Kinetics of humoral deficiency in CART19-treated children and young adults with acute lymphoblastic leukaemia

Deyà‐Martínez, Àngela; Alonso‐Saladrigues, Anna; García, Ainhoa; Faura, Anna; Torrebadell, Montserrat; Vlagea, Alexandru; Catalá, Albert; Esteve‐Solé, Ana; Juan, Manel; Rives, Susana; Alsina, Laia

doi:10.1038/s41409-020-01027-6

Cited by 12 publications

(13 citation statements)

References 31 publications

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“…CAR T cells show two types of on-target activity against healthy cells. (1) Engineered CD19 CAR T cells eliminate not only malignant but also healthy B cells (Deya-Martinez et al, 2021). Similarly, BCMA CAR T cells eliminate malignant and healthy plasma cells that provide long-term protection from infectious agents by high-level antibody production (Raje et al, 2019).…”

Section: Neurotoxicitymentioning

confidence: 99%

Understanding and treating the inflammatory adverse events of cancer immunotherapy

Dougan

Luoma

Dougan

et al. 2021

Cell

144

164

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Section: Neurotoxicitymentioning

confidence: 99%

Understanding and treating the inflammatory adverse events of cancer immunotherapy

Dougan

Luoma

Dougan

et al. 2021

Cell

144

164

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“…Additionally, pediatric patients with a prior history of allogeneic hematopoietic cell transplant (AlloHCT) or immunoglobulin G (IgG) levels <400mg/dL have also been associated with increased risk of infection ( 14 ). Immune reconstitution and recovery of bone marrow function have also been identified as important factors in mitigating infections after CAR T cell therapy, though limited information is available in the pediatric setting ( 8 , 15 , 16 ).…”

Section: Introductionmentioning

confidence: 99%

Infectious Complications in Pediatric, Adolescent and Young Adult Patients Undergoing CD19-CAR T Cell Therapy

et al. 2022

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CD19-specific chimeric antigen receptor (CAR) T cell therapy has changed the treatment paradigm for pediatric, adolescent and young adult (AYA) patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, data on the associated infectious disease challenges in this patient population are scarce. Knowledge of infections presenting during treatment, and associated risk factors, is critical for pediatric cellular therapy and infectious disease specialists as we seek to formulate effective anti-infective prophylaxis, infection monitoring schemas, and empiric therapy regimens. In this work we describe our institutional experience in a cohort of 38 pediatric and AYA patients with CD19-positive malignancy treated with lymphodepleting chemotherapy (fludarabine/cyclophosphamide) followed by a single infusion of CD19-CAR T cells (total infusions, n=39), including tisagenlecleucel (n=19; CD19/4-1BB) or on an institutional clinical trial (n=20; CD19/4-1BB; NCT03573700). We demonstrate that infections were common in the 90 days post CAR T cells, with 19 (50%) patients experiencing a total of 35 infections. Most of these (73.7%) occurred early post infusion (day 0 to 28; infection density of 2.36 per 100 patient days-at-risk) compared to late post infusion (day 29 to 90; infection density 0.98 per 100 patient days-at-risk), respectively. Bacterial infections were more frequent early after CAR T cell therapy, with a predominance of bacterial blood stream infections. Viral infections occurred throughout the post infusion period and included primarily systemic reactivations and gastrointestinal pathogens. Fungal infections were rare. Pre-infusion disease burden, intensity of bridging chemotherapy, lymphopenia post lymphodepleting chemotherapy/CAR T cell infusion and development of CAR-associated hemophagocytic lymphohistiocytosis (carHLH) were all significantly associated with either infection density or time to first infection post CAR T cell infusion. A subset of patients (n=6) had subsequent CAR T cell reinfusion and did not appear to have increased risk of infectious complications. Our experience highlights the risk of infections after CD19-CAR T cell therapy, and the need for continued investigation of infectious outcomes as we seek to improve surveillance, prophylaxis and treatment algorithms.

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“…However, potential long-term adverse events, such as prolonged cytopenia and immune deficiency, as well as infections, have raised widespread concern. 23-25 To our knowledge, this is the first systematic study to analyze the kinetics of B-cell and plasma cell aplasia and hypogammaglobulinemia after anti-BCMA CAR T-cell therapy in patients with R/R MM, and the results may facilitate the management of infectious complications in patients with long-term follow-up.…”

Section: Discussionmentioning

confidence: 96%

Humoral immune reconstitution after anti-BCMA CAR T-cell therapy in relapsed/refractory multiple myeloma

Wang

Xia

et al. 2021

Blood Advances

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Systematic and dynamic humoral immune reconstitution is little known for relapse/refractory (R/R) multiple myeloma (MM) patients who received anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR)-T cell therapy. We investigated the kinetics of B cell, normal plasma cell and immunoglobulin recovery in 40 patients who achieved ongoing response after anti-BCMA CAR-T cell therapy. All patients developed B-cell aplasia and the median duration of B-cell aplasia was 70 days (23-270). B cell count reached nadir on a median of day 7 and returned to baseline level on a median of day 97. BCMA positive cells in bone marrow turned undetectable on a median time of day 28 (13-159) in 94.87% (37/39) patients. Normal plasma cells in bone marrow were first re-detectable on a median of day 212. All patients developed a significant decrease in serum IgG, IgA, and IgM on a median of day 60. Recovery of serum IgG, IgM and IgA was observed in 53.33% (8/15) patients (non- IgG MM), 73.08% (19/26) patients (non- IgM MM) and 23.81% (5/21) patients (non- IgA MM) at 1-year, respectively. Median times to IgG, IgM and IgA recovery were on day 386, 254 and not reached during follow-up, respectively. Virus-specific IgG levels decreased with loss of protection. Twenty-three of 40 (57.5%) patients developed a total of 44 infection events. No infection-related deaths. These results reveal a 7-month aplasia of bone marrow normal plasma cells and a longer hypogammaglobulinemia, suggesting a profound and lasting humoral immune deficiency after anti-BCMA CAR-T cell therapy, especially for IgA.

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Kinetics of humoral deficiency in CART19-treated children and young adults with acute lymphoblastic leukaemia

Cited by 12 publications

References 31 publications

Understanding and treating the inflammatory adverse events of cancer immunotherapy

Understanding and treating the inflammatory adverse events of cancer immunotherapy

Infectious Complications in Pediatric, Adolescent and Young Adult Patients Undergoing CD19-CAR T Cell Therapy

Humoral immune reconstitution after anti-BCMA CAR T-cell therapy in relapsed/refractory multiple myeloma

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