RESEARCH LETTER TO THE EDITOR: Safety and feasibility of stem cell boost as a salvage therapy for severe hematotoxicity after CD19 CAR T-cell therapy Kai Rejeski,1-3 Andreas Burchert,4 Gloria Iacoboni,5,6 Pierre Sesques,7 Lars Fransecky,8 Veit B€ ucklein,1,2 Corinna Trenker,4 Rafael Hernani, Ralph Naumann, Jonas Sch€afer, Viktoria Blumenberg, Christian Schmidt,1 Kristina Sohlbach,4 9 10 4 1-3 Michael von Bergwelt-Baildon,1,3 Emmanuel Bachy,7 Pere Barba,5,6 and Marion Subklewe1-3 1 Department of Medicine III, Hematology and Oncology, University Hospital, LMU Munich, Munich, Germany; 2Laboratory for Translational Cancer Immunology, LMU Gene Center, Munich, Germany; 3German Cancer Consortium (DKTK), Munich Site, and German Cancer Research Center, Heidelberg, Germany; 4Department of Internal Medicine, Hematology, Oncology and Immunology, Philipps University Marburg and University Hospital Giessen and Marburg, Campus Marburg, Marburg, Germany; 5Department of Hematology, Vall d’Hebron Institute of Oncology (VHIO), University Hospital Vall d’Hebron, Barcelona, Spain; 6Department of Medicine, Universitat Aut onoma of Barcelona (UAB), Bellaterra, Spain; 7Hospices Civils de Lyon, Universit e Claude Bernard Lyon 1, INSERM 1052, Pierre-B enite, France; 8Medical Department II–Hematology and Oncology, University Hospital Schleswig-Holstein, Kiel, Germany; 9Department of Hematology, Hospital Clınico Universitario, Institute for Research INCLIVA, Valencia, Spain; and 10 Medical Department III–Hematology and Oncology, St. Marien-Krankenhaus Siegen, Siegen, Germany The advent of chimeric antigen receptor T-cell therapy (CAR-T) has substantially improved clinical out- comes for refractory B-cell malignancies.1-4 Real-world evidence has underlined the role of hematological toxicity, which is common and substantially contributes to infectious complications and non-relapse mor- tality (NRM) after CD19 CAR-T.5-8 Hematotoxicity can be delayed and prolonged in nature, and neutro- phil recovery is typically biphasic with intermittent recovery followed by a second dip.9,10 Clinically challenging cases of profound granulocyte colony-stimulating factor (G-CSF) refractory aplasia have been reported.8,11,12 While the pathomechanism remains incompletely understood, impaired pre–CAR-T hematopoietic reserve and inflammation10 and cytokine release syndrome (CRS)-related cytokine pat- terns13 have been discussed. For refractory cytopenia, stem cell transplantation represents the last resort, either from an allogeneic donor or an autologous product from previous collection. However, its role in the context of CAR-T–related hematotoxicity remains ill defined, and experience is limited.11,12 In this retrospective observational study, we therefore describe clinical characteristics, bone marrow (BM) findings, engraftment and hematopoietic reconstitution, and survival outcomes in 12 patients receiving stem cell boost for severe CAR-T–related hematological toxicity. We surveyed institutional databases across 6 European CAR-T centers (supplemental Figure 1). Exclu- sion criteria included active infection and poor performance status. Clinical metadata were collected with institutional review board approval and in accordance with the Declaration of Helsinki. The indication was severe pancytopenia or long-lasting G-CSF or transfusion dependency (persistent cytopenia group). Immunotoxicity was graded as previously described (supplemental Methods).7,10,14 Neutrophil engraft- ment was defined as the first of 3 consecutive days achieving a sustained absolute neutrophil count (ANC) .500/mL without growth factor support.15,16 Platelet engraftment was defined as a platelet count .20 G/L and transfusion independence $7 days.17 Cumulative incidence curves were calculated as the time to engraftment from Kaplan-Meier estimates, censoring the observation time on the date of pro- gression, or death. Patients already fulfilling the criteria for lineage-specific engraftment on the day of transplant were excluded from the respective analysis. Efficacy outcomes were assessed according to Lugano criteria for B-cell Non-Hodgkin Lymphoma (B-NHL) and minimal residual disease (MRD) status for B-cell precursor acute lymphoblastic leukemia (BCP-ALL).3 NRM was defined as death after CAR-T without prior relapse or progression. Kaplan-Meier estimates were used to assess progression-free sur- vival (PFS) and overall survival (OS). We encountered 13 cases between April 2019 and March 2022. One patient was excluded due to active infection and poor performance status (supplemental Figure 1). Nine patients received axicabta- gene ciloleucel, 2 received tisagenlecleucel, and 1 received brexucabtagene autoleucel (Table 1). At Submitted 7 April 2022; accepted 15 June 2022; prepublished online on Blood The full-text version of this article contains a data supplement. Advances First Edition 24 June 2022; final version published online 16 August 2022. © 2022 by The American Society of Hematology. Licensed under Creative DOI 10.1182/bloodadvances.2022007776. Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC- For original data and material, please contact marion.subklewe@med.uni-muenchen.de. ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved. 23 AUGUST 2022 • VOLUME 6, NUMBER 16 4719 4720 RESEARCH LETTER Table 1. Baseline clinical characteristics and attributes of stem cell boost and subsequent engraftment Demographics and baseline patient characteristics Prior autologous/ # Age Sex Pathology CAR product ECOG IPI Prior lines allogeneic SCT Bridging therapy BM infiltration LDH (U/L) HT score 1 44 F DLBCL, NOS Axi-cel 1 3 4 Haploidentical R-Benda, R-GEMOX N 451 4 SCT, 2 y prior 2 61 M HGBL (DH) Tisa-cel 1 4 2 — R-ICE N 1431 6 3 59 M DLBCL, non-GCB Axi-cel 1 1 4 — 2 x R-CHOP Y (5% to 10%) 237 7 (trFL) 4 36 F BCP-ALL Axi-cel 0 N/A 4 Peripheral blood Vincristine 1 Y (80%) 333 7 SCT from MUD dexamethasone (10/10), 1 y prior 5 53 M DLBCL Axi-cel 2 2 4 Autologous SCT R-ICE 1 venetoclax N 145 $3* 6 65 F DLBCL (trFL) Axi-cel 1 2 4 Autologous SCT R-Benda Y 148 $4* 7 58 M DLBCL Axi-cel 1 2 3 — R-ICE N 497 $4* 8 71 F MCL Brexu-cel 1 MIPI: int risk 6 Autologous SCT R-Bortezomib N 331 $4* 9 67 M DLBCL Axi-cel 0 1 2 — R-ICE N 187 $4* 10 52 F DLBCL Axi-cel 0 2 2 — R-DHAC N 320 2 11 55 F DLBCL (trFL) Axi-cel 2 2 2 — R-DHAOx N 698 3 12 23 M BCP-ALL Tisa-cel 2 N/A 8 Allogeneic SCT, None Y (90%) 965 5 1 1 4 y prior Total 57 (36-71) M/F 6:12 9 LBCL, 2 ALL, 10/12 CD28z 1 (0-2) 2 (1-4) 4 (2-8) AlloSCT: 3/12 (25%), Bridging: 11/12 (92%) 4/12 (33%) 332 (145-1431) 4 (2-7) (median, 1 MCL AutoSCT: 3/12 (25%) range) 23 AUGUST 2022 • VOLUME 6, NUMBER 16 Stem cell boost Neutrophil engraftment after boost Platelet engraftment after boost Total no. of ANC (G/L) Day after Indication for Stem cell CD341 infused cells on day of Day of engraftment PLT count (G/L) Day of # CAR-T stem cell boost source selection (3106 CD34/kg) boost (n 5 11) on day of boost engraftment (n 5 9) 1 343 Persistent neutropenia* Allo — 7.5 0.8 15 73 — 2 35 Pancytopenia Auto — 3.6 0 9 33 12 3 41 Pancytopenia Auto Yes 3.1 0 12 12 Death prior to engraftment 4 146 Pancytopenia Allo Yes 3.0 0.2 6 21 16 5 55 Persistent cytopenia*/† Auto — 4.6 0.6 29 7 29 6 212/617 Persistent neutropenia* Auto — 2.1/2.2 0.5 124 133 — 23 AUGUST 2022 • VOLUME 6, NUMBER 16 7 46/93 Pancytopenia Auto — 3.0/3.0 0.04 14 2 34 (2nd boost for pers. thrombocytopenia) 8 84 Persistent Auto — 4.9 7.9 — 34 Progression prior thrombocytopenia† to engraftment 9 370 Persistent neutropenia* Auto — 1.7 0.9 14 85 — 10 48 Pancytopenia Auto Yes 2.6 0 16 11 31 11 399 Persistent cytopenia*/† Auto Yes 6.0 1.1 8 33 21 12 42 Pancytopenia Allo Yes 5.5 0.6 21 7 14 Median 69 (35-617) Pancytopenia: 6/12, 9 autoSCT, 5/12 (42%) 3.1 (1.7-7.5) 0.50 (0-7.9) Engraftment: 11/11 27 (2-133) Engraftment: 7/9 (Range) persistent 3 alloSCT (100%), Day: 15 (6-124) (78%), Day: 21 (12-34) cytopenia: 6/12 Characteristics are provided for all included patients (n 5 12). Bridging therapy was defined as antineoplastic therapy administered between CAR-T indication and infusion. Prior to stem cell boost, 3 patients (#1, 7, 10) fulfilled platelet engraftment criteria and 1 patient fulfilled criteria for neutrophil engraftment (#9). These patients were excluded from the calculation of median time to engraftment. Axi-cel, Axicabtagene ciloleucel; Brexu-cel, Brexucabtagene autoleucel; DLBCL, diffuse large B-cell lymphoma; ECOG, Eastern Cooperative Oncology Group Performance Status; HGBL, high-grade B-cell lymphoma; HT score, CAR-HEMATOTOX score10; IPI, international prognostic index; LDH, lactate dehydrogenase; MCL, mantle cell lymphoma; MUD, matched unrelated donor transplantation; Tisa-cel, Tisagenlecleucel; trFL, transformed follicular lymphoma; *Indication for stem cell boost was long-lasting G-CSF dependency. †Indication for stem cell boost was ongoing platelet transfusion dependency. Patient 7 received a second boost for persistent thrombocytopenia. RESEARCH LETTER 4721 A Duration of cytopenia B Management strategies of hematotoxicity 100 100% 80 Percent of patients (%) Neutropenia 60 40 50% Thrombocytopenia 20 17% 17% 0 20 40 60 80 100 130 160 0 Cumulative days after CAR-T (prior to SCT) G-CSF TPO- Anti- Glucocorticoid agonist cytokine C 30-day neutrophil engraftment 30-day platelet engraftment 100 100 n = 11 n=9 90 82% * 90 80 80 Cumulative incidence Cumulative incidence 70 70 60% ** 60 60 50 50 40 40 30 30 20 20 10 10 0 0 0 3 6 9 12 15 18 21 24 27 30 0 3 6 9 12 15 18 21 24 27 30 Day after stem cell boost Day after stem cell boost D 10000 300 250 #1 6000 200 #2 #3 Platelet count (G/l) 2000 150 #4 #5 ANC/Pl 1500 #6 100 #7* #8 1000 #9 50 #10 500 #11 #12 0 0 0 5 10 15 20 25 30 35 40 45 0 5 10 15 20 25 30 35 40 45 Day after stem cell boost Day after stem cell boost E Overall and progression-free survival from CAR-T F Objective response (day 90) 100 100 92% ORR 75 80 Probability of survival Overall survival (median OS 17 months, 1-yr: 55%) 50% CR % of patients 60 (n = 6) 50 40 25 Progression-free survival (median PFS: 6 months, 1-yr: 46%) 42% PR 20 (n = 5) 8% (n = 1) 0 0 0 180 360 540 720 900 ORR PD Days after CAR-T Figure 1. 4722 RESEARCH LETTER 23 AUGUST 2022 • VOLUME 6, NUMBER 16 lymphodepletion, the median Eastern Cooperative Oncology Group engraftment (r 5 20.57; P 5 .05; supplemental Figure 4). A his- Performance Status was 1 (range, 0-2). Six patients presented with topathologic example of engraftment is displayed for a patient a prior history of stem cell transplantation, and an additional 6 with BCP-ALL with underlying BM involvement (patient #12; patients had collected but not received autologous CD341 periph- supplemental Figure 2A). Of note, the patient with mantle cell eral stem cells due to progressive disease. Baseline laboratory find- lymphoma developed post-boost leukemic relapse (patient #8), rais- ings were notable for an elevated lactate dehydrogenase (median ing concern for potential contamination. However, flow cytometric 332 U/L) and pronounced baseline cytopenia and inflammation analysis of the apheresis product demonstrated no evidence of lym- (supplemental Table 1), as evidenced by high CAR-HEMATOTOX phoma. When studying survival outcomes, we observed 1-year PFS scores (median, 4; range, 2-7).10 Hypocellularity and underlying infil- and OS of 46% and 55%, respectively (Figure 1E), comparable to tration were frequent in the 8 patients with pre–CAR-T BM studies other real-world reports.5,6 Median PFS was 6 months and median (supplemental Table 2). The toxicity profile between CAR-T and OS was 17 months. Best overall and complete response rates stem cell boost was dominated by hematotoxicity and severe infec- were 92% and 50%, respectively (Figure 1F). One-year NRM was tions (supplemental Table 3). Median duration of severe neutropenia 8% (1 infection; supplemental Figures 2 and 3). and thrombocytopenia was 42 days, respectively (Figure 1A). In conclusion, our study indicates that stem cell boost represents a Severe infections were noted in 58% of patients, whereas grade clinically feasible strategy for persistent cytopenia after CD19 CAR- $3 CRS was not observed. One patient died of an invasive fungal T with high engraftment rates, resolution of cytopenia in most cases, infection on day 58 after CAR T in the setting of burgeoning hema- and encouraging survival outcomes. Median engraftment times were topoietic recovery after boost (patient #3; supplemental Figure 2). comparable to published reports for stem cell transplantation in gen- Peak inflammatory markers were particularly notable for high serum eral, even without conditioning chemotherapy.18-21 Engraftment sup- ferritin levels (median, 6542; supplemental Table 1). Post–CAR-T ports the notion that prolonged and/or persistent cytopenia after BM studies revealed hypocellular marrow in 9/9 patients and T-cell CD19 CAR-T is primarily driven by dysfunction of the hematopoietic lymphocytosis in 3/9 patients (supplemental Table 2). To overcome stem and progenitor cell compartment, as opposed to primarily neutropenia, all patients received G-CSF, and half received a TPO- immunogenic phenomena driven by CAR or non–CAR-bearing agonist (Figure 1B), initiated after a median of 17 and 42.5 days, immune cells. In contrast, autologous grafts are rarely successful respectively (supplemental Table 4). Anticytokine therapy was infre- in acquired BM deficiency syndromes caused by persistent quently applied; however, transfusion dependency was common. T-cell–mediated BM suppression such as aplastic anemia.22 Nota- Median day of stem cell boost was 69 days (range, 35-617) bly, 4 patients displayed underlying BM infiltration prior to CD19 (Table 1). The indication was severe pancytopenia in 6 cases and CAR-T, suggesting that changes to the microenvironment may per- persistent neutropenia or thrombocytopenia in 6 cases. Two sist even after tumor cell lysis and can be overcome by stem cell patients received .1 stem cell boost. The stem cell source was an engraftment (supplemental Figure 2). Underlying BM disease may autologous product in most cases (9/12), although 3 patients predispose for local inflammatory processes that propagate the received stem cells from a previous allogeneic donor with no subse- functional suppression of hematopoietic stem and progenitor cells quent evidence of graft-versus-host disease. None of the treated via cytokines or chemokines.9 In sepsis, inflammatory signatures can patients received conditioning chemotherapy. CD341selection was facilitate hematopoietic stem cell exhaustion23 and induce remodel- performed in 5 patients whereas the other patients received an ing of the BM niche.24 In such a setting, stem cell rescue may pro- unmanipulated (whole) product. The median day-of-transplant ANC vide the necessary reset, enabling the BM niche to recover from the was 0.5 (range, 0-7.9), while the median transplant-day platelet inflammatory stress inherent to cytokine storm.13,25 This study has count was 27 (range, 2-133). The median total number of infused several relevant limitations. It was retrospective, uncontrolled, and CD341 cells was 3.1 3 106/kg (range, 1.7-7.5). Neutrophil engraft- limited to small patient numbers, which restricts drawing firm conclu- ment was eventually noted in all patients, and the 30-day cumulative sions. The potential benefit of earlier stem cell rescue remains engraftment rate was 82% (Figure 1C). Median time to neutrophil unclear, although shortening the phase of critical neutropenia likely engraftment in evaluable patients was 15 days (range, 6-124). prevents severe infectious events.8 Future prospective studies must Platelet engraftment was eventually observed in 7/9 patients, with address the question of optimal timing and patient selection in larger 1 patient ultimately engrafting after a second autologous stem cell cohorts, including the use of preemptive stem cell apheresis in boost (patient #7). Median time to platelet engraftment in evaluable select high-risk patients for potential later use. patients was 21 days (range, 12-34) with a 30-day engraftment rate Acknowledgments: The authors thank the patients and their of 60% (Figure 1C). Individual neutrophil and platelet recovery families for their participation in this study. curves are outlined in Figure 1D. In general, day-of-transplant This work was supported by a fellowship from School of Oncol- platelet counts were inversely correlated with the day-of-platelet ogy of German Cancer Consortium (DKTK) (K.R.) and was funded Figure 1 (continued) Stem cell boost for severe CAR T-related hematotoxicity is safe and clinically feasible. (A) Median cumulative duration of severe thrombocytopenia (platelet count , 50 G/L) and severe neutropenia (ANC/m) in days between CAR infusion and stem cell rescue. Box and whiskers indicated the median and interquartile range. (B) Overview of management strategies of hematological toxicity prior to stem cell rescue. (C) Cumulative incidence rate of neutrophil (left) and platelet (right) engraftment in the first 30 days after CAR infusion. *An additional patient (#7) engrafted on day 124. **Two additional patients engrafted after day 30 (#8, 11). (D) Spider plot depicting neutrophil (left) and platelet (right) recovery for the first 45 days following stem cell boost. Each patient is color coded. Patient #7 (light blue) received a second autologous stem cell boost due to persistent thrombocytopenia. (E) Kaplan-Meier estimates of OS (gray) and PFS (dark gray) for the entire study cohort (n 5 12). Median survival and 1-year survival rates are depicted. (F) Summary of best overall response at day 90. CR, complete response; PD, progressive disease; PR, partial response. 23 AUGUST 2022 • VOLUME 6, NUMBER 16 RESEARCH LETTER 4723 by the Else Kro €ner Forschungskolleg; a Deutsche Forschungsge- References meinschaft (DFG; German Research Foundation) research grant provided within the Sonderforschungbereich (SFB-TRR 388/1 2021–452881907) and DFG research grant (451580403) (M.S.); 1. Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and the Bavarian Elite Graduate Training Network (M.S.), the Wilhelm- activity of axicabtagene ciloleucel in refractory large B-cell lymphoma Sander Stiftung (project no. 2018.087.1) (M.S.), the Else-Kr€ oner- (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019;20(1):31-42. Fresenius Stiftung (M.S., K.R., V. B€ ucklein, V. Blumenberg), and the Bavarian Center for Cancer Research (BZKF). 2. Schuster SJ, Bishop MR, Tam CS, et al; JULIET Investigators. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell Contribution: K.R. and M.S. conceived the study; K.R., A.B., K.S., lymphoma. N Engl J Med. 2019;380(1):45-56. G.I., P.S., L.F., V. B€ ucklein, C.T., R.H., R.N., J.S., V. Blumenberg, C.S., 3. Shah BD, Ghobadi A, Oluwole OO, et al. KTE-X19 for relapsed or K.S., M.v.B.-B., E.B., P.B., and M.S. conducted the investigation; K.R. refractory adult B-cell acute lymphoblastic leukaemia: phase 2 performed formal analysis and visualization; K.R. and M.S. conceived results of the single-arm, open-label, multicentre ZUMA-3 study. the methodology; K.R. and M.S. wrote the original draft; K.R., A.B., Lancet. 2021;398(10299):491-502. G.I., P.S., L.F., V. B€ ucklein, C.T., R.H., R.N., J.S., V. Blumenberg, C.S., 4. Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-cell therapy in K.S., M.v.B.-B., E.B., P.B., A.B., and M.S. reviewed and edited the relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020; writing; all authors read and approved the final manuscript. 382(14):1331-1342. Conflict-of-interest disclosure: K.R. received research funding 5. Nastoupil LJ, Jain MD, Feng L, et al. Standard-of-care axicabtagene and travel support from Kite/Gilead and honoraria from Novartis. ciloleucel for relapsed or refractory large B-cell lymphoma: results K.S. received honoraria and travel support from Kite/Gilead. G.I. from the US Lymphoma CAR T Consortium. J Clin Oncol. 2020; received consultancy fees and honoraria from Novartis, Roche, Kite/ 38(27):3119-3128. Gilead, Bristol-Myers Squibb, AbbVie, Janssen, Sandoz, Miltenyi, 6. Bethge WA, Martus P, Schmitt M, et al. GLA/DRST real-world and AstraZeneca. P.S. received research funding from Chugai, outcome analysis of CAR-T cell therapies for large B-cell lymphoma Novartis, and Kite/Gilead. R.H. received honoraria from Kite/Gilead, in Germany. Blood. 2022;blood.2021015209. Novartis, Merck Sharp & Dohme, Janssen, and Celgene and 7. Hill JA, Li D, Hay KA, et al. Infectious complications of CD19- research funding from Kite/Gilead. R.N. received consultancy fees targeted chimeric antigen receptor-modified T-cell immunotherapy. and honoraria from Amgen, AstraZeneca, Bristol-Myers Squibb, Cel- Blood. 2018;131(1):121-130. gene, Cellex Patient Treatment, GlaxoSmithKline, Janssen-Cilag, 8. Rejeski K, Perez A, Iacoboni G, et al. The CAR-HEMATOTOX Kite/Gilead, Oncopeptides, Sanofi, and Takeda. V. B€ ucklein risk-stratifies patients for severe infections and disease progression received honoraria from AMGEN, research funding from Celgene, after CD19 CAR-T in R/R LBCL. J Immunother Cancer. 2022; honoraria from Pfizer, research funding from Kite/Gilead, and hono- 10(5):e004475. raria from Novartis. V. Blumenberg received honoraria and research 9. Fried S, Avigdor A, Bielorai B, et al. Early and late hematologic funding from Novartis; consultancy fees, honoraria, and research toxicity following CD19 CAR-T cells. Bone Marrow Transplant. funding from Gilead; research funding from Celgene; and research 2019;54(10):1643-1650. funding and honoraria from Janssen. C.S. received consultancy fees 10. Rejeski K, Perez A, Sesques P, et al. CAR-HEMATOTOX: a and honoraria from Celgene, Kite/Gilead, and Novartis. M.v.B.-B. model for CAR T-cell-related hematologic toxicity in relapsed/ received consultancy fees, research funding, and honoraria from refractory large B-cell lymphoma. Blood. 2021;138(24): MSD Sharp & Dohme, Novartis, Roche, Kite/Gilead, Bristol-Myers 2499-2513. Squibb, Astellas, Mologen, and Miltenyi. P.B. received honoraria from 11. Rejeski K, Kunz WG, Rudelius M, et al. Severe Candida glabrata Amgen, BMS, Gilead, Incyte, Miltenyi Biotec, Novartis, and Pfizer pancolitis and fatal Aspergillus fumigatus pulmonary infection in the not related to the present article. A.B. received honoraria and served setting of bone marrow aplasia after CD19-directed CAR T-cell on the advisory board for Kite/Gilead, BMS, Pfizer, and Incyte and therapy: a case report. BMC Infect Dis. 2021;21(1):121. received research support from AOP Health. M.S. received research 12. G€odel P, Sieg N, Heger JM, et al. Hematologic rescue of CAR funding from Morphosys; consultancy fees and research funding T-cell-mediated prolonged pancytopenia using autologous from Novartis; consultancy fees from Janssen; research funding peripheral blood hematopoietic stem cells in a lymphoma patient. from Seattle Genetics; consultancy fees, honoraria, and research HemaSphere. 2021;5(3):e545. funding from AMGEN; consultancy fees and honoraria from Cel- 13. Juluri KR, Wu V, Voutsinas JM, et al. Severe cytokine release gene; consultancy fees, honoraria, and research funding from Kite/ syndrome is associated with hematologic toxicity following CD19 Gilead; and consultancy and research funding from Roche AG. The CAR T-cell therapy. Blood Adv. 2021. remaining authors declare no competing financial interests. 14. Lee DW, Santomasso BD, Locke FL, et al. ASTCT Consensus ORCID profiles: K.R., 0000-0003-3905-0251; G.I., 0000-0003- grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow 0805-9288; L.F., 0000-0002-3658-0284; V.B€ ucklein, 0000-0001- Transplant. 2019;25(4):625-638. 7391-7280; R.H., 0000-0003-1043-8076; J.S., 0000-0001-8852- 1457; V.Blumenberg, 0000-0003-1379-0876; E.B., 0000-0003- 15. Wolff SN. Second hematopoietic stem cell transplantation for the treatment of graft failure, graft rejection or relapse after allogeneic 2694-7510; M.S., 0000-0003-3905-0251. transplantation. Bone Marrow Transplant. 2002;29(7):545-552. Correspondence: Marion Subklewe, Department of Medicine 16. Reich-Slotky R, Bachegowda LS, Ancharski M, Gergis U, van III–Hematology/Oncology, University Hospital, LMU Munich, Besien K, Cushing MM. Engraftment for CD34 selected stem cell Marchioninistrasse 15/81377 Munich, Germany; e-mail: marion. products is not compromised by cryopreservation. Transfusion. subklewe@med.uni-muenchen.de. 2016;56(4):893-898. 4724 RESEARCH LETTER 23 AUGUST 2022 • VOLUME 6, NUMBER 16 17. Teltschik HM, Heinzelmann F, Gruhn B, et al. Treatment of graft peripheral blood stem cells in diffuse-large B-cell lymphoma. Bone failure with TNI-based reconditioning and haploidentical stem Marrow Transplant. 2007;39(9):523-527. cells in paediatric patients. Br J Haematol. 2016;175(1): 21. Fenske TS, Hari PN, Carreras J, et al. Impact of pre-transplant 115-122. rituximab on survival after autologous hematopoietic stem cell transplantation for diffuse large B cell lymphoma. Biol Blood Marrow 18. Bento L, Gutierrez A, Novelli S, et al; Grupo Espa~nol de Transplant. 2009;15(11):1455-1464. Trasplante Hematopoy etico (GETH) and Grupo Espa~ nol de Linfoma y Trasplante Aut ologo (GELTAMO). Allogeneic 22. Young NS. Aplastic anemia. N Engl J Med. 2018;379(17): stem cell transplantation as a curative option in relapse/refractory 1643-1656. diffuse large B cell lymphoma: Spanish multicenter GETH/ 23. Zhang H, Rodriguez S, Wang L, et al. Sepsis induces hematopoietic GELTAMO study. Bone Marrow Transplant. 2021;56(8): stem cell exhaustion and myelosuppression through distinct 1919-1928. contributions of TRIF and MYD88. Stem Cell Reports. 2016;6(6): 19. Tian C, Li Y, Liu S, et al. Modified conditioning regimen with 940-956. idarubicin followed by autologous hematopoietic stem cell 24. Yin F, Qian H, Duan C, Ning B. The bone marrow niche transplantation for invasive B-cell non-Hodgkin’s lymphoma patients. components are adversely affected in sepsis. Mol Biomed. 2020; Sci Rep. 2021;11(1):4273. 1(1):10. 20. Kamezaki K, Kikushige Y, Numata A, et al. Rituximab does not 25. Fajgenbaum DC, June CH. Cytokine storm. N Engl J Med. 2020; compromise the mobilization and engraftment of autologous 383(23):2255-2273. 23 AUGUST 2022 • VOLUME 6, NUMBER 16 RESEARCH LETTER 4725