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Case Report
Successful Treatment of Autoimmune Hemolytic Anemia with Sirolimus after Allogeneic Hematopoietic Stem Cell Transplantation: A Case Report
Clin Pediatr Hematol Oncol 2023;30:91-4.
Published online October 31, 2023
© 2023 Korean Society of Pediatric Hematology-Oncology

Hyun Jin Park1, Jung Yoon Choi1, Kyung Taek Hong1, Bo Kyung Kim1 and Hyoung Jin Kang1,2

1Department of Pediatrics, Seoul National University College of Medicine and Seoul National University Cancer Research Institute, Seoul, 2Wide River Institute of Immunology, Hongcheon, Korea
Correspondence to: Hyoung Jin Kang
Department of Pediatrics, Seoul National University College of Medicine and Seoul National University Cancer Research Institute, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea
Tel: +82-2-2072-3304
Fax: +82-2-3675-0993
E-mail: kanghj@snu.ac.kr
ORCID ID: orcid.org/0000-0003-1009-6002
Received May 11, 2023; Revised May 15, 2023; Accepted May 18, 2023.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Autoimmune hemolytic anemia (AIHA) is a common complication after hematopoietic stem cell transplantation (HSCT). Although post-HSCT AIHA is associated with poor prognosis and is more resistant to treatment than primary AIHA, the standard treatment has not yet been determined. We report a case of post-HSCT AIHA, which occurred 9 years after unrelated donor bone marrow transplantation for acute biphenotypic leukemia. Steroid treatment was initially effective but prolonged steroid usage, due to recurrent relapses, caused avascular necrosis. Although rituximab was unsuccessful in preventing relapses, sirolimus was effective in allowing the discontinuation of steroid treatment and sustaining transfusion-free status. Sirolimus, previously reported to be effective in pediatric post-HSCT AIHA and AIHA after solid organ transplantation, may be effective in adult post-HSCT AIHA as well.
Keywords: Autoimmune hemolytic anemia, Hematopoietic stem cell transplantation, Sirolimus
Introduction

Autoimmune hemolytic anemia (AIHA) is a well-known complication after hematopoietic stem cell transplanta-tion (HSCT). Although the specific mechanism has yet to be identified, the autoimmunity derived from donor lymphocytes is known to destruct red blood cells. According to previous reports, the incidence of AIHA after HSCT is estimated to be between 1-6%, much greater than that of the general population [1-3].

The optimal treatment for AIHA after HSCT is not established and most centers use corticosteroid for the first-line therapy. However, compared to primary AIHA, AIHA after HSCT is known to be more refractory with more frequent relapses under steroid treatment [1]. Rituxi-mab, anti-CD20 monoclonal antibody, was also commonly used either combined with steroid as first-line therapy or as second-line therapy. Although various immunosup-pressants from classic types to newly developed target agents were used to treat refractory cases, none were effective [1-3].

Sirolimus, the mammalian target of rapamycin (mTOR) inhibitor, was initially introduced to prevent rejection in kidney transplantation. However its effect on cell survival was emphasized, and is now applied to treat other diseases [4]. Based on treatment responses in AIHA after solid organ transplantations, sirolimus has been proposed as a possible treatment option for AIHA after HSCT in pediatric patients [5]. A recent study showed response of sirolimus in primary relapsed/refractory autoimmune cytopenia [6]. However, the report of sirolimus treatment in adult post-HSCT AIHA is very limited [1,2]. In this case report, we examine the successful treatment with sirolimus in adult patient of AIHA after allogenic HSCT.

Case Report

A 24-year-old male was treated with sirolimus for steroid dependent persistent AIHA.

Presented with facial swelling, pleural effusion and leukocytosis, the patient was diagnosed with acute biphenotypic leukemia at 8 years of age. He failed to achieve remission with induction chemotherapy of acute myeloid leukemia. He received reinduction chemothe-rapy of acute lymphoblastic leukemia and achieved complete remission. He received bone marrow transplanta-tion (BMT) from a male HLA-matched (10/10) unrelated donor. The donor’s blood type was A+ D+ and the recipient’s blood type was O D+. The conditioning regimen consisted of busulfan (12.8 mg/kg), etoposide (10 mg/kg), cyclophosphamide (60 mg/kg), and rabbit-antithymocyte globulin (r-ATG, 7.5 mg/kg). Cyclosporin A, methotrexate, and additional r-ATG (3.75 mg/kg) were used for prophylaxis of graft-versus-host disease (GvHD). Stage 1 gut-GvHD, which is grade II acute GvHD, occurred on day 24. Symptoms resolved after administering methyl-prednisolone. There was neither chronic GvHD nor CMV infection during follow-up.

At 18 years of age, 9 years after BMT, the patient visited the emergency room with symptoms of dizziness and jaundice. In laboratory test, macrocytic normochromic anemia, hemoglobin (Hb) level of 6.9 g/dL, elevated reticulocyte counts of 17.16%, and normal white blood cell and platelet counts were identified. Biochemical analysis of blood showed both increased total and direct bilirubin levels, 5.8 mg/dL and 1.31 mg/dL respectively, increased lactate dehydrogenase level of 709 IU/L, decreased haptoglobin level of less than 7 mg/dL, and increased plasma hemoglobin level of 34.8 mg/dL. Direct antiglobulin test (DAT), grade 4 positivity with polyspecific human Immuno-globulin G, and indirect antiglobulintest (IAT) were posi-tive. At that point, his blood type changed to A+ D+, and anti-A and anti-B isoagglutinin appeared negative and positive, respectively. In bone marrow examination, mild hypocellular marrow with erythroid hyperplasia was found with no evidence of relapse. Donor/recipient DNA in quantitative chimerism test, using short tandem repeat method, was monitored every 6 months, since mixed chimerism was detected from 2 months after BMT. Recipient DNA ratio increased 16.87%, compared to previous result (11.77%).

For autoimmune hemolytic anemia, the patient was treated with prednisolone 2 mg/kg/day leading to increase of Hb level (10.2 g/dL) (Fig. 1). However, anemia recurred while tapering prednisolone off and we increased dosage of prednisolone. When third relapse (Hb level 8.0 g/dL) occurred at 20 years of age, 10.5 years after BMT, rituximab (375 mg/m2) was administered once a week for 4 weeks with increasing dose of prednisolone. With combination therapy, Hb level recovered up to 14.3 g/dL. Concurrently, the patient displayed bilateral hip and knee pain. Pelvis magnetic resonance imaging revealed bilateral osteonecrosis of femur, suggesting avascular necrosis. Therefore, we tried early tapering corticosteroid off and changed prednisolone to deflazacort for bone-sparing effect. After 10 months of discontinuing corticosteroid, the fourth relapse of hemolytic anemia occurred. We administered sirolimus (3 mg/m2 once on day 0, 1 mg/m2 once daily for maintenance) and adjusted dosage with monitoring blood level for target trough level of 4-12 ng/mL. Corticosteroid was not used due to persistent joint pain. After treated with sirolimus, his Hb level was recovered and maintained more than 10 mg/dL. Since DAT has still remained positive, we have not tried to taper sirolimus off. He has sustained not only disease-free status but also transfusion-free status up to date of report.

Figure 1. Treatment course and re-sponse of AIHA. AIHA, autoim-mune hemolytic anemia; AVN, avascular necrosis; Hb, hemo-glo-bin; HSCT, hematopoietic stem cell transplantation.

This case was approved by the Institutional Review Board of Seoul National University Hospital (E-2007- 063-1140).

Discussion

Post-HSCT AIHA is associated with increased mortality and poor prognosis. Considering other concomitant post- HSCT complications including thrombotic microangiopathy, infection, and GvHD, differential diagnosis may be dif-ficult. In addition, the major or minor ABO-incom-patibility can cause immune hemolysis with positive DAT result. Risk factors include younger age (<15 years), non-malignant disease, stem cell sourced from cord blood, unrelated donor, HLA mismatch donor, development of chronic GvHD, and CMV reactivation [1,2,7].

There is no established guideline for post-HSCT AIHA. First-line treatment of post-HSCT AIHA is steroid therapy, but relapses or refractory rates are known to be higher than that of primary AIHA [1,6]. Intravenous immunoglobulin showed limited effect as first-line therapy. Rituximab, most frequently used therapy for second-line treatment, showed 88% of response rate when combined with steroid as first-line treatment, and 49% when used as second-line treatment. Although other immunosup-pressants including azathioprine, mycophenolate mofetil, cyclosporine, and cyclophosphamide were used, their application gradually decreased due to high toxicity and limited efficacy [1-3,5].

Young age at transplantation and unrelated donor is known risk factors of post-HSCT AIHA for this patient [2,3,7]. The time of occurrence, 9 years after HSCT, was longer than previous reports. The median time to onset of AIHA from HSCT was about 6 months in two large retrospective studies but the range were wide, from 1 month to 55 months [2,3]. Although mixed donor/recipient chimerism was present at the onset of AIHA in this case, contribution of alloimmune hemolysis is not clear. Recipient chimerism had been on the rise before AIHA and increased up to 27.44% even after the resolution of AIHA with steroid therapy. His blood type changed from O to A+ and anti-A isoagglutinin was negative. Indeed, the impact of mixed chimerism on post-HSCT AIHA is con-troversial. Kruizinga, et al. showed mixed chimerism incidence was not significantly higher in autoimmune cytopenia group [7].

Although he responded to steroid treatment, discon-tinuance of steroid led to AIHA recurrence and the long- term use of steroid caused avascular necrosis. Rituximab combination seemed to be effective, therefore early tapering of steroid was possible. However, another relapse occurred and forced us to consider other options. Through close drug-level monitoring, the patient was able to continue sirolimus therapy without severe adverse effects. There was no more recurrence.

Based on the pathogenesis of AIHA, biologic agents have been adopted for refractory AIHA. Bortezomib and alemtuzumab were introduced to target B-cells. Bortezomib showed treatment responses in 12 out of 19 patients (63.2%) from 7 reports [1,3]. Daratumumab, targeting plasma cell and approved for multiple myeloma, showed responses in all 3 cases [1]. In light of T-cell regulation, abatacept therapy was administered, and all 3 patients showed responses [1].

Sirolimus, inducing abnormal T-cells apoptosis and increasing regulatory T-cells, showed promising outcomes in various secondary autoimmune cytopenia [4]. Compared to other biologic agents, sirolimus has several advantages; relatively low prices, long history of drug usage, and possible monitoring of drug concentration. There have been some concerns that sirolimus can induce throm-botic microangiopathy (TMA). Sirolimus-induced TMA is associated with combined calcineurin inhibitor and excessive drug level [8]. Our patient did not use calcineurin inhibitor at the time of AIHA and drug level could be monitored. Based on these conditions and the success in AIHA following pediatric post-HSCT and solid organ trans-plantation, we administered sirolimus to our patient.

In conclusion, we report a case of steroid-dependent post-HSCT AIHA, successfully treated with sirolimus as a third-line therapy. Sirolimus, used to treat refractory pediatric AIHA or AIHA after solid organ transplantation, could be a cost-effective and relatively safe therapeutic option in adult AIHA after HSCT. Further studies would be necessary to determine the standard therapy for post- HSCT AIHA.

Acknowledgments

This research was supported by a grant (20182MFDS 443) from Ministry of Food and Drug Safety in 2020.

Conflict of Interest Statement

The authors have no conflict of interest to declare.

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October 2023, 30 (2)
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  • Hyoung Jin Kang 

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