overall survival (OS); this observation has driven increased interest in adapting pediatric regimens for middle-aged adults w/ ALL/LBL. However, greater risk of toxicities associated w/ asparaginase complicates administration of pediatric-inspired regimens in adults. We therefore designed a pediatric-inspired chemotherapy regimen w/ doses of pegaspargase (PEG) rationally synchronized to limit overlapping toxicities w/ other chemotherapeutic agents. Methods: We conducted a phase II multi-center trial in adults ages 18-60 w/ newly-diagnosed Philadelphia chromosome-negative (Ph-) ALL/LBL (NCT01920737). Pts w/ Ph+ ALL or Burkitt-type ALL were ineligible. The treatment regimen consisted of 2-phase induction (I-1, I-2), followed by consolidation w/ 2 courses of alternating high-dose methotrexate-based intensification and reinduction, followed by 3 years of maintenance (Figure 1). PEG 2000 IU/m2 was administered in each of the 6 intensive courses of induction/consolidation at intervals of ≥4 weeks. Minimal residual disease (MRD) was assessed in bone marrow (BM) by multiparameter flow cytometry (FACS) on day (d) 15 of I1 and following I-1 and I-2. Any detectable MRD (even <0.01% of BM WBCs) was considered positive. Toxicities were assessed by CTCAE v4.0. Results: 39 pts were enrolled (30M, 9F), w/ B-ALL (n=28), T-ALL (n=7), B-LBL (n=3), and T-LBL (n=5). Median age at start of treatment was 38.3 years (range 20.2-60.4), w/ 18 pts age 40-60. Grade 3-4 toxicities associated w/ PEG are summarized in Table 1. Grade 3-4 hyperbilirubinemia was observed post-PEG in I-1 in 9 pts, but only recurred thereafter in 1/8 pts resuming PEG. Pts completing consolidation on protocol (n=16) received median of 6 doses of PEG (range, 2-6). Four pts developed hypersensitivity to PEG and subsequently received Erwinia asparaginase. PEG was discontinued in 4 additional pts due to hepatotoxicity (n=2), pancreatitis (n=1), and physician preference (n=1). Of pts w/ available response assessments, 35/36 (97%) achieved morphologic complete response (CR) or CR w/ incomplete hematologic recovery (CRi) following I-1 (n=34) or I-2 (n=1). Both pts not achieving CR/CRi after I-I had early T-precursor ALL; one of these pts was withdrawn from study, and the other (w/ M2 marrow after I-1) achieved CR after I-2. Of the pts w/ ALL (excluding LBL) w/ available BM MRD assessments, 11/28 (39%) achieved undetectable MRD by FACS following I-1; 18/22 (82%) achieved undetectable MRD by FACS following I-2. Of the pts w/ LBL w/ available BM MRD assessments, 7/7 (100%) achieved or maintained undetectable MRD by FACS following I-1 and I-2. Ten pts underwent allogeneic hematopoietic cell transplantation (alloHCT) in CR1. Seven pts experienced relapse at median 15.2 months from start of treatment (range, 5.4-30.4), of whom 6 subsequently underwent 1st (n=5) or 2nd (n=1) alloHCT. Of the 11 pts w/ ALL w/ undetectable MRD following I-1, only one has relapsed. Five patients have died, including 2 pts in CR1 (from sepsis and multi-organ system failure), and 3 pts in relapse. At median follow-up of 22.3 months among surviving pts (range, 1.0-48.1), median EFS and OS (Figure 2A&B) have not been reached (EFS not censored at alloHCT). 3-year EFS was 62.1% (95% CI: 38.4-78.9%) and 3-year OS was 80.0% (95% CI: 57.5-91.4%). Conclusions: PEG can be incorporated into pediatric-inspired chemotherapy regimens w/ manageable toxicity for appropriately selected adults up to age 60 w/ Ph- ALL/LBL. While PEG-related AEs are common, few pts require permanent discontinuation of asparaginase. Grade 3-4 hyperbilirubinemia was common, particularly post-I-1, but recurred infrequently when PEG was continued. Two induction courses resulted in a high rate of MRD negativity post-I-2 and translated to a low rate of relapse. Though further follow-up is required, 3-year EFS is encouraging. Data regarding asparaginase enzyme activity and silent inactivation w/ neutralizing anti-PEG antibody will be presented. Ongoing and future studies will additionally investigate whether incorporating novel therapies (e.g. blinatumomab, nelarabine) into frontline consolidation therapy may reduce risk of relapse among adults receiving PEG-containing regimens. Disclosures Geyer: Dava Oncology: Honoraria. Ritchie:Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; NS Pharma: Research Funding; Incyte: Consultancy, Speakers Bureau; ARIAD Pharmaceuticals: Speakers Bureau; Astellas Pharma: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding. Rao:Kite, a Gilead Company: Employment. Tallman:Daiichi-Sankyo: Other: Advisory board; AROG: Research Funding; Cellerant: Research Funding; AbbVie: Research Funding; BioSight: Other: Advisory board; Orsenix: Other: Advisory board; ADC Therapeutics: Research Funding. Douer:Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Consultancy; Pfizer: Honoraria; Spectrum: Consultancy. Park:Kite Pharma: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; Novartis: Consultancy; Shire: Consultancy; Pfizer: Consultancy; Adaptive Biotechnologies: Consultancy.

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.

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.

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.

Characterization of Fever, Infection, and Cytokine Release Syndrome (CRS) in Adult Patients with Relapsed or Refractory B-Precursor Acute Lymphoblastic Leukemia Treated with Blinatumomab

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2530-2530 ◽  
Author(s):  
Yogin B Patel ◽  
Hagop M. Kantarjian ◽  
Deborah Thomas ◽  
Susan O'Brien ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Research Funding ◽  
Antimicrobial Agents ◽  
Lymphoblastic Leukemia ◽  
Cohort Analysis ◽  
Philadelphia Chromosome ◽  
Confounding Factors ◽  
Single Temperature ◽  
Culture Positive ◽  
Culture Negative

Abstract Background: Infections are a significant cause for morbidity and mortality in patients with acute lymphoblastic leukemia (ALL). In this population, fever remains the best clinical indicator of infection. Fever is also the hallmark clinical sign of CRS. Blinatumomab is a novel bispecific T-cell engaging immunomodulatory antibody recently approved for relapsed refractory Philadelphia Chromosome negative ALL. Infections can occur in approximately 25% of patients receiving blinatumomab, and it also has a black-box warning for CRS. Given that fever can indicate both infection and/or CRS, here we aim to characterize and describe the incidence of fever and relevant clinical outcomes that can occur with blinatumomab treatment. Methods: Patients treated with blinatumomab at our institution from February 2012 to February 2015 were included in this single-center retrospective cohort analysis. Only patients who received a complete cycle of blinatumomab were included in this study. Baseline characteristics including age, gender, and number of prior therapies were collected. Fever was defined as a single temperature ≥38.3°C at any point during the treatment cycle. Culture data, radiographic imaging, antimicrobial therapy and progress notes were reviewed to determine incidence of neutropenia, febrile neutropenia (FN), culture positive FN, culture negative FN with high clinical suspicion for infection, CRS, and culture positive FN in addition to CRS. Results: A total 40 patients completed 72 cycles of blinatumomab during the study period. The patient population was mostly male (73%) with a median age of 29 years (range: 19-76) and had received a median of 3 prior therapies. Fever occurred in 68% (n=27) of all patients during the first cycle, and it occurred in 54% (n=39) of all cycles. Fever during the first cycle was associated with response [Complete Response (CR), CR with incomplete blood count recovery (CRi)] to blinatumomab - 50% (n=20) of patients with fever had response compared to 30% (n=12) of patients without fever and no response (p<0.001). Culture positive infections were noted in 31% (n=22) of all cycles. A small proportion of cycles, 14% (n=10), had an active or incompletely treated infection immediately prior to the start of therapy. After adjustment for confounding factors (i.e., infection at baseline, contaminate cultures, asymptomatic bacteruria), the culture positive rate was 18% (n=13). Neutropenia, FN, and CRS was observed in 60% (n=43), 42% (n=30), and 36% (n=26) of cycles, respectively. Non-neutropenic fever occurred in 13% (n=9) of the cycles. Of those with FN, 50% (n=15) were culture positive, 3% (n=1) were culture negative with high suspicion for infection and after adjustment for confounding factors, the culture positive FN rate decreased to 33% (n=10). FN in addition to CRS occurred in 25% of cycles (n=18); 28% (n=5) of these cycles were culture positive but after adjustment for confounding factors, this rate decreased to 17% (n=3). Conclusions: The current analysis indicates that with blinatumomab about half of the cycles commonly experience fever and that FN remains a concern. Interestingly, high rates of culture positive FN were observed; however, after adjustment for confounding factors this rate decreased to rates comparable to those observed with other hematologic therapies. In this setting clinicians should continue to treat FN with broad-spectrum antimicrobial agents. Furthermore, patients with FN in addition to CRS receiving blinatumomab have low culture positive rates, which suggests that fever may be related to CRS as opposed to FN. While more research is needed, our data also demonstrates that fever correlates with response to blinatumomab. Disclosures Cortes: Pfizer: Consultancy, Research Funding; ARIAD Pharmaceuticals Inc.: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Teva: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding.

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.

scholarly journals A Comprehensive Cancer Center Experience with Hyper-CVAD Plus Ponatinib As Frontline Therapy for Adult Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4394-4394
Author(s):  
Tamer Othman ◽  
Benjamin Moskoff ◽  
Matthew Tenold ◽  
Tali Azenkot ◽  
Margaret Krackeler ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Bacterial Infection ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Blast Crisis ◽  
Philadelphia Chromosome ◽  
Mixed Phenotype ◽  
Philadelphia Chromosome Positive

Abstract Background Ponatinib, a third-generation BCR-ABL1 tyrosine kinase inhibitor (TKI), + hyper-CVAD showed remarkable activity against Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), and may be superior to chemotherapy + earlier generation TKIs in terms of depth of remission, event-free survival (EFS), and overall survival (OS). However, this regimen's efficacy and tolerability have yet to be externally validated. Here, we summarize our real-world experience with ponatinib + hyper-CVAD for untreated Ph+ ALL and other Ph+ acute or blast phase leukemias. Methods We retrospectively analyzed all adults treated at the University of California, Davis (UCD) from March 2012 to May 2021 with ponatinib + hyper-CVAD upfront. The primary endpoints were 3-year OS and EFS. Secondary endpoints were complete molecular response (CMR), measurable residual disease (MRD) negativity by multiparameter flow cytometry (MFC), complete cytogenetic response (CCyR) rates, and adverse events (AEs). Time to event analyses were done via the Kaplan-Meier method. Patients alive were censored at their last follow-up date. Patients undergoing allogeneic hematopoietic cell transplant (HCT) after 6 months of achieving complete remission (CR) were censored at the time of HCT for the landmark analysis. Patients with missing data were excluded from the response analyses. Results We identified 13 Ph+ ALL patients who received ponatinib + hyper-CVAD for initial induction. The baseline characteristics for the Ph+ ALL patients are summarized in Table 1. The median follow-up was 16 months. The median number of hyper-CVAD cycles completed was 8 (range, 1-8) with ponatinib. Two patients proceeded to HCT in CR1, one at 3.5 months after starting induction, and due to difficulty controlling the patient's concurrent multiple myeloma prior to HCT and recovery from anti-neoplastic therapy, the second was delayed to 46 months after starting induction. The 3-year OS and EFS with ponatinib + hyper-CVAD were each 92% (95% confidence interval, 78.9-100) (Figure 1). Landmark analysis completed 6 months following CR showed a 3-year OS of 100% in patients treated with ponatinib + hyper-CVAD without HCT in first CR (CR1). The CMR, CCyR, and MRD-negativity by MFC rates with ponatinib were all 92.3% (12/13). The median time to CMR, CCyR, and MRD-negativity by MFC were 51 days, 22 days, and 53 days, respectively. Notable AEs with ponatinib include neutropenic fever (92%), bacterial infection (69%), transaminitis (38%), venous thromboembolism (31%), invasive fungal infection (15%), hemorrhage (15%), cerebrovascular accident (CVA) (15%), and tumor lysis syndrome (8%). One patient died during induction with ponatinib due to a bacterial infection. Two patients switched to a different TKI due to a CVA after 4 and 24 months. Only 2 patients did not complete 8 cycles of hyper-CVAD, due to death during induction (n=1) and proceeding to HCT after 3 cycles (n=1). As for similar Ph+ leukemias, 3 chronic myeloid leukemia with lymphoid blast crisis (CML-LBC), 1 CML with mixed phenotype blast crisis (CML-MPBC), and 1 with mixed phenotype acute leukemia (MPAL) were treated with ponatinib + hyper-CVAD. The MPAL patient achieved CMR within 55 days, while the CML-MPBC and 2 CML-LBC patients achieved CMR after HCT. The third CML-LBC patient is in CR with ongoing treatment. After median follow-up of 25 months, all 5 were alive, and only the MPAL patient relapsed 28 months after starting treatment and 1 year after HCT. Conclusion To our knowledge, this is the first report externally validating the efficacy and tolerability of ponatinib + hyper-CVAD for Ph+ ALL. We also show the feasibility of using this regimen in patients with Ph+ CML-LBC, CML-MPBC and MPAL. Despite the small sample size and retrospective nature, our study supports existing data demonstrating that this regimen challenges both the designation of Ph+ ALL as a high-risk disease and the trend to transplant in CR1. Our findings support that ponatinib + hyper-CVAD should be considered a standard of care for Ph+ ALL. Figure 1 Figure 1. Disclosures Kaesberg: Incyte: Speakers Bureau. Rosenberg: Takeda, Janssen: Speakers Bureau. Abedi: BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Speakers Bureau; Seattle Genetics: Speakers Bureau. Tuscano: Genentech, Pharamcyclics, Abbvie, BMS, Acrotech, Seattle Genetics, Takeda: Research Funding. Jonas: AbbVie, BMS, Genentech, GlycoMimetics, Jazz, Pfizer, Takeda, Treadwell: Consultancy; 47, AbbVie, Accelerated Medical Diagnostics, Amgen, AROG, Celgene, Daiichi Sankyo, F. Hoffmann-La Roche, Forma, Genentech/Roche, Gilead, GlycoMimetics, Hanmi, Immune-Onc, Incyte, Jazz, Loxo Oncology, Pfizer, Pharmacyclics, Sigma Tau, Treadwell: Research Funding; AbbVie: Other: Travel reimbursement. OffLabel Disclosure: Ponatinib is approved for Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy. In this study, we described outcomes with ponatinib in combination with hyperCVAD in the frontline setting, which is off-label.

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