Title: When CAR-T Is Not Enough: Haploidentical Transplantation After Sequential Immunotherapy Failure
Submitted by: Dr. Paolo Clementi, haematology trainee at University of Brescia and ASST Spedali Civili di Brescia, Italy
Physician expert perspective: Prof. Daniele Avenoso, Associate Professor at University of Brescia and ASST Spedali Civili di Brescia, Italy
Clinical Case Summary
A 34-year-old woman presented with bulky primary mediastinal diffuse large B-cell lymphoma (DLBCL), stage IIA, characterized by a bulky anterior mediastinal mass, superior vena cava syndrome, and an isolated BCL6 rearrangement. Bone marrow evaluation was negative. She received frontline immunochemotherapy with R-CHOP followed by R-polatuzumab-CHP but remained primarily refractory, with persistent metabolically active disease confirmed on repeat biopsy. She subsequently underwent leukapheresis and received axicabtagene ciloleucel (axi-cel) following R-ESHAP bridging chemotherapy. Although CAR-T therapy was well tolerated apart from grade 1–2 cytokine release syndrome, PET-CT performed one month later demonstrated progressive disease. Sequential salvage with glofitamab failed to induce disease control, while mediastinal radiotherapy followed by loncastuximab tesirine achieved only stable disease. With no further standard therapeutic options available, she proceeded to haploidentical hematopoietic cell transplantation (haplo-HCT) from her father. The post-transplant course was complicated by multiple severe infectious complications, including viral reactivations, polymicrobial pneumonia requiring intensive care, BK virus cystitis, and idiopathic pneumonia syndrome. Despite these events, she recovered successfully. Five months after transplantation, CT imaging demonstrated complete remission, although PET imaging was deferred because of ongoing inflammatory complications.
Question
Which of the following is the most appropriate conclusion regarding the management of this patient?
A. CAR-T failure excludes the possibility of long-term remission with subsequent cellular therapy.
B. Patients with persistent active lymphoma should never proceed to allogeneic transplantation.
C. Haploidentical HCT may provide durable disease control through a graft-versus-lymphoma effect in selected patients with CAR-T-refractory disease.
D. Bispecific antibodies must be continued until complete metabolic remission before transplantation.
E. Severe post-transplant infectious complications indicate treatment failure and poor lymphoma control.
Expert Perspective
This case describes a young woman with primary refractory large B-cell lymphoma, initially presenting as bulky mediastinal disease with adverse clinical features and incomplete response to frontline immunochemotherapy. Despite exposure to modern sequential strategies - including pola-R-CHP, platinum-based bridging, axi-cel CAR-T, glofitamab, radiotherapy and loncastuximab— - he disease remained refractory, ultimately leading to haploidentical HCT as a rescue strategy. The case captures a major unmet need in aggressive lymphoma: disease progression after anti-CD19 CAR-T. This remains a biologically and clinically difficult setting, with no universally accepted standard of care. In this patient, early progression one month after axi-cel, with Deauville 5 disease, identified a particularly high-risk scenario1. Subsequent failure of glofitamab and only stable disease after loncastuximab plus mediastinal radiotherapy further underlined the absence of durable disease control with conventional post-CAR-T salvage approaches.
The decision to proceed to allo-HCT despite persistent disease was therefore clinically aggressive but understandable. In young, fit patients with chemorefractory lymphoma and exhausted standard options, allogeneic transplantation remains one of the few interventions with curative potential, mainly through a graft-versus-lymphoma effect2,3. The use of a haploidentical father donor highlights both the feasibility and complexity of this approach when no matched unrelated donor is available. The post-transplant course also illustrates the price of this strategy. The patient experienced substantial infectious and inflammatory complications, including SARS-CoV-2 infection, adenovirus reactivation, polymicrobial pneumonia requiring ICU admission and mechanical ventilation, CMV involvement, BK-virus cystitis/pyelonephritis, Streptococcus mitis bacteremia, and idiopathic pneumonia syndrome. These events are not incidental details: they define the therapeutic risk of pursuing allo-HCT in a heavily pretreated post-CAR-T patient.
The most important observation is that, five months after transplant, the patient is in complete remission by CT scan, despite entering transplant with persistent refractory disease. PET was appropriately deferred because concomitant infections and inflammation would have made interpretation unreliable. This remission strongly suggests a clinically meaningful graft-versus-lymphoma effect, although longer follow-up and metabolic reassessment will be essential before drawing durable efficacy conclusions.
Overall, this case supports the concept that allo-HCT can still have a role in selected young patients with large B-cell lymphoma after CAR-T failure, particularly when disease control is otherwise unattainable4. However, it should not be read as proof of a broadly applicable strategy. Rather, it highlights the need for better prospective evidence defining who should proceed to transplant, when to transplant, how much disease burden is acceptable, and which bridging therapies best preserve both lymphoma control and transplant fitness.
Correct Answer – C
References
- Iacoboni, G. et al. Treatment outcomes in patients with large B-cell lymphoma after progression to chimeric antigen receptor T-cell therapy. Hemasphere 8, e62 (2024).
- Zurko, J. et al. Allogeneic transplant following CAR T-cell therapy for large B-cell lymphoma. Haematologica108, 98–109 (2023).
- Sammassimo, S. et al. A Cellular Therapy with Haploidentical Peripheral Hematopoietic STEM CELL Transplantation MAY be a Therapeutic Option in Patients with Relapsed Lymphoma with Chemorefractory Disease. Blood 132, 2189 (2018).
- Dreger, P. et al. CAR T cells or allogeneic transplantation as standard of care for advanced large B-cell lymphoma: an intent-to-treat comparison. Blood Advances 4, 6157–6168 (2020).
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