Incorporating Immunotherapy Into the Treatment Strategies of B-Cell Adult Acute Lymphoblastic Leukemia: The Role of Blinatumomab and Inotuzumab Ozogamicin

2018 ◽  
pp. 574-578 ◽  
Author(s):  
Hagop Kantarjian ◽  
Elias Jabbour
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Pediatric Population ◽  
Lymphoblastic Leukemia ◽  
Treatment Strategies ◽  
Clinical Activity ◽  
Inotuzumab Ozogamicin ◽  
Term Survival ◽  
Drug Conjugates ◽  
Cure Rates

Monoclonal antibodies and bispecific antibody constructs hold considerable promise in improving the outcomes of patients with acute lymphoblastic leukemia (ALL). Antibody-drug conjugates such as inotuzumab ozogamicin and the bispecific T-cell engager blinatumomab represent novel antibody constructs that have shown substantial clinical activity in ALL. Although most studies have focused on the use of these agents in the salvage setting, incorporation of these antibodies into the frontline regimens is imperative to improve long-term survival for patients with ALL and to increase the cure rates of adult ALL to the levels achieved in the pediatric population.

scholarly journals How I treat relapsed acute lymphoblastic leukemia in the pediatric population

Blood ◽  
2020 ◽  
Vol 136 (16) ◽  
pp. 1803-1812 ◽  
Author(s):  
Stephen P. Hunger ◽  
Elizabeth A. Raetz
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Pediatric Population ◽  
Lymphoblastic Leukemia ◽  
Treatment Options ◽  
Survival Rates ◽  
Treatment Decision ◽  
Term Survival ◽  
Hematopoietic Stem ◽  
The Past

Abstract Relapsed acute lymphoblastic leukemia (ALL) has remained challenging to treat in children, with survival rates lagging well behind those observed at initial diagnosis. Although there have been some improvements in outcomes over the past few decades, only ∼50% of children with first relapse of ALL survive long term, and outcomes are much worse with second or later relapses. Recurrences that occur within 3 years of diagnosis and any T-ALL relapses are particularly difficult to salvage. Until recently, treatment options were limited to intensive cytotoxic chemotherapy with or without site-directed radiotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). In the past decade, several promising immunotherapeutics have been developed, changing the treatment landscape for children with relapsed ALL. Current research in this field is focusing on how to best incorporate immunotherapeutics into salvage regimens and investigate long-term survival and side effects, and when these might replace HSCT. As more knowledge is gained about the biology of relapse through comprehensive genomic profiling, incorporation of molecularly targeted therapies is another area of active investigation. These advances in treatment offer real promise for less toxic and more effective therapy for children with relapsed ALL, and we present several cases highlighting contemporary treatment decision-making.

Myths and Lessons from the Adult/Pediatric Interface in Acute Lymphoblastic Leukemia

Hematology ◽  
2006 ◽  
Vol 2006 (1) ◽  
pp. 128-132 ◽  
Author(s):  
Stephen E. Sallan
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Clinical Oncology ◽  
Lymphoblastic Leukemia ◽  
Response To Therapy ◽  
Adult Patients ◽  
Term Survival ◽  
Adults And Children ◽  
Outcome Differences ◽  
Cure Rates

Abstract The development of effective therapy for children with acute lymphoblastic leukemia (ALL) is one of the great successes of clinical oncology, with long-term survival achieved in over 80% of patients. However, cure rates for adults with ALL remain relatively low, with only 40% of patients cured. With an age-unrestricted, biology-based approach, we anticipate a better understanding about why these outcome differences exist, and think that by extending successful pediatric clinical programs to include adult patients with ALL, we can directly compare uniformly treated adults and children in terms of response to therapy, toxicity and underlying biology.

scholarly journals The Colony-Stimulating Factor 3 Receptor M696T Mutated in a Patient with Ph+ Acute Lymphoblastic Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 13-13
Author(s):  
Xin Chen ◽  
Bichen Wang ◽  
Aiming Pang ◽  
Erlie Jiang ◽  
Yajing Chu ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Myelogenous Leukemia ◽  
Unrelated Donor ◽  
Colony Stimulating Factor ◽  
Term Survival ◽  
Long Term Survival ◽  
Tumor Transformation ◽  
Stimulating Factor

Purpose: Colony-stimulating factor 3 receptor (CSF3R) mutations have been identified in a variety of myeloid disorders, such as severe congenital neutropenia (SCN), chronic neutrophilic leukemia (CNL), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and atypical chronic myelogenous leukemia (aCML). Although CSF3R point mutations (e.g., T618I) are emerging as key players in CNL/aCML, the significance of rarer CSF3R mutations is unknown. We report a case of philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) with the M696T mutation in CSF3R gene and assess the pathogenicity of the CSF3R M696T mutation in Ph+ ALL. Experimental Design: Here we report on a 32-year-old female who presented with asthenia. The initial hematological workup revealed white blood cell (WBC) count of 97 x 109/L (normal range 4-10 x 109/L). There was 84% prolymphocyte in the bone marrow. The immunophenotype of the blasts as judged from flow cytometry was in accordance with a B-ALL. The fusion gene for BCR-ABL P210 was positive. Hot mutation closely related to diseases was: CSF3R (nucleotide change c.2087 T>C, amino acid change p.M696T, mutation frequency 50.4%). Cytogenetic analysis showed 46, XX, t (9;22) (q34;q11). The patient was diagnosed as Ph+ ALL with the CSF3R M696T mutation and achieved Long-term survival after unrelated donor hematopoietic stem cell transplantation. Meanwhile we performed a series of experiments using murine interleukin 3 (IL-3)-dependent Ba/F3 cell line to evaluate the transforming capacity of the CSF3R M696T mutation. The phosphorylation of STAT3 was analyzed by G-CSF dependence assays and immunoblot analysis to evaluate the CSF3R M696T mutation contribution to the tumor transformation ability of Ba/F3 cells. Results: This patient achieved complete remission with chemotherapy in combination with tyrosine kinase inhibitor (TKI) and long-term survival by unrelated donor transplantation. We confirmed the presence of a CSF3R M696T germline mutation in this patient, and the mutation was inherited from her mother. The experiments in vitro result showed the CSF3R M696T mutation harbors marginal contribution to the tumor transformation ability of Ba/F3 cells. CSF3R M696T mutation was neutral in tumor transformation ability. Conclusions: We believe that TKI is still effective in patients with the CSF3R M696T mutation in Ph+ ALL. Donor with CSF3R M696T mutation might still be selected. Disclosures No relevant conflicts of interest to declare.

Intensive Asparaginase Therapy in Young Adult Patients with Acute Lymphoblastic Leukemia: Treatment Patterns and Barriers to Asparaginase Use

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4913-4913
Author(s):  
Leonard S Sender ◽  
Tina Doede ◽  
Megan P. Hall ◽  
Celine Bernard
Keyword(s):  
Overall Survival ◽  
Acute Lymphoblastic Leukemia ◽  
Young Adult ◽  
Lymphoblastic Leukemia ◽  
Adult Patients ◽  
Employment Equity ◽  
Term Survival ◽  
The Past ◽  
Equity Ownership

Abstract Background : Although considerable progress has been made in treating acute lymphoblastic leukemia (ALL) in the pediatric population, with long-term survival exceeding 80%, the prognosis for adolescents, young adult, and adult patients with ALL remains poor, with only 30%-45% of patients achieving long-term survival. Several studies suggest that young adult patients have superior overall survival when treated with intensive "pediatric-inspired" regimens that include the use of asparaginase [Dombret H, et al. Curr Hematol Malig Rep. 2014;9(2):158-164]. Despite these results, many young adult patients with ALL continue to be treated with chemotherapy regimens that include little or no asparaginase. The goal of this study was to assess the views and practices of hematologists and oncologists with respect to asparaginase use in young adult patients with ALL. Methods : This study was conducted between May 14 and June 22, 2015, and consisted of a 10-minute online quantitative survey, with a 10-minute per-patient chart audit component for up to 4 charts provided by participating physicians. The survey targeted physicians treating young adult patients (aged 18-40 years) with ALL. To be included in the final analysis, physicians were required to be board certified with 2-30 years in practice, with ≥75% of their time spent in direct patient care and ≥20% of their time spent in an academic setting (NCCN/NCI or academic/teaching hospital). Inclusion criteria also required that physicians' total ALL patient volume (young adults and adults aged >40 years) was greater than 5 over the past 2 years, that the physician primarily treats adult patients, and has personally managed and treated at least 1 young adult ALL patient in the past 2 years. Results: The study included results reported by a total of 63 practicing physicians for 189 young adult patients with ALL (62% were aged 25-40 years). Sixty percent (114/189) of young adult patients were treated with a protocol that included asparaginase, and only 29% (55/189) on a pediatric-inspired protocol. The most common protocols reported for patients receiving asparaginase included the pediatric-inspired CALGB 10403 (18%, 21/114), as well as regimens with more limited asparaginase use, including augmented hyper-CVAD (29%, 33/114) and CALGB 8811 (12%, 14/114). Overall 40% (75/189) of young adult patients were treated with protocols that did not include asparaginase, most commonly hyper-CVAD (77%, 58/75). Fifty percent (18/36) of responding physicians using hyper-CVAD reported the perception of similar outcomes with nonasparaginase regimens as with asparaginase-intensive regimens. When questioned about the greatest barrier to the use of intensive asparaginase-containing regimens, 88% (7/8) of responding physicians reported safety and tolerability concerns. Conclusion: Only 6 out of 10 patients in the study were treated with an asparaginase-containing regimen; of all patients, less than 1 out of 3 received a pediatric-inspired regimen. Fifty-three percent (60/114) of asparaginase-receiving patients were treated on a regimen that structures asparaginase dosing intermittently between alternating courses. Pediatric-inspired regimens include intensive asparaginase therapy and have consistently shown improvements in overall survival when compared with traditional adult protocols in clinical trials [Dombret H, et al. Curr Hematol Malig Rep. 2014;9(2):158-164]. Support: This study was funded by Jazz Pharmaceuticals. Disclosures Sender: Jazz Pharmaceuticals: Research Funding, Speakers Bureau. Doede:Jazz Pharmaceuticals: Employment, Equity Ownership. Hall:Jazz Pharmaceuticals: Employment, Equity Ownership. Bernard:Jazz Pharmaceuticals: Employment, Equity Ownership.

scholarly journals Moving immunotherapy into the front line in ALL

Hematology ◽  
2019 ◽  
Vol 2019 (1) ◽  
pp. 209-217 ◽  
Author(s):  
Amanda Winters ◽  
Lia Gore
Keyword(s):  
Myeloid Leukemia ◽  
Lymphoblastic Leukemia ◽  
Chemotherapy Resistance ◽  
Psychosocial Problems ◽  
Front Line ◽  
Antibody Drug Conjugate ◽  
Inotuzumab Ozogamicin ◽  
Term Survival ◽  
The Past

Abstract Although almost 90% of children with acute lymphoblastic leukemia (ALL) and ∼60% of children with acute myeloid leukemia are cured with frontline therapy, relapse and chemotherapy resistance are significant challenges that contribute to morbidity and mortality. Even with long-term survival, the acute and chronic burdens of therapy are major issues for patients and families. Long-term side effects occur, including cardiac, endocrinologic, neurcognitive, orthopedic, and psychosocial problems, and healthy survivorship is frequently compromised. With goals of minimizing relapse and/or decreasing traditional chemotherapy-associated toxicities, exploration of immunotherapeutic strategies has moved to the forefront in pediatric cancer. New immunotherapy approaches provide a major paradigm shift in oncology overall, often curing previously incurable patients. The past several years have yielded successful uses across a variety of malignancies, and enthusiasm continues to rise for applying these therapies more broadly. Herein we discuss current approaches incorporating the bispecific T-cell engager blinatumomab, the antibody-drug conjugate inotuzumab ozogamicin (InO), and CD19-directed chimeric antigen receptor T cells in children with relapsed/refractory B-cell ALL and discuss the potential for using these immunotherapies in the treatment of newly diagnosed children.

Inotuzumab ozogamicin (CMC-544) compared to chemotherapy in patients (pts) with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL): A retrospective comparison.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7095-7095
Author(s):  
Stefan Faderl ◽  
Nitin Jain ◽  
Susan Mary O'Brien ◽  
Deborah A. Thomas ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Survival Rates ◽  
Standard Of Care ◽  
Inotuzumab Ozogamicin ◽  
Term Survival ◽  
Retrospective Comparison ◽  
Multi Agent ◽  
Historical Controls

7095 Background: Modern multi-agent chemotherapy (CT) regimens result in complete remission (CR) rates of 80-90% and long-term survival rates of 40% in pts with ALL. The most common reason for treatment failure is relapse of the disease. Post-relapse therapies lead to second CR in 30-40% of pts with a 5-year survival of <10%. CD22 expression occurs in >90% of pts with ALL. Inotuzumab ozogamicin (IO) is a CD22 monoclonal antibody bound to a toxin, calecheamicin. We reported overall response rate of 57% with single-agent IO in R/R ALL (Kantarjian, Lancet Oncology 2012). Methods: We analyzed the outcomes of patients with R/R ALL treated with single-agent IO (n=90) vs. historical controls (n=292) treated with combination CT at our institution from 1990-2008. IO was dosed at 1.8 mg/m2 every 3-4 weeks (first 41 pts), and later weekly dosing (0.8 mg/m2 day 1, 0.5 mg/m2 on days 8 and 15, every 3-4 weeks). Fifty-percent of historical controls were treated with hyper-CVAD CT (n=147). Results: The median age in the IO cohort was 39.5 years (yrs) (range 4-84) and in the CT cohort was 37 yrs (range 14-81). Overall CR/CRp rate was 49% with IO vs. 29% with CT. In salvage 1, CR/CRp rate was significantly better with IO [66% vs. 40% with CT (p=0.007)]. When only hyper-CVAD-based regimens were included, the CR/CRp was not statistically different (66% with IO vs. 56% with hyper-CVAD, p=0.332). In salvage 1, the median overall survival (OS) was 9.2 months (mos) with IO vs. 6.2 mos with CT (p=0.06 compared with IO) vs. 7.9 mos with hyper-CVAD (p=0.48 compared with IO). In salvage 2, CR/CRp rate was better with IO vs. CT (44% vs. 16%, p=<0.001); OS was not different (4.3 mos vs. 2.5 mos, p=0.74). In salvage 3, CR/CRp rate was better with IO vs. CT (46% vs. 19%, p=0.03); OS was also better with IO vs. CT (6.6 mos vs. 2.6 mos, p=0.01). In salvage 4, CR/CRp rate was better with IO vs. CT (27% vs. 9%, p=0.01); OS was not statistically different (7.4 mos vs. 1.9 mos, p=0.09). Conclusions: In pts with R/R ALL, outcomes after single-agent IO are better than pts treated with CT alone. In addition, IO has fewer side effects than CT. IO has the potential to replace multi-agent CT as standard of care for treatment of pts with R/R ALL.

Achievement of Minimal Residual Disease Negativity By Multiparameter Flow Cytometry Is an Important Therapeutic Endpoint in Patients with Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia Receiving Salvage Treatment

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2916-2916 ◽  
Author(s):  
Nicholas J. Short ◽  
Hagop M. Kantarjian ◽  
Jeffrey L. Jorgensen ◽  
Farhad Ravandi ◽  
Musa Yilmaz ◽  
...  
Keyword(s):  
Research Funding ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Advisory Board ◽  
Multiparameter Flow Cytometry ◽  
Inotuzumab Ozogamicin ◽  
Term Survival ◽  
Minimal Residual

Abstract Background: Minimal residual disease (MRD) assessment by multiparameter flow cytometry (MFC) is prognostic for survival in newly diagnosed patients (pts) with acute lymphoblastic leukemia (ALL). The significance of achieving MRD negativity in the relapsed/refractory setting is less clear. Methods: Between 6/2010 and 5/2015, we identified 130 adult pts with relapsed/refractory B-cell ALL treated at our institution with either inotuzumab ozogamicin (n=75), blinatumomab (n=20) or mini-hyper-CVD plus inotuzumab ozogamicin (HCVD+InO; n=35) in either salvage 1 (S1; n=68) or salvage 2 (S2; n=62). MRD by MFC was assessed on remission bone marrow specimens at the time of achievement of CR/CRp/CRi. The MRD assay used a 15-marker, 6-color panel with a sensitivity of ≤0.01%. Results: Of the initial 130 pts, 78 (60%) achieved morphological response with a median time to response of 30 days (range, 13-99 days) and are the subject of this analysis. Of the 78 responding pts, 41 (53%) received inotuzumab, 11 (14%) blinatumomab, and 26 (33%) HCVD+ino. 46 pts (59%) were in S1 and 32 (41%) in S2. The median number of cycles to best response was 1 (range, 1-3). MRD negativity was achieved in 41 pts (53%). MRD negativity rates for pts in CR, CRp, and CRi were 57%, 53%, and 16%, respectively. Among pts who achieved remission, MRD negativity was achieved in 17 pts (41%) with inotuzumab, 8 (73%) with blinatumomab, and 16 (62%) with HCVD+InO (P=0.10). 26 pts (57%) in S1 and 15 (47%) in S2 became MRD-negative (P=0.40). The median follow-up duration was 27 months (range, 6-55 months). The median event-free survival (EFS) was 12 months in pts who achieved MRD negativity vs. 6 months in those who remained MRD-positive (P=0.09). The median overall survival (OS) was 17 months versus 9 months, respectively (P=0.18). Among pts in S1, achieving MRD negativity was associated with a longer EFS (median 18 months versus 7 months; 2-year EFS rate 46% versus 17%; P=0.06; Figure 1A) and OS (median 27 months versus 9 months; 2-year OS 52% versus 36%; P=0.15; Figure 1B). EFS and OS were similar in S2 regardless of MRD response. As expected, among pts who achieved MRD negativity, those in S1 had longer EFS (median 18 months vs. 5 months; P=0.001) and OS (median 27 months vs. 7 months; P=0.01) compared to those in S2. In contrast, for pts who remained MRD-positive, EFS and OS were similar regardless of salvage status (P=0.41 and P=0.39, respectively). In a 2-month landmark analysis of 64 pts, survival >2 years was observed in all groups of pts regardless of salvage treatment, salvage status or MRD status. 42 (66%) of the pts in this analysis underwent allogeneic stem cell transplantation (alloSCT). EFS and OS did not significantly differ between pts who did or did not undergo alloSCT, although a clear trend for improved long-term survival with alloSCT was observed. Among pts who achieved MRD negativity, the median EFS was 17 months and 12 months, and 2-year EFS rates were 46% and 28% for pts who underwent alloSCT vs. those who did not (P=0.24). The median OS was 24 months and 23 months, and 2-year OS rates were 55% and 46%, respectively (P=0.41). Pts who achieved MRD negativity after S1 treatment and then underwent alloSCT had the best outcomes. Of the 22 pts who achieved MRD negativity after S1 treatment, the median EFS for pts who underwent alloSCT (n=14) compared to those who did not (n=8) was not reached vs. 18 months, and the median OS was not reached vs. 27 months, respectively (P=0.28 for both). Among the 14 pts who achieved MRD negativity after S1 treatment and subsequently underwent alloSCT, 10 (71%) are still alive with a median follow-up of 24 months (range, 5-55 months). Conclusions: In patients with relapsed/refractory ALL, achievement of MRD negativity is associated with improved outcomes. Patients with relapsed/refractory ALL who achieve MRD negativity in S1 can achieve excellent long-term survival, especially if alloSCT is performed. Disclosures O'Brien: Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. DiNardo:Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Agios: Other: advisory board, Research Funding. Jain:Genentech: Research Funding; Incyte: Research Funding; BMS: Research Funding; Celgene: Research Funding; Infinity: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Novimmune: Consultancy, Honoraria; Abbvie: Research Funding; Seattle Genetics: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Konopleva:Cellectis: Research Funding; Calithera: Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy.

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