scholarly journals Effectiveness and Security of a Modified CALGB10403 in Adolescents and Young Adults with Acute Lymphoblastic Leukemia in Low-and-Middle-Income Countries: A Multicentric Experience in Central America

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2284-2284
Author(s):  
Juan Rangel-Patiño ◽  
Lee-Tsai Yu Ling ◽  
Victor Itaí Urbalejo Ceniceros ◽  
Maria Elena Monserrat Luna Perez ◽  
Karla Adriana Espinosa ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Central America ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Middle Income ◽  
Middle Income Countries ◽  
Grade 3 ◽  
Poor Outcomes ◽  
Related Mortality

Abstract Background: Mexico and Central America have a high incidence of acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA). Chemotherapy with Hyper-CVAD has been widely used with poor outcomes, with a 3-year overall survival (OS) of 25.7% in this group of age. In low-and middle-income countries (LMIC), limitations in supportive care such as low access to neutrophil stimulant agents, antifungal prophylaxis and limited intensive care access, may increase treatment-related mortality. On the other hand, reports suggest that specific high-risk subgroups may be more frequent in Hispanic patients from Mexico and Central America. We hypothesize that the use of a less-myeloablative regimen, based on L-asparaginase could overcome the bad outcomes previously reported. Methods We modified the original CALGB 10403 based on local drug-access. We include patients with newly diagnosed Philadelphia-negative B- or T-cell ALL between 14-49 years from 4 centers in Mexico and one in Guatemala. We modified the regimen as following: replaced pegaspargase by E. Coli asparaginase, thioguanine by 6-mercapatopurine and incorporate rituximab 375mg/m2 for 6 doses in CD20 positive patients. After the first interim analysis (October 2019), we replaced the prednisone by dexamethasone during induction. Minimal residual disease (MRD) was assessed by flow cytometry after induction and after first consolidation. We considered high-risk karyotype if MLL-rearrangements, complex or hypodiploid and high-white blood cell count (WBC) if >30 x10 3/mcL for B-ALL or >100 x10 3/mcL for T-ALL. The main objective was to evaluate OS and as secondary objectives to evaluate complete response (CR) rate, relapse-free survival (RFS) and to assess the safety of this regimen. Results From January 2017 to December 2020, 95 patients have been enrolled with a median age of 23 years (range 14-49). One third (34.6%) had overweight and 11.7% were obese. The majority (92.6%) had a B-cell ALL and a normal karyotype (81.2%). The median WBC was 18.4 x10 3/mcL (0.2-427.7) and 40.9% had a high-WBC. During induction, adverse events (AE) included grade 3/4 elevated bilirubin (21.1%), transaminases (14.7%), hyperglycemia (14.7%), hypofibrinogenemia (44.2%), thrombosis (10.5%), hypersensitivity (2.2%) and pancreatitis (2.1%). During consolidation, AE included grade 3/4 hepatic toxicity (18.9%), hypertriglyceridemia (14.8%), thrombosis (5.3%) and pancreatitis (2.1%). Neutropenic fever occurred in 55.8% during induction (grade 4: 31.5%), and in 32.9% during consolidation (grade 4/5: 5.3%). A dose adjustment due to AE was required in 22.1% during induction and in 23.2% during consolidation. The induction related-mortality (IRM) rate was 7.4% The CR rate was 87.8%. After-induction, MRD was <0.01% in 39.1%, 0.01-0.1% in 39.1% and > 0.1% in 24.6%. Post-consolidation MRD was only measured in 43 patients and was <0.01% in 37.2%. During follow-up, 26.7% relapsed: 62.5% bone marrow (BM) relapses, 25.0% central nervous system (CNS) relapses and 12.5% CNS + BM relapses. Eight patients (8.4%) received an allogeneic-stem cell transplant (HSCT) as consolidation. The 2-year OS was 72.1%. The post-induction MRD <0.1% was associated with a better OS (figure 1A) (HR: 0.17 (95%CI: 0.06-0.55), p=0.003) and a high-WBC with an inferior OS (figure 1B) (HR: 4.13 (95%CI: 1.68-10.14), p=0.002). The 2-year RFS was 65.2%. The post-induction MRD <0.1% was associate with a better RFS (figure 1C) (HR: 0.19 (95%CI: 0.07-0.50), p=0.001) and a high-WBC and overweight / obesity with an inferior RFS (HR: 4.08 (95%CI: 1.71-9.73), p=0.001 and 2.50 (95%CI: 1.06-5.86), p=0.036 respectively) (figure 1D). Conclusions: The adoption of modified CALGB10403 regimen in Central America based on local resources is feasible. It is associated with a significant improvement in the OS and decrease in IRM when compared with previous reports. Despite a very high-rate of hepatic and metabolic toxicities, these were manageable. As reported by other groups, MRD, high-WBC and overweight/obesity are associated with poor outcomes. Despite being encouraging results, a significant number of patients persist with positive MRD and the main cause of dead is disease progression. Access to cellular therapies, and BiTes is cost restricted in LMIC. Hence, we should generate strategies to intensify treatment in MRD positive patients and expand transplant access to overcome outcomes. Figure 1 Figure 1. Disclosures Rangel-Patiño: Bristol: Consultancy; Abbvie: Speakers Bureau. Ceniceros: Amgen: Speakers Bureau. Espinosa: Amgen: Speakers Bureau; Janssen: Consultancy; Pfizer: Consultancy. Amador: Abbvie: Consultancy, Speakers Bureau; Bristol: Consultancy. Cabrero Garcia: Takeda: Speakers Bureau; Abbvie: Speakers Bureau; Roche: Speakers Bureau; Janssen: Speakers Bureau; Astellas: Consultancy; BD: Speakers Bureau. Inclan-Alarcon: Janssen: Speakers Bureau; Boehringer: Speakers Bureau. Neme Yunes: Janssen: Consultancy, Speakers Bureau; Bristol: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Bristol: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Abbvie: Speakers Bureau. Meillon-García: Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Roche: Speakers Bureau; Astellas: Consultancy. Apodaca: Sanofi: Consultancy; Asofarma: Consultancy, Speakers Bureau; Abbvie: Speakers Bureau. Demichelis: Bristol/Celgene: Consultancy, Speakers Bureau; Astellas: Consultancy; Gilead: Consultancy; ASH: Research Funding; Abbvie: Consultancy, Speakers Bureau; AMGEN: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Jazz: Consultancy.

scholarly journals Pediatric-Inspired Regimens Are Associated with Better Outcomes When Compared with Hypercvad in Hispanic Adolescents and Young Adults with Acute Lymphoblastic Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3877-3877 ◽  
Author(s):  
Roberta Demichelis ◽  
Karla Adriana Espinosa ◽  
Juan Rangel-Patiño ◽  
Emmanuel Almanza ◽  
Ana Cooke
Keyword(s):  
Young Adults ◽  
Prognostic Factors ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
B Cell ◽  
Relapse Rate ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Control Group ◽  
Poor Outcomes

Background Acute lymphoblastic leukemia (ALL) is frequent in Mexico, representing 51% of acute leukemia in adults. Hispanic ethnicity is associated with high-risk features and poor outcomes. We previously reported a multicenter experience in Mexico, where the majority of our ALL-patients (67%) were adolescents and young adults (AYA), mostly treated with HyperCVAD and with poor outcomes: 3-year overall survival (OS) of 25.7%. Many groups have demonstrated better outcomes with pediatric-inspired regimens (PIR) in the AYA-group, with long term OS > 60%. In 2016-2017 we changed the standard of care from HyperCVAD to PIR in two of the centers from the previously mentioned study. Methods We included AYA-patients with the diagnosis of Philadelphia-negative ALL treated with PIR (ALL-BFM 90 or CALGB 10403) between March 2016 and June 2019 in two centers in Mexico City. Both regimens were modified from the original: we used E. Coli asparaginase instead of pegaspargase and mercaptopurine instead of thioguanine. We compared these patients with our common historic database of patients with the same characteristics diagnosed between February 2009 and June 2015, treated with HyperCVAD. Hyperleukocytosis was defined as a white blood cell count > 30 x103/mcL for B-cell ALL and > 100 x103/mcL for T-cell ALL. Patients with t(v;11q23), hypodyploid or complex karyotype were considered high-risk. Baseline characteristics of both groups were compared with Chi-square or Mann-Whitney U test. We estimate OS by Kaplan-Meier method and compared groups by log-rank test. Multivariate Cox proportional hazards regression was used to evaluate independent prognostic factors associated with OS. Results We compared 73 patients treated with PIR with a control group of 137 patients treated with HyperCVAD. The patients treated with PIR received either ALL-BFM 90 (N=46) or CALGB 10403(N=27). The median follow-up was 49.8, 23.3 and 12.7 months for HyperCVAD, ALL-BFM 90 and CALGB 10403 respectively. Patients treated with PIR were slightly older than those in the control group (median 24 vs. 20 years, p=0.005) and presented with high-risk karyotype more frequently (31.9% vs. 12.2%, p=0.042). Most of the patients were B-cell ALL (91.8% for PIR and 95.6% for HyperCVAD; p=0.349). Comparing PIR vs. HyperCVAD, there were no differences in the proportion of patients with hyperleukocytosis (33.3% vs. 25.0%, p=0.128) or obesity (24.7% vs. 16.4%, p=0.192). The induction related mortality was 5.7% for the entire group with a trend that favors PIR (1.4% vs. 8.0%, p=0.061). In patients treated with PIR, the 4-week complete remission (CR) rate was higher (79.5% vs. 64.2%, p=0.027) and the relapse rate was lower (41.5% vs. 60.0%, p=0.027). Patients treated with PIR were more frequently treated with allogeneic stem-cell transplant (alloSCT) in first CR: 19.2% vs. 7.3%, p=0.017. The median OS was significantly higher with PIR than with HyperCVAD, with a median of 19.0 months (3.3-25.4 months) vs. 11.1 months (7.3-14.8 months), and a 18-month OS of 53% vs. 33%, p=0.017. When comparing the two different PIR (ALL-BFM 90 vs. CALGB 10403), the patients treated with ALL-BFM 90 had more frequently high-risk karyotypes (46% vs. 10.5%, p=0.012). Both regimens were associated with similar 4-week CR rate (78.3% vs. 81.5%, p=1). OS was higher with the CALGB 10403 with an 18 month-OS of 79% vs. 42% with the ALL-BFM 90 (p=0.044). When adjusted for high-risk karyotype, the benefit on OS was no longer significant. In the multivariate analysis for OS, the independent significant prognostic factors were: treatment with a PIR (HR 0.428, 95% CI 0.221-0.826, p=0.011), alloSCT in first CR (HR 0.316, 95% CI 0.106-0.938, p=0.038) and high-risk karyotype (HR 2.695 95% CI 1.272-5.560, p=0.009). Discussion Although different groups have shown the benefit of PIR in the AYA-patients, the MD Anderson group couldn´t found any benefit from using the augmented BFM when compared to HyperCVAD. In our experience, the outcomes with HyperCVAD are poor in this group. In this report, the treatment with PIR was associated with a higher CR rate, lower relapse rate and better OS when compared with our historical HyperCVAD in AYA-patients. The benefit on survival was independent of other risk factors or alloHSCT. The main limitation of the study is the comparison with a historical group. However, given the general trend to treat these patients with RIP, a prospective randomized study in this regard is unlikely. Disclosures Demichelis: Abbvie: Speakers Bureau; AMGEN: Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Shire: Speakers Bureau.

scholarly journals Conventional and Flowcytometric Minimal Residual Disease Based Risk Stratified Post Remission Therapy Improves Survival in Ph-Negative Pediatric Acute Lymphoblastic Leukemia- Single Centre Experience from South India

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4119-4119
Author(s):  
Rema Ganapathy ◽  
Aswathy Ashok Beenakumari ◽  
Syamaprasad Vinayakumar ◽  
Remya Sudevan ◽  
Renjitha Bhaskaran ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Risk Stratification ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Treatment Algorithm ◽  
Middle Income ◽  
Middle Income Countries ◽  
Minimal Residual

Abstract Background: Children with Acute Lymphoblastic Leukemia (ALL) in Low Middle income countries(LMIC) face major challenges including treatment abandonment and poor overall survival (OS) and event-free survival (EFS).The preliminary data and results of outcome of Pediatric ALL from our pediatric hematology-oncology center which follows BFM based ALLtreatment protocol has been published in 2015 in ASH forum.Due to non availability of Polymerase chain reaction (PCR)based Minimal residual disease(MRD)analysis, we use multiparametric flowcytometry (FCM) based MRD analysis for remission assessment and risk stratification in our patients. Within resource constraints, we present evidence that outcomes comparable with that seen in high income (HIC)and upper middle income countries(UMIC) can be achieved with a post remission therapy guided by a risk stratification incorporating FCM MRD. Methods: Following IRB approval,an ambidirectional cohort study was performed using clinical information and outcomes of all patients aged 1to 14 years treated for newly diagnosed B- or T-ALL between January 1,2015 and December 31, 2020. AIEOP BFM ALL 2009 protocol with modifications was followed as the institutional protocol in all patients.The treatment algorithm is mentioned in Figure 1. Patients who underwent multiparametric FCM MRD analysis at the end of Induction IA and whose 6 months follow up details were available were included in the analysis. Patients with Ph positive ALL and those who died during Induction IA were excluded. FCM MRD analysis was performed after Induction IA on Day 33.MRD level above 0.01% was considered positive.MRD assessment was repeated following Induction IB on Day 74 in patients who had MRD positivity on Day 33. At the end of Induction IB patients were risk stratified into High risk(HR) and non High risk(Non HR).HR features included Hypodiploidy(<45chromosomes), Positivity for MLL/AF4 or t(4:11),poor prednisolone response(absolute blast count in peripheral blood ≥1 x 10^9/l on Day 8 of initiation of prednisolone) and non remission on Day33. Patients who had persistent MRD positive on Day74 were reallocated to high risk. Treatment with HR protocol was initiated for high risk patients whenever financially manageable.Statistical analysis was done using SPSS version 21 OS and EFS were assessed by Kaplan-Meier method Patients were censored at last follow-up. Results: Median follow-up time was 33.5(4-102) months . Study had 102(n=102) consecutive Ph negative patients who underwent induction therapy. Six patients (5.88%) died during induction IA;96(n=96) children who continued treatment were included in further analysis. The mean age at diagnosis was 6(1-14) years .Forty seven (48.95%)patients were male..B-ALL n=84(87.5%) and T ALL n=12.(12.5%). Four patients(4.16%) had CNS disease at diagnosis. Three children (3.13%) had high risk cytogenetics.Ten children (10.42%)in the cohort had poor prednisolone response. Five patients(5.20%) didnot achieve morphological remission on Day33. Fifteen (15.63%) patients were risk stratified as HR during IA. Four more (4.16%) were reallocated to HR in view of persistent MRD positivity after Induction IB. At median follow-up, the OS was 95.35%±2.65(95% CI 90.16-100.54) and the EFS 94.48%±2.74 (95% CI, 89.11%-99.84%).Female gender predicted better EFS (p=0.042).The EFS of patients without CNS disease at presentation was significantly better(93.5% Vs 23.2% p=0.000). The EFS at median follow up of patients in re HR cohort was 64.19% Vs 97.81% in non HR (p=0.010). EFS by risk stratification is shown in Figure II. Conclusion:Our study suggests that FCM MRD can be successfully incorporated into the treatment algorithm in a resource limited setting. With FCM MRD were able to identify an additional subset of HR patients who otherwise would have been stratified into non HR group. In a prospective cohort , FCM MRD could be tested at an earlier time point in IA induction to facilitate identification of early drug responsive patients with lowest risk of relapse. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Phase I Study of Ixazomib Added to Chemotherapy in the Treatment of Acute Lymphoblastic Leukemia in Older Adults

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 41-42
Author(s):  
Philip C. Amrein ◽  
Karen K. Ballen ◽  
Kristen E. Stevenson ◽  
Traci M. Blonquist ◽  
Andrew M. Brunner ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Lymphoblastic Leukemia ◽  
Complete Remission ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Advisory Committees ◽  
Survival Estimate ◽  
Grade 3 ◽  
Experienced Grade

Introduction: While progress has been made in the treatment of childhood leukemia, the outlook for patients >60 years of age with acute lymphoblastic leukemia (ALL) is poor with complete remission rates (CR) of approximately 60% and 3-year survivals (OS) of less than 15%. Intensified treatment in a later CALGB trial showed little improvement with a CR=61% and 5-year OS=6% (Stock, Cancer 2013). Ixazomib is an oral proteasome inhibitor, which has shown single agent activity and promising combination activity in pediatric ALL patients (Messinger, Blood 2012). We sought to assess the safety and tolerability, as well as early efficacy of adding ixazomib to a current MGH-DFCI/HCC multi-agent regimen for older adults with ALL. Methods: Patients aged 51 to 75 years of age with newly diagnosed B-ALL and T-ALL were screened for eligibility. Patients with mature ALL (including Burkitt's) were excluded. Patients with Philadelphia chromosome positive ALL (BCR-ABL1+) were eligible, and dasatinib was added to the chemotherapy on Day 10 for these patients. The chemotherapy treatment schedule from induction through maintenance is outlined in Table 1. A standard 3 + 3 patient cohort dose escalation design was used to determine the maximum tolerated dose (MTD) of ixazomib during induction for these patients, the primary objective of the trial. After consolidation I, patients in complete remission (CR) with a suitable donor were offered a hematopoietic stem cell transplantation (HSCT) as per institutional guidelines. Those not going to HSCT continued therapy as noted in the table. Results: There were 19 patients with B-ALL enrolled, none with T-ALL. Among these patients, 7 harbored BCR-ABL1 rearrangements. The median age was 65 years, 74% were male, and 90% had a performance status 0 or 1. The MTD was 2.3 mg of ixazomib, as 2 patients at 3.0 mg developed DLT's: a grade 3 peripheral neuropathy and a grade 5 acute kidney injury (Table 2). Grade 3 and 4 toxicities encountered at any time consisted mainly of grade 4 neutropenia in 13 patients and grade 4 thrombocytopenia in 12 patients. One patient experienced grade 3 neutropenia and 5 patients experienced grade 3 thrombocytopenia. Two patients with grade 2 neuropathy did not meet the definition of DLT. Among the 19 patients, 15 (79%, [95% confidence interval (CI), 54-94%]) achieved CR (14) or CRi (1), and 5 patients went on to HSCT. The median follow-up time was 2 years (range, 1-5) for 8 patients remaining alive. The 1-year overall survival estimate was 53% [95% CI, 29-72%], while the 2-year overall survival estimate was 47% [95% CI, 24-67%]. Conclusions: A dose of 2.3 mg of ixazomib in combination with induction chemotherapy among older patients with ALL was well-tolerated and associated with a promising rate of complete remission. Disclosures Amrein: Takeda: Research Funding; AstraZeneca: Consultancy, Research Funding; Amgen: Research Funding. Brunner:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; AstraZeneca: Research Funding; Forty-Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Hobbs:Novartis: Honoraria; Celgene/BMS: Honoraria; Jazz: Honoraria; Constellation: Honoraria, Research Funding; Incyte: Research Funding; Merck: Research Funding; Bayer: Research Funding. Neuberg:Celgene: Research Funding; Pharmacyclics: Research Funding; Madrigak Pharmaceuticals: Current equity holder in publicly-traded company. Fathi:Takeda: Consultancy, Research Funding; Agios: Consultancy, Research Funding; PTC Therapeutics: Consultancy; Amphivena: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Newlink Genetics: Consultancy; Pfizer: Consultancy; Blueprint: Consultancy; Trillium: Consultancy; Kura Oncology: Consultancy; Forty Seven: Consultancy; Jazz: Consultancy; Boston Biomedical: Consultancy; BMS/Celgene: Consultancy, Research Funding; Kite: Consultancy; Trovagene: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Abbvie: Consultancy. OffLabel Disclosure: MLN 9708, ixazomib is FDA approved for multiple myeloma. In this trial it is used to treat acute lymphoblastic leukemia.

scholarly journals Randomized, Parallel Group, Open-Label Bioequivalence Trial of Intramuscular Pegaspargase in Patients With Relapsed Acute Lymphoblastic Leukemia

2020 ◽  
pp. 1009-1016
Author(s):  
Manjunath Nookala Krishnamurthy ◽  
Gaurav Narula ◽  
Khushboo Gandhi ◽  
Ankita Awase ◽  
Ruta Pandit ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Reference Product ◽  
Lymphoblastic Leukemia ◽  
High Price ◽  
Maximum Plasma ◽  
Open Label ◽  
Middle Income ◽  
Middle Income Countries ◽  
Parallel Group ◽  
Low And Middle Income

PURPOSE Pegylated asparaginase is comparatively safer than native asparaginase in the management of acute lymphoblastic leukemia (ALL). However, the high price and nonavailability in low- and middle-income countries limits its use. In 2014, the first generic of pegaspargase (Hamsyl) was approved in India for use as a second-line treatment option for ALL. The aim of this study was to assess whether the generic pegaspargase (the test product) was bioequivalent with the reference product (Oncaspar). PATIENTS AND METHODS This study was an open-label, parallel-group, comparative pharmacokinetic study in pediatric patients with relapsed ALL receiving their first dose (1,000 IU/m2) of pegaspargase administered intramuscularly. Patients were randomly assigned 1-to-1 to either the test or the reference product. The 2 formulations were considered equivalent if the 90% CIs for area under the plasma asparaginase activity–time curve (AUC0-t) geometric mean test-to-reference ratio was within 75% to 133%. RESULTS Twenty-nine patients (6-18 years of age) were enrolled in this study, of whom 24 completed the study criteria and were considered for safety analysis (5 patients were ineligible for the assessment). Three patients were excluded from analysis, because of presence of anti-asparaginase antibodies, leaving 21 patients who were considered for bioequivalence pharmacokinetics data. The point estimate of AUC0-t for the test-to-reference ratio was 95.05 (90% CI, 75.07% to 120.33%). Maximum plasma concentration, trough concentrations (day 14), half-life, volume of distribution, drug clearance, and changes in the asparagine and glutamine levels were not significantly different between products. Adverse events were comparable in both groups. CONCLUSION Generic and reference pegaspargase had equivalent pharmacokinetics with comparable safety. This could be a safe and cost-effective alternative for patients with ALL, especially in low- and middle-income countries.

scholarly journals Omics techniques and biobanks to find new biomarkers for the early detection of acute lymphoblastic leukemia in middle-income countries: a perspective from Mexico

2017 ◽  
Vol 74 (3) ◽  
pp. 227-232
Author(s):  
William Alejandro Aguirre-Guillén ◽  
Tania Angeles-Floriano ◽  
Briceida López-Martínez ◽  
Hortensia Reyes-Morales ◽  
Albert Zlotnik ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Early Detection ◽  
Lymphoblastic Leukemia ◽  
Middle Income ◽  
Middle Income Countries ◽  
New Biomarkers

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 Outcomes after Reinfusion of CD19-Specific Chimeric Antigen Receptor (CAR)-Modified T Cells in Children and Young Adults with Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 474-474
Author(s):  
Regina M. Myers ◽  
Kaitlin Devine ◽  
Yimei Li ◽  
Sophie Lawrence ◽  
Allison Barz Leahy ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Alternative Therapy ◽  
Car T ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Grade 3 ◽  
Relapsed Disease

Abstract Background: CAR-modified T cells targeting CD19 have produced remarkable responses in relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL); however, relapse continues to be a substantial challenge. CD19+ relapses, which account for 33-78% of relapses, are associated with loss of CAR T-cell surveillance due to short persistence. Thus, strategies to improve functional persistence to prevent and treat CD19+ relapsed disease are crucial. Here, we report our experience administering reinfusions of murine or humanized 4-1BB CD19 CAR T cells in an effort to prolong persistence in patients with demonstrated short persistence to mitigate relapse risk, treat CD19+ relapsed disease, and produce responses after nonresponse to initial CAR infusion. Methods: This analysis included patients aged &lt;30 years treated with a murine CD19 CAR construct, either investigational CTL019 (NCT01626495, NCT02906371) or commercial tisagenlecleucel, or a humanized CD19 CAR construct, huCART19 (NCT02374333), who received ≥1 reinfusion of the same CAR product due to: 1) clinical signs of poor persistence within 6 months (mos) of initial infusion, including peripheral B-cell recovery (BCR) or CD19+ hematogones in the bone marrow, 2) new CD19+ minimal residual disease (MRD) or relapse, or 3) nonresponse to initial infusion. The huCART19 trial included patients who had previously received a CAR T cell product (CAR-exposed), whereas all patients reinfused with CTL019/tisagenlecleucel were CAR-naïve at initial infusion. The primary outcome was complete response (CR) at day 28 after reinfusion, defined as complete remission with establishment or maintenance of B-cell aplasia. Secondary outcomes included CRS incidence, cumulative incidence of relapse (CIR) and overall survival (OS). Results: Among 229 CAR-naïve and 33 CAR-exposed patients treated with CD19 CAR between 2012-2020, 81 received ≥1 reinfusion (investigational CTL019, n=44; commercial tisagenlecleucel, n=11; huCART19, n=13 CAR-naïve and n=13 CAR-exposed). In addition, 18 patients received PD-1 blockade after their first (n=11) or subsequent (n=7) reinfusions. Indications for first reinfusion were peripheral BCR (CAR-naïve, n=32; CAR-exposed, n=6), hematogones (CAR-naïve, n=21; CAR-exposed, n=4), CD19+ MRD/relapse (CAR-naïve, n=10, CAR-exposed, n=0), and nonresponse to initial infusion (CAR-naïve, n=5, CAR-exposed, n=3). CRS grade ≥2 (Penn scale) occurred in 19 patients (grade 2, n=13; grade 3, n=4; grade 4, n=2). Grade 3-4 events only occurred in patients with active disease at time of reinfusion. Twenty-two patients had an inpatient admission within 30 days of first reinfusion, of which 7 required intensive care unit admission Among the 63 patients reinfused for relapse prevention, 33 (52%) had a CR at day 28. With a median duration of follow-up of 38 mos, 13 experienced a subsequent relapse (7 CD19+, 4 CD19-, 2 CD19-subset negative), 4 received alternative therapy or allogeneic hematopoietic stem cell transplantation (HSCT) in remission, and 16 remain in remission without further therapy at a median of 39 mos after first reinfusion. The median duration of B-cell aplasia was 8 mos (IQR 2-35) after reinfusion. Of the 30 with no response (NR), 10 had a subsequent CD19+ relapse, 15 received alternative therapy or HSCT, and 5 remain in remission without further therapy at a median of 43 mos after reinfusion. CIR and OS were not statistically significantly different between patients with CR or NR (CIR, p=0.26; OS, p=0.25) (Figure A-B). However, at 24 mos after reinfusion, CIR was 29% (95% CI, 11-44%) for CR compared to 61% (95% CI, 24-80%) for NR; OS was 90% (95% CI, 80-100%) for both groups. Of the 10 patients reinfused for relapse, 5 (50%) had a CR; 2 subsequently experienced a CD19+ relapse, 2 received an HSCT in remission, and 1 remains in remission without further therapy at 18 mos after reinfusion. Of the 8 patients reinfused for nonresponse to initial infusion, 7 were evaluable; none had a CR, and all died at a median of 2.5 mos after reinfusion. Conclusions: Reinfusion of CTL019/tisagenlecleucel or huCART19 is safe, may prolong B-cell aplasia in patients with short CAR persistence and reduce relapse risk, and can induce remissions in patients with CD19+ relapsed disease. Thus, reinfusion may provide an alternative to HSCT for short persistence. However, reinfusion is not effective for patients with nonresponse to initial CAR infusion. Figure 1 Figure 1. Disclosures Callahan: Novartis: Speakers Bureau. Rheingold: Optinose: Other: Spouse's current employment; Pfizer: Research Funding. June: Tmunity, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Current equity holder in publicly-traded company; Novartis: Patents & Royalties; AC Immune, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Consultancy. Grupp: Novartis, Roche, GSK, Humanigen, CBMG, Eureka, and Janssen/JnJ: Consultancy; Novartis, Adaptimmune, TCR2, Cellectis, Juno, Vertex, Allogene and Cabaletta: Other: Study steering committees or scientific advisory boards; Novartis, Kite, Vertex, and Servier: Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Steering committee, Research Funding. Maude: Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Wugen: Consultancy.

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