Introduction: With the increasing use of blinatumomab in relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), including minimal residual disease (MRD)-positive cases, awareness of its adverse effects has gradually improved. Pneumocystis jirovecii pneumonia (PCP) associated with blinatumomab therapy is rare. Case Presentation: We present a case of PCP in a patient undergoing blinatumomab therapy. A 70-year-old female diagnosed with Philadelphia-like CRLF2 overexpression B-cell precursor ALL received blinatumomab as consolidation therapy after achieving complete remission with prior induction chemotherapy. On the second day of blinatumomab infusion, she developed intermittent low-grade fever, and chest computed tomography (CT) revealed subtle infiltrates and nodules. Despite empiric trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis, she progressed to significant shortness of breath and type I respiratory failure, with increased lactate dehydrogenase and β-D-glucan assays. Chest CT showed diffuse ground-glass opacities with scattered small nodules. The dry cough prompted next-generation sequencing of peripheral blood, which tested positive for pneumocystis jirovecii without evidence of other pathogens. Consequently, the patient was diagnosed with PCP. The first cycle of blinatumomab had to be discontinued, and therapeutic dosages of TMP-SMX and dexamethasone were administered, resulting in full recovery and stable condition during follow-ups. Conclusion: PCP is rare in B-cell precursor ALL patients receiving blinatumomab therapy but manifests with early onset and rapid disease progression. Despite prophylaxis, PCP infection cannot be ignored during blinatumomab therapy. Therefore, heightened attention is warranted when using blinatumomab therapy.

In recent years, new immunotherapies and targeted agents have been increasingly utilized in relapsed or refractory acute lymphoblastic leukemia (ALL). Among these, blinatumomab has demonstrated remarkable efficacy in relapsed or refractory cases and in minimal residual disease (MRD)-positive ALL [1, 2]. Meanwhile, as the use of blinatumomab has risen, the associated risk of infection has become more apparent [3], particularly in relation to Pneumocystis jirovecii pneumonia (PCP), albeit rare. PCP is an opportunistic lung infection characterized by exertional dyspnea, dry cough, subfebrile temperature or fever, elevated lactate dehydrogenase (LDH), and diffused ground-glass opacities (GGO) with or without cystic lesions on chest computed tomography (CT) [4]. Given its rapid disease progression, which carries a heightened risk of respiratory failure and increased mortality, early diagnosis and treatment of acute PCP infection are crucial. Therefore, we present this rare case of PCP in the patient undergoing blinatumomab therapy.

A 70-year-old female patient diagnosed with Philadelphia-like CRLF2 overexpression B-cell precursor ALL was admitted to our hospital in 2021. She underwent induction chemotherapy of the VDLD regimen (vindesine, idarubicin, dexamethasone, and pegylated asparaginase) on August 1, 2021, and achieved complete remission. However, she experienced complications of chemotherapy-induced bone marrow suppression, febrile neutropenia, and bloodstream infection of Pseudomonas aeruginosa. Treatment with granulocyte colony-stimulating factor and meropenem led to complete recovery by August 21. Her past medical history included hypertension and steroid-induced diabetes, both of which recovered after induction chemotherapy. Additionally, she underwent cholecystectomy due to cholecystolithiasis and thyroid nodulectomy with normal thyroid function.

For consolidation therapy following prior induction chemotherapy, she received blinatumomab on September 10th (9 μg per day during the first week and 28 μg per day during the next 3 weeks) via continuous infusion. Her white blood cell (WBC) count was 9.84 × 109/L, and the lymphocyte count was 1.55 × 109/L on September 8th. On the second day of blinatumomab infusion, she presented with subfebrile fever, which was thought attributed to mild cytokine release syndrome (CRS) and managed with loxoprofen. The WBC and lymphocyte count were 10.9 × 109/L and 0.91 × 109/L on September 10, separately. However, on the 9th day after blinatumomab use, she experienced intermittent fever without obvious respiratory symptoms, and her WBC count increased to 18.1 × 109/L. Chest CT revealed subtle infiltrates and nodules. The patient received empiric treatment with piperacillin/tazobactam, acyclovir, and 160 mg trimethoprim (TMP)/800 mg sulfamethoxazole (SMX) daily for PCP infection prophylaxis. Despite treatment, the fever persisted, and loxoprofen was administered as needed.

On the 17th day of blinatumomab treatment, she developed obvious shortness of breath, and her pulse oxygen saturation decreased to 78%. Chest CT showed diffuse GGO with scattered small nodules (as shown in Fig. 1). Additionally, her lymphocyte count decreased to 0.59 × 109/L, C-reactive protein increased from 2.41 to 109.75 (reference <3) mg/L, LDH increased from 250 to 413 (reference <250) U/L, and β-D-glucan assays showed 298.6 (reference <100.5) pg/mL, all indicative of possible PCP infection. The dry cough with no sputum prompted next-generation sequencing of peripheral blood, which tested positive for pneumocystis jirovecii without evidence of other pathogens. Consequently, the patient was diagnosed with PCP.

Fig. 1.

Rapid progression and recovery of PCP in chest computed tomography. PCP, Pneumocystis jirovecii pneumonia.

Fig. 1.

Rapid progression and recovery of PCP in chest computed tomography. PCP, Pneumocystis jirovecii pneumonia.

Close modal

Therapeutic dosages of TMP-SMX (15 mg/kg/day of the TMP component) and dexamethasone (8 mg IV twice a day for 5 days, gradually tapered over 14 days) were administered, and the first cycle of blinatumomab had to be stopped. She ultimately achieved complete recovery, and an additional four cycles of blinatumomab with prophylaxis of PCP (160 mg TMP/800 mg SMX daily) were administered. As of now, MRD has consistently been negative during follow-ups.

In patients undergoing blinatumomab treatment who present with fever, respiratory distress, and elevated inflammatory factors, CRS is suspected [5, 6]. However, thorough exclusion of infections is necessary. Recently, the risk of infection associated with blinatumomab use was summarized [3], with PCP being rare. The core study of blinatumomab in ALL showed that only 1 out of 267 (0.4%) patients had PCP [1], and PCP events were not reported in other studies [7]. Moreover, PCP events were not indicated in the Food and Drug Administration (FDA) clinical review. Wang et al. [8] reported a case of a Philadelphia chromosome-positive ALL patient with PCP pneumonia who received treatment with both a tyrosine kinase inhibitor (TKI) and blinatumomab, with the PCP infection being considered more associated with the use of TKI. Here, we report a case of PCP infection after the use of blinatumomab alone.

PCP is a common cause of infection, especially in hematooncologic and posttransplant patients, as well as those under immunosuppressive drugs due to autoimmune diseases [4]. Obtaining organisms through lung specimens is challenging due to poor sensitivity; therefore, the diagnosis of PCP relies on a combination of risk factors, symptoms, radiographic findings, confirmation of organisms, and response to therapy [9]. Recently, new molecular methods have been developed for PCP diagnosis. In a case-control study, β-D-glucan with a cutoff level of 200 pg/mL combined with a positive Pneumocystis jirovecii PCR result in serum had a sensitivity and specificity of 92% and 90%, respectively, in PCP diagnosis [10]. However, further studies are needed to explore the significance of noninvasive tests in PCP diagnosis. In this case, the patient exhibited typical manifestations of fever, rapid progression of respiratory failure, elevation in β-D-glucan and LDH, diffuse GGO in CT, and a positive Pneumocystis jirovecii PCR result in serum, leading to the diagnosis of PCP.

In a previous report, So et al. [3] summarized the infectious risks and complications in adult leukemic patients receiving blinatumomab, indicating that host factors (e.g., neutropenia/lymphopenia) play a key role in PCP, especially low CD4+ T lymphocyte counts in cases of HIV patients, with lower respiratory infections being most commonly observed. The antitumor activity of blinatumomab is achieved by the establishment of a transient BiTE-induced cytolytic synapse between T cells and CD19+ target tumor cells. Polyclonal T cells are activated by blinatumomab in the presence of CD19+ target cells, inducing proteolytic activation and serial lysis in tumor cells via perforin or granzyme-mediated cell destruction by upregulation of CD25 and CD69 as well as cell adhesion molecules, and releasing inflammatory cytokines [11]. In past studies of CAR T-cell therapy, after depletion of CD19+ B cells, the recovery of CD4+ T cells was delayed, whereas CD8+ T cells recovered early [12]. Consequently, it is speculated that the depletion of CD19+ B cells after the use of blinatumomab may have affected lymphocyte function. In our case, there were no other risk factors for PCP infection, while the patient had lymphopenia only after blinatumomab treatment, which might have induced the PCP infection. Thus, prophylactic treatment may be necessary for those with risk factors for PCP, including viral coinfection, underlying malignancy or lung disease, immunosuppression, hypogammaglobulinemia, and abnormalities in immune cell quantity and quality [13]. Additionally, it is noteworthy that although TMP-SMX prophylaxis significantly reduces the frequencies of PCP, PCP could still develop in up to 27% of susceptible HIV-infected patients [14] and also in non-HIV immunocompromised patients [15, 16]. Therefore, PCP cannot be ignored even with prophylaxis, and monitoring for respiratory symptoms, temperature, and pulse oxygen saturation is crucial.

In conclusion, PCP is a rare condition in B-cell precursor ALL patients receiving blinatumomab therapy but manifests with early onset and rapid disease progression. Thus, more attention should be paid when using blinatumomab therapy.

The authors thank all of the physicians taking care of the patient in our hospital.

This retrospective review of patient data did not require ethical approval in accordance with local/national guidelines. Written informed consent for publication of the details of the medical case and images was obtained from the patient.

The authors have no conflicts of interest to declare.

This study was financially supported by the National Natural Science Foundation of China (Grant No. 82200230, for SKN) and National High Level Hospital Clinical Research Funding (Grant No. 2022-PUMCH-A-260, for SKN). The funders had no role in the design, data collection, data analysis, and reporting of this study.

Y.Y., K.S., and L.Z. designed the study. Y.Y. and K.S. wrote the manuscript. Y.Y. and H.L. took care of the patient and collected the data. K.S. and L.Z. examined the patient and edited the manuscript. All authors read and approved the final manuscript.

Additional Information

Yue Yin and Kaini Shen contributed equally to this work.

The data that support the findings of this study are not publicly available due to privacy reasons but are available from the corresponding author upon reasonable request.

1.
Kantarjian
H
,
Stein
A
,
Gokbuget
N
,
Fielding
AK
,
Schuh
AC
,
Ribera
JM
, et al
.
Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia
.
N Engl J Med
.
2017
;
376
(
9
):
836
47
.
2.
Gokbuget
N
,
Dombret
H
,
Bonifacio
M
,
Reichle
A
,
Graux
C
,
Faul
C
, et al
.
Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia
.
Blood
.
2018
;
131
(
14
):
1522
31
.
3.
So
W
,
Pandya
S
,
Quilitz
R
,
Shah
B
,
Greene
JN
.
Infectious risks and complications in adult leukemic patients receiving blinatumomab
.
Mediterr J Hematol Infect Dis
.
2018
;
10
(
1
):
e2018029
.
4.
Salzer
HJF
,
Schafer
G
,
Hoenigl
M
,
Gunther
G
,
Hoffmann
C
,
Kalsdorf
B
, et al
.
Clinical, diagnostic, and treatment disparities between HIV-infected and non-HIV-infected immunocompromised patients with pneumocystis jirovecii pneumonia
.
Respiration
.
2018
;
96
(
1
):
52
65
.
5.
Lee
DW
,
Gardner
R
,
Porter
DL
,
Louis
CU
,
Ahmed
N
,
Jensen
M
, et al
.
Current concepts in the diagnosis and management of cytokine release syndrome
.
Blood
.
2014
;
124
(
2
):
188
95
.
6.
Frey
NV
,
Porter
DL
.
Cytokine release syndrome with novel therapeutics for acute lymphoblastic leukemia
.
Hematology Am Soc Hematol Educ Program
.
2016
;
2016
(
1
):
567
72
.
7.
Martinelli
G
,
Boissel
N
,
Chevallier
P
,
Ottmann
O
,
Gokbuget
N
,
Rambaldi
A
, et al
.
Long-term follow- up of blinatumomab in patients with relapsed/refractory Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukaemia: final analysis of ALCANTARA study
.
Eur J Cancer
.
2021
;
146
:
107
14
.
8.
Wang
X
,
Li
H
,
Li
J
,
Zhang
M
,
He
P
.
Pneumocystis jiroveci Pneumonia secondary to tyrosine kinase inhibitor with blinatumomab therapy: a case report
.
Int Immunopharmacol
.
2023
;
115
:
109636
.
9.
White
PL
,
Backx
M
,
Barnes
RA
.
Diagnosis and management of Pneumocystis jirovecii infection
.
Expert Rev Anti Infect Ther
.
2017
;
15
(
5
):
435
47
.
10.
Hammarstrom
H
,
Grankvist
A
,
Broman
I
,
Kondori
N
,
Wenneras
C
,
Gisslen
M
, et al
.
Serum-based diagnosis of Pneumocystis pneumonia by detection of Pneumocystis jirovecii DNA and 1,3-β-D-glucan in HIV-infected patients: a retrospective case control study
.
BMC Infect Dis
.
2019
;
19
(
1
):
658
.
11.
Goebeler
ME
,
Bargou
R
.
Blinatumomab: a CD19/CD3 bispecific T cell engager (BiTE) with unique anti-tumor efficacy
.
Leuk Lymphoma
.
2016
;
57
(
5
):
1021
32
.
12.
Wang
Y
,
Li
H
,
Song
X
,
Qi
K
,
Cheng
H
,
Cao
J
, et al
.
Kinetics of immune reconstitution after anti- CD19 chimeric antigen receptor T cell therapy in relapsed or refractory acute lymphoblastic leukemia patients
.
Int J Lab Hematol
.
2021
;
43
(
2
):
250
8
.
13.
Fishman
JA
.
Pneumocystis jiroveci
.
Semin Respir Crit Care Med
.
2020
;
41
(
1
):
141
57
.
14.
Bonora
S
,
Di Perri
G
,
Vento
S
,
Cazzadori
A
,
Concia
E
.
Failure of prophylaxis against PCP in patients with HIV infection
.
AIDS Patient Care STDS
.
1998
;
12
(
11
):
843
8
.
15.
Park
JW
,
Curtis
JR
,
Moon
J
,
Song
YW
,
Kim
S
,
Lee
EB
.
Prophylactic effect of trimethoprim- sulfamethoxazole for pneumocystis pneumonia in patients with rheumatic diseases exposed to prolonged high-dose glucocorticoids
.
Ann Rheum Dis
.
2018
;
77
(
5
):
644
9
.
16.
Stern
A
,
Green
H
,
Paul
M
,
Vidal
L
,
Leibovici
L
.
Prophylaxis for Pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients
.
Cochrane Database Syst Rev
.
2014
;
2014
(
10
):
CD005590
.