scholarly journals Superior Survival Outcome of Blinatumomab Compared to Mitoxantrone-Etoposide-Cytarabine Salvage for Adult Patients with Relapsed or Refractory B-Cell Precursor Acute Lymphoblastic Leukemia: A Propensity Score-Matched Cohort Analysis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2309-2309
Author(s):  
Jae-Ho Yoon ◽  
Gi June Min ◽  
Sung-Soo Park ◽  
Silvia Park ◽  
Sung-Eun Lee ◽  
...  
Keyword(s):  
Propensity Score ◽  
Board Of Directors ◽  
Lymphoblastic Leukemia ◽  
Cohort Analysis ◽  
Matched Cohort ◽  
Cell Precursor ◽  
Advisory Committees ◽  
Allogeneic Hct ◽  
Advanced Line ◽  
Related Mortality

Abstract Background: Complete remission (CR) rate and long-term overall survival (OS) is very poor in patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (R/R BCP-ALL). Previous clinical trials revealed a good remission rate and a safe bridging role to allogeneic-HCT compared to various standard treatments, and several real-world data have been reported. Aim: Here, we analyzed outcome of blinatumomab versus our conventional intensive chemotherapy by propensity score-matched analysis. Methods: From 2009 to 2020, 197 consecutive R/R BCP-ALL were treated with mitoxantrone-etoposide-cytarabine (MEC, n=113) or blinatumomab (n=84), and allogeneic-HCT was planned in patients with CR. For propensity score-matching, the MEC and blinatumomab cohorts were matched in a 1:1 ratio using 5 criteria of age < 35 years old, short CR duration < 12 months, adverse-risk karyotype including Ph-chromosome at relapse, previous allogeneic-HCT, and first-line salvage or not. We compared CR rate, regiment related mortality, and OS with cumulative incidence of relapse (CIR) and non-relapse mortality (NRM). Results: Matched cohort consisted of 52 patients for each salvage group and matched criteria were the same exactly. Median age was 42 years and 34 (65.4%) patients were > 35 years old. There were 22 (42.3%) primary refractoriness, 9 (17.3%) post-chemotherapy relapse and 21 (40.4%) post-HCT relapse. Among 30 relapsed patients, 19 (63.3%) were early relapse with CR duration less than 12 months. There were 25 (48.1%) with poor-risk karyotype at relapse of which 10 were Philadelphia-chromosome. Extramedullary relapse was observed in 14 (26.9%) and 8 (15.4%) were advanced-line salvage. CR rate was significantly higher in blinatumomab (78.8% vs. 53.8%, p=0.012) and more patients proceeded to allo-HCT (80.8% vs. 46.2%, p<0.001). Regimen-related mortality was significantly higher in MEC (40.4% vs. 1.9%, p<0.001). After median follow-up of 32.5 months (range 6.2 to 131.2), 3-year OS of blinatumomab and MEC was 33.2% and 15.4% (p<0.001), and 3-year NRM was 30.3% and 51.9% (p=0.004), respectively. After CR achievement, CIR was not significantly different (46.9% vs. 60.0%). In multivariate analysis, CR duration < 12 months was related with poor OS with high CIR. MEC regimen showed poor OS with high NRM. High NRM was also related with advanced-line salvage. Conclusion: Our matched cohort analysis clearly showed that blinatumomab is superior to MEC salvage regimen. However, we are observing relapse in up to 50% after blinatumomab and following allo-HCT still shows high NRM. Further combinatorial using novel therapeutics are needed for R/R BCP-ALL. Figure 1 Figure 1. Disclosures Kim: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AIMS Biosciense: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AML-Hub: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; BMS & Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boryung Pharm Co.: Consultancy; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Consultancy, Honoraria; LG Chem: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria; Pintherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Honoraria, Speakers Bureau; SL VaxiGen: Consultancy, Honoraria; VigenCell: Consultancy, Honoraria. Lee: Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Early MRD-Negativity May Predict for Favorable Outcome Irrespective of Allotransplantation in TKI-Treated Patients with Ph-Positive Acute Lymphoblastic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1598-1598
Author(s):  
Helena Hohtari ◽  
Marjatta Sinisalo ◽  
Tapio Nousiainen ◽  
Perttu Koskenvesa ◽  
Ulla Wartiovaara-Kautto ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Causes Of Death ◽  
Lymphoblastic Leukemia ◽  
Advisory Committees ◽  
Term Survival ◽  
Educational Grant ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract Introduction Tyrosine kinase inhibitors (TKIs) such asimatiniband dasatinib have markedly improved treatment results in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Almost all patients achieve at least a complete hematological remission with induction therapy consisting of TKImonotherapyor TKI in combination with reduced-intensity chemotherapy and corticosteroids. In eligible patients, allogeneic hematopoietic stem cell transplantation (alloHSCT) has been recommended in first complete remission, but its role inpatientsachieving rapid and deep molecular remissions with TKI-driven therapy is unresolved. Methods We analyzed data fromPh+ ALL patients in the Finnish Hematological Registry (FHR), a population-based database maintained by the Finnish Hematology Association, which includes patients participating in clinical study protocols sponsored by theTheFinnish Leukemia Group, and patients treated outside of clinical trials. The FHR contains detailed information on baseline (demographics, laboratory values,cytogenetics, molecular assays) and follow-up (therapies given and outcome). Minimal residual disease (MRD) was evaluated by standardized RQ-PCR for the bone marrow BCR-ABL1 transcripts with a minimum sensitivity of 10e-5. Therapy responses were coded according to the EuropeanLeukemiaNetguidelines. Data from 128Ph+ALLpatients diagnosed between 1983-2016 were included in the analyses. Survival outcomes were calculated with the Kaplan-Meier method and compared with the log-rank test. Differences between groups were evaluated with the independent samples t-test for parametric numeric variables. Results Of the 128 patients included in the analyses, 78 patients (61%) had received TKI treatment and 50 patients were treated prior the TKI era. The TKIs used wereimatiniband dasatinib and majority of patients concurrently received combination chemotherapy for induction and consolidation. Of the patients not treated with TKIs, 19/50 (38%) received an allotransplant and the overall survival (OS) at 5 years was 58% in the allotransplanted vs. 3% in thenontransplantedpatients (P<0.001). Of the patients treated with TKIs, 45/78 (58%) patients received analloHSCT. The mean age in thealloHSCTgroup was 41 years and in the non-alloHSCTgroup 62 years. OS at 5 years was better in thealloHSCTgroup (62% vs. 48%, P=0.004), but when analyzing causes of death, more deaths due to causes other than leukemia or its treatment were observed in the non-alloHSCTpatients (21% vs. 0 %), related to the competing causes of death in this older group of patients. In addition, there was more treatment-related mortality inalloHSCTpatients (22% vs. 6%). Relapse-free survival did not differ between transplanted and non-transplanted patients at 5 years (73 % vs. 57 %, P=0.42; Figure top panel). In TKI-treated patients, a trend for better OS was observed in patients who were MRD-negative at 3 months (Figure bottom panel). Discussion Our data indicate that up to 50% of patients withPh+ALLexperience long-term survival with TKI-driven therapy and noalloHSCT. However, robust predictive biomarkers are needed for selecting patients in whom the treatment-related mortality and morbidity ofalloHSCTare not warranted and could be treated with TKI-driven therapies only. MRD-negativity at 3 months may select for better outcome, but larger studies are needed for confirmation. In addition, disease-specific genomic andtranscriptomicprofiles (e.g. IKZF1, CDKN2 mutations) andimmunoreconstitutionmay prove valuable in this context. The advent of novel potent MRD-eradicating agents, such asbispecificCD3/CD19 antibodies, may further indicate re-evaluation of the role ofalloHSCTinPh+ALL. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Mustjoki: Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Ariad: Research Funding. Säily:Celgene: Other: Educational grant for congress participation; Amgen: Other: Educational grant for congress participation. Remes:Teva: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees. Porkka:Celgene: Research Funding.

scholarly journals Multi-Institution Review of Adult Early T-Cell Precursor Acute Lymphoblastic Leukemia/Lymphoma (ETP-ALL)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3715-3715 ◽  
Author(s):  
Bijal D. Shah ◽  
Uma Borate ◽  
Vamsi K Kota ◽  
Ling Zhang ◽  
Deniz Peker ◽  
...  
Keyword(s):  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Demographic Data ◽  
Bone Marrow Involvement ◽  
P Value ◽  
Allogeneic Transplant ◽  
Cell Precursor ◽  
Advisory Committees

Abstract Background: The Early T-cell precursor (ETP) variant of acute lymphoblastic lymphoma/leukemia (ALL) is a recognized high risk variant, recognized by the absence of CD1a, with aberrant myeloid antigen expression (CD13, CD33, CD117, and CD34), and frequent absence of CD4 or CD8. Treatment intensification may improve outcome in this subset. We undertook a multi-center retrospective analysis to explore clinical features, treatment exposure, and outcomes in ETP ALL as compared to non-ETP variants. Methods Adult T-ALL/T-LBL cases were compiled from 3 high volume cancer centers between the years 2003-2015. Data collected included patient demographics, tumor characteristics (white count at diagnosis, flow cytometry, FISH, cytogenetics, bone marrow involvement), treatment regimens and patient outcomes. ETP cases were defined as definite (CD1a-/CD8-/myeloid+) or probable (CD1a unk/CD8-/myeloid+, or CD1a-/myeloid+ with CD4+ and/or CD8+). All other cases were defined as non-ETP. Demographic data were compared using independent t-test assuming non-equal variance. OS and PFS were calculated from diagnosis and compared by Kaplan Meier and log-rank testing. Results Among 95 cases, 33 met criteria for definite/probable ETP (35%). OS and PFS data were indistinguishable between these groups (p=0.24, p=0.34), and were subsequently analyzed as a single group. Within the ETP group, no factors were associated with OS, including histology (CD1a+ vs unk, CD3cyt vs CD3sur, CD5dim vs CD5+, CD1a+/13+ vs CD1a+/13-, or CD13, CD33, CD117, CD34, & TdT status), marrow blast burden, peripheral blast burden, white blood cell count (wbc), hemoglobin (hgb), platelet count (plt), cytogenetics/FISH status, chemotherapy choice, or allogeneic transplant (in CR1 or at any time). With regards to PFS, only the inclusion of asparaginase with induction was associated with outcome (p=0.009), while all other covariates failed to show any significance. The ETP group was compared with the non-ETP subset (table 1). ETP were more likely to abuse marijuana, possibly reflecting unrecognized pesticide exposure, and were more likely to abnormalities of chrom 5 & 7. ETP trended towards lower response and higher rate of relapse, with lower PFS. Comparison of OS was not significant, likely related to small numbers (5y OS 37% vs 22%, figure 1). Non-ETP failed to show PFS benefit with frontline asparaginase, otherwise no treatment differences were apparent. Conclusions In this muti-center cohort we were able to identify and characterize ETP cases, confirming poor outcomes. Improvement in PFS among ETP patients treated with frontline asparaginase warrants attention and prospective confirmation. Unfortunately, OS remains poor independent of treatment or receipt of allogeneic transplant, suggesting a critical need remains for development and study novel therapies. Table 1. ETP Non-ETP p-value Median Age 37.45 34.74 0.42 Male 82% 66% 0.89 FamilyHx of Lymph/Leuk 21% 8% 0.112 FamilyHx of Ca 42% 25% 0.09 THC 24% 5% 0.021 P blasts 40% 28% 0.158 >25% M blasts 30% 55% 0.0571 WBC 78.45 76.55 0.948 wbc>100 24% 24% 0.995 Hgb 10.72 11.78 0.148 hgb<12 67% 47% 0.097 plt 151.59 138.66 0.644 Chrom 5/7 40% 7% 0.005 Remission 61% 79% 0.096 Relapse 76% 58% 0.073 OS 27.00 22.00 0.595 PFS 13.00 17.00 0.048 PFS Asp ETP (asp no vs yes) 12 59 0.009 non-ETP (asp no vs yes) 17 15 0.777 Figure 1. Figure 1. Disclosures Shah: Acetylon: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PLexus Communications: Honoraria; Pharmacyclics: Speakers Bureau; Rosetta Genomics: Research Funding; Seattle Genetics: Research Funding. Kota:Pfizer: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Research Funding. Hathaway:OnQ Health: Research Funding.

scholarly journals A Phase II Study of Dasatinib and Dexamethasone As Primary Therapy Followed By Hematopoietic Cell Transplantation for Adults with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: CALGB Study 10701 (Alliance)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2782-2782 ◽  
Author(s):  
Matthew J. Wieduwilt ◽  
Jun Yin ◽  
Meir Wetzler ◽  
Geoffrey L. Uy ◽  
Bayard L Powell ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Advisory Committees ◽  
Allogeneic Hct ◽  
Cns Prophylaxis ◽  
Autologous Hct

Abstract Background: Potent inhibitors of BCR-ABL1have improved remission results and altered post-remission therapy for Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Dasatinib plus dexamethasone followed by hematopoietic cell transplantation (HCT) promises high response rates, reduced toxicity, and durable remissions. Methods: We conducted a Phase II trial at 17 U.S. centers with the primary objective being to estimate the 3-year overall survival and disease-free survival of patients with Ph+ ALL treated with dasatinib and dexamethasone for remission induction and intensification, central nervous system (CNS) prophylaxis, consolidation with reduced-intensity conditioning (RIC) allogeneic HCT, autologous HCT, or etoposide and cytarabine, and dasatinib-based maintenance. Eligible patients had untreated Ph+ ALL, were ≥18 years old, and had normal cardiac function. Induction (Course I) used dasatinib 140 mg oral daily and dexamethasone 10 mg/m2/day oral or intravenous (IV) days 1-7. For patients with ≤20% blasts in the Course I, Day 15 bone marrow biopsy, intensification (course II) continued daily dasatinib with another 7 days of dexamethasone. Those with >20% lymphoblasts also received vincristine (VCR) and daunorubicin (DNR). Patients (n=3) not in CR/CRi after Course II received a second induction (Course III) with dasatinib, cyclophosphamide, VCR, DNR, and dexamethasone. After Course II or III, CNS prophylaxis (Course IV) consisted of IV VCR and IV, oral, and intrathecal methotrexate (MTX). Dasatinib was restarted at serum [MTX] <0.05 microM. Course V consisted of HCT or chemotherapy. Patients aged 18-70 years with an HLA-matched donor underwent RIC allogeneic HCT; otherwise they underwent autologous HCT. Allogeneic HCT conditioning used fludarabine 30 mg/m2/day IV day -7 through -3, alemtuzumab 20 mg/day IV day -7 through -3, and melphalan 140 mg/m2 once on day -2. GVHD prophylaxis with tacrolimus began day -2. Patients undergoing autologous HCT received etoposide 10 mg/kg/day (age >65 years, 5 mg/kg/day) continuous IV for 4 days and cytarabine 2 g/m2 (age >65 years, 1 g/m2) IV every 12 hours for 8 doses (EA) then G-CSF for mobilization. Autologous HCT conditioning used melphalan 100 mg/m2/day on days -2 and -1. Patients >70 years or unable to undergo HCT received EA alone. Dasatinib maintenance (Course VI) began on day 30 of Course V and continued for 12 months and until 2 consecutively negative bone marrow BCR-ABL1RT-PCR assays 3 months apart or until relapse. Dasatinib levels were measured on day 15 of induction. Results: Sixty-six patients enrolled from 12/15/2010 to 11/14/2014; 65 received dasatinib and are evaluable. Median age was 60 years (22-87); 49% were male. Median presenting WBC count was 23.1 x 103/ul (0.3-453.6). No deaths occurred during induction or intensification. CR or CRi occurred 31 patients (48%) by Day 15 of induction and in 62 patients overall (95%; CR 86%). Median dasatinib levels in serum and CSF on Day 15 of induction were 30.3 ng/mL (<3-308) and 0.29 ng/mL (<0.2-1.37), respectively suggesting approximately 1% of plasma dasatinib penetrates into the CSF, less than the unbound fraction (6%). Fifty-four patients started Course IV, 38 Course V, and 37 Course VI. Fourteen patients continue on protocol therapy. Of 38 patients receiving Course V, 22 had allogeneic HCT, 6 had autologous HCT, and 10 had EA chemotherapy. Median age of allogeneic HCT recipients was 61 years (31-69). Robust autologous stem cell mobilization was observed [median CD34+ cell count, 90 x 106/kg (31-166, n=6)]. Dasatinib maintenance was feasible after allogeneic HCT, autologous HCT, and chemotherapy alone with no missed doses in 59%, 83%, and 63% of cycles, respectively. Ten patients have relapsed with one isolated CNS relapse. No relapses have occurred after allogeneic HCT with 3 relapses after autologous HCT and one after Course V EA alone. Median follow up for survivors is 22.8 months (longest, 51 months). There have been 23 deaths: 5 treatment-related (4 after allogeneic HCT, 1 after course V EA), 16 disease-related and 2 unrelated. Conclusions: Dasatinib with dexamethasone yields CR rates comparable to those reported with tyrosine kinase inhibitors combined with conventional chemotherapy. Post-remission therapy with reduced-intensity allogeneic HCT, autologous HCT, or chemotherapy followed by dasatinib maintenance is feasible. Survival follow up is maturing. Disclosures Stock: Sigma-Tau: Honoraria, Research Funding; Royalties for a chapter in Up to Date: Patents & Royalties; ADC Therapeutics: Honoraria; Amgen: Honoraria; Gilead Sciences: Honoraria. Beumer:Bristol-Myers Squibb: Research Funding. Stone:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Juno Therapeutics: Consultancy; Karyopharm: Consultancy; Sunesis Pharmaceuticals: Consultancy; Agios: Consultancy; Amgen: Consultancy; Celator: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Jansen: Consultancy; Merck: Consultancy; ONO: Consultancy; Roche: Consultancy; Seattle Genetics: Consultancy; Xenetic Biosciences: Consultancy. Larson:Bristol-Myers Squibb: Consultancy; Astellas: Consultancy, Research Funding.

scholarly journals Superior Survival with Post-Remission Pediatric-Inspired Chemotherapy Compared to Myeloablative Allogeneic Hematopoietic Cell Transplantation in Adolescents and Young Adults with Ph-Negative Acute Lymphoblastic Leukemia in First Complete Remission: Comparison of CALGB 10403 to Patients Reported to the CIBMTR

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 261-261 ◽  
Author(s):  
Matthew J. Wieduwilt ◽  
Wendy Stock ◽  
Anjali S. Advani ◽  
Selina M. Luger ◽  
Richard A. Larson ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Cox Model ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Allogeneic Hct ◽  
Disease Free ◽  
First Complete Remission

Optimal post-remission therapy for adolescents and young adults (AYAs, 16-39 years) with Ph-negative (Ph-) acute lymphoblastic leukemia (ALL) in first complete remission (CR1) is not well established. We hypothesized that post-remission therapy with a pediatric-inspired regimen would yield superior outcomes to myeloablative allogeneic HCT for AYA patients with Ph- ALL in CR1. We compared overall survival (OS), disease-free survival (DFS), relapse, and non-relapse mortality (NRM) for patients receiving post-remission therapy on CALGB 10403 to a contemporary matched AYA cohort undergoing myeloablative allogeneic HCT in CR1 reported to the CIBMTR (Table). The allogeneic HCT cohort consisted of patients 16-39 years of age with Ph- ALL in CR1 undergoing myeloablative transplant from a matched sibling/relative or unrelated donor using peripheral blood or bone marrow stem cells between 11/2002 and 8/2012 in the United States. Patients receiving post-remission therapy with pediatric-inspired chemotherapy had superior OS (P&lt;0.0001), DFS (P=0.0011), and NRM (P&lt;0.001) compared to allogeneic HCT. Patterns of relapse were time-dependent and examined in the Cox model. In multivariate analysis of Cox model, receiving allogeneic HCT was associated with inferior OS (HR 1.99, 95% CI 1.5-2.65, P &lt;0.001), inferior DFS (HR 1.51, 95% CI 1.17-1.94, P 0.002), and increased NRM (HR 3.93, 95% CI 2.53-6.10, P &lt;0.001; Figure). In the early post-remission period (≤15 months after CR1), relapse was more likely with allogeneic HCT (HR 1.63, 95% CI 1.03-2.59, p=0.04) whereas beyond 15 months after CR1 relapse was more likely in the chemotherapy arm (HR 0.35, 95% CI 0.19-0.62, P &lt;0.001; Figure). Obesity (BMI ≥30) was independently associated with inferior OS (HR 2.22, 95% CI 1.69-2.91, P&lt;0.001), inferior DFS (HR 1.96, 95% CI 1.52-2.53, P &lt;0.001), increased relapse (1.90, 95% CI 1.37-2.64, P &lt;0.001), and increased NRM (HR 1.99, 95% CI 1.33-2.97, P &lt;0.001). Extramedullary disease at diagnosis was independently associated with inferior OS (HR 1.34, 95% CI 1.00-1.79, P=0.05). We conclude from this large retrospective study that post-remission therapy with pediatric-inspired chemotherapy as given on CALGB 10403 was superior to allogeneic HCT in CR1 for OS, DFS, and NRM in AYAs with newly-diagnosed Ph-negative B- and T-cell ALL. Late relapse was more likely with chemotherapy whereas early relapse was more likely with allogeneic HCT. Future study should aim to elucidate the impact of measurable residual disease at CR1 and high-risk genetics, including Ph-like ALL, on the superiority of post-remission pediatric-inspired chemotherapy over allogeneic HCT. Figure. Allogeneic HCT (HCT) vs. CALGB 10403 pediatric-inspired chemotherapy (chemo) after CR1: Adjusted (left-truncated) overall survival, disease-free survival, cumulative incidence of relapse, and cumulative incidence of non-relapse mortality. Disclosures Wieduwilt: Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen, Leadiant, Merck, Servier: Research Funding; Reata Pharmaceuticals: Equity Ownership. Stock:Astellas: Membership on an entity's Board of Directors or advisory committees; Research to Practice: Honoraria; Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; UpToDate: Honoraria. Advani:Macrogenics: Research Funding; Abbvie: Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Research Funding; Kite Pharmaceuticals: Consultancy; Glycomimetics: Consultancy, Research Funding. Luger:Ariad: Research Funding; Biosight: Research Funding; Celgene: Research Funding; Cyslacel: Research Funding; Daichi Sankyo: Honoraria; Genetech: Research Funding; Jazz: Honoraria; Kura: Research Funding; Onconova: Research Funding; Pfizer: Honoraria; Seattle Genetics: Research Funding; Agios: Honoraria. Larson:Novartis: Honoraria, Other: Contracts for clinical trials; Agios: Consultancy; Celgene: Consultancy. Tallman:Daiichi-Sankyo: 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; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biosight: Research Funding; Nohla: 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; KAHR: 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; Jazz Pharmaceuticals: 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; UpToDate: Patents & Royalties; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kebriaei:Kite: Honoraria; Jazz: Consultancy; Amgen: Research Funding; Pfizer: Honoraria. Weisdorf:Pharmacyclics: Consultancy; Incyte: Research Funding; Fate Therapeutics: Consultancy.

scholarly journals Genetic Characteristics and Clinical Outcomes of T-Cell Acute Lymphoblastic Leukemia; Myeloid-Suppressive Therapeutic Approach Based on Allogeneic Hematopoietic Cell Transplantation May Benefit in Early T-Cell Precursor Acute Lymphoblastic Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1470-1470
Author(s):  
Jae-Ho Yoon ◽  
Han Bi Lee ◽  
Gi June Min ◽  
Sung-Soo Park ◽  
Silvia Park ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Board Of Directors ◽  
Clinical Outcomes ◽  
Cell Transplantation ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Lymphoblastic Leukemia ◽  
Cell Precursor ◽  
Advisory Committees

Background: Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a recently recognized high-risk subgroup of T-cell ALL. T-cell ALL is characterized by poorer survival outcomes compared to B-cell ALL, but the optimal treatment strategies are not well elucidated yet. Aim: We performed integrative genetic analyses and tried to find important genetic events in T-cell ALL. We also identified clinical outcomes of T-cell ALL including ETP-ALL subgroup, which were treated with myeloid-suppressive chemotherapy followed by allogeneic hematopoietic cell transplantation (allo-HCT) for post-remission therapy. Methods: We enrolled 40 adult patients with T-cell ALL for analyses of gene mutations and treatment outcomes. Integrative genetic analyses were performed with massive parallel sequencing for NOTCH1, FBXW7, DNMT3A, PHF6, RUNX1, KRAS, NRAS, PTEN, GATA3, EZH2 and SH2B3, and multiplex ligation-dependent probe amplification (MLPA) for copy number alterations of several genes. Among them, quantification of CDKN2A and CDKN2B mRNA expression was performed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). All were treated with myeloid-suppressive chemotherapy which consisted of hyper-fractionated cyclophosphamide (300 mg/BSA, every 12 h, days 1-3), vincristine (1.4 mg/BSA, maximum dose 2 mg, days 4 and 11), daunorubicin (45 mg/m2, days 4 and 11), and dexamethasone (40 mg, days 1-4 and days 11-14) for remission induction, followed by consolidation with high-dose cytarabine (2 g/BSA, every 12 h, days 1-5) and mitoxantrone (12 mg/BSA, days 1-2). Above two anthracycline-intensified regimens were alternatively used for further consolidation. For patients not in complete remission (CR), mitoxantrone (12 mg/BSA, d 1-4), cytarabine (2 g/BSA, every 12 h, d 1-4) and etoposide (100 mg/BSA, d 5-7) were used for reinduction. Our strategy for T-cell ALL in CR was to offer allo-HCT according to the donor availability. Results: We identified 16 patients with ETP-ALL presenting 1 or more stem cell or myeloid marker with absence of CD1a, CD5, and CD8 expression, and 24 patients with non-ETP-ALL. For genetic mutation profiles between ETP-ALL and non-ETP-ALL, we found DNMT3A was more frequently observed in ETP-ALL (25% vs. 12.5%), while FBXW7 (33.3% vs. 6.2%) and RUNX1 (25.0% vs. 0.0%) were more frequently observed in non-ETP-ALL. We also observed that CDKN2A expression was significantly higher in ETP-ALL (0.053 vs. 0.001, p=0.017). In total, 33 (82.5%) patients achieved CR (24 after induction, 9 after reinduction) and their estimated 5-year overall survival (OS) was 31.3% with median survival of 18.9 months. All 16 (100%) patients with ETP-ALL achieved CR (13 after induction, 3 after reinduction), while non-ETP-ALL in 17 (70.8%, 11 after induction, 6 after reinduction) patients. Estimated 5-year OS of ETP-ALL was 41.7% and non-ETP-ALL was 24.3% (p=0.135). Finally, 12 (75.0%) out of 16 ETP-ALL and 11 (45.8%) out of 24 non-ETP-ALL underwent allo-HCT in CR and their 5-year OS was 55.6% and 45.5%, respectively. Conclusion: Our data suggested different genetic predisposition between ETP-ALL and non-ETP-ALL and myeloid-suppressive chemotherapy showed a good CR rate in ETP-ALL. Myeloid-suppressive chemotherapy induced CR followed by post-remission allo-HCT can be a good solution for improving poor survival outcome of ETP-ALL. Disclosures Kim: Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Amgen: Honoraria; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Honoraria; BL & H: Research Funding. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding.

scholarly journals Comorbidities Reduce Response to Induction Treatment and Survival in Adults with Philadelphia-Negative Acute Lymphoblastic Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2587-2587 ◽  
Author(s):  
Ilaria Tanasi ◽  
Veronica Tagliaferri ◽  
Cristina Tecchio ◽  
Fiorenza Aprili ◽  
Giovanna De Matteis ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Board Of Directors ◽  
Prognostic Value ◽  
Lymphoblastic Leukemia ◽  
Age Group ◽  
Cell Precursor ◽  
Advisory Committees ◽  
Risk Class ◽  
Pre Treatment

Background. Comorbidities have a well-established prognostic value in the majority of hematologic neoplasms. However, the impact of comorbidities on adult patients with acute lymphoblastic leukemia (ALL) has been poorly investigated to date. Aims. In this retrospective study of a monocentric cohort of 112 adults with Philadelphia-negative (Ph-neg) ALL consecutively diagnosed between 1990 and 2018 we aimed to assess the association between comorbidities at diagnosis and remission rate, the frequency and severity of adverse events (AE) during frontline treatment, and long-term outcome. Patients and methods. Patients were included, regardless of age, if treated within or according to clinical protocols aimed at curing. Patients initially treated with low-intensity/palliative care were not considered. Ph-positive patients were excluded, as their treatment modalities markedly changed over years due to the availability of tyrosine kinase inhibitors. Patients were defined as high risk if one or more of the following features were present: WBC >30x109/L for B-cell precursor (BCP) or >100x109/L for T-cell precursor (TCP), pro-B, early or mature T ALL phenotype, high risk cytogenetics (according to the ESMO 2016 guidelines), or central nervous system involvement. Comorbidities recorded at diagnosis were classified according to the Charlson Comorbidity Index (CCI). Classification and grading of AE was performed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Responses were defined according to the ESMO 2016 guidelines. Minimal residual disease (MRD) was assessed by 6- or 8-colour flow cytometry with a 10-4 sensitivity. Variables tested for association with complete remission (CR) and MRD-negative status were: age group (stratified into quartiles), gender, phenotype (BCP or TCP), WBC, karyotype, risk class, and CCI score. Event-free survival (EFS) was calculated from the first CR to relapse or death. Overall survival (OS) was calculated from diagnosis until death. EFS and OS were estimated using the Kaplan-Meier method. Results. Median age at diagnosis was 43 years (range 14-75). BCP and TCP were 78% and 22%, respectively. Overall, 51 patients (46%) were considered as standard risk, 46 (41%) as high risk, and 15 (13%) were unclassifiable due to the lack of cytogenetics. CCI score distribution was as follows: 0 (n=66; 59%), 1 (n=18; 16%), 2 (n=9; 8%), and ≥3 (n=19; 17%). CR after induction therapy was obtained by 95/112 patients (85%). CCI was the only variable significantly associated to CR achievement (0-1 vs ≥2: 91% vs 68%; p=0.012). MRD status at the end of induction was evaluable in 64 out of 95 patients in CR and was negative in 28 (44%). No pretreatment variable predicted for the achievement of MRD complete response. Eight patients (7%) died before the first response evaluation; early death rate was significantly higher in patients with CCI ≥2 than in patients with CCI 0-1 (21% vs 2%; p=0.003). Conversely no differences in AE frequency and severity were observed according to CCI (p=0.847) or age group (p=0.881). After a median follow-up of 35 months, 46 patients (41%) were alive. OS was significantly longer in patients with CCI 0-1 as compared to CCI ≥2 (median 87 months, 95%CI: 31 to not reached vs 13 months, 95%CI: 5-36; p<0.001). Notably, pre-treatment risk stratification lost prognostic value in predicting OS and EFS in CCI 0-1 patients, while in CCI ≥2 patients retained its significance (Figure). Overall, 58 patients (52%) were primary refractory or relapsed. Relapse rate was similar according to age groups, phenotype, risk class, and CCI score. CR rate after salvage treatment (CR2) was higher in younger patients (≤43 vs >43 years: 81% vs 44%; p=0.014) and tended to be higher in patients treated with blinatumomab or inotuzumab rather than with standard chemotherapy (82% vs 55%, p=0.17). While there were no differences in CR2 according to CCI group, median survival after first relapse was 12.1 months (95%CI: 7.83-15.24) for CCI 0-1 vs 6.92 months (95%CI: 2.49-12.59) for CCI≥2(p=0.021). Conclusions. Comorbidities have a significant prognostic impact in intensively-treated adults with Ph-neg ALL. Patients with low comorbidities (CCI 0-1) had superior CR rates and less incidence of toxic death after induction, and pre-treatment high risk features did not have a detrimental impact in this group. Figure Disclosures Krampera: Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Bonifacio:Incyte: Honoraria; Pfizer: Honoraria; Novartis: Honoraria, Research Funding; Amgen: Honoraria.

scholarly journals Allogeneic Hematopoietic Cell Transplantation in Patients ≤ 60 Years with Intermediate-Risk Acute Myeloid Leukemia in First Remission - Results of the Randomized Etal-1 Trial-

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 173-173
Author(s):  
Martin Bornhaeuser ◽  
Christoph Schliemann ◽  
Johannes Schetelig ◽  
Christoph Rollig ◽  
Michael Kramer ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Intermediate Risk ◽  
Advisory Committees ◽  
Allogeneic Hct ◽  
Unrelated Donors ◽  
First Remission ◽  
Related Mortality

Abstract Allogeneic hematopoietic cell transplantation (HCT) offers the highest chance for cure in patients with adverse-risk acute myeloid leukemia (AML) when performed in first remission (CR1). In contrast, patients in CR1 with favorable risk do not seem to benefit from allogeneic HCT due to the inherent risk of transplant-related mortality. Donor vs. no donor comparisons as well as prospective matched-pair analyses have suggested that allogeneic HCT performed in intermediate-risk AML may provide a higher probability of overall survival or relapse-free survival in patients ≤ 60 years of age with an acceptable risk for transplant-related mortality. On the other hand, many intermediate-risk patients relapsing after conventional chemotherapy may be successfully salvaged by allogeneic HCT. The role of allogeneic HCT in cytogenetically defined intermediate-risk AML patients in CR1 was addressed by a prospective randomized trial performed in 16 centers in Germany. Key inclusion criteria were: AML with intermediate-risk cytogenetics, first CR or CRi after conventional induction therapy, age of 18-60 years, and availability of an HLA-matched sibling or unrelated donor. For unrelated donors, a 9 out of 10 HLA allelic match was acceptable except for patients with an NPM1 mutation, for whom full 10/10 allele matching was required. Randomization was stratified according to age (&lt; 40 vs. 40-60), NPM1/FLT3, and CEBP-alpha mutational status and unrelated vs. related donor availability. Endpoints included overall-survival as primary outcome and relapse-free survival (RFS), cumulative incidence of relapse, treatment-related mortality, and quality of life measured according to the short form (36) health status. From 2010 - 2018, 143 patients in CR1 were randomized into Arm A (n=76, allogeneic HCT) and Arm B (n=67, conventional consolidation and allo-HCT only in case of relapse). In July 2018, the trial was stopped prematurely due to slow accrual (143 out of 356 pts. randomized). Median age of the trial cohort was 51 years (range, 19-60), with 42% exhibiting an NPM1 and 25% a FLT3 mutation. A normal karyotype was reported in 84% of the included patients. All mentioned characteristics did not differ between both treatment arms. Sibling donors were available for 44 (31% of patients), matched unrelated donors for 99 (69%) patients. According to the intent-to-treat analysis, the probability of survival at 2 years was 71% (95% CI 60-81%) and 84% (95% CI 73-92%) in Arm A (Transplant) and Arm B (conventional consolidation), respectively (p=0.120, Figure 1A). RFS after allogeneic HCT was 69% (95% CI 57-80%) compared to 41% (95% CI 29-54%) after conventional consolidation (p=0.001, Figure 1B). Primary allogeneic HCT reduced the cumulative incidence of relapse at 2 years from 57% [95%-CI 46-71%] after conventional consolidation to 20% [95%-CI 13-31%] after HCT (p&lt;0.001). Non-relapse mortality at 2 years after primary allogeneic HCT was 9% [95%-CI 5-19%] compared to 2% [95%-CI 0-11%] after consolidation (p=0.017).Most importantly, all 38 patients relapsing in arm B (33 hematologic, 4 molecular and 1 extramedullary) proceeded to allogeneic HCT as salvage therapy. Multivariable Cox regression analysis revealed a status of CRi compared to CR before randomization to be associated with a significantly higher risk of death (HR 3.3, p=0.009). SF (36) scoring suggested a trend towards a lower physical functioning throughout the first 3 months after randomization in the primary HCT arm. No significant differences in vitality, mental health, social and emotional functioning could be documented between both treatment arms. In summary, the results of this first prospective randomized trial did not show that allogeneic HCT performed immediately after achievement of CR1 in patients with cytogenetically defined intermediate-risk AML ≤ 60 years of age conveys an overall survival advantage. However, allogeneic HCT in CR1 significantly reduced the relapse risk and was not associated with relevant impairments in quality of life. Although the limited statistical power of the trial does not allow definitive conclusions, delayed allogeneic transplantation seems to be a potential treatment algorithm in CR1 intermediate-risk AML with an available donor. Figure 1 Figure 1. Disclosures Schliemann: Jazz Pharmaceuticals: Consultancy, Research Funding; Roche: Consultancy; Philogen S.p.A.: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; AstraZeneca: Consultancy; Boehringer-Ingelheim: Research Funding; Novartis: Consultancy; Abbvie: Consultancy, Other: travel grants; Astellas: Consultancy; BMS: Consultancy, Other: travel grants. Schetelig: Roche: Honoraria, Other: lecture fees; Novartis: Honoraria, Other: lecture fees; BMS: Honoraria, Other: lecture fees; Abbvie: Honoraria, Other: lecture fees; AstraZeneca: Honoraria, Other: lecture fees; Gilead: Honoraria, Other: lecture fees; Janssen: Honoraria, Other: lecture fees . Glass: Riemser: Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau; Kite: Consultancy; BMS: Consultancy; Novartis: Consultancy; Helios Klinik Berlin-Buch: Current Employment. Platzbecker: Janssen: Honoraria; Celgene/BMS: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Geron: Honoraria; AbbVie: Honoraria. Burchert: Novartis: Honoraria, Research Funding; AOP Orphan: Honoraria, Research Funding; Pfizer: Honoraria; Incyte: Honoraria; Gilead: Honoraria; BMS: Honoraria. Haenel: Jazz: Consultancy, Honoraria; GSK: Consultancy; Bayer Vital: Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Celgene: Consultancy, Honoraria. Mueller: Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; CTI: Membership on an entity's Board of Directors or advisory committees; Gentium: Other: Travel Support; Gilead: Other: Travel Support; Janssen: Other: Travel Support; Novartis: Other: Travel Support; Pfizer: Other: Travel Support; Sanofi: Other: Travel Support. Berdel: Philogen S.p.A.: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees. Stelljes: Novartis: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Kite/Gilead: Consultancy, Speakers Bureau; Celgene/BMS: Consultancy, Speakers Bureau; Medac: Speakers Bureau; Amgen: Consultancy, Speakers Bureau.

scholarly journals Association of Health Insurance Status with Outcomes of Sepsis in Adult Patients: A Retrospective Cohort Study

2021 ◽  
Vol 18 (11) ◽  
pp. 5777
Author(s):  
Gaon-Sorae Wang ◽  
Kyoung-Min You ◽  
You-Hwan Jo ◽  
Hui-Jai Lee ◽  
Jong-Hwan Shin ◽  
...  
Keyword(s):  
Health Insurance ◽  
Propensity Score ◽  
Hospital Mortality ◽  
Cohort Analysis ◽  
Adult Patients ◽  
Multivariate Logistic Regression Model ◽  
Insurance Status ◽  
Matched Cohort ◽  
Health Insurance Status ◽  
Significant Difference

(1) Background: Sepsis is a life-threatening disease, and various demographic and socioeconomic factors affect outcomes in sepsis. However, little is known regarding the potential association between health insurance status and outcomes of sepsis in Korea. We evaluated the association of health insurance and clinical outcomes in patients with sepsis. (2) Methods: Prospective cohort data of adult patients with sepsis and septic shock from March 2016 to December 2018 in three hospitals were retrospectively analyzed. We categorized patients into two groups according to their health insurance status: National Health Insurance (NHI) and Medical Aid (MA). The primary end point was in-hospital mortality. The multivariate logistic regression model and propensity score matching were used. (3) Results: Of a total of 2526 eligible patients, 2329 (92.2%) were covered by NHI, and 197 (7.8%) were covered by MA. The MA group had fewer males, more chronic kidney disease, more multiple sources of infection, and more patients with initial lactate > 2 mmol/L. In-hospital, 28-day, and 90-day mortality were not significantly different between the two groups and in-hospital mortality was not different in the subgroup analysis. Furthermore, health insurance status was not independently associated with in-hospital mortality in multivariate analysis and was not associated with survival outcomes in the propensity score-matched cohort. (4) Conclusion: Our propensity score-matched cohort analysis demonstrated that there was no significant difference in in-hospital mortality by health insurance status in patients with sepsis.

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 &gt;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.

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