The patient was a 24-year-old white male without pretransplant autoimmune conditions, diagnosed with precursor-B-cell acute lymphoblastic leukemia (ALL) in 2008. Cytogenetic analysis demonstrated near hypertriploid karyotype with trisomy 4, 10, and 17. After being treated with multiagent chemotherapy according to the AALL0232 protocol, he achieved complete remission. Six years later, he relapsed and was treated with the pediatric R3 protocol, achieving a second complete morphologic remission. He then received consolidation with cyclophosphamide 70 mg/m2 and total body irradiation (TBI, 1000 cGy) followed by an allogeneic HSCT from an HLA-matched unrelated female donor in February of 2015. Prophylaxis of GVHD consisted of a single dose of posttransplant cyclophosphamide (50 mg/Kg), tacrolimus, and mycophenolate mofetil. Donor and Recipient HLA type was A*03 : 01/24 : 02, B*07 : 02/50 : 01, C*07 : 02/06 : 02, Bw6, DRB1*04 : 01/07 : 01, and DQB1*03 : 01/02 : 02. The dose of infused total nucleated cells was 1.18 x 109 cells/kg with 92% viability, including 1.11 x 107 CD34+ cells/kg and 2.44 x 108 CD3+ cells/kg of body weight. Full donor CD3, CD20, and CD15 chimerism was attained by day +28. Of note, this was a minor ABO-incompatible HSCT as the patient's blood group was A+, whereas the donor was O+.
On day +3 post-HSCT, the patient developed a nonpruritic, erythematous rash on his chest, abdomen, and extremities. A skin biopsy revealed interface dermatitis consistent with a drug reaction. He was transfused one unit of irradiated iRBCs on each of day +3, +5, +7, +8, and +10 (Figure 1(a)). The blood type of the iRBC units was A, O, O, O, and A, respectively. Additionally, two units of irradiated apheresis platelets (iPLTs) were transfused on days +3 and +10. Shortly after receiving the iRBC unit on day +10, the patient complained of worsening back pain and was noted to have decreased urine output, which prompted a transfusion reaction workup (Table 1). The blood samples collected before and after the transfusion were reported as A+ with mixed-field reaction, consistent with the presence of group O RBCs likely from his recent transfusions of O iRBCs. Although the plasma color posttransfusion was amber and did not show overt hemolysis, the serum haptoglobin was low and lactate dehydrogenase (LDH) and bilirubin levels were higher than pretransfusion values. A posttransfusion direct agglutination test (DAT) was also microscopically positive for IgG and C3 (1+) compared with a DAT on his pretransfusion blood sample, which was negative for IgG and microscopically positive for C3. His antibody screen was negative both pre- and posttransfusion, indicating that a non-ABO circulating alloantibody was unlikely present. At this point, it was evident that the blood bank had erroneously issued a group A iRBC unit using the electronic crossmatching method only. A serologic posttransfusion crossmatch could not be performed because the iRBC unit was not returned to the laboratory. However, clerical checks confirmed that the most recently given iRBC unit was A+.
During the transfusion reaction workup, anti-A was newly identified in the patient's plasma at a titer 8, which was present in both samples collected immediately before and following the transfusion implicated in the reaction. A posttransfusion urinalysis showed moderate (3+) hemoglobinuria and 3-10 red blood cells/40x field, and both of which were absent in a urine sample collected before the transfusion of the triggering iRBC unit on day +10. Blood urea and creatinine both rose from normal values pretransfusion to abnormally high values postreaction (Table 1). The workup collectively indicated an acute hemolytic transfusion reaction with acute kidney injury, likely due to anti-A from the donor reacting with transfused and patient's own group A RBCs. In addition to receiving corticosteroids, an emergent red blood cell exchange was performed. During the procedure, approximately 70% of the patient's circulating red cells were replaced with seven units of group O iRBCs to achieve a final hematocrit of 24%. Following the exchange, the patient's clinical condition improved gradually, including his kidney function and hemoglobin level, which rose and remained above 7 g/dL. The haptoglobin returned to normal within 48 hours, and his blood type converted to group O by day +94.
Around days +60 and +111, the patient developed acute gastrointestinal and cutaneous GVHD, respectively. He received systemic corticosteroids, immunosuppression with tacrolimus, and later, rituximab. As a steroid-sparing agent and for poor compliance with tacrolimus, he was also started on mycophenolate mofetil.
In light of the history of HT in the donor, the patient was monitored with serum free-T4 (fT4) levels (Figure 1(b)), thyroid-stimulating hormone (TSH) (Figure 1(c)) and the presence of autoantibodies directed against the thyroid. His thyroid panel pretransplant was normal, including the absence of detectable antibodies. On transplant day +3, he also had normal TSH and fT4 of 0.744 microIU/mL (reference range: 0.45-5.5 microIU/mL) and 1.25 ng/dL (reference range: 0.62-1.57 ng/dL), respectively. On re-evaluation on day +46, TSH and T4 levels remained within the normal range while antithyroglobulin (anti-TG) and antithyroid peroxidase (anti-TPO) were undetectable. However, on day +358, TSH was 0.047 microIU/ml and fT4 was 1.62 ng/dL suggesting an initial hyperthyroid phase followed by a hypothyroid phase from day +372 with a high TSH (79.6 microIU/mL). Anti-TG was detected at a titer of 3 U (reference range: <0.5 U) at this time indicating the development of autoimmune hypothyroidism. Concurrent decrease thyroid function and the appearance of anti-TG antibodies in the serum suggest that complement-mediated injury may have also contributed the thyroid gland injury. Therefore, thyroid replacement therapy was initiated. An ultrasound on day +511 revealed a normal thyroid gland without evidence of nodules or parenchymal abnormalities and no increased blood flow. Grade 2 parenchymal echogenicity, high vascularity, and paratracheal lymph nodes enlargement typically seen on thyroid ultrasound during hypothyroidism were missing possibly because the patient has already been on replacement therapy for several months and was in an euthyroid state.
Further follow-up on day +813 showed normal thyroid function and undetectable antithyroid antibodies. However, the patient was not compliant with his thyroid hormone replacement therapy for a long period during which fT4 level was low and TSH was high (Figures 1(b) and 1(c)). During this period, the patient complained of fatigue and had two admissions to the hospital for sepsis for which he recovered. Following several sessions of patient education on the importance of taking prescribed medications, the patient resumed thyroid hormone replacement therapy and both fT4 and TSH levels returned to normal values around day +2498 posttransplant. Seven years later, the patient remains on thyroid replacement therapy. The latest posttransplant course was complicated by oral and cutaneous chronic GVHD.