Cases presentation
Patient №1 (Fig 1, a). A 15-year-old boy diagnosed with X-linked lymphoproliferative syndrome type 1 (deletion in exon 1 of the SH2D1A gene in the hemizygous state) was transplanted from a haploidentical donor (father) with TCRαβ+/CD19+ depleted peripheral hematopoietic stem cells. In the early post-transplantation period (from Day +12) he experienced an “engraftment syndrome” – maculopapular rash on the trunk and palmar-plantar erythema equivalent to acute GVHD stage II, skin-2. The immunosuppression was initiated with methylprednisolone 2 mg/kg/day for 3 days, taped to 1 mg/kg/day. Against the background of a decrease in the dose of methylprednisolone, the patient’s condition worsened from Day +17: progression of the acute GVHD to stage III (GI-3, skin-3), and upper intestinal lesion with the development of severe nausea, vomiting, lack of appetite, severe abdominal pain syndrome requiring morphine. Patient suffered a GI hemorrhagic syndrome (gastroscopy results). No pathogens were identified in the feces. The patient’s condition was at risk of infectious complications due to presence of CMV viremia. On Day +21 the patient was diagnosed with acute GVHD stage 4 (GI-4, hemorrhagic colitis; skin - 4, generalized erythroderma). Further, the dose of corticosteroids was increased, and a multiple correction of the immunosuppressive therapy was also performed. Ruxolitinib, etanercept, cyclosporine A (CSA), and alemtuzumab were used at the recommended dosage, without GVHD improvement. After alemtuzumab (Day +24), there occurred a decrease in the number of T-cells to 40 cells/µl, followed by their rise to 92 cells on Day +28, and subsequent growth dynamics.
The multiple immunosuppressive therapy was ineffective, patient’s condition progressively worsened, there were risks of severe infectious complications, and leukapheresis was impossible. We have therefore developed a modification of ECP without leukapheresis, as compassionate therapy. Since we were well aware that the number of targeted cells received is extremely small, the ECP schedule was set to 4 procedures per week.
On Day + 29 we started the micro-ECP therapy. For 5 consecutive weeks, the patient received 4 micro-ECP treatments per week as described before. On the second week of micro-ECP therapy GVHD progression stopped, and on the third week we could already see a clear regression. The skin manifestations did not worsen and turned into hyperpigmentation, hemorrhagic colitis completely disappeared, and the volume of stool decreased. On Day +56 (fourth week of micro-ECP treatment), the skin syndrome was represented by residual hyperpigmentation of the chest, abdomen, back, upper limbs; intestinal syndrome - thick stool once in 2-3 days. The immunosuppressive therapy and the frequency of micro-ECP procedures were gradually decreased to 1 in 4 weeks by 22 weeks. However, from the Day +320 a folliculitis-like rash appeared on the abdomen, chest and back (chronic GVHD?) - methylprednisolone dose was augmented and CSA was changed to ruxolitinib. The frequency of micro-ECP procedures was increased to 1 per week, followed by a gradual decrease to 1 at 4 weeks to 65 weeks.
The total duration of micro-ECP therapy was 69 weeks. The graft function is currently satisfactory. There are no signs of progression of chronic GVHD. Immunosuppressive therapy: ruxolitinib 5 mg x 3 times a day, prednisolone 2.5 mg x 2 times a day.
Patient №2 (Fig 1, b). A 2-year-old girl diagnosed with acute myeloid leukemia, M2, t(X;11)(q24;q23) KMT2A/SEPT6 gene after allogeneic bone marrow transplantation from a haploidentical donor (father). The early post-transplant period was complicated by mucositis grade 3, neutropenic enterocolitis. The first signs of acute GVHD appeared on Day +5 - skin lesions-2, Grade I. Treatment with methylprednisolone (1mg/kg) and etanercept was started. Despite the ongoing therapy, from Day +12 progression of acute GVHD with an increase skin lesions up to grade 3 and elevation of bilirubin (acute GVHD III) was noted. Immunosuppressive therapy was modified - a short course of high-dose methylprednisolone (5mg/kg) followed by a gradual reduction; ruxolitinib was added to therapy for 3 days with a single injection of tocilizumab (162mg). Against the background of the therapy, GVHD progressed to generalized erythroderma with the formation of several small bullae (Grade IV).
The patient also suffered multiple infectious complications: CMV-viremia (Day +18), treated with ganciclovir 10 mg/kg followed by switching to foscarnet (for 2 weeks) due to a decrease in neutrophils; COVID-19 associated pneumonia from Day +24, treated with remdesivir. Taking into account the need to control GVHD and to reduce immunosuppressive therapy (viral infections, high-risk AML), a course of extracorporeal photopheresis was indicated. We decided to start micro-ECP course from Day +27. The response to micro-ECP was obtained in the first week as a lack of progression of GVHD, in the second week as regression of skin and liver GVHD. At 4 weeks of micro-ECP, there were no signs of active GVHD. Subsequently, the immunosuppressive therapy was reduced, and the frequency of micro-ECP procedures was gradually reduced. There was no recurrence of GVHD, and after 27 weeks of micro-ECP treatment the patient was discharged from hospital without immunosuppressive therapy, and with complete healing of GVHD.