Blinatumomab In pediatric relapsed/refractory B-cell acute lymphoblastic leukemia: RIALTO expanded access study final analysis

The safety and efficacy of blinatumomab, a CD3/CD19-directed bispecific T-cell engager molecule, for treatment of pediatric relapsed/refractory B-cell precursor acute lymphoblastic leukemia (R/R B-ALL) were examined in an open-label, single-arm, expanded access study (RIALTO). Children (>28 days, <18 years) with CD19+ R/R B-ALL received up to five cycles of blinatumomab by continuous infusion (cycle: 4 weeks on/2 weeks off). The primary endpoint was incidence of adverse events. Secondary endpoints included complete response (CR) and measurable residual disease (MRD) response within the first two cycles, relapse-free survival (RFS), overall survival (OS) and allogeneic hematopoietic stem cell transplant (alloHSCT) after treatment. At final data cutoff (1/10/20), 110 patients were enrolled (median age, 8.5 years; 88% ≥5% blasts at baseline). Blinatumomab treatment resulted in a low incidence of grade 3-4 cytokine release syndrome (n=2 [1.8%]) and neurologic events (n=4 [3.6%]). No blinatumomab-related fatal adverse events were reported. The probability of response was not affected by the presence of cytogenetic/molecular abnormalities. Median OS was 14.6 months (95%CI: 11.0─not estimable) and was significantly greater for MRD responders versus MRD non-responders (not estimable vs 9.3; HR 0.18, 95%CI: 0.08─0.39). One-year OS probability was higher for patients who received alloHSCT versus without alloHSCT post-blinatumomab (87% versus 29%). Median RFS for MRD responders (n=57) was 8.0 months (95%CI:3.4─10.1) versus 2.8 months (95%CI: 0.3─9.2) for MRD non-responders (n=10). Of patients achieving CR after 2 cycles, 73.5% (95%CI: 61.4%-83.5%) proceeded to alloHSCT. These findings support the use of blinatumomab as a safe and efficacious treatment for pediatric R/R B-ALL. (ClinicalTrials.gov identifier NCT02187354)

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Bispecific T-cell engaging antibodies in B-cell precursor acute lymphoblastic leukemias: focus on blinatumomab

Therapeutic Advances in Hematology ◽

10.1177/2040620720919632 ◽

2020 ◽

Vol 11 ◽

pp. 204062072091963

Author(s):

Jose-Maria Ribera ◽

Eulalia Genescà ◽

Jordi Ribera

Keyword(s):

T Cell ◽

B Cell ◽

De Novo ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Development Program ◽

Cell Transplant ◽

Cell Precursor ◽

Hematopoietic Stem ◽

Clinical Development Program

Bispecific T-cell engaging antibodies are constructs engineered to bind to two different antigens, one to a tumor-specific target and the other to CD3-positive T cells or natural killer (NK) cells. Blinatumomab engages CD19 and CD3, performing effective serial lysis. The clinical development program in acute lymphoblastic leukemia (ALL) includes clinical trials in relapsed or refractory (R/R) patients and in B-cell precursor (BCP) ALL patients with measurable residual disease. Several trials are currently being conducted in de novo BCP-ALL, either in induction, consolidation, or before or after hematopoietic stem cell transplant. Combination with other targeted therapies or with other immunotherapeutic approaches are also underway. Several strategies are aimed to optimize the use of blinatumomab either by overcoming the mechanisms of resistance (e.g. inhibition of PD-1/PD-L1) or by improvements in the route of application, among others.

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Targeting Survivin with YM155 As a Potential Therapy in Pediatric Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood.v118.21.2490.2490 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2490-2490

Author(s):

Abdusebur Jemal ◽

Jeffrey W Tyner ◽

Mathew Thayer ◽

Markus Muschen ◽

Brian J. Druker ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

B Cell ◽

Cell Lines ◽

Lymphoblastic Leukemia ◽

Ectopic Expression ◽

Survivin Expression ◽

Cell Transplant ◽

Hematopoietic Stem ◽

Pediatric Acute Lymphoblastic Leukemia ◽

Pediatric All

Abstract Abstract 2490 Background: Pediatric Acute Lymphoblastic Leukemia (ALL) remains the most common pediatric malignancy. Despite advances in treatment and outcomes, there continue to be subsets of patients that are refractory to standard intensive chemotherapy and hematopoietic stem cell transplant. Therefore, novel gene targets for therapy are needed to further advance treatment for this disease. Survivin, a member of the chromosome passenger complex and inhibitor of apoptosis has been shown to be over-expressed in malignant cells and in relapsed ALL. Therefore, survivin may be a potential target for therapy in pediatric ALL. The selective survivin suppressant, YM155 (Astellas) has been shown to inhibit survivin expression and activate cell death in multiple cell lines. Early phase I studies show promise in both tolerability and possible efficacy in B-cell malignancies. Therefore, this drug may have the potential of improving treatment for pediatric B-cell precursor ALL. Design/methods: Pediatric lymphoblastic cell lines, fresh primary lymphoblast cells from newly diagnosed patients with ALL and xenografted patient samples were used in this study. Cells were incubated in the presence of YM155 at doses ranging from 1nM to 10μM. Viability was measured using a standard methane-thiosulfonate viability assay. Activation of apoptosis was identified using the Guava nexin Annexin V binding assay for cell lines. Results: Treatment of ALL cell lines, primary patient samples and xenograft samples show a dose-dependent sensitivity to YM155 by both activation of apoptosis and by cell viability. IC50 doses for the majority of the samples are in the low nanomolar range (Table). Interestingly, there is some variability amongst patient samples suggesting possible variable responses in vivo. Ectopic expression of survivin in cell lines treated with YM155 rescues the effect of the drug. Further, t(9;22) positive ALL samples, including primary patient, xenograft, and dasatinib resistant samples remain significantly sensitive to YM155. For dasatinib sensitive Ph+ALL samples, combination therapy suggest an additive effect by isobologram analysis. Conclusion: Pediatric ALL samples remain sensitive to treatment with YM155 in cell lines, primary patient and xenografted samples. The results of these experiments will be used as a foundation to develop a comprehensive understanding of the mechanisms of survivin dependence in pediatric ALL. Future studies will also be designed to develop YM155 as an additional therapy for pediatric acute lymphoblastic leukemia. Disclosures: Druker: Cylene:; MolecularMD:; Novartis:; Bristol-Myers-Squibb:.

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A Successful Re-Induction Regimen for Relapsed Pediatric Acute Lymphoblastic Leukemia.

Blood ◽

10.1182/blood.v110.11.863.863 ◽

2007 ◽

Vol 110 (11) ◽

pp. 863-863

Author(s):

Jason Ackerman ◽

Douglas Hawkins ◽

Karyn Brundige ◽

Laura Eisenberg ◽

Blythe Thomson

Keyword(s):

Stem Cell ◽

Acute Lymphoblastic Leukemia ◽

T Cell ◽

B Cell ◽

Induction Therapy ◽

Lymphoblastic Leukemia ◽

Cell Transplant ◽

Hematopoietic Stem ◽

Induction Regimen ◽

First Relapse

Abstract Background: Acute Lymphoblastic Leukemia (ALL) is the most common form of malignancy in children. Advances in treatments have made ALL the disease highly curable; however relapse is the most common form of treatment failure. The prognosis for relapsed ALL is poor, and the ability to achieve a durable second remission is influenced by the length of the initial remission and, potentially, the re-induction therapy chosen. We present a series of 60 pediatric ALL patients with first relapse (54 pre B-cell and 6 T-cell) treated with a standardized four-drug induction therapy followed by either intensification therapy or hematopoietic stem cell transplant (HSCT). Methods: Patients treated at Children’s Hospital and Regional Medical Center, Seattle, WA with a common re-induction regimen for first relapse ALL were reviewed in this IRB-approved retrospective study. Patients included isolated or combined bone marrow (BM) relapse, isolated central nervous system (CNS) relapse alone, or isolated testicular relapse. Re-induction consisted of a four-drug combination of dexamethasone (dex) (day 0-6, 14-20), vincristine (VCR) (weekly for 4 weeks), peg-aspargase (weekly for 4 weeks), and idarubicin (10 mg/m2/day × 2-3 doses) and intrathecal triple (ITT) drug therapy. After achieving second complete remission (CR2), patients proceeded to HSCT or continued chemotherapy at the discretion of the physician. Allogeneic HSCT was total body irradiation based and a variety of stem cell sources. Continuation chemotherapy was alternating blocks every 3 weeks for up to 8 courses: Block A, consisting of dex, VCR, 6-thioguanine (TG), peg-asparagase and methotrexate (MTX) and ITT, and Block B, consisting of etoposide and ifosfamide and ITT. Maintenance chemotherapy with MTX, VCR and TG with cranial, craniospinal or testicular radiation completed the two year regimen. Results: Among the 54 pre-B-cell patients, there were 32 with BM relapse (either isolated or with CNS), 16 CNS relapses, and 6 testicular relapses. CR2 was achieved in 96% of the patients. Two did not achieve remission, dying of toxicity during re-induction. BM (± CNS) Isolated CNS Testicular Duration of CR1 n 3 yr. EFS (95% CI) n 3 yr. EFS (95% CI) n 3 yr. EFS (95% CI) <18 months 5 0% (± 52%) 3 67% (± 54%) - - >18 months 27 39% (± 24%) 13 75% (± 26%) 6 67% (± 38%) Among the patients with BM relapse, the 3 year Event Free Survival (EFS) was 33.2% (95% CI: ± 20.8%). The 3 year EFS for the 18 who proceeded to HSCT was 35.0% (95% CI: ± 27.4%), while 3-year EFS for chemotherapy only patients was 31.7% (95% CI: ± 31.8%). There were 6 patients with T-cell relapsed disease, which were evaluated separately. Their EFS was 0% (95% CI: ±46%) at three years, and 2 failed to achieve CR2. Discussion: We present a large single institution series of patients treated with a common reinduction regimen followed by chemotherapy or HSCT. Although intensive, the regimen was tolerable (less than 4% toxic death rate) and highly successful in achieving CR2. Among the patients with later BM relapse, there was minimal difference in 3-year EFS between chemotherapy and HSCT, offering a reasonable continuation chemotherapy regimen to these patients. Our data confirmed the excellent outcome of isolated CNS and testicular relapse and the poor outcome of very early relapse and T cell disease.

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Clinical-biological characteristics and treatment outcomes of pediatric pro-B ALL patients enrolled in BCH-2003 and CCLG-2008 protocol: a study of 121 Chinese children

Cancer Cell International ◽

10.1186/s12935-019-1013-9 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 2

Author(s):

Chao Gao ◽

Shu-Guang Liu ◽

Zhi-Xia Yue ◽

Yi Liu ◽

Jing Liang ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

B Cell ◽

Treatment Outcomes ◽

Residual Disease ◽

Early Stage ◽

Lymphoblastic Leukemia ◽

Biological Characteristics ◽

Hematopoietic Stem ◽

Dismal Prognosis ◽

Cell Acute Lymphoblastic Leukemia

Abstract Background Although leukemic blast cells of Pro-B cell acute lymphoblastic leukemia (ALL) are arrested at the same stage of B cell differentiation, the immature B cell subtype is still biologically heterogeneous and is associated with diverse outcomes. This study aimed to explore the clinical-biological characteristics of pediatric pro-B ALL and factors associated with outcomes. Methods This study enrolled 121 pediatric patients aged 6 months to 14 years with newly diagnosed CD19+CD10− pro-B cell acute lymphoblastic leukemia (pro-B ALL) treated at Beijing Children’s Hospital from March 2003 to October 2018. Genetic abnormalities, immunophenotypic markers, minimal residual disease (MRD) at early treatment stage and long-term outcomes of children treated on two consecutive protocols were analyzed. Results KMT2A rearrangements were the most frequent abnormalities (incidence rate 33.06%), and were associated with lower frequency of CD13, CD33, CD22 and CD34 expression and higher frequency of CD7 and NG2 expression. Higher frequency of CD15 and CD133 expression was found in KMT2A-AFF1+ patients, exclusively. Presence of CD15 and absence of CD34 at diagnosis correlated with the high burden of MRD at the early stage of treatment. Outcomes were more favorable in patients older than 1 year, with absence of CD20 expression and KMT2A rearrangements, and with MRD lower than 1% at the end of induction and 0.1% before consolidation. Increased intensity of chemotherapy based on MRD analysis did not improve outcomes significantly (5-year EFS 73.9 ± 6.5% for BCH-2003 and 76.1 ± 5.3% for CCLG-2008, P = 0.975). Independent adverse prognostic factors were MRD ≥ 0.1% before consolidation and presence of KMT2A gene rearrangements (odds ratios [ORs] 9.424 [95% confidence interval (CI) 3.210, 27.662; P < 0.001]; 4.142 [1.535, 11.715, P = 0.005]; respectively). Conclusions Pediatric pro-B ALL is a heterogeneous disease. Genetic analysis and MRD evaluation can predict patients with dismal prognosis; however, intensive chemotherapy alone does not improve outcomes of these patients and targeted therapy or hematopoietic stem cell transplantation may be required.

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Pericardial Relapse of Acute Lymphoblastic Leukemia (ALL)

Case Reports in Oncological Medicine ◽

10.1155/2021/9953230 ◽

2021 ◽

Vol 2021 ◽

pp. 1-3

Author(s):

Diana V. Maslov ◽

Ambuga Badari

Keyword(s):

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

B Cell ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Peripheral Blood Smear ◽

Cell Transplant ◽

Shortness Of Breath ◽

Pericardial Window ◽

Relapsed Disease

Acute lymphoblastic leukemia (ALL) is a neoplasm of the B cell or T cell. Diagnosis is made by peripheral blood smear and bone marrow biopsy. Those with relapse/measurable residual disease (MRD) present with fever, weakness, fatigue, and easy bruising due to bone marrow infiltration (Kantarjian et al., 2017). A 59-year-old male with history of relapsed acute lymphoblastic leukemia and allogeneic stem cell transplant presented to the Emergency Department (ED) multiple times with shortness of breath. 2D Echo revealed recurrent pericardial effusion. His MRD was discovered in the pericardium. He underwent the creation of a pericardial window with cytology and culture which confirmed B cell lymphoblastic leukemia/lymphoma, consistent with relapsed disease. We present a case of a patient with B-ALL and MRD who presented with symptoms of shortness of breath. His MRD was discovered not in the bone marrow, but in the pericardium.

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Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia

Blood ◽

10.1182/blood-2017-08-798322 ◽

2018 ◽

Vol 131 (14) ◽

pp. 1522-1531 ◽

Cited By ~ 222

Author(s):

Nicola Gökbuget ◽

Hervé Dombret ◽

Massimiliano Bonifacio ◽

Albrecht Reichle ◽

Carlos Graux ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Complete Remission ◽

B Cell ◽

Minimal Residual Disease ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Cell Precursor ◽

Hematopoietic Stem ◽

Grade 3 ◽

Minimal Residual

Abstract Approximately 30% to 50% of adults with acute lymphoblastic leukemia (ALL) in hematologic complete remission after multiagent therapy exhibit minimal residual disease (MRD) by reverse transcriptase–polymerase chain reaction or flow cytometry. MRD is the strongest predictor of relapse in ALL. In this open-label, single-arm study, adults with B-cell precursor ALL in hematologic complete remission with MRD (≥10−3) received blinatumomab 15 µg/m2 per day by continuous IV infusion for up to 4 cycles. Patients could undergo allogeneic hematopoietic stem-cell transplantation any time after cycle 1. The primary end point was complete MRD response status after 1 cycle of blinatumomab. One hundred sixteen patients received blinatumomab. Eighty-eight (78%) of 113 evaluable patients achieved a complete MRD response. In the subgroup of 110 patients with Ph-negative ALL in hematologic remission, the Kaplan-Meier estimate of relapse-free survival (RFS) at 18 months was 54%. Median overall survival (OS) was 36.5 months. In landmark analyses, complete MRD responders had longer RFS (23.6 vs 5.7 months; P = .002) and OS (38.9 vs 12.5 months; P = .002) compared with MRD nonresponders. Adverse events were consistent with previous studies of blinatumomab. Twelve (10%) and 3 patients (3%) had grade 3 or 4 neurologic events, respectively. Four patients (3%) had cytokine release syndrome grade 1, n = 2; grade 3, n = 2), all during cycle 1. After treatment with blinatumomab in a population of patients with MRD-positive B-cell precursor ALL, a majority achieved a complete MRD response, which was associated with significantly longer RFS and OS compared with MRD nonresponders. This study is registered at www.clinicaltrials.gov as #NCT01207388.

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A Phase I study of inotuzumab ozogamicin in pediatric relapsed/refractory acute lymphoblastic leukemia (ITCC-059 study)

Blood ◽

10.1182/blood.2020007848 ◽

2020 ◽

Author(s):

Erica Brivio ◽

Franco Locatelli ◽

Marta Lopez-Yurda ◽

Andrea Malone ◽

Cristina Diaz de Heredia ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Phase I ◽

Phase I Study ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Sinusoidal Obstruction Syndrome ◽

Cell Transplant ◽

Antibody Drug Conjugate ◽

Inotuzumab Ozogamicin ◽

Hematopoietic Stem

This Phase I study investigated the recommended Phase II dose (RP2D) of inotuzumab ozogamicin (InO), a CD22-directed antibody-drug conjugate, in pediatric patients with multiple-relapsed/refractory (R/R) CD22-positive acute lymphoblastic leukemia (ALL). Patients (≥1-<18 years) received three InO doses (Days 1, 8, 15) per course. Dose-escalation was based on dose-limiting toxicities (DLT) during Course 1 . Dose level 1 (DL1)=1.4 mg/m2 (0.6-0.4-0.4 mg/m2); DL2=1.8 mg/m2 (0.8-0.5-0.5 mg/m2). Secondary endpoints included safety, anti-leukemic activity, and pharmacokinetics. Twenty-five patients (23 evaluable for DLT) were enrolled. In Course 1, first cohort, 1/6 (DL1) and 2/5 (DL2) patients experienced DLTs; subsequent review considered DL2 DLTs to be non-dose-limiting. Dose was de-escalated to DL1 while awaiting protocol amendment to re-evaluate DL2 in a second cohort, where 0/6 (DL1) and 1/6 (DL2) patients had a DLT. Twenty-three patients experienced Grade 3-4 adverse events; hepatic sinusoidal obstruction syndrome was reported in two patients after subsequent chemotherapy. Overall response rate after Course 1 was 80% [95% CI: 59-93%] (20/25 patients; DL1=75% [43-95%], DL2=85% [55-98%]); 84% [60-97%] of responders obtained minimal residual disease-negative CR; 12-month overall survival was 40% [95% CI: 25-66%]. Nine patients received hematopoietic stem cell transplant or chimeric-antigen receptor T-cells after InO. InO median maximum concentrations were comparable to simulated adult concentrations. InO was well tolerated, demonstrating anti-leukemic activity in heavily pre-treated children with CD22-positive R/R ALL. RP2D was established as 1.8 mg/m2/course, as in adults.

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Improving Stratification for Children With Late Bone Marrow B-Cell Acute Lymphoblastic Leukemia Relapses With Refined Response Classification and Integration of Genetics

Journal of Clinical Oncology ◽

10.1200/jco.19.01694 ◽

2019 ◽

Vol 37 (36) ◽

pp. 3493-3506 ◽

Cited By ~ 4

Author(s):

Cornelia Eckert ◽

Stefanie Groeneveld-Krentz ◽

Renate Kirschner-Schwabe ◽

Nikola Hagedorn ◽

Christiane Chen-Santel ◽

...

Keyword(s):

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

B Cell ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Induction Treatment ◽

Poor Responders ◽

Hematopoietic Stem ◽

Cell Acute Lymphoblastic Leukemia ◽

Response Classification

PURPOSE Minimal residual disease (MRD) helps to accurately assess when children with late bone marrow relapses of B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) will benefit from allogeneic hematopoietic stem-cell transplantation (allo-HSCT). More detailed dissection of MRD response heterogeneity and the specific genetic aberrations could improve current practice. PATIENTS AND METHODS MRD was assessed after induction treatment and at different times during relapse treatment until allo-HSCT (indicated in poor responders to induction; MRD ≥ 10−3) for patients being treated for late BCP-ALL bone marrow relapses (n = 413; median follow-up, 9.4 years) in the ALL-REZ BFM 2002 trial/registry (ClinicalTrials.gov identifier: NCT00114348 ). RESULTS Patients with both good (MRD < 10−3) and poor responses to induction treatment reached excellent event-free survival (EFS; 72% v 65%) and overall survival (OS; 82% v 74%). Patients with MRD of 10−2 or greater after induction had reduced EFS (56%), and their MRD persisted until allo-HSCT more frequently than it did in patients with MRD of 10−3 or greater to less than 10−2 ( P = .037). Patients with 25% or more leukemic blasts after induction (early nonresponders) had the poorest prognosis (EFS, 22%). Interestingly, patients with MRD of 10−3 or greater before allo-HSCT (late nonresponders) still had an EFS of 50% and OS of 63%, which in principle justifies allo-HSCT in these patients. From a panel of selected candidate genes, TP53 alterations (frequency, 8%) were the only genetic alteration with independent prognostic value in any MRD-based response subgroup. CONCLUSION After induction treatment, MRD-based treatment stratification resulted in excellent survival in patients with late relapsed BCP-ALL. Prognosis could be further improved in very poor responders by intensifying treatment directly after induction. TP53 alterations can be defined as a novel genetic high-risk marker in all MRD response groups in late relapsed BCP-ALL. Here we identified early and late nonresponders to be considered as events in future trials.

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Genetic Profile and Clinical Implications of PDGFRB Fusion in Adult B-Cell Acute Lymphoblastic Leukemia: A Retrospective Analysis

10.21203/rs.3.rs-389583/v1 ◽

2021 ◽

Author(s):

Guofa Xu ◽

Xie-bing Bao ◽

Li-min Liu ◽

Man Wang ◽

Zhi-bo Zhang ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

B Cell ◽

Kinase Inhibitor ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Intensive Therapy ◽

Genetic Profile ◽

Hematopoietic Stem ◽

Car T ◽

Cell Acute Lymphoblastic Leukemia

Abstract Background:To investigate the pathogenesis, genetic changes, treatment and prognosis of adult B-cell acute lymphoblastic leukemia (B-ALL) with platelet-derived growth factor receptor B (PDGFRB) fusion. Method：Clinical characteristics, treatment process and prognosis of 7 adult B-ALL patients with PDGFRB fusion were presented respectively, and the PDGFRB fusion was confirmed by fluorescence in situ hybridization, RNA sequencing and Polymerase Chain Reaction. Results: 7 adult B-ALL patients with PDGFRB fusion were presented respectively. There were 5 males and 2 females, with a median age of 21 (range, 17-39) years and a median white blood cell count of 7.85 (range, 2.30-111.25) ×10^9/L. The fusion partners were EBF1, SMIM3 and TERF2. Three of 7 cases received tyrosine kinase inhibitor (TKI) targeted therapy, and 4 of 7 cases received chimeric antigen receptor T -cell (CAR-T) therapy. A total of 6 (85.71%) cases underwent haploid hematopoietic stem cell transplantation (Haplo-HSCT). Overall response rate was 71.43% (4/7), and the common adverse reactions during induction were febrile neutropenia and nausea. Seventy-five percent (3/4) and 100% (6/6) of patients were minimal residual disease negative after CAR-T and Haplo-HSCT. To the last follow-up, 2 of 7 cases relapsed in 2 and 7 months after remission, respectively, and the estimated 36 months of Event-free survival and Overall survival was 75.0% and 66.7%.Conclusions: intensive therapy combined with CAR-T or TKI is needed to achieve deep remission, and sequential Haplo-HSCT may improve the prognosis of adult B-ALL with PDGFRB fusion.

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Bortezomib and rituximab in de novo adolescent/adult CD20-positive, Ph-negative pre-B-cell acute lymphoblastic leukemia

Blood Advances ◽

10.1182/bloodadvances.2020003368 ◽

2021 ◽

Vol 5 (17) ◽

pp. 3436-3444

Author(s):

Hasmukh Jain ◽

Manju Sengar ◽

Vasu Babu Goli ◽

Jayashree Thorat ◽

Prashant Tembhare ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Confidence Interval ◽

B Cell ◽

De Novo ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Optimal Number ◽

Cell Transplant ◽

Historical Cohort ◽

Cell Acute Lymphoblastic Leukemia

Abstract The expression of CD20 in precursor B-cell acute lymphoblastic leukemia (B-ALL) is associated with poor outcomes. The addition of rituximab to intensive chemotherapy in CD20+ ALL has led to improved outcomes in several studies. However, there is no clear evidence regarding the optimal number of doses and its benefit without an allogeneic stem cell transplant. Achieving measurable residual disease (MRD)-negative status postinduction would reduce the requirement for a transplant. Novel approaches are needed to induce a higher proportion of MRD-negative complete remission in patients with high-risk ALL. Given bortezomib’s activity in relapsed ALL and its synergism with rituximab in B-cell lymphomas, the addition of bortezomib to rituximab and chemotherapy may provide an incremental benefit in CD20+ precursor B-ALL. We conducted a phase 2 study to test the activity of bortezomib and rituximab in combination with a pediatric-inspired regimen during induction therapy in newly diagnosed adolescents and adults (aged >14 years) with CD20+, Philadelphia-negative precursor B-ALL; bone marrow MRD negativity at the end of induction was the primary end point. From December 2017 through August 2019, a total of 35 patients were enrolled. End-of-induction MRD-negative status was achieved in 70.9% of patients, as opposed to 51.7% in the historical cohort treated with chemotherapy alone. MRD-negative rates improved to 87.5% post-consolidation. At a median follow-up of 21 months, event-free survival and overall survival rates were 78.8% (95% confidence interval, 66-94) and 78.7% (95% confidence interval, 65.8-94), respectively. There was no significant increase in toxicity with bortezomib and rituximab compared with the historical cohort. The incidence of neuropathy was 26% (all less than grade 3). The combination of bortezomib, rituximab, and a pediatric-inspired ALL regimen was active and well tolerated in de novo CD20+ Philadelphia-negative precursor B-ALL. This trial was registered with the Clinical Trials Registry-India as CTRI/2017/04/008393(http://ctri.nic.in/Clinicaltrials).

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