Immediate hypersensitivity reactions to parenteral cyclosporine in patients with thalassemia major undergoing hematopoietic stem cell transplantation: a case report and review of the literature

Abstract

Background

Allogeneic hematopoietic stem cell transplantation is a definitive cure for eligible patients with thalassemia major, and calcineurin inhibitors are essential for preventing graft-versus-host disease. Although invaluable, there are few reports of life-threatening hypersensitivity reactions associated with calcineurin inhibitors. These reactions are generally rare but seem to be more prevalent among patients with thalassemia.

Case presentation

Herein, we retrospectively report four cases of patients with thalassemia major who developed hypersensitivity reactions to parenteral cyclosporine. The cases include one 19-year-old Caucasian female and three Caucasian males, aged 17, 10, and 20 years, respectively. The patients exhibited symptoms of varying severity, necessitating different management strategies. The reactions occurred either immediately or within a few minutes after the onset of cyclosporine infusion and were often worsened by rechallenge. In all cases, cyclosporine was eventually replaced with tacrolimus or sirolimus. A comprehensive literature review was conducted to investigate the basis of severe immunoglobulin E-mediated hypersensitivity reactions to calcineurin inhibitors in patients with thalassemia major undergoing hematopoietic stem cell transplantation.

Conclusions

Several immunogenic factors may potentially increase the susceptibility of these patients to hypersensitivity reactions to Cremophor-containing medications. While severe reactions to calcineurin inhibitors remain rare, clinicians should be aware of the potential for serious adverse events in patients with thalassemia.

Graphical Abstract

Introduction

Calcineurin inhibitors (CNIs), such as cyclosporine (CsA) and tacrolimus (TAC), play a crucial role in the prophylaxis of graft-versus-host disease (GVHD), a major immune-related complication and the main life-threatening side effect of hematopoietic stem cell transplantation (HSCT). GVHD occurs owing to the vulnerability of the recipient’s immune system. To reduce the morbidity and mortality associated with this complication, HSCT conditioning protocols typically include the early initiation of CNIs. While hypersensitivity reactions to CNIs are generally rare, they can manifest in various forms, ranging from urticaria to anaphylactic shock. Most hypersensitivity reactions to CsA are attributed to one of the formulation's excipients, polyoxyethylated castor oil (Cremophor EL) [1,2,3]. However, reports from the adverse drug reactions monitoring system at our referral center have indicated a noticeably higher incidence of these reactions among younger adult transfusion-dependent thalassemia (TDT) patients. In contrast, such reactions remain rare in other populations undergoing HSCT.

On the basis of numerous documented cases, we retrospectively present four cases of anaphylactic reactions to CsA in TDT patients admitted to the HSCT wards of the Research Institute of Oncology, Hematology, and Cell Therapy (RIOHCT) affiliated with Tehran University of Medical Sciences (TUMS) between January 2023 and April 2024. This report follows the latest CARE case report guidelines [4]. Additionally, we review the literature on hypersensitivity reactions to parenteral CNIs in allogeneic HSCT recipients and the possible risk factors and mechanisms.

Case reports

Case 1

A 19-year-old Caucasian female (A.D.) was admitted in January 2023 with a confirmed diagnosis of beta-thalassemia major. While preparing for allogeneic HSCT from a related full-match donor, A.D. developed generalized pruritus and decreased oxygen saturation following the standard intravenous (IV) infusion of CsA. These symptoms appeared with the first dose, starting only a few minutes after the onset of a 6-h IV infusion of CsA, and rapidly worsened. A.D. was treated with IV corticosteroids (100 mg of hydrocortisone) and antihistamines (25 mg of diphenhydramine followed by 5 mg of chlorpheniramine), along with oxygen therapy. The severity of the reaction increased with each subsequent dose, leading to the permanent discontinuation of CsA. A.D. was switched to IV TAC, which was cautiously tapered up to the therapeutic levels and tolerated despite mild reactions. Following successful engraftment and recovery from HSCT complications, A.D. was finally discharged with oral TAC. No clear history of allergic reactions was available.

Case 2

A 17-year-old Caucasian male (M.T.), diagnosed with beta-thalassemia major, was admitted on January 2023 and presented with generalized pruritus, followed by chest distress and hypotension, while preparing for allogeneic HSCT from an unrelated matched donor. The symptoms occurred shortly after the onset of a 6-h IV infusion of CsA and rapidly worsened. MT received treatment with IV corticosteroid (100 mg of hydrocortisone) and antihistamines (25 mg of diphenhydramine followed by 5 mg of chlorpheniramine), along with oxygen therapy to manage the reaction. Owing to the severity of the reaction, a rechallenge was not performed, and switching to parenteral TAC resulted in the recurrence of the anaphylactic reaction. Even after desensitization, M.T. could not tolerate TAC. Despite medication interactions, we cautiously switched to oral sirolimus. However, MT developed hepatotoxicity owing to the concomitant administration of voriconazole and sirolimus, leading to further substitution of sirolimus with oral mycophenolate mofetil. Successfully recovered from HSCT complications, M.T. was finally discharged. No history of allergic reactions was available.

Case 3

A 10-year-old Caucasian male (A.R.) was admitted in March 2023 with TDT major as a candidate for allogeneic HSCT from a full-match sibling donor and experienced severe pruritus and burning at the infusion site immediately after the onset of the CsA IV infusion. These symptoms started with the first dose and were resolved in less than 1 hour with IV antihistamine (5 mg of chlorpheniramine). Upon rechallenge, AR developed urticaria and chest distress with decreased oxygen saturation, which were managed with IV administration of corticosteroid (200 mg of hydrocortisone) and oxygen therapy. After switching to IV TAC, urticaria with severe pruritus recurred but was resolved by IV antihistamine (5 mg of chlorpheniramine), thus TAC was eventually tolerated. AR was finally discharged with oral TAC after successful engraftment and recovery from HSCT complications. No clear history of allergic reactions was available.

Case 4

A 20-year-old Caucasian male (A.T.) diagnosed with beta-thalassemia major was admitted on April 2024 for allogeneic HSCT from a full-match sibling donor and experienced flushing, pruritus, and urticaria while receiving the first two doses of IV CsA while preparing for HSCT. The initial infusion of CsA was administered through a typical IV line without inline filters or any premedication. For the subsequent dose, A.T. was premedicated with IV antihistamine (10 mg of diphenhydramine), and CsA was administered using an IV set with a 0.22-micron inline filter. Despite these measures, both infusions resulted in moderate symptoms, including flushing and pruritus that progressed to urticaria within 3 hours. Readministration of IV antihistamines provided temporary relief, and symptoms were ultimately resolved by administration of IV corticosteroid (100 mg of hydrocortisone). Owing to the moderate severity of these reactions, a rechallenge was performed with the third dose, along with full-dose premedication including IV corticosteroid (100 mg of hydrocortisone), H1 antagonist (10 mg of diphenhydramine), and H2 antagonist (40 mg of famotidine). However, A.T. developed an anaphylactic reaction characterized by a considerable decrease in oxygen saturation. This reaction was managed with the coadministration of acetaminophen (1 g), antihistamine (10 mg of diphenhydramine), and corticosteroid (100 mg of hydrocortisone), all in IV form, along with oxygen therapy. Following the discontinuation of CsA, A.T. tolerated a very low dose of oral TAC, which was gradually tapered up to the therapeutic levels and continued after discharge with successful engraftment and recovery from HSCT complications. At the time of admission, A.T. had no available history of allergic reactions. However, during hospitalization, he developed a transient fever with the infusion of packed red blood cells and experienced anaphylaxis with parenteral vitamin K.

Detailed demographics and clinical characteristics of the four cases are presented in Table 1.

Table 1 Characteristics of the cases

Literature review and discussion

A systematic search was conducted on PubMed using a strategy developed on 15 May 2024. The search terms included “hematopoietic stem cell transplantation,” “hypersensitivity,” and “calcineurin inhibitor,” focusing on case studies with human subjects, with no restriction on language, time, or age group. A summary of the results is provided in Table 2.

Table 2 Summary of available case reports and case series on hypersensitivity reactions with CNIs in allogeneic HSCT recipients

Beta-thalassemia is an inherited disease that causes chronic anemia due to impaired synthesis of hemoglobin, with a wide range of phenotypic severity of the disease. Although the prognosis has improved significantly in recent years, HSCT has remained the only available definitive cure for patients with thalassemia major, also known as TDT [13]. Alloimmunization is a well-known complication of multiple blood transfusions, as antigen typing is not yet widely implemented for TDT patients [14]. Despite this valuable knowledge, the etiology of type I IgE-mediated allergic reactions in this specific condition has not been well studied.

Hypersensitivity reactions with parenteral CsA were first reported in renal transplant recipients in 1984 by Kahan et al., followed by Habboush and Hann’s report of anaphylaxis in an allogeneic stem cell recipient in 1986 [5, 15]. Owing to the successful rechallenge with oral CsA, Kahan suggested that Cremophor EL (one of the excipients in the parenteral formulations) might be responsible for these reactions. Similar results from patients who underwent HSCT were reported by Takamatsu et al., showing that reactions to parenteral formulations of both CsA and TAC were resolved after switching to a Cremophor-free oral CsA formulation [7]. Cremophor EL (polyoxyethylated castor oil) is used as a carrier, solubilizer, and emulsifier in parenteral CNI formulations, as well as some oral CsA formulations (as the diluent) and other medications such as IV vitamin K, with probable cross-hypersensitivity reactions [11, 16]. Although some reports have claimed successful switches to oral CsA formulations, Taghvaye-Masoumi et al. hypothesized that oral TAC might be preferred in cases of severe hypersensitivity, as it does not contain components that are structurally similar to Cremophor EL [11].

As discussed by Volcheck and Van Dellen, several immune and nonimmunologic mechanisms should be considered for hypersensitivity reactions to Cremophore EL, although the exact mechanism is still unknown [17]. After a comprehensive literature review, a possible role of IgE-mediated pathways is highlighted on the basis of skin testing, timing, and characteristics of the reactions. In our cases, most patients did not have a clear history of drug allergies or any reliable history of previously administered medications to assess. Additionally, skin testing was not performed. However, all patients exhibited symptoms immediately after the first dose of parenteral CsA, which worsened following the rechallenge.

Except for Taghvaye-Masoumi et al., most reported cases were in leukemic patients who underwent HSCT or solid organ transplant. No other reports are available for thalassemia major; however, these patients are not unfamiliar with immunologic hypersensitivity reactions. In 2005, Palma-Carlos studied the effects of minor thalassemia on the clinical presentations of allergy in Southern Europe [18]. The results demonstrated an increased risk of asthma in respiratory allergy with the coexistence of beta-thalassemia. Another multicenter retrospective study in Canada, including 92 pediatric patients with TDT, aimed to investigate the effect of prophylactic blood product antigen matching on preventing alloimmunization and assessed the association between patient characteristics and alloimmunization [19]. This study revealed that alloimmunization and a positive history of receiving transfusions outside of Canada are significantly correlated; however, there is no correlation between the number of transfusions received and alloimmunization. This could be attributed to the probable lower levels of antigen matching for transfusions in those TDT patients from other countries. Similarly, antigen typing was not performed for any of our cases before receiving transfusions, which may potentially be another risk factor in these patients.

As comprehensively discussed by Cappellin et al., allergic reactions may occur as a result of plasma proteins. Mild reactions are generally IgE mediated, and patients with IgA deficiency or anti-IgA antibodies are prone to severe forms [20]. It has also been shown that IgE levels were significantly higher in beta-thalassemia patients, although this is not correlated with the number of transfusions received [21]. The results from Vierucci et al. demonstrated significantly higher levels of IgE in splenectomized patients with positive serological markers of hepatitis B virus infection. Noting that higher IgE levels are found in various diseases, including liver disease, even in the absence of an allergen, they accurately discussed the potential role of transfused antigens and hepatic iron overload in provoking high IgE levels. Among our cases, only one patient (A.D.) had a positive hepatitis B virus infection marker (reactive HBcAb), but all cases showed different levels of hepatic iron overload, with two patients (A.D. and A.T.) exhibiting mild hepatomegaly. Additionally, all patients were transfusion-dependent from a very early age and had high ferritin levels.

Regarding the incidence and prevalence of hypersensitivity reactions to parenteral cyclosporine, available data are limited. Taghvaye-Masoumi et al. reported hypersensitivity reactions in approximately 1.2% of HSCT recipients who were administered cyclosporine [11]. However, this percentage may vary depending on the population and specific conditions. Unfortunately, comprehensive epidemiological data on the prevalence of such reactions in thalassemia major patients undergoing HSCT are not well documented, highlighting the need for further research in this area.

Our study has several limitations, including its retrospective nature. Additionally, variations in the treatment of reactions and subsequent modifications were observed owing to differences in physician approaches. To the best of our knowledge, this report represents the first case series focusing on hypersensitivity reactions to CNIs in patients with TDT, with a particular emphasis on its prevalence context.

Conclusion

TDT patients are at increased risk for severe IgE-mediated hypersensitivity reactions to medications containing Cremophor EL. Factors such as comorbidities and the nature of TDT contribute to this heightened susceptibility. In the absence of antigen typing before transfusion, cautious approaches including premedication and test dosing should be considered to better manage and mitigate these reactions. Further research is needed to establish standardized practices.