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 Blinatumomab Is Well Tolerated Maintenance Therapy Following Allogeneic Hematopoietic Cell Transplantation for Acute Lymphoblastic Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1298-1298 ◽  
Author(s):  
Partow Kebriaei ◽  
Pinaki P Banerjee ◽  
Christina Ganesh ◽  
Mecit Kaplan ◽  
Vandana Nandivada ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Checkpoint Inhibitors ◽  
Lymphoblastic Leukemia ◽  
Advisory Committees ◽  
Active Disease

Background: Patients with high-risk or multiply relapsed B-lineage acute lymphoblastic leukemia (ALL) have a very high rate of relapse, even after allogeneic hematopoietic cell transplantation (HCT). In an effort to reduce the risk for relapse, we investigated the role of blinatumomab (Blin), a bi-specific T cell immunotherapy targeting CD19, as maintenance therapy following allogeneic HCT for adult patients with advanced B ALL. We rationalized that this is an ideal agent with little cytotoxicity, and the potential to provide immune protection against disease relapse during the first year post HCT when graft versus leukemia (GVL) is still maturing. Methods: Adult patients with B-ALL deemed high risk for relapse defined as disease stage beyond CR1, any active disease including MRD, or presence of high risk molecular mutations or karyotype at time of HCT, or patients with evidence of MRD immediately following HCT, were eligible for study enrollment; prior Blin treatment was allowed. Patients with active disease defined as >5% malignant blasts or active GVHD requiring steroid therapy post HCT were excluded. Patients were scheduled to receive 4 cycles of Blin as a continuous intravenous infusion at the dose of 28 microgram/24 hours over 4 weeks, with the first cycle to be administered within the first 3 months post HCT after count recovery; the subsequent cycles were administered at 6, 9, and 12 months following HCT (day of hematopoietic progenitor cell infusion). Dose escalation for cycle 1 and hospitalization for observation during cycles 1 and 2 followed standard FDA issued guidelines. Results: 14 patients enrolled to date with 12 patients treated with median age 30 years (range, 21-65 years); two patients did not proceed with treatment due to graft versus host disease (GVHD). Patient characteristics and outcomes are listed in Table 1. The median days to start of therapy post HCT was 84 (range, 38-105 days). The treatment was well tolerated with no reported cytokine release syndrome, GVHD, graft failure, or grade 5 adverse events (AE). A cumulative 26 cycles of Blin were administered with 7 Blin-related grade 3 or 4 AEs reported (leukopenia n=4, transaminitis n=2, rash n=1). Grade 2 neurotoxicity manifesting as confusion and dysphagia requiring temporary suspension of therapy and short course steroids noted in 1 patient. Median follow up was 8.5 months post HCT (range 2-35 months). All 4 patients who were MRD positive prior to start of Blin have progressed and 2 have died. None of the 8 patients who were MRD negative post transplant has relapsed. We performed multiparametric flow cytometry studies on serial peripheral blood patient samples collected prospectively at multiple time points to measure T cell subsets, T-cell function and cell surface expression of various checkpoint inhibitors including PD1, TIGIT, Tim3, 2B4 and CD160. Samples were studied on an X-20 Fortessa, and the data analyzed using Kaluza software. Interestingly, the 4 patients who progressed on Blin maintenance had lower CD8 to CD4 ratio compared to non-progressors (17:60 vs. 46:42) (Figure 1). Furthermore, compared to healthy controls, we observed higher levels of checkpoint molecules as multiple checkpoints per cell. PD1 and TIGIT upregulation and co-expression were more common in progressing patients compared to non-progressors (Figure 2). Conclusion: We observed that Blin maintenance following allogeneic HCT for B ALL is well tolerated. More patients need to be treated to confirm the efficacy of this approach. This approach is encouraging for high risk ALL patients who are MRD negative post transplant. Strategies to increase CD8 levels and blockade against checkpoint inhibitors may overcome resistance to therapy. Disclosures Kebriaei: Amgen: Research Funding; Jazz: Consultancy; Pfizer: Honoraria; Kite: Honoraria. Ravandi:Xencor: Consultancy, Research Funding; Selvita: Research Funding; Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Menarini Ricerche: Research Funding; Cyclacel LTD: Research Funding. Jabbour:Adaptive: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding. Kantarjian:AbbVie: Honoraria, Research Funding; Novartis: Research Funding; Jazz Pharma: Research Funding; Agios: Honoraria, Research Funding; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Immunogen: Research Funding; Amgen: Honoraria, Research Funding; Astex: Research Funding; Ariad: Research Funding. Champlin:Sanofi-Genzyme: Research Funding; Johnson and Johnson: Consultancy; Actinium: Consultancy.

scholarly journals Allogeneic Hematopoietic Cell Transplantation May Improve Long-Term Outcomes in Patients with Ph-like Acute Lymphoblastic Leukemia with CRLF2 Overexpression

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4598-4598
Author(s):  
Paul Koller ◽  
Rima M. Saliba ◽  
Celina Ledesma ◽  
Gabriela Rondon ◽  
Uday Popat ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Board Of Directors ◽  
Cell Transplantation ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Lymphoblastic Leukemia ◽  
Hematopoietic Cell ◽  
Advisory Committees ◽  
Landmark Analysis

Introduction: Philadelphia (Ph) like acute lymphoblastic leukemia (ALL) is a high risk subtype of ALL, with the majority of patients overexpressing CRLF2; CRLF2 overexpression is associated with particularly poor outcomes (Jain, Blood, 2017). To date, the efficacy of hematopoietic cell transplantation (HCT) in these patients is unknown. Methods: In this retrospective study, we evaluated patients with CRLF2 overexpressed ALL who received or did not receive HCT. CRLF2 status was identified via FISH or multi-parameter flow cytometry. We identified 55 patients treated at our institution from 1992-2019 who had CRLF2 overexpression at diagnosis and achieved a first complete remission (CR1). To account for potential survival bias in the HCT group, outcomes between the two groups were compared in a landmark analysis starting at 3 months since CR1. Results: Baseline characteristics and treatment outcomes are described in Table 1. The median age was 32 years and 34 years, respectively, for HCT vs. non-HCT groups. In both groups, patients received high-intensity induction therapy with or without asparaginase. Patients who did not receive HCT were more likely (63%) to have been diagnosed prior to 2013, whereas all those treated with HCT were diagnosed after 2013. This difference reflects a change in practice at our institution after the description of CRLF2 overexpression as a poor prognostic factor. Median peripheral blood platelet count (102 k/uL vs 46 k/uL, p=0.02) and bone marrow blasts (76% vs 91%, p=0.02) at diagnosis were different between the HCT and non-HCT groups, respectively. In the HCT group, the majority of patients underwent myeloablative conditioning (n= 11, 79%) with a matched donor (n=9, 64%). With a median follow up of 26 months from CR1 in both groups, landmark analysis showed a trend for lower 3-year progression rate (25% vs 66%, HR=0.3, p=0.08) and improved progression-free survival (PFS) (51% vs 22%, HR=0.6, p=0.3) and overall survival (OS) (59% vs 35%, HR=0.6, p=0.3) in the HCT versus non-HCT groups. The median PFS was 16 months for the non-HCT group, and has not been reached for the HCT group. In the HCT group, PFS appears to have reached a plateau at 14 months, with 6 of 14 patients remaining alive in remission at a median follow-up of 24 months (range 17-41). Conclusions: CRLF2 overexpression in ALL is associated with a high rate of progression. Allogeneic HCT is beneficial against relapse, showing a trend for improved PFS and OS.A larger sample size and longer follow up is needed to confirm these findings. Disclosures Popat: Bayer: Research Funding; Incyte: Research Funding; Jazz: Consultancy. Oran:AROG pharmaceuticals: Research Funding; Astex pharmaceuticals: Research Funding. Qazilbash:Bioclinical: Consultancy; Genzyme: Other: Speaker; Amgen: Consultancy, Other: Advisory Board; Autolus: Consultancy. Ciurea:Miltenyi: Research Funding; Spectrum: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees, Other: stock holder. Jain:BMS: Research Funding; Cellectis: Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jabbour:Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Kantarjian:Astex: Research Funding; Takeda: Honoraria; BMS: Research Funding; Ariad: Research Funding; AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Agios: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Jazz Pharma: Research Funding; Pfizer: Honoraria, Research Funding; Immunogen: Research Funding; Cyclacel: Research Funding. Konopleva:Astra Zeneca: Research Funding; Kisoji: Consultancy, Honoraria; Ablynx: Research Funding; Agios: Research Funding; Calithera: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Ascentage: Research Funding. Kebriaei:Pfizer: Honoraria; Kite: Honoraria; Amgen: Research Funding; Jazz: Consultancy.

Outcomes of Patients with CRLF2-Overexpressing Acute Lymphoblastic Leukemia without Down Syndrome: A Report from the Children's Oncology Group

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 45-46
Author(s):  
Sarah K Tasian ◽  
Yunfeng Dai ◽  
Meenakshi Devidas ◽  
Kathryn G Roberts ◽  
Richard C Harvey ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Down Syndrome ◽  
Acute Lymphoblastic Leukemia ◽  
Board Of Directors ◽  
Clinical Outcomes ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Newly Diagnosed ◽  
Oncology Group ◽  
Advisory Committees

Background: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) occurs in 5-30% of children and adolescents/young adults (AYAs) with B-ALL, is driven by genetic alterations that induce constitutive cytokine receptor and kinase signaling, and is associated with poor clinical outcomes across the older pediatric-to-adult age spectrum (Tasian Blood 2017c, Reshmi Blood 2017, Roberts Blood 2018). Rearrangement and/or overexpression of cytokine receptor-like factor 2 (CRLF2+) occurs in 50% of Ph-like ALL cases with frequently co-occurring JAK2 or JAK1 point mutations or IL7R indel mutations. This study reports the clinical outcomes of children and AYAs with newly-diagnosed National Cancer Institute (NCI) standard-risk (SR) or high-risk (HR) CRLF2+ ALL without Down syndrome treated on four successive Children's Oncology Group (COG) phase 3 clinical trials from 2003 to 2018. Methods: We retrospectively assessed demographic characteristics, laboratory data, and clinical outcomes of 3757 patients with B-ALL treated on COG trials AALL0331 and AALL0932 (SR) and AALL0232 and AALL1131 (HR) whose diagnostic leukemia specimens were analysed by low-density microarray (LDA), fluorescence in situ hybridization, polymerase chain reaction (PCR), and/or anchored multiplex PCR testing (Harvey and Tasian Blood Advances 2020). Minimal residual disease (MRD) was assessed by flow cytometry at the end of induction (EOI) and at the end of consolidation for a subset of EOI MRD+ patients. Results: We identified 77/1541 (5.0%) SR and 244/2216 (11.0%) HR patients with CRLF2+ B-ALL in this cohort. Amongst those with diagnostic leukemia specimens analysed by LDA, 57/72 (79.2%) of SR CRLF2+ and 175/213 (82.2%) of HR CRLF2+ patients were positive for the Ph-like gene expression profile with an 8-gene score ≥0.5. P2RY8-CRLF2 fusions and IGH-CRLF2 translocations were detected in 64/77 (83.1%) and 10/77 (13.0%) of SR CRLF2+ patients and in 98/244 (40.2%) and 103/244 (42.2%) of HR CRLF2+ patients, respectively. CRLF2 rearrangements or F232C mutations were not found in the remaining 3 SR and 43 HR CRLF2+ patients, although other Ph-like alterations were discovered in some (n=3 IGH-EPOR fusions, 1 IL7R indel). Importantly, CRLF2+ vs non-CRLF2-overexpressing (CRLF2-) status was associated with older age (10.8 ±6.5 vs 7.8 ±5.8 years [mean ±SD], p<0.0001), leukocytosis (diagnostic white blood cell count 77.5 ±98.5 vs 49.8 ±119.4 x 10e9/L [mean ±SD], p<0.0001), and higher rates of EOI MRD positivity at a ≥0.01% threshold (47.9% vs 30.1%, p<0.0001), which appeared largely driven by the Ph-like HR cohort as expected (57.9% MRD+ vs 42.1% MRD- in HR CRLF2+ and 44.6% MRD+ vs 55.4% MRD- in SR CRLF2+ patients, p<0.003). Overall, CRLF2+ patients had inferior 5-year event-free survival (EFS; 63.3% ±3.1 vs 82.1% ±0.7, p<0.0001) and overall survival (OS; 79.6% ±2.6 vs 90.5% ±0.6, p<0.0001) compared to CRLF2- patients (Figure 1A-B) and a greater 5-year cumulative incidence of relapse (CIR; 30.4% ±2.7 vs 13.2% ±0.6, p<0.001). While 5-year EFS and OS were particularly poor in Ph-like CRLF2+ HR patients (56.3% ±4.6 and 75.4% ± 3.9, respectively) and non-Ph-like CRLF2+ HR patients (EFS 63.7% ±10.2 and OS 74.4% ±8.9), outcomes for Ph-like CRLF2+ SR (EFS 87.2% ±4.5 and OS 94.5% ±3.1) and non-Ph-like CRLF2+ SR patients (EFS 86.2% ±9.3 and OS 100%) were quite good (p<0.0001 for both EFS and OS; Figure 1C-D). Discussion: Patients with newly-diagnosed CRLF2+ B-ALL treated on frontline COG trials have higher rates of EOI MRD positivity, inferior survival, and increased CIR compared to their CRLF2- counterparts. EFS is especially poor in children and AYAs with NCI HR CRLF2+ ALL, particularly those with the Ph-like expression profile. Conversely, outcomes for children with NCI SR CRLF2+ ALL are reasonably favourable, irrespective of Ph-like status. Development of successful treatment strategies to decrease relapse and to improve survival remains a major therapeutic gap for NCI HR CRLF2+ ALL patients. Current clinical trials are studying the potential efficacy of kinase inhibitor addition to chemotherapy for children, adolescents, and adults with HR Ph-like ALL harboring CRLF2 rearrangements/other JAK pathway alterations or ABL class kinase fusions (NCT0240717, NCT02723994, NCT02883049, NCT03571321). Figure 1 Disclosures Tasian: Gilead Sciences: Research Funding; Incyte Corporation: Research Funding; Aleta Biotherapeutics: Membership on an entity's Board of Directors or advisory committees. Borowitz:Amgen: Honoraria. Mullighan:AbbVie, Inc.: Research Funding; Illumina: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau. Hunger:Novartis: Consultancy; Amgen: Current equity holder in publicly-traded company, Honoraria. Raetz:Pfizer: Research Funding; Celgene/BMS: Other. Loh:Pfizer: Other: Institutional Research Funding; Medisix Therapeutics: Membership on an entity's Board of Directors or advisory committees.

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 Retrospective Comparison between 12-Gray and 8-Gray Total Body Irradiation (TBI) before Allogeneic Hematopoietic Cell Transplantation in Patients with Acute Lymphoblastic Leukemia in First Complete Remission

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1783-1783
Author(s):  
Alexandros Spyridonidis ◽  
Myriam Labopin ◽  
Bipin B. Savani ◽  
Sebastian Giebel ◽  
Christoph Schmid ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Complete Remission ◽  
Board Of Directors ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Lymphoblastic Leukemia ◽  
Advisory Committees ◽  
Free Survival ◽  
Total Body ◽  
First Complete Remission

Abstract Introduction: Total body irradiation (TBI) continues to be an important part of the conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT) in acute lymphoblastic leukemia (ALL). Previous dose escalation studies showed that higher than 12-Gray (Gy) was toxic and did not provide any apparent survival benefit - at least in patients (pts) transplanted in first complete remission (CR1) - thus establishing 12-Gy as the standard TBI dosage. Whether 8-Gy instead of 12-Gy TBI is sufficient in ALL CR1, as has been prospectively demonstrated for AML CR1 (Lancet Oncol 2012; 13: 1035-1044), has not yet been studied. Methods : In this registry-based retrospective study of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (ALWP-EBMT), we compared outcomes of ALL-CR1 pts who underwent a matched-sibling donor (MSD) or matched-unrelated donor (MUD) allo-HCT (94% peripheral blood stem cells) with TBI-based conditioning at a total dose of 12-Gy vs 8-Gy. Patients included in this analysis had received fludarabine (Flu) as the sole chemotherapy counterpart of TBI (12-Gy vs 8-Gy TBIFlu). Results: The median follow up for the whole cohort (n=639 pts) was 22.5 months (95% CI, 17.2-24.1) and did not differ between the 8-Gy (n=494) and 12-Gy (n= 145) TBIFlu treated pts. 25% pts had B-precursor ALL, 54% Philadelphia (Ph)-positive ALL and 21% T-ALL (p=0.008 between groups). Patients conditioned with 8-Gy TBIFlu were older than 12-Gy TBIFlu treated pts (median 55.7 vs 40.3 years, IQR 50.2-61.3 vs 27-50.2 years, &lt;0.0001) and more frequently received in vivo T-cell depletion (71% vs 40%, &lt;0.0001). All other characteristics were well balanced between 8-Gy vs 12-Gy groups including time from diagnosis to HCT (5.5 vs 5.8 months), Karnofksy &lt;90% (34% vs 26%), minimal residual disease (MRD) positivity at HCT (37% vs 43%), MUD (72% vs 68%) and type of GvHD prevention. Engraftment failure was low and below 2% in both groups. Overall, 29% and 27% of 8-Gy vs 12-Gy treated patients died, with the main causes of death not differing between groups (relapse 41% vs 44%, infections 26% vs 24%, GVHD 12.6% vs 12.7%, respectively). Both in univariate and in the age-adjusted Cox proportional-hazards analysis, relapse (REL), non-relapse mortality (NRM), leukemia-free survival (LFS), overall survival (OS), and GVHD-free, relapse-free survival (GRFS) were not influenced by TBI dose (Figure 1, Table 1). These results were confirmed when we focused on pts aged &lt;55 years (median age 47 years; 8-Gy 229 pts vs 12-Gy 131 pts). In the multivariate analysis, an incremental age of 10 years was associated with increased NRM risk (hazard ratio [HR] 1.66, 95% CI, 1.25-2.22) and reduced OS (HR 1.32, 1.09-1.59). Ph+ and T-ALL pts had significantly better survival outcomes than Ph- B-ALL pts, mainly due to significantly fewer relapses (Table 1). Conclusion: Although there were limitations to this study (TBI dose and age were correlated; missing data on TBI fractionation; missing MRD data for nearly one-third of the pts) this retrospective analysis was able to investigate the effect of TBI total dose independently from the chemotherapy counterpart (TBIFlu regimen only) and suggests that 12-Gy and 8-Gy results in similar outcomes in ALL patients transplanted in CR1. Whether this is also true for more advanced disease (&gt;=CR2) and/or young adults) cannot be answered, as our study included only CR1 pts, few of whom were below 25 years of age. The reduced REL risk of Ph+ B-ALL pts is probably due to the increased use of tyrosine kinase inhibitors (TKIs) pre- and post-transplant. Clinically, these results suggest 8-Gy TBI as sufficient for ALL patients transplanted in CR1 with no additional benefit of augmenting the conditioning intensity to 12-Gy, a finding which should be validated in prospective trials. Figure 1 Figure 1. Disclosures Spyridonidis: Menarini: Current Employment. Labopin: Jazz Pharmaceuticals: Honoraria. Giebel: Janssen: Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau. Peric: Therakos: Honoraria; servier: Honoraria; MSD: Honoraria; Astellas: Honoraria; NOVARTIS: Honoraria; Abbvie: Honoraria; Pfizer: Honoraria. Schönland: Janssen: Honoraria, Other: Travel grants, Research Funding; Pfizer: Honoraria; Prothena: Honoraria, Other: Travel grants; Takeda: Honoraria, Other: Travel grants; Sanofi: Research Funding. Kröger: Novartis: Research Funding; Riemser: Honoraria, Research Funding; Sanofi: Honoraria; Neovii: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Gilead/Kite: Honoraria; Celgene: Honoraria, Research Funding; AOP Pharma: Honoraria. Stelljes: Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Kite/Gilead: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Medac: Speakers Bureau; Celgene/BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau. Schroeder: JAZZ: Honoraria, Research Funding. McDonald: BioCryst Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ganser: Novartis: Honoraria; Jazz Pharmaceuticals: Honoraria; Celgene: Honoraria. Wulf: Novartis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Clinigen: Consultancy, Honoraria. Bazarbachi: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hikma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Targeted Treatment and Survival Following Relapse after Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia and MDS in the Contemporary Era

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4567-4567
Author(s):  
Sanghee Hong ◽  
Lisa Rybicki ◽  
Donna Corrigan ◽  
Betty K. Hamilton ◽  
Ronald Sobecks ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Cell Transplantation ◽  
Research Funding ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Treatment Strategies ◽  
Targeted Agents ◽  
Advisory Committees ◽  
Survival After Relapse ◽  
Grade Ii

Introduction: Relapse is the most frequent cause of treatment failure after allogeneic hematopoietic cell transplantation (alloHCT). While transplant-related mortality has decreased substantially over the last few decades, little progress has been made in outcomes and no standard of care exists for patients (pts) with post-alloHCT relapse. In the recent era, several new therapies, including targeted agents, have been approved for ALL, AML, and MDS. We conducted a study to evaluate outcomes of pts with these diseases who relapse after alloHCT in the contemporary period with routine availability of these newer therapeutic agents. Methods: We performed a single-institution retrospective cohort study to review treatment strategies and outcomes of relapse post-alloHCT. We identified 420 adult pts who received their first alloHCT in 2010-2018 using any conditioning regimen or donor source. Overall, 115 (27%) pts experienced relapse (ALL=17/64 [27%], AML=67/242 [28%], MDS=31/114 [27%]) and were included in the analysis. Results: Myeloablative (54%) matched-unrelated donor grafts (50%) were the most common types of HCTs. Peripheral blood stem cell graft (49%) and bone marrow graft (48%) were used the most. Median time from alloHCT to relapse was 5 (range 1-65) months, and 83% of relapses occurred within the first year. Only 24% and 11% of pts experienced grade II-IV acute and any chronic GVHD prior to relapse, respectively. Seven of 17 pts had Philadelphia chromosome positive ALL. Mutation panel was tested in 56% of AML and MDS. Median follow-up period after relapse was 19 (range 6-80) months. The estimated survival after relapse for all diseases was 32% (95% CI 24-41%) at 6 months, 21% (14-28%) at 12 months, and 14% (8-21%) at 24 months (Fig 1). Excluding pts treated with supportive care only, the majority received a combination of different treatments; pts with ALL received median 3 (range 1-5), pts with AML received median 2 (1-4), and pts with MDS received median 1 (1-3) agent. Targeted therapies used for ALL pts included blinatumomab (n=5) and BCR-ABL targeting tyrosine kinase inhibitors with (n=2) or without (n=4) chemotherapy. Among AML pts, targeted agents were used in 15 pts (sorafenib [n=7], 2 each with enasidenib, gemtuzumab ozagamicin, and ivosidenib, and 1 each with venetoclax and SEL24 [a dual pan-PIM/FLT3 inhibitor]). One pt each was treated with enasidenib, gemtuzumab ozagamicin, and PTC299 (an inhibitor of VEGFA mRNA translation) followed by SEL24 for MDS. Second alloHCTs (n=5) were performed median 5 (range 1-16) months after first HCT and median 1 month (range 0-5 months) after relapse. Two pts received no bridging therapy, while 3 pts received chemotherapy (n=2) or donor lymphocyte infusions (DLI [n=1]) prior to the second transplant. DLI without second transplant was used in 25 pts at a median of 20 (range 3-18) months after ALL relapse, median 2 (range 0-13) months after AML relapse, and median 3 (range 1-5) months after MDS relapse. Following DLI, 53% pts developed GVHD. Targeted therapy was associated with a trend towards better survival compared to other therapies (Fig 2, HR 0.65, 95% CI 0.41-1.03, p=0.06). Based on multivariable analysis, matched unrelated (vs. matched sibling, HR 1.70, p=0.027) or haploidentical donor grafts (HR 2.69, p=0.003), presence of grade II-IV acute GVHD before relapse (HR 2.46, p<0.001), and less than 12 months from HCT to relapse (<6 vs. >12 months, HR 6.34, p<0.001; 6-12 vs. >12 months, HR 3.16, p=0.005) were adverse prognostic features with survival after relapse post-alloHCT (Table 1). Conclusion: Outcomes of pts with ALL, AML, and MDS who relapse following alloHCT remain poor in the contemporary era when several newer therapies, including targeted agents, are available for their treatment. Targeted agents were used only in a minority of post-alloHCT relapses likely due to the combination of pt status, absence of the target mutation, the agents' availability, and other factors. Pts who developed grade II-IV acute GVHD and had shorter "disease-free" duration from unrelated or haploidentical donor grafts had the significantly shorter survival following relapse. More innovative treatment strategies to prevent and treat relapse post-alloHCT are needed. Disclosures Hill: Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celegene: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; TG therapeutics: Research Funding; Genentech: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding. Anwer:In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Majhail:Atara Bio: Consultancy; Anthem, Inc.: Consultancy; Nkarta: Consultancy; Mallinckrodt: Honoraria; Incyte: Consultancy.

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.

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

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

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

scholarly journals Poor Outcomes of HLA-Mismatched Allogeneic Hematopoietic Cell Transplantation and High Ferritin Levels after a Reduced-Intensity Conditioning Regimen in Patients with Advanced Myelofibrosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5742-5742
Author(s):  
Han Bi Lee ◽  
Jae-Ho Yoon ◽  
Gi June Min ◽  
Sung-Soo Park ◽  
Silvia Park ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Cell Transplantation ◽  
Research Funding ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Reduced Intensity Conditioning ◽  
Advisory Committees ◽  
Reduced Intensity

Allogeneic hematopoietic cell transplantation (allo-HCT) preconditioning intensity, donor choice, and graft-versus-host disease (GVHD) prophylaxis for advanced myelofibrosis (MF) have not been fully elucidated. Thirty-five patients with advanced MF were treated with reduced-intensity conditioning (RIC) allo-HCT. We searched for matched sibling (n=16) followed by matched (n=10) or mismatched (n=5) unrelated and familial mismatched donors (n=4). Preconditioning regimen consisted of fludarabine (total 150 mg/m2) and busulfan (total 6.4 mg/kg) with total body irradiation≤ 400cGy. All showed engraftments, but four (11.4%) showed either leukemic relapse (n=3) or delayed graft failure (n=1). Two-year overall survival (OS) and non-relapse mortality (NRM) was 60.0% and 29.9%, respectively. Acute GVHD was observed in 19 patients, and grade III-IV acute GVHD was higher with HLA-mismatch (70% vs. 20%, p=0.008). Significant hepatic GVHD was observed in nine patients (5 acute, 4 chronic), and six of them died. Multivariate analysis revealed inferior OS with HLA-mismatch (HR=6.40, 95%CI 1.6-25.7, p=0.009) and in patients with high ferritin level at post-HCT D+21 (HR=7.22, 95%CI 1.9-27.5, p=0.004), which were related to hepatic GVHD and high NRM. RIC allo-HCT can be a valid choice for advanced MF. However, HLA-mismatch and high post-HCT ferritin levels related to significant hepatic GVHD should be regarded as poor-risk parameters. Disclosures Kim: Handok: Honoraria; Amgen: Honoraria; 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; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Honoraria; BL & H: Research Funding; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding.

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.

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