Outcome of Pneumocystis jirovecii pneumonia (PcP) in post-CAR-T patients with hematological malignancies

doi:10.21203/rs.3.rs-4613232/v1

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Outcome of Pneumocystis jirovecii pneumonia (PcP) in post-CAR-T patients with hematological malignancies

https://doi.org/10.21203/rs.3.rs-4613232/v1

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Background

Pneumocystis jirovecii pneumonia (PcP) is an opportunistic infection associated with immunocompromised patients. The development of novel immunotherapies has promoted the incidence of PcP. This study describes the clinical course and outcome of PcP in chimeric antigen receptor (CAR) T cell recipients with hematological malignancies.

Methods

This is a retrospective case series of CAR-T recipients diagnosed with PcP in our center. The cases were all confirmed by metagenomic next-generation sequencing of clinical samples. The demographic, clinical, and outcome data were retrieved from the patients’ medical charts and electronic medical record system.

Results

In total, 8 cases of PcP were identified. The underlying malignancies included T-acute lymphoblastic leukemia (ALL) (n = 1), diffuse large B cell lymphoma (DLBCL) (n = 4), and B-ALL (n = 3). One patient received short-term sulfamethoxazole-trimethoprim (SMZ-TMP) while the others had no prophylaxis. Four patients had neutropenia/lymphopenia at the diagnosis of PcP, and two patients had immunosuppressants within one month before PcP manifestation. The median time from CAR-T infusion to PcP diagnosis was 98.5 days (range 52–251). Seven patients recovered from PcP after proper management while one died of septic shock.

Conclusion

PcP can occur after different CAR-T product, and the long-term depletion of immune cells seems to be related to PcP. SMZ-TMP is effective in this setting. More real-world experience of CAR-T therapy is required to assess the incidence and outcome of PcP in this population.

Pneumocystis pneumonia

Hematological malignancy

Adoptive cell therapy

Primary prophylaxis

Pneumocystis jirovecii is an opportunistic pathogen which causes Pneumocystis pneumonia (PcP), a life-threatening infection mostly seen in human immunodeficiency virus (HIV)-infected patients. As novel immunotherapies are now used in a wide spectrum of diseases, non-HIV, immunocompromised population at risk of PcP are increasing because of iatrogenic immunosuppression.[1] The incidence, course, and outcome of PcP in the setting of rituximab therapy have been widely reported,[2] while PcP cases in recipients of another immunotherapy with similar mechanism — chimeric antigen receptor (CAR)-T therapy — have been scarce. Despite the unprecedented efficacy in hematological malignancies, CAR-T cells induce profound immune cell depletion resulting in an immunocompromised state, to which the underlying malignancies and prior treatments also contribute.[3]

Herein, we report 8 cases of PcP in leukemia and lymphoma patients who received CAR-T therapy.

CAR-T recipeints diagnosed with PcP within follow-up at the our center from November 2020 to September 2022 were included.

A diagnosis of PcP was established when all three of the following criteria were met: 1) P. jirovecii DNA detected by metagenomic next-generation sequencing (mNGS); 2) characteristic radiological manifestations in chest computed tomography (CT); 3) clinical symptoms of pneumonia.

Neutropenia was defined as a neutrophil count < 1000/mL, while lymphopenia was defined as a lymphocyte count < 500/mL.

The clinical data were collected from the electronic medical record system.

Cohort Characteristics

In total, 8 patients were diagnosed with PcP during long-term follow-up. The median age was 60 years-old (range 50-70) at PcP diagnosis. One patient had a history of allogeneic hematopoietic stem cell transplantation. The underlying malignancies included T-acute lymphoblastic leukemia (ALL) (n = 1), diffuse large B cell lymphoma (DLBCL) (n = 4), and B-ALL (n = 3), and in accordance with it, CAR-T cells targeting CD7, CD19, and CD22 were infused, respectively. All patients with leukemia reached complete remission/response (CR), 1 with positive minimal residual disease (MRD) and 3 with negative MRD; while 3 patients with DLBCL achieved CR and 1 partial response (PR). (Table 1)

Table 1. Baseline characteristics of patients.

Patient No.

Gender

Age^*

Primary Disease

Previous
Cellular Therapy

CAR-T
Target

Source
of CAR-T

Lymphodepletion Regimen^#

Best Response

Consolidation Therapies between Response and PcP

Immunosuppressive Agent(s) within 1 month before PcP

Prophylaxis for PcP after CAR-T Infusion

Last Neutropenia before PcP
Manifestation (days)

Last Lymphopenia before PcP
Manifestation (days)

Male

T-ALL

allo-HSCT

CD7

HSC Donor

BM: CR, MRD(-)
EMD: SD

None

Never

Female

DLBCL

None

CD19

Autologous

FACE

PD-1 mAb

Steroid

None

Male

DLBCL

None

CD19

Autologous

FACE

PD-1 mAb

None

Male

DLBCL

None

CD19

Autologous

None

Male

DLBCL

None

CD19

Autologous

FACE

PD-1 mAb

None

SMZ-TMP

107

Female

B-ALL

CD19 CAR-T
CD22 CAR-T

CD19-22

Autologous

CR, MRD(-)

None

Female

B-ALL

CD19 CAR-T
CD22 CAR-T
CD19+CD22 CAR-T

CD19

Autologous

FCE

CR, MRD(-)

None

Male

B-ALL

CD19 CAR-T

CD19

Autologous

CR, MRD(+)

Multiple Chemotherapy

1. Cytotoxic Chemotherapy
2. Steroid

None

^*Age at CAR-T infusion.

^#F stands for fludarabine, C stands for cyclophosphamide, A stands for anthracycline, E stands for etoposide.

Abbreviations: ALL, acute lymphoid leukemia; DLBCL, diffuse large B cell lymphoma; allo, allogeneic; HSCT, hematopoietic stem cell transplantation; CAR-T, chimeric antigen receptor T cell; HSC, hematopoietic stem cell; BM, bone marrow; CR, complete remission/response; MRD, minimal residual disease; EMD, extramedullary disease; SD, stable disease; PR, partial response; PcP, Pneumocystis jirovecii pneumonia; PD-1, programmed death-1; mAb, monoclonal antibody; SMZ-TMP, sulfamethoxazole-trimethoprim

Immunosuppression and Prophylaxis before PcP

Two patients received immunosuppressive agents within 1 month before PcP manifestations, including corticosteroids (Patient 2, prednisone 30mg daily; and Patient 8, dexamethasone 10mg daily) and cytotoxic chemotherapies (Patient 8, because of the relapsed primary disease). Other treatments between CAR-T infusion and PcP manifestation which were assumed to be of no significant immunosuppression included sintilimab (Patients 2, 3, and 5 as consolidation for primary disease) and corticosteroids (Patient 4, methylprednisolone 4mg daily). (Figure 1)

Figure 1. Brief timelines for each patients.

Abbreviations: No., number; SMZ-TMP, sulfamethoxazole-trimethoprim; PD-1, programmed death-1; mAb, monoclonal antibody; PcP, Pneumocystis jirovecii pneumonia.

^*Patient 4 was not included because of the incompleteness of his follow-up data.

Based on the protocols in our center, there has been no routine prophylaxis against P. jirovecii after infusion, while Patient 5 had been taking sulfamethoxazole-trimethoprim (SMZ-TMP) until 20 days after infusion because of suspected PcP during the myelosuppression resulted from previous chemotherapy.

Clinical Course and Outcome

Brief timelines for each patients are presented in Figure 1. Leukopenia was transient in Patients 1, 2, and 3, while Patients 5, 6, 7, and 8 developed PcP during recurrent or persistent neutropenia and/or lymphopenia.

All the cases of pneumonia manifested at least 50 days from CAR-T infusion (52-251 days, median 98.5 days). The clinical presentations and outcome are summarized in Table 2. Most patients presented mild manifestations consisting of fever and nonproductive cough, and recovered rapidly after treatment based on SMZ-TMP. Three patients had comorbid viral and bacterial infections, including 2 with tuberculosis. Fortunately, 7 out of 8 patients recovered from PcP after treatment, while one (Patient 4) died of septic shock resulted from systemic infection. Given the emergency, he was treated at a lower local hospital rather than our center, and detailed disease course was not available.

Table 2. PcP-related manifestations, treatments, and outcomes.

Patient No.	Time from CAR-T Infusion to PcP Manifestation (days)	Initial Manifestations	Primary Disease Status at PcP diagnosis	Decisive Diagnosing Technique	PcP Treatment	PcP outcome	Infectious Co-morbidity (Pathogen/Site)
1	60	1. Fever 2. Cough	BM: CR, MRD(-) EMD: SD	mNGS of BALF	1. SMZ-TMP 2. Caspofungin 3. Steroid	Remission	None
2	89	1. Fever 2. Cough	CR	mNGS of BALF	1. SMZ-TMP 2. Caspofungin 3. Steroid 4. IVIg	Remission	None
3	115	1. Fever 2. Cough	CR	mNGS of BALF	1. SMZ-TMP 2. Caspofungin 3. Steroid	Remission	None
4	251	1. Fever	CR	mNGS of PB	1. Caspofungin 2. Steroid	Death	None
5	108	1. Fever 2. Cough	PR	mNGS of BALF	1. SMZ-TMP 2. Caspofungin	Remission	1. Mycobacterium tuberculosis/BALF 2. CMV/Blood & Aqueous humour
6	52	1. Fever 2. Fatigue 3. Dyspnea	CR, MRD(-)	mNGS of PB	1. SMZ-TMP 2. Caspofungin 3. Steroid	Remission	1. CMV/Blood 2. BKV/Blood
7	159	1. Fever 2. Cough 3. Dyspnea	CR, MRD(-)	mNGS of BALF	1. SMZ-TMP 2. Steroid	Remission	1. Stenotrophomonas maltophilia/BALF 2. Mycobacterium tuberculosis/BALF 3. Human Coronavirus NL63/BALF 4. CMV/Blood 5. CNS infection suspected without direct evidence.
8	89	1. Fever 2. Cough	Relapsed	mNGS of BALF	1. SMZ-TMP 2. Caspofungin 3. Steroid	Remission	None

Abbreviations: CAR-T, chimeric antigen receptor T cell; PcP, Pneumocystis jirovecii pneumonia; BM, bone marrow; CR, complete remission/response; MRD, minimal residual disease; EMD, extramedullary disease; SD, stable disease; PR, partial response; mNGS, metagenomic next-generation sequencing; BALF, bronchoalveolar lavage fluid; PB, peripheral blood; SMZ-TMP, sulfamethoxazole-trimethoprim; IVIg, intravenous immunoglobulin; CMV, cytomegalovirus; BKV, BK polyomavirus; CNS, central nervous system.

Representative Case

Patient 7 had struggled through multiple infections ever since CAR-T infusion, in concordance with the prolonged and profound lymphopenia and neutropenia. Half a year after CAR-T infusion, she presented at our center with dyspnea, productive cough, and fever. A chest CT suggested severe pneumonia, thus, a bronchoscopy was warranted to get quick and accurate identification of possible pathogens. mNGS of BALF detected various pathogens including P. jiroveci, Stenotrophomonas maltophilia, Mycobacterium tuberculosis, and Human Coronavirus NL63. Meanwhile, cytomegalovirus reactivation was detected in peripheral blood. After the administration of combined drug treatment (meropenem for S. maltophilia, SMZ-TMP + caspofungin for P. jiroveci, ganciclovir for cytomegalovirus, isoniazid + ethambutol for tuberculosis, and linezolid to prevent potential additional infections), complex infection was mostly contained. Unfortunately, her impaired respiratory and immune systems were too vulnerable to resist another attack of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), and eventually died of consequent respiratory failure 1 month post the diagnosis of PcP.

PcP has long been recognized as an acquired immunodeficiency syndrome (AIDS)-defining illness, and one of the most common opportunistic infection in human immunodeficiency virus (HIV)-infected patients.[4] However, different from decades ago, more cases of PcP are currently found in non-HIV patients than in patients with it.[5] Common risk factors of PcP development in patients without HIV include the use of immunosuppressive agents, hematopoietic stem cell or solid organ transplantation, and malignancies or inflammatory conditions (particularly when cytotoxic or immunologic treatments are involved).[5,6] Although the use of CAR-T cells for treating various tumors is increasing, data concerning the incidence, outcome, and disease course of PcP in post-CAR-T setting is scarce. A single-center retrospective cohort study including 280 CD19 CAR-T recipients with B cell lymphoma reported a cumulative incidence of 1.07% (3/280) with prophylaxis in a median follow-up of 259 days; other studies with smaller sample sizes identified cumulative incidences range from 1.67% to 7.32%.[7–9]

In this study, we described 8 cases of PcP in differently targeted CAR-T recipients, which shows that this complication is not restricted to CD19 CAR-T. Nonetheless, there is no established guideline or consensus on the prophylaxis in CAR-T recipients, and data currently available are far from enough to conduct evident-based conclusion. Considering the prevalence of P. jirovecii exposure/colonization in vast population,[10,11] the disease should be taken seriously in the real-world application of CAR-T cells. The experiences in hematopoietic stem cell transplantation recipients and rituximab recipients might be helpful. Routine prophylaxis against P. jirovecii is now widely accepted in these two patient populations, while the duration varies greatly from center to center.[12,13] Even with prophylaxis, PcP cases have occasionally occurred right after the cessation, which shows that a defined period might not be optimal for every patient, personalized prophylactic regimen should be tailored.

To our knowledge, this is the largest case series describing PcP in post-CAR-T patients, and the first report of PcP in patients receiving CD7 CAR-T. The benefit of bacterial and viral prophylaxis after CAR-T therapy has been recognized by different recommendations,[14,15] while routine PcP prophylaxis is still under debate because of the rarity of the disease and possible severe adverse events, e.g., myelosuppression, induced by prophylactic agents. Although our case series does not establish a conclusion that CAR-T recipients must be given PcP prophylaxis, it does highlight the importance of being vigilant for PcP in such patients. Long-term follow-up of CAR-T recipients in the real-world setting will aid our understanding of immune reconstitution of CAR-T therapy and allow for personalized anti-PcP prophylaxis.

ALL

acute lymphoid leukemia

DLBCL

diffuse large B cell lymphoma

allo

allogeneic

HSCT

hematopoietic stem cell transplantation

CAR-T

chimeric antigen receptor T cell

HSC

hematopoietic stem cell

bone marrow

complete remission/response

MRD

minimal residual disease

EMD

extramedullary disease

stable disease

partial response

PcP

Pneumocystis jirovecii pneumonia

PD-1

programmed death-1

mAb

monoclonal antibody

SMZ-TMP

sulfamethoxazole-trimethoprim

Ethics approval, consent to participate, and consent for publication

The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the First Affiliated Hospital of Zhejiang University School of Medicine. Informed consents were obtained from all subjects involved in the study.

Availability of data and materials

The data presented in this study are available on request from the corresponding authors. The data is not publicly available due to the privacy of the patients.

Competing interests

All of the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Fundings

This work was supported by funding from the National Natural Science Foundation of China (grant No. 81730008, 81770201, He Huang), National Natural Science Foundation of China (grant No. 82270234, Yongxian Hu), and National Natural Science Foundation of China (No. 81800178, Mingming Zhang).

Author’s Contributions

Study concept and design: Y.H. and H.H.. Data collection: C.Z., W.L., M.Z., Y.D., S.F., J.F., and R.H.. Data interpretation: C.Z., W.L., M.Z., and Y.D.. First draft: C.Z., W.L., M.Z., and Y.D.. Critical revision for important intellectual content: S.F., J.F., and R.H., Y.H., H.H., J.S..

All authors have read and agreed with the submission of the manuscript for publication.

Acknowledgements

The authors acknowledge the support of Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

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No competing interests reported.

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You are reading this latest preprint version

Outcome of Pneumocystis jirovecii pneumonia (PcP) in post-CAR-T patients with hematological malignancies

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Version 1

Abstract

Background

Methods

Results

Conclusion

Figures

Introduction

Methods

Results

Discussion

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1