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Successful Treatment of Refractory and Relapsed CNS Acute Lymphoblastic Leukemia With CD-19 CAR-T Immunotherapy: A Case Report.

ABSTRACT: In recent decades, survival was significantly improved in B cell acute lymphoblastic leukemia (B-ALL) patients. But refractory and relapsed B-ALL still has aggressive clinical behavior and poor prognosis. Especially, the patients with central nervous system infiltration is very difficult to achieve complete remissions with routine treatment. Chimeric antigen receptor-modified T-cell therapy targeting CD-19 has shown to be a beneficial treatment approach in refractory and relapsed B cell acute lymphoblastic leukemia (r/r ALL). However, there are very few studies reporting to treatment of refractory and relapsed B cell ALL with central nervous system infiltration. Here, we reported one single case of a patient diagnosed with relapsed B cell ALL with CNS infiltration who was successfully treated by second generation CAR containing a co-stimulator CD28 or 4-1BB therapy. Long-term proliferation of CAR-T cells in peripheral blood and bone marrow was observed more than 18 months. After CAR-T treatment, the patient got toxicity of grade 1 cytokine release syndrome and achieved significantly 36 months event free survival of follow-up. It is suggested that CD-19 CAR containing CD28 or 4-1BB costimulatory may be an effective therapy in refractory and relapsed B cell ALL with central nervous system infiltration. Its toxicity is mild, and its safety is high. Clinical Trial Registration:ClinicalTrials.gov Identifier: NCT02349698.

SUBMITTER: Htun KT

PROVIDER: S-EPMC8427303 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Children with other extramedullary relapse of acute lymphoblastic leukemia are currently poorly characterized. We aim to assess the prevalence and the clinical, therapeutic and prognostic features of extramedullary localizations other than central nervous system or testis in children with relapse of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) treated on a relapsed ALL protocol.Patients and methodsPatients with relapse of ALL and LBL, treated according to the multicentric ALL-REZ BFM trials between 1983 and 2015, were analyzed for other extramedullary relapse (OEMR) of the disease regarding clinical features, treatment and outcome. Local treatment/irradiation has been recommended on an individual basis and performed only in a minority of patients.ResultsA total of 132 out of 2323 (5.6%) patients with ALL relapse presented with an OEMR (combined bone marrow relapse n = 78; isolated extramedullary relapse n = 54). Compared to the non-OEMR group, patients with OEMR had a higher rate of T-immunophenotype (p < 0.001), a higher rate of LBL (p < 0.001) and a significantly different distribution of time to relapse, i.e., more very early and late relapses compared to the non-OEMR group (p = 0.01). Ten-year probabilities of event-free survival (pEFS) and overall survival (pOS) in non-OEMR vs. OEMR were 0.38 ± 0.01 and 0.32 ± 0.04 (p = 0.0204) vs. 0.45 ± 0.01 and 0.37 ± 0.04 (p = 0.0112), respectively. OEMRs have been classified into five subgroups according to the main affected compartment: lymphatic organs (n = 32, 10y-pEFS 0.50 ± 0.09), mediastinum (n = 35, 10y-pEFS 0.11 ± 0.05), bone (n = 12, 0.17 ± 0.11), skin and glands (n = 21, 0.32 ± 0.11) and other localizations (n = 32, 0.41 ± 0.09). Patients with OEMR and T-lineage ALL/LBL showed a significantly worse 10y-pEFS (0.15 ± 0.04) than those with B-Precursor-ALL (0.49 ± 0.06, p < 0.001). Stratified into standard risk (SR) and high risk (HR) groups, pEFS and pOS of OEMR subgroups were in the expected range whereas the mediastinal subgroup had a significantly worse outcome. Subsequent relapses involved more frequently the bone marrow (58.4%) than isolated extramedullary compartments (41.7%). In multivariate Cox regression, OEMR confers an independent prognostic factor for inferior pEFS and pOS.ConclusionOEMR is adversely related to prognosis. However, the established risk classification can be applied for all subgroups except mediastinal relapses requiring treatment intensification. Generally, isolated OEMR of T-cell-origin needs an intensified treatment including allogeneic stem cell transplantation (HSCT) as a curative approach independent from time to relapse. Local therapy such as surgery and irradiation may be of benefit in selected cases. The indication needs to be clarified in further investigations.

Project description:Adults with relapsed/refractory B-acute lymphoblastic leukemia (ALL) have a complete remission (CR) rate of 20-45% and median overall survival of 3-9 months, depending on the duration of the first remission and number of lines of salvage therapy. Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only curative option for adult patients with relapsed/refractory ALL, and achievement of CR is a crucial step before alloHSCT. Blinatumomab is a bispecific T-cell engager (BiTE®) antibody construct with dual specificity for CD19 and CD3, simultaneously binding CD3-positive cytotoxic T cells and CD19-positive B cells, resulting in T-cell-mediated serial lysis of normal and malignant B cells. It recently gained accelerated approval by the US Food and Drug Administration (FDA) for the treatment of relapsed/refractory Philadelphia chromosome-negative ALL, based on a large phase II trial of 189 adults with relapsed/refractory B-ALL, which showed a CR/CRh (CR with partial hematologic recovery) of 43% after two cycles of treatment. Toxicities include cytokine-release syndrome (CRS) and neurologic events (encephalopathy, aphasia, and seizure). CRS can be alleviated by step-up dosing and dexamethasone, without affecting the cytotoxic effect of blinatumomab. The cause of neurologic toxicity is unclear but is also observed with other T-cell therapies and may relate to variable expression of CD19 within the brain. This review encompasses the preclinical rationale of using the BITE® class of compounds (blinatumomab being the only one that is FDA approved), with clinical data using blinatumomab in the relapsed/refractory setting (pediatrics and adults), the minimal residual disease setting (adults), as well as Philadelphia chromosome-positive ALL. The review also examines the main adverse events: their prevention, recognition, and management; possible mechanisms of resistance; causes of relapse. It also summarizes future trials evaluating the drug earlier in the treatment course to improve activity.

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Successful Treatment of Refractory and Relapsed CNS Acute Lymphoblastic Leukemia With CD-19 CAR-T Immunotherapy: A Case Report.

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