Methotrexate/rituximab/zanubrutinib

Abstract

Pulmonary infection, decreased WBC and platelet count and muscle soreness: case report A 39-year-old man developed pulmonary infection, decreased WBC and platelet count during treatment with rituximab and methotrexate and muscle soreness during treatment with zanubrutinib for Epstein-Barr virus-associated post-transplantation lymphoproliferative disorder (EBV-PTLD) [not all routes and outcomes stated]. The man was diagnosed with acute lymphoblastic leukaemia in November 2018. He was treated with 8 cycles of chemotherapy combined with imatinib, which resulted in complete remission. He underwent haploidentical allogeneic haematopoietic stem cell transplantation on 25 September 2019 under a conditioning regimen with cytarabine, cyclophosphamide, busulfan, antithymocyte globulin and methyl-N-2-chloroethyl-N-cyclohexyl-N-nitrosourea. He additionally received ciclosporin [cyclosporine] and mycophenolate mofetil and a short-course of methotrexate for prophylaxis against graft-versus-host disease. However, neutrophils and platelets were engrafted on post-transplant day 13 and 14, respectively. He also received aciclovir [acyclovir] and ganciclovir for prevention of virus infection. On post-transplant day 90, he was admitted to the hospital due to headache, vomiting and dizziness. Based on the clinical presentation and laboratory findings, Toxoplasma gondii and cerebral toxoplasmosis were considered. Therefore, he was treated with sulfamethoxazole and clindamycin. After one week of treatment, his clinical signs completely resolved. However, a marked decrease in the size of the lesions and perifocal oedema was noted after 2 weeks. Therefore, he was discharged, and his treatment was switched to azithromycin and sulfamethoxazole. One month after discharge, near resolution of the multiple lesions and perifocal oedema was noted. On post-transplant day 203, he presented with a recurring headache along with reducing right-sided power and binocular diplopia. On post-transplant day 223, he was readmitted to the hospital. On examination, he had positive Babinski sign on the right side. On post-transplant day 244, his clinical condition progressed with urinary incontinence, recurrent seizures, memory loss, lethargy and transient consciousness disturbance. Subsequently, monomorphic diffuse large B-cell lymphoma with Epstein-Barr virus (EBV) infection were considered. Based on the clinical presentation and laboratory findings, a diagnosis of EBV-PTLD in CNS was made on post-transplant day 250. Therefore, ciclosporin was stopped; however, mycophenolate mofetil therapy was continued. On post-transplant day 252, he received chemotherapy with a single dose of rituximab 375 mg/m2 followed by high-dose methotrexate 6g on post-transplant day 256. After methotrexate and rituximab therapy, his consciousness improved and the seizure disappeared. However, his headache persisted. During rituximab and methotrexate chemotherapy, the WBC and platelet counts decreased. He additionally developed pulmonary infection secondary to the rituximab and methotrexate therapy. Due to the inability to tolerate rituximab and methotrexate chemotherapy, he underwent whole-brain radiotherapy on post-transplant day 280 for 47 days. During radiotherapy, the platelet and WBC counts further decreased. Subsequently, the platelet and WBC counts gradually recovered to normal. At the end of radiotherapy, his headache improved and the language impairment and dyskinesia also recovered gradually. After radiotherapy, he achieved partial response, and his condition was stable. However, residual intracranial lesions were still persisted. Thereafter, he refused to receive further systemic chemotherapy. On post-transplant day 382, he received oral zanubrutinib 80mg daily concomitantly with posaconazole for the prevention of fungal infection. One day after the initiation of zanubrutinib therapy, he developed transient systemic migrating muscle soreness. The man’s therapy with zanubrutinib was stopped. As a result, muscle soreness resolved one day after the discontinuation of the zanubrutinib therapy. The man’s therapy with oral zanubrutinib was restarted; however, no side-effects were reported. The blood count examination revealed normalisation of platelet count along with the improvement in his lowest WBC count. After starting zanubrutinib, his dizziness and headache resolved. On last follow-up in February 2021 (on post-transplant day 516), he was alive without any clinical symptoms of PTLD, and his zanubrutinib treatment was continued.