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 Prognostic Factors for Survival after Allogeneic Transplantation in Acute Lymphoblastic Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4597-4597
Author(s):  
Christine Greil ◽  
Monika Engelhardt ◽  
Gabriele Ihorst ◽  
Hartmut Bertz ◽  
Reinhard Marks ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Response Rate ◽  
Lymphoblastic Leukemia ◽  
Research Support ◽  
Significant Difference

Acute lymphoblastic leukemia (ALL) is a heterogeneous disease and treatment guidelines are still evolving. Allogeneic stem cell transplantation (allo-SCT) offers a potentially curative option and is recommended in first relapse and for high-risk patients in first complete remission (CR). Survival after allo-SCT could be substantially improved due to better risk stratification, patient selection and adapted treatment protocols leading to reduced non-relapse mortality (NRM). Prognostic factors for survival after allo-SCT still need to be defined: pheno- and genotype, patients´ age, conditioning regimens and remission status prior to allo-SCT are under discussion. We analyzed the outcome of 180 consecutive ALL patients who received allo-SCT at the Freiburg University Medical Center between 1995 and 2018 with regard to treatment response, survival, adverse reactions, and performed subgroup analyses to identify prognostic factors. The median age in our cohort was 37 years (ys), 19% were older than 55 ys. 27% were diagnosed with Philadelphia (Ph)-positive ALL, 24% with T-ALL. 36% were treated with relapsed/refractory disease. 48% of allo-SCTs were conducted with a HLA-matched, 19% with a HLA-mismatched unrelated and 33% with a related donor. In 61% the conditioning regimen included total body irradiation (TBI). In 48% no minimal residual disease (MRD) was detected prior to allo-SCT, 20% were transplanted in MRD-positive CR. The overall response rate was 86%, with MRD-negativity in 78%. With a median follow up of 10 ys, we observed a median overall survival (OS) of 23 months and a median progression free survival (PFS) of 11 months. The 10ys-OS was 33%, the 10ys-PFS 31%. The cumulative incidence of relapse was 68% at 10 ys, the cumulative incidence of NRM 12%. Acute graft-versus-host disease (GvHD) III-IV° occurred in 17%, severe chronic GvHD in 9%. Survival was significantly better in patients reaching MRD-negative CR before allo-SCT (10ys-OS 48% vs. 19%, p<0.0001; 10ys-PFS 46% vs. 17%, p<0.001) and in thoses receiving TBI (10ys-OS 40% vs. 19%, p<0.01; 10ys-PFS 37% vs. 19%, p<0.001). There was no significant difference in survival between patients younger or older than 55 ys (10ys-OS 37% vs. 21%, p=0.183; 10ys-PFS 34% vs. 21%, p=0.208) and between those diagnosed with T-, Ph-positive or -negative B-ALL (10ys-OS 41% vs. 35% vs. 29%, p=0.298; 10ys-PFS 38% vs. 33%. vs. 27%, p=0.238). Due to lower NRM, survival improved depending on the year of allo-SCT (10ys-OS 1995-2000 22% vs. 2001-2010 32% vs. 2011-2018 n.r., p<0.01; 10ys-PFS 20% vs. 30% vs. n.r., p<0.01). With a very long follow-up and high rate of MRD-assessment, we observed a high response rate and a low rate of severe GvHD. Our data confirm that allo-SCT enables long-term survival in high-risk ALL, suggest that, in certain subgroups, survival may be best in patients transplanted in CR and receiving TBI for conditioning, including the relevant observation that allo-SCT can be performed in carefully selected elderly patients. Disclosures Finke: Medac: Honoraria, Other: research support, Speakers Bureau; Neovii: Honoraria, Other: research support, Speakers Bureau; Riemser: Honoraria, Other: research support, Speakers Bureau. Wäsch:Pfizer: Consultancy; Sanofi: Other: Travel, Research Funding; Celgene: Other: travel, Research Funding; Jazz: Other: travel, Research Funding; Amgen: Consultancy; Gilead: Consultancy; Sanofi: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Amgen: Other: travel, Research Funding; Gilead: Other: travel, Research Funding.

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 &gt;30 x10 3/mcL for B-ALL or &gt;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 &lt;0.01% in 39.1%, 0.01-0.1% in 39.1% and &gt; 0.1% in 24.6%. Post-consolidation MRD was only measured in 43 patients and was &lt;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 &lt;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 &lt;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 Clinical Features and Survival According to Minimal Residual Disease in a Colombian Population Diagnosed with B-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4459-4459
Author(s):  
Angela María Peña ◽  
Sandra Vanesa Rios ◽  
Luis Antonio Salazar ◽  
Manuel Rosales ◽  
Sara Ines Jimenez ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
B Cell ◽  
Research Funding ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Advisory Board ◽  
The Other ◽  
Minimal Residual

Abstract Introduction Acute lymphoblastic leukemia (ALL) is a clonal hematopoietic disorder that originates from B or T lymphoid progenitors and has well validated prognostic and predictive factors that influence outcomes. One of the strongest prognostic factors is the detection of minimal residual disease (MRD) which measures residual cell population after treatment when a morphologic complete response has been achieved. MRD positivity is associated with a higher risk of relapse and poor response to chemo or radiotherapy Objectives The aim of the study was to assess the prognostic impact of post-induction MRD status in a cohort of ALL Colombian patients in terms of relapse-free survival (RFS) and overall survival (OS). Methods This is a retrospective observational study conducted at a Colombian university hospital and included a cohort of ALL patients diagnosed between 2013 and 2020 treatment according to protocol PETHEMA (Spanish Program for Hematology Treatments). MRD was measured with 8-color flow cytometry evaluate on bone marrow. MRD status was classified as negative MRD (NMRD) or positive MRD (PMRD) based on a sensitivity threshold of &lt;0,01% or ≥0,01% leukemic cells, respectively, following to international guides. Demographic and clinical characteristics were analyzed using descriptive statistics. Kaplan-Meier method was used to assess overall RFS and OS. Results A total 128 patients were included. The median age at diagnosis was 34 years (range 0-89 years), 54% were men, 26% were overweight, 22% obese, 6.2% had type 2 DM (T2DM), and most had a ECOG PS of £2 (94%). Most patients (80.5%) had high risk according PETHEMA, B-ALL and were classified as ALL-2 (58%) according to FAB classification with Pre-B cell ALL being the most common phenotype (54.7%). Ph+ ALL was diagnosed in 12% of patients. Most used treatments protocols were PETHEMA-AR and PETHEMA-RI in 43.8% and 11.6% of patients, respectively. Post-induction MRD measurement was available in 98 patients, 36 (36.7%) had NMRD and 62 (63.3%) PMRD. From the 36 patients with NMRD, eight patients (22.2%) received Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT): two of them, were transplanted in first complete remission, one because of high risk and the other one for BCR-ABL positivity. The other six patients received alloHSCT in second remission and all of them relapsed after late consolidations. Finally, alloHSCT was done in 28 patients with PMRD (45.2%). The 12-month OS for patients with NMRD was 68.7% (95%CI 50.5-81.2) compared to 63.7% (95%CI 50.3-74.4) in the ones with PMRD, p=0.375. 12-month RFS was 83.3% (95%CI 61.5-93.4) in patients with NMRD and 90.0% (95%CI 72.1-96.7) in patients with PMRD, p=0.436. (Figure 1). OS was significantly higher for the PMRD patients who underwent AlloHSCT 96.4% (95%CI 77.2-99.4) versus not underwent 36.8% (95%CI 20.6-53.2), HR: 0.39 (95%CI 0.005-0.29) p=0.002 (Figure 2). Conclusion MRD assessment is a strong prognostic in ALL, however it was not associated with significant differences in RFS or OS in this single institution cohort of Colombian patients. Patients with PMRD taken to AlloHSCT had superior OS compared to NMRD that underwent transplant. A small sample size and short follow-up could explain our results. Larger cohorts with extended follow up and with different MRD methods are needed to better understand the role of MRD assessment in minority ALL populations, such as Colombian patients. Figure 1 Figure 1. Disclosures Peña: Amgen: Research Funding. Salazar: Amgen: Research Funding. Sandoval-Sus: BMS: Other: Advisory Board, Speakers Bureau; SeaGen, Janssen, MassiveBio, TG: Other: Advisory Board. Sossa: Amgen: Research Funding.

scholarly journals PI3Kδ Inhibition Enhances Sensitivity of Primary High-Risk Childhood B-Cell Acute Lymphoblastic Leukemia Cells to Glucocorticoid Chemotherapy

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2572-2572
Author(s):  
Jessica A.O. Zimmerman ◽  
Mimi Fang ◽  
Arunkumar Modi ◽  
Adam Dupuy ◽  
Sarah K. Tasian ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Cell Viability ◽  
B Cell ◽  
Peripheral Blood ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Lymphoid Cells ◽  
Cell Acute Lymphoblastic Leukemia

Introduction: Despite excellent 5-year survival for most patients with B-cell acute lymphoblastic leukemia (B-ALL), those with high-risk (HR) B-ALL continue to have inferior outcomes. The prognosis is even worse for patients who respond poorly to chemotherapy, and improvements to current therapy approaches are needed. Glucocorticoids (GCs) are a key component of chemotherapy regimens. Rapid response to GC monotherapy is a well-documented predictor of favorable outcomes, while slow response to GCs correlates with poor outcomes. We hypothesized that enhancing specific GC toxicity to B-ALL cells can improve clinical outcomes for high-risk patients without increasing systemic toxicity. PI3Kδ is a promising target for this purpose. PI3Kδ is a critical component of the B-cell receptor cell-survival pathway; it restrains GC signaling, while GCs repress its expression. PI3Kδ expression is restricted to lymphoid cells, making it an appealing precision target to enhance GC toxicity in lymphoid cells while minimizing risk of increased systemic GC-associated toxicity. We previously demonstrated synergy between dexamethasone (dex) and the FDA-approved isoform-selective PI3Kδ inhibitor idelalisib (idela) in B-ALL cell lines, patient specimens, and patient-derived xenograft models (Kruth et al Blood 2017). In clinical practice, both dex and prednisone (pred) are essential components of childhood ALL chemotherapy. In this study, we sought to elucidate the extent to which idela in combination with dex or pred could induce synergistic killing of HR B-ALL specimens with various genetic backgrounds. Methods: Peripheral blood or bone marrow from patients ages 1-31 years with newly-diagnosed NCI HR or standard-risk (SR) B-ALL at the University of Iowa Stead Family Children's Hospital was obtained after informed consent on an Institutional Review Board-approved research study. Mononuclear cells were isolated from the specimens via Ficoll gradients and cultured in vitro in 384-well plates. Immediately after isolation, cells were treated with serial dilutions of the GCs dex or pred and idela in RPMI1640+10% FBS medium. Cell viability was measured with PrestoBlue (Invitrogen) after 72 hours of treatment. Survival curves were plotted to determine the LD50 of each drug using GraphPad. Dose effects around the LD50 for each drug were analyzed using Compusyn to determine if the drug combination was synergistic (combination index, CI <1), additive (CI=1), or antagonistic (CI >1). Results: As of August 1, 2019, 5 HR B-ALL patient specimens of various genetic alterations have been tested. Two patients were high-risk at diagnosis due to steroid pre-treatment (MAP011) or by NCI risk criteria (age >10 years and/or WBC count >50K/mm3; MAP014). Three patients with initially SR B-ALL were upstaged due to minimal residual disease (MRD) >1% at day 8 in peripheral blood (MAP012) or marrow MRD ≥0.01% at end of induction (MAP009, MAP010). In our in vitro studies, only one sample (MAP014) showed reduced viability with GC alone, while 4 specimens (all except MAP012) responded to idela alone. Most specimens showed a synergistic response to dex or pred in combination with idela with greater reduction in cell viability compared to GC monotherapies. Surprisingly, one specimen (MAP010) had an antagonistic response with pred and idela combination. This near-haploid B-ALL specimen had reduced viability with idela monotherapy, but an antagonistic response with single-agent pred, raising the question of whether GC/idela synergy is influenced by genetic background. Conclusions: In pilot studies, idela sensitized HR B-ALL cells to GC chemotherapy and is a promising strategy for further evaluation in a larger cohort of specimens. Our results highlight the potential impact of genetic heterogeneity within childhood B-ALL upon differential therapeutic responses to standard steroid chemotherapy and demonstrate a potential precision medicine approach to augment GC sensitivity via combination with selective PI3Kδ inhibition. Disclosures Tasian: Gilead Sciences: Research Funding; Aleta Biotherapeutics: Membership on an entity's Board of Directors or advisory committees; Incyte Corportation: Research Funding.

scholarly journals A Modified CALGB-10403 in Hispanic Adolescent and Young Adults with Philadelphia -Negative Acute Lymphoblastic Leukemia: Promising Results Despite a High-Rate of Metabolic and Hepatic Toxicities

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1352-1352
Author(s):  
Juan Rangel-Patiño ◽  
Alvaro Cabrero Garcia ◽  
Carolina Balderas-Delgado ◽  
Lauro Fabian Amador ◽  
Yvette Neme Yunes ◽  
...  
Keyword(s):  
Overall Survival ◽  
Young Adults ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cell ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
High Rate ◽  
Related Mortality

Background: Acute lymphoblastic leukemia (ALL) represents 51% of acute leukemias in adults in Mexico. Poor outcomes have been reported, with a 3-year overall survival (OS) of 25.7% in the group of adolescents and young adults (AYA). In ALL, Hispanic ethnicity has been associated with more high-risk features and more treatment-related toxicity. Recently the results of the pediatric-inspired regimen CALGB 10403 in AYA ALL-patients have been published with encouraging results. We modified the original regimen based on the drug-access in Mexico and we incorporate Rituximab in CD20 positive patients. Methods We included patients with newly diagnosed B- or T-cell ALL between 17 and 45 years. Patients with Philadelphia chromosome-ALL were excluded. We enrolled patients from 4 centers in Mexico. We replicated the CALGB 10403 protocol, with the following modifications: replaced pegaspargase (2,500 IU/m2) with E. Coli asparaginase (6,000 IU/m2/day for 6 doses in alternate days). During the delayed intensification we replaced thioguanine 60mg/m2/day with 6-mercapatopurine 60mg/m2/day. We incorporated rituximab 375mg/m2 at D1 and D29 during remission consolidation, D1 and D21 in interim maintenance and D1, D29 and D50 in delayed intensification. The central nervous system (CNS) prophylaxis was given as a triple-drug (methotrexate 12.5mg, cytarabine 60mg and dexamethasone 8mg), with a total of 11 intratecal administrations, 7 during the induction/consolidation courses and 4 during maintenance. Minimal residual disease (MRD) was assessed by flow cytometry after induction and after first consolidation. The aims of this study were to evaluate complete response (CR) rate, progression-free survival (PFS), overall survival (OS), and to assess the safety of this regimen. Result From January 2017 to May 2019 thirty-eight patients (23 men, 15 women) have been enrolled. Median follow-up is 11 months (range 1-30). Median age is 23 years (range 18-41). The 100% of patients are of Hispanic ethnicity. Obesity (BMI≥30) was reported in 18%. Thirty patients had an evaluable karyotype: 83% were normal, and 13% with MLL-rearrangements. The majority were B-cell ALL (90%), and 10% were T-cell ALL. Median WBC was 19.5 x103/mcL (range: 0.7-427.7) and 32% had hyperleukocytosis. Among the B-cell ALL patients, 53% were CD20 positive. CNS disease was presented at diagnosis in only one patient (3%). Thirty-three patients (86%) achieved CR, thirty (81%) after the first induction and three after the extended induction therapy. There was only one death during induction therapy (2.6%). After induction, 41% had negative MRD (&lt;0.01%). Grade 3 /4 hepatic toxicity was reported in 58% patients, hyperglycemia in 24% and hypertriglyceridemia in 34%. The rest of toxicities are summarized in Table 1. During induction ten patients (19%) required dose adjustment because of toxicity. During consolidation, 42% required treatment modifications because of toxicity. After induction, we had no treatment-related mortality. At the last follow-up twenty-three patients continue in the protocol. Four patients already received Allo-SCT. The relapse-rate is 31.2% with half of these patients with CNS-disease at relapse. Nine patients have died: one during induction, six with progression or refractory disease and one after Allo-SCT. The 18-months PFS and OS rates were 80% and 84%, respectively. Median PFS is 23 months (CI 95% 17 to 29 months), and median OS was not been reached. Negative-MRD after induction was associated with excellent outcomes: 18-months OS 100% vs. 45.3%, p=0.008 (figure 1). Obesity was associated with worse OS (18-month 22% vs. 80%, p=0.03) and PFS (22% vs. 79.1%, p=0.026) Conclusion: Mexican patients treated with a modified CALGB 10403 protocol had similar response rates than reported in the original protocol but with more toxicity, mainly hepatic and metabolic. However, induction-related mortality was low and we had no treatment-related toxicity after induction. We presume that the high-rate of toxicities can be related with the genetic and environmental metabolic risk factors plenty described in our population. The modified CALGB showed encouraging results in this Hispanic population, hence we have to explore lower dose schedule based in patient characteristics and asparaginase levels. Disclosures Neme Yunes: Abbvie: Speakers Bureau; Janssen: Speakers Bureau; Novartis: Speakers Bureau. Demichelis:Abbvie: Speakers Bureau; Celgene: Speakers Bureau; AMGEN: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Shire: Speakers Bureau.

scholarly journals Identification and Validation of Serum Autoantibodies in Children with B-cell Acute Lymphoblastic Leukemia by Serological Proteome Analysis

2021 ◽  
Author(s):  
Runhong Yu ◽  
Shiwei Yang ◽  
Yufeng Liu ◽  
Zunmin Zhu
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Western Blot ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Immunohistochemical Analysis ◽  
Enzyme Linked Immunosorbent Assay ◽  
Control Group ◽  
Healthy Children ◽  
Expression Levels ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Purpose: Study was by intention to screen serum autoantibodies that may contribute to the early detection of B-cell acute lymphoblastic leukemia (B-ALL) in children.Patients and methods: The total protein from three pooled B-ALL cell lines(NALM-6, REH and BALL-1 cells) was separated using two-dimensional gel electrophoresis(2-DE), which was followed by Western blot by mixed serum from B-ALL patients (n=20) or healthy children(n=20). We obtained and analyzed the images of 2-D gel and Western blot by PDQuest software,and then identify the spots of immune responses in B-ALL samples compared with those in control samples.The proteins from spots were identified using mass spectrometry (MS). The autoantibodies against α-enolase and voltage-dependent anion-selective channel protein 1(VDAC1) were further validated on the use of enzyme-linked immunosorbent assay(ELISA). The protein expression levels of the candidate antigens α-enolase and VDAC1 in B-ALL were thoroughly studied by immunohistochemical analysis.Results: Six protein dots were identified with MS as Aconitase,apoptosis-inducing factor(AIF),dihydrolipoamide dehydrogenase(DLD), α-enolase,medium-chain acyl-CoA dehydrogenase(MCAD) and VDAC 1.The frequencies of autoantibodies against α-enolase and VDAC1 in children with B-ALL were 27% and 23%, respectively, which were significantly higher than those in normal controls(4% and 0). Immunohistochemical analysis showed the expression of α-enolase and VDAC1 was positive in 95% and 85% of B-ALL patients, respectively, but negative expression levels were showed in the control group. Conclusion: This study incidates that α-enolase and VDAC1 may be the antigen associated with B-ALL .α-enolase and VDAC1 autoantibodies may develop into potential serological markers of B-ALL in children.Other proteins also need to be confirmed in a large number of serum samples.

scholarly journals Inotuzumab Ozogamicin Is an Effective Salvage Therapy in Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia with High-Risk Molecular Features, Including TP53 Loss

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3888-3888 ◽  
Author(s):  
Xiaochuan Yang ◽  
Amber C. King ◽  
Charlene C. Kabel ◽  
Christopher J. Forlenza ◽  
Jae H. Park ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
B Cell ◽  
Response Rate ◽  
Lymphoblastic Leukemia ◽  
Advisory Board ◽  
Inotuzumab Ozogamicin ◽  
Ras Mutations ◽  
Molecular Features ◽  
Cell Acute Lymphoblastic Leukemia

Introduction: Adults with (w/) B-cell acute lymphoblastic leukemia (B-ALL) exhibit high rates of complete response (CR) to induction chemotherapy, but relapse is common. Inotuzumab ozogamicin (IO), an antibody-drug conjugate targeting CD22, achieves high rates of CR in patients (pts) w/ relapsed/refractory (R/R) B-ALL and is FDA-approved for R/R B-ALL in adults. It remains unknown whether cytogenetic and molecular features associated w/ decreased response rate and poor prognosis following conventional chemotherapy are associated w/ response to IO. As such, we investigated the relationship between several high-risk genetic alterations and outcome following IO treatment in pts w/ R/R B-ALL. Methods: We reviewed electronic medical records of pts of all ages w/ R/R B-ALL or chronic myeloid leukemia in lymphoid blast phase (CML-LBP) receiving IO at Memorial Sloan Kettering Cancer Center (MSK) between January 2011 and April 2019. The primary objective was to assess whether recurrent cytogenetic or molecular features were associated w/ achievement of CR or CR w/ incomplete hematologic recovery (CRi), w/ or w/o measurable residual disease (MRD), and disease-free (DFS) and overall survival (OS) following IO. Secondary objectives included association of baseline clinical features, including central nervous system (CNS) or other extramedullary (EM) disease, w/ outcomes post-IO. MRD was defined as any unequivocal evidence of B-ALL detectable by RT-PCR (Ph+ ALL) or flow cytometry (FACS). Genomic alterations were defined by MSK IMPACT-Heme (Cheng, J Mol Diagn, 2015), FoundationOne Heme, or similar platforms. A set of selected high-risk (HR) features in Philadelphia chromosome-negative (Ph-) B-ALL was defined prior to the analysis (HR: mutations/loss of TP53, IKZF1/3, CDKN2A, CREBBP; activating RAS mutations; "Ph-like" profile). DFS and OS were computed using Kaplan-Meier methods and compared between groups using log-tank tests. Results: 32 pts (13F, 19M) w/ R/R B-ALL (n=31) or CML-LBP (n=1) treated w/ IO were identified. IO was given as monotherapy in 27 pts and w/ other systemic therapy in 5 pts (mini-hyper-CVD-like regimen, n=4; ponatinib, n=1). Median age at start of IO was 45 years (range 3-78). 10 pts had undergone prior allogeneic hematopoietic cell transplantation (alloHCT). Seven and 15 pts had a history of CNS disease or other EM involvement by B-ALL, respectively, including 3 and 6 pts immediately prior to IO, respectively. Pts received a median 3 lines of salvage prior to IO, including prior CD19-targeted immunotherapy (blinatumomab and/or CAR-T cells) in 24 pts(Table 1). Among 27 pts w/ Ph- B-ALL, 12 had the selected HR features (Table 2). Five pts had Ph+ ALL (n=4) or CML-LBP (n=1) and 5/5 harbored ABL1 kinase domain point mutations (4/5 w/ T315I mutation). 22 pts had at least one successful molecular profiling panel.29 patients had initial cytogenetic studies, of whom 28 patients had evaluable karyotypes. 23 pts had best response to IO of CR/CRi (MRD-, n=15; MRD+, n=8). 9 pts had no objective response to ≥1 cycle of IO. Of the 12 Ph- pts w/ selected HR mutations, 11 achieved CR/CRi. Notably, 6/6 pts w/ TP53 mutation/deletion and 5/5 pts w/ IKZF1/3 mutations (3/3 pts w/ both TP53 & IKZF mutations) achieved CR/CRi. Both pts w/ Ras mutations and 2/3 w/ Ph-like B-ALL achieved CR/CRi. 7/11 HR responders underwent alloHCT post-IO (3 had undergone pre-IO alloHCT). Pts w/ Ph- B-ALL w/ HR mutations demonstrated similar CR/CRi rate and OS to pts w/ Ph- B-ALL w/o defined HR mutations (Fig 1A-B). In contrast, only 1/5 pts w/ Ph+ ALL achieved CR/CRi (was MRD+) and 4/5 showed persistent B-ALL. OS was superior among pts w/ Ph- vs Ph+ B-ALL post-IO (8.0 vs 1.9 months, p=0.0068, Fig 1C). Among pts w/ EM disease immediately prior to IO, 3/6 achieved CR/CRi, including CR in 1 pt w/ a cardiac mass. Median DFS was 3.2 months vs. not reached following achievement of MRD+ vs MRD- CR, respectively (p=ns, Fig 1D). Conclusions: HR molecular features associated w/ poor response to chemotherapy were not associated w/ inferior response rate and overall prognosis following IO in this small series. Notably, pts w/ Ph+ ALL (all w/ ABL1 mutations) exhibited suboptimal response, possibly as pts received IO only in advanced disease states following TKI failure. This small report supports investigation of IO in frontline therapy for pts w/ B-ALL w/ HR mutations to spare unnecessary toxicities of chemotherapy and bridge successfully to alloHCT. Disclosures King: Genentech: Other: Advisory Board ; Astrazeneca: Other: Advisory board; Incyte: Other: Advisory Board. Park:Allogene: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Autolus: Consultancy; GSK: Consultancy; Incyte: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; Takeda: Consultancy. Geyer:Dava Oncology: Honoraria; Amgen: Research Funding. OffLabel Disclosure: Inotuzumab ozogamicin is not FDA approved for pediatric patients with relapsed/refractory B-cell acute lymphoblastic leukemia.

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