Cytokine Release Syndrome Following Peripheral Blood Stem Cell Haploidentical Hematopoietic Cell Transplantation with Post-Transplantation Cyclophosphamide

Otoukesh, Salman; Elmariah, Hany; Yang, Dongyun; Clark, Mary C.; Siraj, Madiha; Ali, Haris; Mogili, Krishnakar; Arslan, Shukaib; Nishihori, Taiga; Nakamura, Ryotaro; Pidala, Joseph; Marcucci, Guido; Forman, Stephen J.; Anasetti, Claudio; Malki, Monzr M. Al; Bejanyan, Nelli

doi:10.1016/j.jtct.2021.11.012

Cited by 18 publications

(14 citation statements)

References 34 publications

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“…CRS rate in this trial was consistent with our institutional rate. 32 Despite of the short follow-up period, short-term outcomes indicated that optimizing the conditioning regimen intensity could overcome the arguably higher rate of relapse described in earlier reports in this population. 3,4 …”

Section: Discussionmentioning

confidence: 90%

Total marrow and lymphoid irradiation as conditioning in haploidentical transplant with posttransplant cyclophosphamide

Malki¹,

Palmer²,

Tsai³

et al. 2022

Blood Advances

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Posttransplant cyclophosphamide (PTCy) platform has shown low rates of graft-versus-host disease (GVHD) and nonrelapse mortality (NRM) after haploidentical hematopoietic cell transplantation (HaploHCT). However, because of the limited disease control, relapse rate remains a major cause of treatment failure in high-risk patients. Total marrow and lymphoid irradiation (TMLI) allows for delivery of high radiation to bone marrow and other targeted structures, without increasing off-target radiation exposure and toxicity to end organs. In this phase 1 trial, 31 patients with high-risk and/or active primary refractory leukemias or myelodysplastic syndrome underwent peripheral blood stem cell HaploHCT with TMLI, fludarabine, and cyclophosphamide as the conditioning regimen. Radiation dose was escalated in increments of 200 cGy (1200-2000 cGy). GVHD prophylaxis was PTCy with tacrolimus/mycophenolate mofetil. Grade 2 toxicities by the Bearman scale were mucositis (n = 1), hepatic (n = 3), gastrointestinal (n = 5), and cardiac (n = 2). One patient (1800 cGy) experienced grade 3 pulmonary toxicity (dose-limiting toxicity). At a follow-up duration of 23.9 months for the whole cohort; 2-year NRM was 13%. Cumulative incidence of day 100 grade 2 to 4 and 3 to 4 acute GVHD was 52% and 6%, respectively. Chronic GVHD at 2 years was 35%. For patients treated with 2000 cGy, with a median follow-up duration of 12.3 months, 1-year relapse/progression, progression-free survival, and overall survival rates were 17%, 74%, and 83%, respectively. In conclusion, HaploHCT-TMLI with PTCy was safe and feasible in our high-risk patient population with promising outcomes.

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Section: Discussionmentioning

confidence: 90%

Total marrow and lymphoid irradiation as conditioning in haploidentical transplant with posttransplant cyclophosphamide

Malki¹,

Palmer²,

Tsai³

et al. 2022

Blood Advances

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“…Uppuluri et al 6 described their experience of haploidentical HSCT with PTCy in 16 children with PID (one had SCID) in which CRS was noted in 75% transplants and 2 children including 1 SCID patient (T−B−NK+) succumbed to grade V CRS. Sudden deterioration of our patient after stem cell infusion was due to the development of severe CRS possibly driven by donor T lymphocytes causing IRIS 7–10 . Since SCID patients have a complete lack of host immunity, the transfer of mature antigen-experienced T cells from the donor can lead to sudden immune reconstitution and thus triggering IRIS.…”

Section: Discussionmentioning

confidence: 88%

“…4,5 Peripheral blood haploidentical HSCT with PTCy is known to be associated with CRS. 6,7 Uppuluri et al 6 described their experience of haploidentical HSCT with PTCy in 16 children with PID (one had SCID) in which CRS was noted in 75% transplants and 2 children including 1 SCID patient (T−B−NK+) succumbed to grade V CRS. Sudden deterioration of our patient after stem cell infusion was due to the development of severe CRS possibly driven by donor T lymphocytes causing IRIS.…”

Section: Discussionmentioning

confidence: 99%

“…Sudden deterioration of our patient after stem cell infusion was due to the development of severe CRS possibly driven by donor T lymphocytes causing IRIS. [7][8][9][10] Since SCID patients have a complete lack of host immunity, the transfer of mature antigen-experienced T cells from the donor can lead to sudden immune reconstitution and thus triggering IRIS. Our patient had disseminated BCG infection which could also be contributory in the initiation of IRIS as the mother was immunized with the BCG vaccine in childhood so she must be having cytotoxic T cells specific for BCG which were transferred to the infant with peripheral blood stem cell product.…”

Section: Discussionmentioning

confidence: 99%

“…Conditioning is used for haploidentical HSCT for SCID either using T-cell depletion or T-cell replete grafts with PTCy for sustained engraftment 4,5 . Peripheral blood haploidentical HSCT with PTCy is known to be associated with CRS 6,7 . Uppuluri et al 6 described their experience of haploidentical HSCT with PTCy in 16 children with PID (one had SCID) in which CRS was noted in 75% transplants and 2 children including 1 SCID patient (T−B−NK+) succumbed to grade V CRS.…”

Section: Discussionmentioning

confidence: 99%

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Fatal Severe Cytokine Release Syndrome Post-haploidentical Stem Cell Transplant With Post-transplant Cyclophosphamide in an Infant With Severe Combined Immunodeficiency and Disseminated Bacille Calmette-Guérin Infection

Arora¹,

Upasana²,

Thakkar³

et al. 2023

Journal of Pediatric Hematology/Oncology

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Introduction: Severe Combined Immunodeficiency (SCID) is a primary immunodeficiency disorder characterized by absent or dysfunctional T lymphocytes, leading to defective cellular and humoral immunity requiring urgent hematopoietic stem cell transplantation (HSCT). We report a case of SCID with disseminated Bacille Calmette-Guérin (BCG) infection who developed cytokine release syndrome (CRS) and possible Immune reconstitution inflammatory syndrome (IRIS) after Haploidentical HSCT with post-transplant cyclophosphamide. Methods: Data were retrospectively retrieved from electronic medical records. Result: A 5-month-old male infant was referred with fever, cough, and generalized maculopapular rash for 15 days, and had pallor without hepatosplenomegaly or lymphadenopathy. He had a history of previous male sibling death at 6 months of age due to pneumonia. Investigations: hemoglobin: 4.7 g/dL, TLC-6.37×103/uL, absolute lymphocytes: 0.98×103/uL, platelets: 319×103/uL, bilateral patchy opacities in both lung fields, and low immunoglobulin levels. Lymphocyte subset analysis revealed T−, B+, NK− SCID. Genetic analysis showed a hemizygous mutation in IL2RG (c.314A>G). The child received intravenous (IV) antibiotics, antifungal, antitubercular drugs, irradiated blood products, and IV immunoglobulins. Urgent haploidentical HSCT from the mother was planned. Conditioning was Fludarabine-40 mg/m2/d for 4 days, cyclophosphamide: 14.5 mg/kg/d for 2 days. He received peripheral blood hematopoietic stem cells with CD34− 15×106 cells/kg and CD3− 805×106 cells/kg. Within 2 hours of stem cell infusion, he developed respiratory distress, fever, shock, and flaring of rash. Methylprednisolone was started in view of CRS. On day+2, he had sudden desaturation and bradycardia needing mechanical ventilation and inotropes. His inflammatory markers were elevated (Ferritin: 3640 ng/mL, IL-6:5000 pg/mL, CRP:255 mg/L). In view of high-grade CRS, he received an injection of tocilizumab 8 mg/kg on day +2 and day +4. He received post-transplant cyclophosphamide 5 mg/kg on day +3. The endotracheal secretion GeneXpert was positive for Mycobacterium supporting the diagnosis of disseminated tuberculosis. Our patient had disseminated BCG infection which could also be contributory in the initiation of IRIS as the mother was immunized with the BCG vaccine in childhood so she must be having cytotoxic T cells specific for BCG, which were transferred to the infant with peripheral blood stem cell product. He succumbed to severe acute respiratory distress syndrome and multiorgan dysfunction on day +5 post-transplant. Conclusions: In haploidentical HSCT of SCID, post-transplant course can be complicated by CRS and IRIS as these patients are inefficient in mounting any response to infused donor lymphocytes resulting in their unregulated growth.

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Combining post-transplant cyclophosphamide with antithymocyte globulin for graft-versus-host disease prophylaxis in hematological malignancies

2023

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Cytokine Release Syndrome Following Peripheral Blood Stem Cell Haploidentical Hematopoietic Cell Transplantation with Post-Transplantation Cyclophosphamide

Cited by 18 publications

References 34 publications

Total marrow and lymphoid irradiation as conditioning in haploidentical transplant with posttransplant cyclophosphamide

Total marrow and lymphoid irradiation as conditioning in haploidentical transplant with posttransplant cyclophosphamide

Fatal Severe Cytokine Release Syndrome Post-haploidentical Stem Cell Transplant With Post-transplant Cyclophosphamide in an Infant With Severe Combined Immunodeficiency and Disseminated Bacille Calmette-Guérin Infection

Combining post-transplant cyclophosphamide with antithymocyte globulin for graft-versus-host disease prophylaxis in hematological malignancies

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