Fatal Early Toxicity After Allogeneic Stem Cell Transplantation in Heavily Pretreated Follicular Lymphoma: Clinical Decision-Making Between Bispecific Antibodies and CAR T-Cell Therapy

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The aim of the paper is to report on the treatment of a patient with FL who went through multiple cycles of treatment and relapse. This paper raises an important problem in the treatment of R/R FL and other blood cancers. The decision-making process on when and what treatments to use after relapse is complex, so both targeted therapies and more clinical trials are necessary to effectively treat patients who have relapsed. It is important to report complicated cases, the treatments received, and the outcomes, which can be used for wider systematic literature reviews and improve patient outcomes. 

• After diagnosis in 2005, the first round of chemotherapy and anti-CD20 monoclonal antibody resulted in CR. How was the CR determined? 

• In 2010, the patient progressed to DLBCL and was treated with R-CHOP, autologous stem cell transplant, and radiation. Was there complete remission at this point?   

• In 2019 the patient relapsed again with FL and was treated with chemotherapy and anti-CD19 monoclonal antibody resulting in CR. How was the CR determined?  

• In 2022, the patient relapsed again with FL and was treated with anti-CD20 monoclonal antibody and lenalidomide. In 2023, the patient didn’t respond to the treatment and FL progression was seen. Some lab results would be helpful to know when the patient stopped responding to treatment. 

• In 2024, the patient was given a bispecific CD3xCD20 antibody and achieved a partial response. How was the partial response determined?  

• In 2025, after the conditioning regime, the patient got an allo-HSCT with GVHD prophylaxis. Unfortunately, the patient died after the infusion 

A table with lab results would be helpful to get a picture of disease progression/resistance 

How was the CR/PR determined at each treatment cycle?  

Was measurable residual disease determined at any point? Could this help in the decision-making process? 

Could next-generation sequencing help in the selection of treatments? 

 

Figure1 – make sure the figure is high resolution 

Line 48 – formatting 

Line 74 - formatting 

Author Response

The aim of the paper is to report on the treatment of a patient with FL who went through multiple cycles of treatment and relapse. This paper raises an important problem in the treatment of R/R FL and other blood cancers. The decision-making process on when and what treatments to use after relapse is complex, so both targeted therapies and more clinical trials are necessary to effectively treat patients who have relapsed. It is important to report complicated cases, the treatments received, and the outcomes, which can be used for wider systematic literature reviews and improve patient outcomes. 

• After diagnosis in 2005, the first round of chemotherapy and anti-CD20 monoclonal antibody resulted in CR. How was the CR determined? 

• In 2010, the patient progressed to DLBCL and was treated with R-CHOP, autologous stem cell transplant, and radiation. Was there complete remission at this point?   

• In 2019 the patient relapsed again with FL and was treated with chemotherapy and anti-CD19 monoclonal antibody resulting in CR. How was the CR determined?  

• In 2022, the patient relapsed again with FL and was treated with anti-CD20 monoclonal antibody and lenalidomide. In 2023, the patient didn’t respond to the treatment and FL progression was seen. Some lab results would be helpful to know when the patient stopped responding to treatment. 

• In 2024, the patient was given a bispecific CD3xCD20 antibody and achieved a partial response. How was the partial response determined?  

• In 2025, after the conditioning regime, the patient got an allo-HSCT with GVHD prophylaxis. Unfortunately, the patient died after the infusion 

R: We thank the reviewer for the thoughtful and constructive comments. We fully agree with the suggestions provided and have incorporated the proposed revisions accordingly. These improvements have strengthened the clarity and overall quality of our manuscript, and we are grateful for the careful evaluation and valuable input. We have incorporated these details into the main text.

A table with lab results would be helpful to get a picture of disease progression/resistance 

R: Thank you for the suggestion. We had also considered creating a table summarizing the various altered analytes throughout the patient’s history. However, upon reviewing the data, we noted, for example, that LDH was elevated only at the initial presentation and was within near-normal range during subsequent relapses. Therefore, we felt that such a table would not provide meaningful information for the reader.

 

How was the CR/PR determined at each treatment cycle?  

R: Thank you for this clarification. At our center, it is standard practice to perform a CT scan during treatment and a PET-CT at the end of therapy. This protocol was applied for each treatment cycle, but we did not include these details in the main text to avoid redundancy and maintain brevity.

 

Was measurable residual disease determined at any point? Could this help in the decision-making process? 

R: We agree with the observation. Unfortunately, our center does not have access to technologies or clinical studies such as circulating free DNA (cfDNA) that would allow monitoring of measurable residual disease (MRD). Moreover, this approach would have been difficult to implement given the patient’s long treatment history.

 

Could next-generation sequencing help in the selection of treatments? 

R: Next-generation sequencing (NGS) is certainly a tool that can support therapeutic decision-making. However, in our specific case, paradoxically, it would not have been helpful, as the patient was heavily pretreated and the key decision point was choosing between bispecific therapy and CAR-T. Ultimately, the selection of the bispecific agent served as a bridge to allogeneic transplantation due to the development of pure red cell aplasia and the associated risk of leukemic evolution.

 

Reviewer 2 Report

Comments and Suggestions for Authors

In this case report Canichella et al describe the treatment of a relapsed Follicular Lymphoma. The patient had received multiple prior lines of therapy, and the authors describe the decision to treat with either CAR or bispecific antibodies as bridging therapy to allogeneic stem cell transplantation. 

The writing is clear and describes the history of treatment for this patient. This is also shown in figure 1. The text within the figure could be made slightly larger and clearer.

The different mechanisms of cation of CAR and bispecific antibodies should be explained in the introduction. 

The rationale for treatment with mosunetuzumab is described, but more detail on the differing targets of mosunetuzumab vs CAR could be expanded ( CD20 vs CD19). Authors should state that the CARs describe target CD19 and how the differing targets may have impacted the outcomes of the patient. This should also be mentioned in the discussion when talking about the need for direct comparisons between CAR and bispecific antibodies,  as it is important to compare therapies that target the same antigen. the abrevisation of mosunetuzumab should also be stated in the main text and not just the abstract. 

Author Response

In this case report Canichella et al describe the treatment of a relapsed Follicular Lymphoma. The patient had received multiple prior lines of therapy, and the authors describe the decision to treat with either CAR or bispecific antibodies as bridging therapy to allogeneic stem cell transplantation. 

The writing is clear and describes the history of treatment for this patient. This is also shown in figure 1. The text within the figure could be made slightly larger and clearer.

The different mechanisms of cation of CAR and bispecific antibodies should be explained in the introduction. 

The rationale for treatment with mosunetuzumab is described, but more detail on the differing targets of mosunetuzumab vs CAR could be expanded ( CD20 vs CD19). Authors should state that the CARs describe target CD19 and how the differing targets may have impacted the outcomes of the patient. This should also be mentioned in the discussion when talking about the need for direct comparisons between CAR and bispecific antibodies,  as it is important to compare therapies that target the same antigen. the abrevisation of mosunetuzumab should also be stated in the main text and not just the abstract. 

R: Thank you for the observation; we have reformulated the introduction according to your suggestion.

Reviewer 3 Report

Comments and Suggestions for Authors

Dear Drs. Canichella, Cerretti, de Fabritiis, Abruzzese, and colleagues: I have reviewed with great interest your manuscript entitled "Tailoring Immunotherapy Between Bispecific Antibody and CAR T-Cell Therapy in a Case of Relapsed Follicular Lymphoma," concerning the therapeutic selection between bispecific antibodies and CAR-T therapy in relapsed/refractory follicular lymphoma (R/R FL). The case presented addresses a relevant and current clinical dilemma in contemporary onco-hematological practice. However, I believe the manuscript requires further revision before its acceptance for publication, for the reasons detailed below with technical and scientific rigor.

1. CHRONOLOGICAL INCONSISTENCIES

Major problem identified:

• Lines 65-67: Indicate that the patient received mosunetuzumab from April 2024 to November 2024 (8 cycles), but later mention that the allo-HSCT was performed in May 2025. This creates a 6-month gap without clarifying what occurred between November 2024 and May 2025.

Required action:

• Correct the entire timeline with accurate and sequential dates.
• Specify if there were maintenance therapies, additional evaluations, or observation periods during this interval.
• Figure 1 should accurately reflect this corrected timeline.

 

2. INSUFFICIENT DESCRIPTION OF THE CLINICAL CASE

Although the history is well documented chronologically, essential clinical data is missing, limiting the interpretation of the case:

2.1. Regarding mosunetuzumab treatment:

• Specific doses administered (cycle 1: step-up dosing; subsequent cycles).
• Response criteria used (Lugano 2014? Quantitative PET-CT with Deauville score?).
• Partial response at line 65: What percentage of tumor reduction? Persistent uptake on PET-CT? What was the criterion for considering the patient eligible for transplantation with only a partial response?

2.2. Regarding the pre-transplant status:

• HCT-CI score (Hematopoietic Cell Transplantation-Comorbidity Index).
• Performance status (ECOG/Karnofsky).
• Status of minimal residual disease (PET-CT prior to conditioning).
• Infectious status: Were active infections (CMV, EBV, fungal) ruled out?
• Pre-transplant pulmonary function (DLCO, FEV1), especially relevant given the outcome of hemorrhagic alveolitis.

2.3. Regarding red cell aplasia (line 66):

• It appeared abruptly without an etiological context.
• Was it secondary to mosunetuzumab? (although this is not a commonly described adverse event).
• Associated with parvovirus B19 infection? (frequent in immunosuppressed patients).
• Related to previous bendamustine? (late myelosuppression).
• This requires clarification, as red cell aplasia may reflect underlying bone marrow involvement, which would increase the risk of post-transplant complications.

2.4. Regarding the allogeneic transplant:

• TBF conditioning details: The doses mentioned are standard, but the following are missing:
• Days of administration of each drug.
• Whether intravenous or oral busulfan was used.
• Pharmacokinetic monitoring of busulfan (AUC target levels).
• Antithymocyte globulin (ATG): Which type? (ATG-Thymoglobulin® or ATG-Fresenius®), total dose and regimen?
• Infectious prophylaxis: Was antifungal, antiviral (acyclovir/valganciclovir), or antibacterial prophylaxis administered?

 

3. INSUFFICIENT ANALYSIS OF THE OUTCOME

The patient died the day after the transplant from hemorrhagic alveolitis, an extremely serious event that warrants a thorough critical analysis, currently absent from the manuscript.

3.1. Etiology of hemorrhagic alveolitis:

Post-allogeneic hematopoietic stem cell transplantation (HSCT) hemorrhagic alveolitis is a rare but devastating complication (incidence <5%), with a mortality rate >80%. Its main causes include:

1. Direct conditioning toxicity (especially busulfan, which has pulmonary tropism).
2. Acute pulmonary infection (CMV, Aspergillus, Pneumocystis, respiratory viruses).
3. Thrombotic microangiopathy (associated with immunosuppressants, hyperacute GVHD).
4. Subclinical pre-existing pulmonary involvement (prior exposure to 30 Gy chest radiotherapy, lines 54-55).
5. Iron overload (line 67: the patient required iron chelation due to multiple transfusions).

Critical unanswered question:

• Was bronchoscopy with bronchoalveolar lavage performed(BAL)? (although likely contraindicated due to instability).
• Clinical autopsy? (essential to identify the definitive cause).
• Was a pre-existing pulmonary infection suspected?
• Were there any radiological findings prior to transplantation (high-resolution chest CT)?

3.2. Retrospectively identifiable risk factors:

• Cumulative therapeutic burden: 5 previous lines of therapy including:
• Fludarabine (line 50): cumulative pulmonary toxicity.
• Chest radiotherapy 30 Gy (line 55): pulmonary vascular endothelial damage.
• Bendamustine (line 56): prolonged myelosuppression.
• Profound immunosuppression

HBV reactivation (line 60) is a marker of severe immune deterioration.

• Red cell aplasia + transfusion dependence: reflects bone marrow involvement and potential iron overload (a risk factor for pulmonary complications).
• Busulfan conditioning: known for pulmonary toxicity, especially in patients with prior exposure to alkylating agents.

This information MUST be included in the Discussion as a retrospective analysis of risk factors.

 

4. DISCUSSION: AREAS FOR SUBSTANTIAL IMPROVEMENT

The discussion is well-structured but overly generic and does not draw specific lessons from the presented case. It requires:

4.1. Critical analysis of the transplant decision:

• Was the indication for allo-HSCT appropriate in this patient?
• Patient approximately 60 years old (calculated from diagnosis in 2005), heavily pretreated, with comorbidities (HBV, aplasia, multiple transfusions).
• Partial (not complete) response to mosunetuzumab. 4.2. Current evidence: The 2020 EBMT (European Society for Blood and Marrow Transplantation) and CIBMTR guidelines recommend allo-HSCT in relapsed/refractory (R/R) disease only in young patients with chemosensitive disease and a low HCT-CI score (Snowden JA et al., Bone Marrow Transplant 2020; PMID: 31831870).

 

Essential reflective question: Was the risk of transplant-related mortality (NRM, non-relapse mortality) acceptable in this context?

4.2. Undiscussed therapeutic alternatives:

• Why was CAR-T not considered as rescue therapy after mosunetuzumab?
• Lisocabtagene maraleucel (liso-cel) has demonstrated efficacy even after bispecific antibodies (BsAbs) (although data are limited).
• Lower acute mortality than allo-HSCT.
• Was consolidation with targeted radiotherapy or maintenance therapy with lenalidomide considered?

4.3. Integration of specific scientific evidence: Studies on the following should be cited:

• Transplant-related mortality in highly pretreated, relapsed/refractory (R/R)FL patients:
• Smith SM et al., Blood Adv 2021;5(23):5372-5382 (PMID: 34758066): 1-year NRM ~20-30% in FL patients after allo-HSCT with RIC.
• CIBMTR registry data specific to FL patients.
• Safety of allo-HSCT after targeted therapies (BsAbs/CAR-T):
• Chong EA et al., Transplant Cell Ther 2022 (PMID: 35609720): Increased risk of pulmonary toxicity post-CAR-T followed by allo-HSCT.
• Emerging data on the safety of allo-HSCT after mosunetuzumab (still scarce, but should be mentioned).
• Indirect comparisons of BsAbs vs CAR-T:
• Morabito F et al., Eur J Haematol 2025 (ref. 6 of the manuscript) is appropriate, but add:
• Jacobson CA et al., Blood 2024 (SCHOLAR-5 analysis).
• Cost-effectiveness data (Luminari S et al., ref. 7) are interesting but secondary in a clinical case report.

 

4.4. Positioning of BsAbs in early lines:

• The conclusion (lines 107-109) mentions earlier use of CAR-T/BsAbs, but does not elaborate on this point with evidence:
• Ongoing trials: CELESTIAL (NCT04245839), LOTIS-7 (NCT04680052).
• Biological rationale: less cumulative immunosuppression, better cellular fitness for CAR-T, lower risk of infection.

5. CONCLUSIONS: REQUIRE REFORMULATION

The current conclusions (lines 103-109) are vague and do not adequately reflect the lessons of the case.

6. METHODOLOGICAL AND FORMAL ASPECTS

6.1. Abstract:

• Requires restructuring to a standard format: Background, Case presentation, Discussion, Conclusions.
• The fatal outcome (currently underestimated) should be explicitly mentioned.

6.2. Title:

• Current: "Tailoring Immunotherapy Between Bispecific Antibody and CAR T-Cell Therapy..."
• Problem: Does not reflect the outcome or the specific complexity.
• Alternative proposal:
• "Fatal Early Toxicity After Allogeneic Stem Cell Transplantation in Heavily Pretreated Follicular Lymphoma: Clinical Decision-Making Between Bispecific Antibodies and CAR T-Cell Therapy"
• (More descriptive and informative)

6.3. Bibliographic references:

Adequate and up-to-date (2019-2025), including key pivotal studies (ZUMA-5, ELARA, TRANSCEND FL, mosunetuzumab data).

 

6.4. Figure 1:

• Useful and clear, but the chronology should be corrected based on comments in point 1.
• Consider adding adverse event markers (HBV reactivation, aplasia, death) for greater visual clarity.

 

6.5. English quality:

• Generally correct, but requires minor revision:
• Line 77: "burden toxicity" → "cumulative toxicity burden"
• Line 79: "resulted particularly complex" → "was particularly complex"
• Consistency in abbreviations (R/R vs RR).

 

FINAL RECOMMENDATION

In my opinion, this manuscript addresses a relevant and current topic, but requires substantial improvements in:

1. Rigor in the case description (temporal inconsistencies, missing data).
2. Critical analysis of the fatal outcome (currently insufficient).
3. Integration of specific evidence on allo-HSCT risks in this context.
4. More concrete conclusions based on lessons learned from the case.

After these revisions, the manuscript will have sufficient merit for publication as an educational case report on decision-making.

Author Response

Referee  3 

Dear Drs. Canichella, Cerretti, de Fabritiis, Abruzzese, and colleagues: I have reviewed with great interest your manuscript entitled "Tailoring Immunotherapy Between Bispecific Antibody and CAR T-Cell Therapy in a Case of Relapsed Follicular Lymphoma," concerning the therapeutic selection between bispecific antibodies and CAR-T therapy in relapsed/refractory follicular lymphoma (R/R FL). The case presented addresses a relevant and current clinical dilemma in contemporary onco-hematological practice. However, I believe the manuscript requires further revision before its acceptance for publication, for the reasons detailed below with technical and scientific rigor.

 

First of all, we would like to express our sincere gratitude to the reviewer for the thorough and insightful evaluation, which was greatly appreciated by our entire group and has significantly contributed to improving the quality and clarity of the clinical case. We hope that the revisions implemented have achieved the level of improvement that was rightly anticipated.

1. CHRONOLOGICAL INCONSISTENCIES

Major problem identified:

• Lines 65-67: Indicate that the patient received mosunetuzumab from April 2024 to November 2024 (8 cycles), but later mention that the allo-HSCT was performed in May 2025. This creates a 6-month gap without clarifying what occurred between November 2024 and May 2025.

R: We appreciate the reviewer’s insightful comment. The temporal gap is attributable to infection-related issues. These factors have now been explicitly detailed in the revised manuscript. They were originally omitted solely for brevity.

Required action: FIGURE

• Correct the entire timeline with accurate and sequential dates.
• Specify if there were maintenance therapies, additional evaluations, or observation periods during this interval.
• Figure 1 should accurately reflect this corrected timeline.

 

1. INSUFFICIENT DESCRIPTION OF THE CLINICAL CASE

Although the history is well documented chronologically, essential clinical data is missing, limiting the interpretation of the case:

2.1. Regarding mosunetuzumab treatment:

• Specific doses administered (cycle 1: step-up dosing; subsequent cycles).
• Response criteria used (Lugano 2014? Quantitative PET-CT with Deauville score?).
• Partial response at line 65: What percentage of tumor reduction? Persistent uptake on PET-CT? What was the criterion for considering the patient eligible for transplantation with only a partial response?

R: We thank the reviewer for the helpful comments. We have now addressed the annotations 

2.2. Regarding the pre-transplant status:

• HCT-CI score (Hematopoietic Cell Transplantation-Comorbidity Index).
• Performance status (ECOG/Karnofsky).
• Status of minimal residual disease (PET-CT prior to conditioning).
• Infectious status: Were active infections (CMV, EBV, fungal) ruled out?
• Pre-transplant pulmonary function (DLCO, FEV1), especially relevant given the outcome of hemorrhagic alveolitis.

R: Thanks for this suggestion. We have now incorporated a sentence in the manuscript clarifying the use of the clinical assessment indices HCT-CI and ECOG. Thank you for drawing our attention to this point.

2.3. Regarding red cell aplasia (line 66):

• It appeared abruptly without an etiological context.
• Was it secondary to mosunetuzumab? (although this is not a commonly described adverse event).
• Associated with parvovirus B19 infection? (frequent in immunosuppressed patients).
• Related to previous bendamustine? (late myelosuppression).
• This requires clarification, as red cell aplasia may reflect underlying bone marrow involvement, which would increase the risk of post-transplant complications.

R: Thank you for this clarification, which we had not included in the previous version of the manuscript for the sake of brevity but have now discussed and integrated. This point is indeed central: given the cumulative therapeutic burden, our patient had begun to show evidence of emerging bone marrow functional impairment. The erythroid aplasia was attributed to pharmacologic toxicity, as no similar toxicity has been described in association with mosunetuzumab; the virological profile was negative, and at that time there was no evidence of marrow involvement by lymphoma.

This constellation of findings was also a key factor prompting us to favor allogeneic transplantation over CAR T-cell therapy. A marrow impairment of this degree carries a high risk for prolonged post–CAR T cytopenias, a long-term complication that can be challenging to manage and that in some cases ultimately necessitates allogeneic transplantation.

 

2.4. Regarding the allogeneic transplant:

• TBF conditioning details: The doses mentioned are standard, but the following are missing:
• Days of administration of each drug.
• Whether intravenous or oral busulfan was used.
• Pharmacokinetic monitoring of busulfan (AUC target levels).
• Antithymocyte globulin (ATG): Which type? (ATG-Thymoglobulin® or ATG-Fresenius®), total dose and regimen?
• Infectious prophylaxis: Was antifungal, antiviral (acyclovir/valganciclovir), or antibacterial prophylaxis administered?

R: We appreciate the reviewer’s comment. We have now clarified the details of the TBF conditioning regimen, specifying that busulfan was administered intravenously and that therapeutic drug monitoring was not available at our center.

Regarding the prophylactic treatments, the standard plan included the following agents: letermovir, acyclovir, and fluconazole. Unfortunately, the patient did not have the opportunity to begin these prophylaxes.

We hope this clarification addresses the reviewer’s concern.

 

 

1. INSUFFICIENT ANALYSIS OF THE OUTCOME

The patient died the day after the transplant from hemorrhagic alveolitis, an extremely serious event that warrants a thorough critical analysis, currently absent from the manuscript.

3.1. Etiology of hemorrhagic alveolitis:

Post-allogeneic hematopoietic stem cell transplantation (HSCT) hemorrhagic alveolitis is a rare but devastating complication (incidence <5%), with a mortality rate >80%. Its main causes include:

1. Direct conditioning toxicity (especially busulfan, which has pulmonary tropism).
2. Acute pulmonary infection (CMV, Aspergillus, Pneumocystis, respiratory viruses).
3. Thrombotic microangiopathy (associated with immunosuppressants, hyperacute GVHD).
4. Subclinical pre-existing pulmonary involvement (prior exposure to 30 Gy chest radiotherapy, lines 54-55).
5. Iron overload (line 67: the patient required iron chelation due to multiple transfusions).

Critical unanswered question:

• Was bronchoscopy with bronchoalveolar lavage performed(BAL)? (although likely contraindicated due to instability).
• Clinical autopsy? (essential to identify the definitive cause).
• Was a pre-existing pulmonary infection suspected?
• Were there any radiological findings prior to transplantation (high-resolution chest CT)?

 

R: thanks, we include these information in the last version of the manuscript

3.2. Retrospectively identifiable risk factors:

• Cumulative therapeutic burden: 5 previous lines of therapy including:
• Fludarabine (line 50): cumulative pulmonary toxicity.
• Chest radiotherapy 30 Gy (line 55): pulmonary vascular endothelial damage.
• Bendamustine (line 56): prolonged myelosuppression.
• Profound immunosuppression

R: We thank the referee for providing the opportunity to further elaborate on this point. As indicated by the HCT-CI, the patient had no organ comorbidities and no active infections at the time of transplantation. An autopsy was not requested. The most plausible explanation remains the high toxic burden of the conditioning regimen, which may have functionally damaged the lungs and triggered this fatal complication.

 

HBV reactivation (line 60) is a marker of severe immune deterioration.

• Red cell aplasia + transfusion dependence: reflects bone marrow involvement and potential iron overload (a risk factor for pulmonary complications).
• Busulfan conditioning: known for pulmonary toxicity, especially in patients with prior exposure to alkylating agents.

This information MUST be included in the Discussion as a retrospective analysis of risk factors.

R: Thank you for your suggestion, which we have incorporated to revise the final section of the discussion.

 

 

1. DISCUSSION: AREAS FOR SUBSTANTIAL IMPROVEMENT

The discussion is well-structured but overly generic and does not draw specific lessons from the presented case. It requires:

4.1. Critical analysis of the transplant decision:

• Was the indication for allo-HSCT appropriate in this patient?
• Patient approximately 60 years old (calculated from diagnosis in 2005), heavily pretreated, with comorbidities (HBV, aplasia, multiple transfusions).
• Partial (not complete) response to mosunetuzumab. 4.2. Current evidence: The 2020 EBMT (European Society for Blood and Marrow Transplantation) and CIBMTR guidelines recommend allo-HSCT in relapsed/refractory (R/R) disease only in young patients with chemosensitive disease and a low HCT-CI score (Snowden JA et al., Bone Marrow Transplant 2020; PMID: 31831870).

 

Essential reflective question: Was the risk of transplant-related mortality (NRM, non-relapse mortality) acceptable in this context?

R: Thank you for your observation. The decision to proceed to transplantation was not straightforward and was made in collaboration with a multidisciplinary team. The critical considerations were not only the partial response to mosunetuzumab but, more importantly, the patient’s immunodeficient state and the onset of transfusion-dependent red cell aplasia, which represents a marker of bone marrow dysfunction and an increased risk of secondary leukemia. Such progression would have necessitated an alternative therapeutic program and a subsequent allogeneic transplant. Although the decision to proceed with transplantation was challenging, it was deemed necessary given the patient’s young age, fitness, heavily pretreated follicular lymphoma, partial response to mosunetuzumab, and development of transfusion-dependent erythroid aplasia. CAR T-cell therapy was not considered feasible due to the high risk of secondary cytopenias

4.2. Undiscussed therapeutic alternatives:

• Why was CAR-T not considered as rescue therapy after mosunetuzumab?
• Lisocabtagene maraleucel (liso-cel) has demonstrated efficacy even after bispecific antibodies (BsAbs) (although data are limited).
• Lower acute mortality than allo-HSCT.
• Was consolidation with targeted radiotherapy or maintenance therapy with lenalidomide considered?

R: As discussed above, CAR T-cell therapy would have nevertheless required additional chemotherapy with fludarabine and could have exposed the patient—given the reduced marrow reserve due to red cell aplasia—to a significant risk of post-CAR T cytopenias. In the worst-case scenario, this could have severely impaired the patient’s quality of life, leading to transfusion dependence, a high risk of infections, and potentially necessitating an allogeneic transplant as a last-resort intervention

4.3. Integration of specific scientific evidence: Studies on the following should be cited:

• Transplant-related mortality in highly pretreated, relapsed/refractory (R/R)FL patients:
• Smith SM et al., Blood Adv 2021;5(23):5372-5382 (PMID: 34758066): 1-year NRM ~20-30% in FL patients after allo-HSCT with RIC.
• CIBMTR registry data specific to FL patients.
• Safety of allo-HSCT after targeted therapies (BsAbs/CAR-T):
• Chong EA et al., Transplant Cell Ther 2022 (PMID: 35609720): Increased risk of pulmonary toxicity post-CAR-T followed by allo-HSCT.
• Emerging data on the safety of allo-HSCT after mosunetuzumab (still scarce, but should be mentioned).
• Indirect comparisons of BsAbs vs CAR-T:
• Morabito F et al., Eur J Haematol 2025 (ref. 6 of the manuscript) is appropriate, but add:
• Jacobson CA et al., Blood 2024 (SCHOLAR-5 analysis).
• Cost-effectiveness data (Luminari S et al., ref. 7) are interesting but secondary in a clinical case report.

 

R: Thank you; we have reintegrated some of the bibliographic references you suggested.

 

 

4.4. Positioning of BsAbs in early lines:

• The conclusion (lines 107-109) mentions earlier use of CAR-T/BsAbs, but does not elaborate on this point with evidence:
• Ongoing trials: CELESTIAL (NCT04245839), LOTIS-7 (NCT04680052).
• Biological rationale: less cumulative immunosuppression, better cellular fitness for CAR-T, lower risk of infection.

1. CONCLUSIONS: REQUIRE REFORMULATION

The current conclusions (lines 103-109) are vague and do not adequately reflect the lessons of the case.

R: thanks we reformulate the conclusion. 

1. METHODOLOGICAL AND FORMAL ASPECTS

6.1. Abstract:

• Requires restructuring to a standard format: Background, Case presentation, Discussion, Conclusions.
• The fatal outcome (currently underestimated) should be explicitly mentioned.

 

R: thanks we restructure the abstract

6.2. Title:

• Current: "Tailoring Immunotherapy Between Bispecific Antibody and CAR T-Cell Therapy..."
• Problem: Does not reflect the outcome or the specific complexity.
• Alternative proposal:
• "Fatal Early Toxicity After Allogeneic Stem Cell Transplantation in Heavily Pretreated Follicular Lymphoma: Clinical Decision-Making Between Bispecific Antibodies and CAR T-Cell Therapy"
• (More descriptive and informative)

R: Thank you; we have decided to use the title you suggested, as it better encompasses the scope of the clinical case.

 

6.3. Bibliographic references:

Adequate and up-to-date (2019-2025), including key pivotal studies (ZUMA-5, ELARA, TRANSCEND FL, mosunetuzumab data).

R: Thanks, we integrated the references.

 

6.4. Figure 1:

• Useful and clear, but the chronology should be corrected based on comments in point 1.
• Consider adding adverse event markers (HBV reactivation, aplasia, death) for greater visual clarity.

 R: Thank you; we have reconstructed the figure following your suggestions.

 

6.5. English quality:

• Generally correct, but requires minor revision:
• Line 77: "burden toxicity" → "cumulative toxicity burden"
• Line 79: "resulted particularly complex" → "was particularly complex"
• Consistency in abbreviations (R/R vs RR).

 R: Thank you for your suggestions.

 

FINAL RECOMMENDATION

In my opinion, this manuscript addresses a relevant and current topic, but requires substantial improvements in:

1. Rigor in the case description (temporal inconsistencies, missing data).
2. Critical analysis of the fatal outcome (currently insufficient).
3. Integration of specific evidence on allo-HSCT risks in this context.
4. More concrete conclusions based on lessons learned from the case.

After these revisions, the manuscript will have sufficient merit for publication as an educational case report on decision-making.

 

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

OVERALL ASSESSMENT

The manuscript has undergone substantial improvement following revisions in response to my comments. The authors have professionally addressed most initial critical observations. However, some areas require refinement before publication.

The manuscript is close to being acceptable, but requires three critical additions in the Discussion to meet publication standards.

 

The mandatory modifications for acceptance are:

 

1. RETROSPECTIVE CRITICAL ANALYSIS OF ALLO-HSCT DECISION

Missing element: Critical reflection on whether transplant was appropriate in this context.

Required content:

• Acknowledge favorable criteria (HCT-CI 0, ECOG 0) versus risk factors (partial response/Deauville 3, transfusion-dependent aplasia, 5 prior lines)
• Cite NRM data: 20-30% at 1-year in R/R FL post-allo-HSCT (EBMT registries)
• Emphasize elevated pulmonary toxicity risk with aplasia + alkylators + prior thoracic RT
• Conclude: need for quantitative NRM prediction models in future cases

Add reference: Smith SM et al., Blood Adv 2021;5(23):5372-5382

2. MULTIFACTORIAL ANALYSIS OF HEMORRHAGIC ALVEOLITIS

I miss a comprehensive etiological analysis beyond "conditioning toxicity." That is the reason for this required content:

• Recognize multifactorial etiology (<5% incidence, >80% mortality)
• List contributing factors: busulfan toxicity (no AUC monitoring), cumulative endothelial damage (RT + fludarabine), iron overload, profound immunosuppression (HBV reactivation)
• Explicitly state limitations: no pre-transplant HRCT, no pulmonary function tests (DLCO/FEV1), no autopsy
• Conclude: mandate pre-transplant pulmonary risk stratification in future cases

3. DISCUSSION OF ALTERNATIVE THERAPEUTIC OPTIONS

Another missing element detected is: Why other strategies were not pursued. Therefore should be include:

• CAR-T as definitive therapy: lower TRM (~5-10% vs 20-30%)
• Post-CAR-T cytopenias manageable versus irreversible conditioning toxicity
• Ultra-reduced intensity conditioning could have minimized pulmonary risk
• Conclude: formal risk-benefit quantitative comparisons needed

MINOR CORRECTIONS

• Terminology consistency verification
• Reference addition as specified

I recommend acceptance contingent upon incorporation of the three critical Discussion additions outlined above. The case has educational value but lacks critical analytical depth. The three additions (~300-400 words) will transform it from descriptive to analytically robust.

 

Author Response

We sincerely thank the reviewer for the insightful and constructive comments, which have greatly enriched the manuscript and improved the clarity and usability of the clinical case. We are also grateful for recognizing the relevance of the case and for guiding us through a progressive refinement of the discussion and its critical elements.

In accordance with the reviewer’s suggestions, we have implemented all the recommended revisions and have adjusted the text to better address the points raised. We hope these changes accurately reflect the reviewer’s expectations and strengthen the overall quality of the manuscript.

Regarding the reference indicated as Smith SM et al., Blood Adv 2021;5(23):5372–5382, we were unfortunately unable to identify this citation in the journal’s archives. However, by searching the specified volume and page range, we found the following article, which we believe corresponds to the intended reference:

Lamaison C, Latour S, Hélaine N, Le Morvan V, Saint-Vanne J, Mahouche I, Monvoisin C, Dussert C, Andrique L, Deleurme L, Dessauge E, Pangault C, Baulande S, Legoix P, Seffals M, Broca-Brisson L, Alessandri K, Carlotti M, Soubeyran P, Merlio JP, Mourcin F, Nassoy P, Recher G, Tarte K, Bresson-Bepoldin L. A novel 3D culture model recapitulates primary FL B-cell features and promotes their survival. Blood Advances. 2021;5(23):5372–5386. doi:10.1182/bloodadvances.2020003949.

We have therefore included this corrected reference in the revised manuscript.

Once again, we thank the reviewer for the valuable input and for contributing to the improvement of our work.