Monoclonal Antibody-Based Therapies in the Treatment of Acute Lymphoblastic Leukemia

2013 ◽  
pp. 294-299 ◽  
Author(s):  
Mark R. Litzow
Keyword(s):  
Monoclonal Antibody ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Response Rates ◽  
Cytotoxic Agents ◽  
Single Chain ◽  
Stages Of Development

Recent studies have suggested that pediatric-intensive chemotherapy regimens can improve outcomes in adults with acute lymphoblastic leukemia (ALL) up to the age of 45. Above this age, toxicities increase. Monoclonal antibody-based therapies bring the promise of increased response rates without excessive toxicity. The addition of rituximab to combination chemotherapy has shown encouraging results. Newer monoclonal antibody-based therapies linked to cytotoxic agents show promise. These include inotuzumab ozogamicin, an anti-CD22 antibody linked to calicheamicin that has produced significant single-agent responses in relapsed and refractory ALL. Other monoclonal antibodies linked to plant or bacterial toxins are in earlier stages of development. Blinatumomab is a novel bispecific T-cell engaging antibody that combines single chain antibodies to CD19 and CD3 and brings a T cell in close proximity to a leukemic lymphoblast with resulting redirected lysis. This agent has demonstrated encouraging results in both the minimal residual disease setting and the relapsed/refractory setting. Autologous chimeric antigen receptor cells have shown promising responses in indolent B-cell lymphoid malignancies and are being tested in ALL. Many of these agents have the potential to increase response rates in older adults. Trials of many of these monoclonal antibody-based therapies are in various stages of development in the treatment of newly diagnosed ALL.

scholarly journals Recent updates for antibody therapy for acute lymphoblastic leukemia

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Le Li ◽  
Ying Wang
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Complete Remission ◽  
Median Survival ◽  
Residual Disease ◽  
Hematologic Malignancy ◽  
Lymphoblastic Leukemia ◽  
Cytotoxic Agents ◽  
Great Promise ◽  
T Cell Therapy

AbstractAcute lymphoblastic leukemia (ALL) is a hematologic malignancy arising from precursors of the lymphoid lineage. Conventional cytotoxic chemotherapies have resulted in high cure rates of up to 90% in pediatric ALL, but the outcomes for adult patients remain suboptimal with 5-year survival rates of only 30%-40%. Current immunotherapies exploit the performance of antibodies through several different mechanisms, including naked antibodies, antibodies linked to cytotoxic agents, and T-cell re-directing antibodies. Compared with chemotherapy, the application of an antibody–drug conjugates (ADC) called inotuzumab ozogamicin in relapsed or refractory (R/R) CD22+. ALL resulted in a complete remission (CR) rate of 81% and an overall median survival of 7.7 months with reduced toxicity. Similarly, blinatumomab, the first FDA-approved bispecific antibody (BsAb), produced a 44% complete response rate and an overall median survival of 7.7 months in a widely treated ALL population. In addition, approximately 80% of patients getting complete remission with evidence of minimal residual disease (MRD) achieved a complete MRD response with the use of blinatumomab. These results highlight the great promise of antibody-based therapy for ALL. How to reasonably determine the place of antibody drugs in the treatment of ALL remains a major problem to be solved for ongoing and future researches. Meanwhile the combination of antibody-based therapy with traditional standard of care (SOC) chemotherapy, chimeric antigen receptor (CAR) T-cell therapy and HSCT is also a challenge. Here, we will review some important milestones of antibody-based therapies, including combinational strategies, and antibodies under clinical development for ALL.

A Systematic Review of Blinatumomab in the Treatment of Acute Lymphoblastic Leukemia: Engaging an Old Problem With New Solutions

2021 ◽  
pp. 106002802098841
Author(s):  
Zachery Halford ◽  
Carli Coalter ◽  
Vanessa Gresham ◽  
Tabitha Brown
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cell ◽  
T Cell Activation ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Phase Iii ◽  
Cytotoxic T Cell ◽  
Bispecific T Cell Engager

Objective: To assess the current literature for blinatumomab in the treatment of adult and pediatric B-cell acute lymphoblastic leukemia (ALL). Data Sources: We conducted a PubMed (inception to December 11, 2020) and ClinicalTrials.gov systematic literature search using the following terms: blinatumomab, Blincyto, lymphoblastic leukemia, and bispecific T-cell engager. Study Selection and Data Extraction: All relevant published articles, package inserts, and meeting abstracts evaluating the use of blinatumomab in ALL were considered for inclusion. Data Synthesis: Blinatumomab, a first-in-class bispecific T-cell engager monoclonal antibody, facilitates cytotoxic T-cell activation and subsequent eradication of CD19-positive B cells. The confirmatory phase III TOWER trial demonstrated superior overall survival (OS) with blinatumomab compared with standard chemotherapy (7.7 months vs 4.0 months) in relapsed and refractory (R/R) B-cell ALL. In the phase II BLAST trial, blinatumomab achieved a complete measurable residual disease (MRD) response in 78% of evaluable patients, with a median OS of 36.5 months. Potentially life-threatening cytokine release syndrome and neurotoxicity occurred in approximately 15% and 65% of patients, respectively. Relevance to Patient Care and Clinical Practice: Following initial Food and Drug Administration approval in 2014, blinatumomab gained expanded approval in pediatric patients and in Philadelphia chromosome-positive R/R ALL. In 2018, blinatumomab became the first and only drug approved for the treatment of persistent MRD in any hematologic malignancy. Emerging data demonstrate promising efficacy with blinatumomab in specific ALL settings, including frontline therapy, as a bridge to transplantation, and in “chemotherapy-free” combination regimens. Conclusions: Blinatumomab provides a paradigm-shifting treatment option; however, many questions surrounding optimal patient selection, sequencing, and cost-effectiveness remain.

scholarly journals G19.4(alpha CD3) x B43(alpha CD19) monoclonal antibody heteroconjugate triggers CD19 antigen-specific lysis of t(4;11) acute lymphoblastic leukemia cells by activated CD3 antigen-positive cytotoxic T cells

Blood ◽  
1992 ◽  
Vol 80 (11) ◽  
pp. 2826-2834
Author(s):  
PM Anderson ◽  
W Crist ◽  
D Hasz ◽  
AJ Carroll ◽  
DE Myers ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Cytotoxic T Cells ◽  
Lymphoblastic Leukemia ◽  
Interleukin 2 ◽  
Cytolytic Activity ◽  
Multiparameter Flow Cytometry ◽  
Specific Lysis

A highly purified, 300-Kd bispecific monoclonal antibody (MoAb) heteroconjugate was prepared by covalently linking the anti-CD3 MoAb, G19.4, to the anti-CD19 MoAb, B43. Dual-color staining techniques and multiparameter flow cytometry confirmed that this alpha CD3 x alpha CD19 heteroconjugate was able to bind to both CD3+ T cells and CD19+ t(4;11) acute lymphoblastic leukemia (ALL) cells. T-cell-mediated lysis of freshly isolated primary bone marrow blasts from nine newly diagnosed ALL patients with a t(4;11)(q21;q23) chromosomal translocation were studied with 51Cr-release assays. Picomolar concentrations of alpha CD3 x alpha CD19 MoAb heteroconjugate effectively triggered lysis of CD19+ t(4;11) ALL cells by interleukin-2- activated CD3+ peripheral blood T-cell (PBTC) effectors but did not augment the cytolytic activity of the same effectors against CD19- T- ALL cells. In contrast to the alpha CD3 x alpha CD19 heteroconjugate, neither the alpha CD3 x alpha CD3 homoconjugate control nor the alpha CD19 x alpha CD72 heteroconjugate control facilitated the cytolysis of t(4;11) ALL blasts. Occupation of the target CD19 binding sites on t(4;11) ALL blasts by preincubation with excess unconjugated alpha CD19 MoAb abrogated the potentiating effects of the alpha CD3 x alpha CD19 heteroconjugate on PBTC-mediated cytolysis. Thus, the cell type- specific cytolysis of t(4;11) ALL blasts by PBTC effectors is dependent on both the alpha CD19 and alpha CD3 moieties of the alpha CD3 x alpha CD19 heteroconjugate. To our knowledge, this is the first description of an effective bispecific antibody that facilitates the T-cell- mediated lysis of t(4;11) ALL blasts.

scholarly journals Detectable Molecular Residual Disease at the Beginning of Maintenance Therapy Indicates Poor Outcome in Children With T-Cell Acute Lymphoblastic Leukemia

Blood ◽  
1997 ◽  
Vol 90 (3) ◽  
pp. 1226-1232 ◽  
Author(s):  
Salvatore P. Dibenedetto ◽  
Luca Lo Nigro ◽  
Sharon Pine Mayer ◽  
Giovanni Rovera ◽  
Gino Schilirò
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Maintenance Therapy ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Strong Predictor ◽  
Blot Hybridization ◽  
Cell Receptor ◽  
Dot Blot ◽  
Poor Outcome

Abstract The aims of this study were twofold: (1) to assess the marrow of patients with T-lineage acute lymphoblastic leukemia (T-ALL) for the presence of molecular residual disease (MRD) at different times after diagnosis and determine its value as a prognostic indicator; and (2) to compare the sensitivity, rapidity, and reliability of two methods for routine clinical detection of rearranged T-cell receptor (TCR). Marrow aspirates from 23 patients with T-ALL diagnosed consecutively from 1982 to 1994 at the Division of Pediatric Hematology and Oncology, University of Catania, Italy, were obtained at diagnosis, at the end of induction therapy (6 to 7 weeks after diagnosis), at consolidation and/or reinforced reinduction (12 to 15 weeks after diagnosis), at the beginning of maintenance therapy (34 to 40 weeks after diagnosis), and at the end of therapy (96 to 104 weeks after diagnosis). DNA from the patients' marrow was screened using the polymerase chain reaction (PCR) for the four most common TCR δ rearrangements in T-ALL (Vδ1Jδ1, Vδ2Jδ1, Vδ3Jδ1, and Dδ2Jδ1) and, when negative, further tested for the presence of other possible TCR δ and TCR γ rearrangements. After identification of junctional rearrangements involving V, D, and J segments by DNA sequencing, clone-specific oligonucleotide probes 5′ end-labeled either with fluorescein or with [γ-32P]ATP were used for heminested PCR or dot hybridization of PCR products of marrows from patients in clinical remission. For 17 patients with samples that were informative at the molecular level, the estimated relapse-free survival (RFS) at 5 years was 48.6% (±12%). The sensitivity and specificity for detection of MRD relating to the outcome were 100% and 88.9% for the heminested fluorescence PCR and 71.4% and 88.9% for Southern/dot blot hybridization, respectively. Predictive negative and positive values were 100% and 90.7% for heminested fluorescence PCR, respectively. The probability of RFS based on evidence of MRD as detected by heminested fluorescence PCR at the time of initiation of maintenance therapy was 100% and 0% for MRD-negative and MRD-positive patients, respectively. Thus, the presence of MRD at the beginning of maintenance therapy is a strong predictor of poor outcome, and the molecular detection of MRD at that time might represent the basis for a therapeutic decision about such patients. By contrast, the absence of MRD at any time after initiation of treatment strongly correlates with a favorable outcome. The heminested fluorescence PCR appears to be more accurate and more rapid than other previously used methods for the detection of residual leukemia.

scholarly journals Phase 2 study of pembrolizumab for measurable residual disease in adults with acute lymphoblastic leukemia

2020 ◽  
Vol 4 (14) ◽  
pp. 3239-3245
Author(s):  
Ryan D. Cassaday ◽  
Kelsey-Leigh A. Garcia ◽  
Jonathan R. Fromm ◽  
Mary-Elizabeth M. Percival ◽  
Cameron J. Turtle ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Quantitative Polymerase Chain Reaction ◽  
Philadelphia Chromosome ◽  
Stevens Johnson Syndrome ◽  
Phase 2 ◽  
Phase 2 Study ◽  
Measurable Residual Disease

Abstract The presence of measurable residual disease (MRD) in acute lymphoblastic leukemia (ALL) confers a poor prognosis. CD19-targeted immunotherapy is effective against MRD but is logistically challenging, potentially toxic, and not applicable to T-cell ALL. We thus hypothesized that inhibition of PD-1 with pembrolizumab could also be effective for MRD, but without lineage restriction. The primary objective of this phase 2 study was to evaluate the efficacy of pembrolizumab in patients with ALL and MRD. Key eligibility criteria included adults with B- or T-cell ALL and MRD detectable by multiparameter flow cytometry or quantitative polymerase chain reaction from bone marrow aspirate (BMA) despite chemotherapy (plus ABL kinase inhibitor if Philadelphia chromosome positive). Pembrolizumab 200 mg IV was given every 3 weeks. Response was assessed by BMA using methods that previously detected MRD. The primary end point was complete MRD response rate. We stopped enrollment early; only 1 of 12 (8%) experienced a complete MRD response, which lasted 3 weeks. Interestingly, this patient had previously received hematopoietic cell transplantation and CD19-targeted chimeric antigen receptor–modified T-cell therapy and was the only patient to experience an immune-related adverse event from pembrolizumab (grade 3 Stevens-Johnson syndrome). Median overall survival from enrollment was 12.7 months. In summary, pembrolizumab had minimal activity against MRD but was generally well tolerated. These data can be compared with ongoing anti-PD-1 combination studies in ALL, and they further establish the role of trials specifically for patients with MRD. This trial was registered at www.clinicaltrials.gov as #NCT02767934.

scholarly journals Frequent ongoing T-cell receptor rearrangements in childhood B- precursor acute lymphoblastic leukemia: implications for monitoring minimal residual disease

Blood ◽  
1995 ◽  
Vol 86 (2) ◽  
pp. 692-702 ◽  
Author(s):  
EJ Steenbergen ◽  
OJ Verhagen ◽  
EF van Leeuwen ◽  
H van den Berg ◽  
AE von dem Borne ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Southern Blot ◽  
T Cell Receptor ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Cell Receptor ◽  
First Relapse ◽  
Minimal Residual

Crosslineage T-cell receptor delta (TCR delta) rearrangements are widely used as tumor markers for the follow up of minimal residual disease in childhood B-precursor acute lymphoblastic leukemia (ALL) by polymerase chain reaction (PCR). The major drawback of this approach is the risk of false-negative results due to clonal evolution. We investigated the stability of V delta 2D delta 3 rearrangements in a group of 56 childhood B-precursor ALL patients by PCR and Southern blot analysis. At the PCR level, V delta 2D delta 3-to-J alpha rearranged subclones (one pathway for secondary TCR delta recombination) were demonstrated in 85.2% of V delta 2D delta 3-positive patients tested, which showed that small subclones are present in the large majority of patients despite apparently monoclonal TCR delta Southern blot patterns. Sequence analysis of V delta 2D delta 3J alpha rearrangements showed a biased J alpha gene usage, with HAPO5 and J alpha F in 26 of 32 and 6 of 32 clones, respectively. Comparison of V delta 2D delta 3 rearrangement status between diagnosis and first relapse showed differences in seven of eight patients studied. In contrast, from first relapse onward, no clonal changes were observed in six patients studied. To investigate the occurrence of crosslineage TCR delta rearrangements in normal B and T cells, fluorescence-activated cell sorter-sorted peripheral blood CD19+/CD3- and CD19-/CD3+ cell populations from three healthy donors were analyzed. V delta 2D delta 3 rearrangements were detected at low frequencies in both B and T cells, which suggests that V delta 2-to-D delta 3 joining also occurs during normal B-cell differentiation. A model for crosslineage TCR delta rearrangements in B-precursor ALL is deduced that explains the observed clonal changes between diagnosis and relapse and is compatible with multistep leukemogenesis of B-precursor ALL.

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