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  • The patient began CODOX M IVAC with rituximab

    2019-06-15

    The patient began CODOX-M/IVAC with rituximab [2]. PET and BM after 2 cycles showed complete remission (CR) and this was confirmed 3 and 6 months later after he completed the full treatment course. There was no delay in administration of each cycle (average: 19 days, 16–21). Eight months after therapy completion he developed flu-like symptoms, WBC 9.1×103/µL, mild anemia and thrombocytopenia 23×103/µL, uric ldv 4.7, LDH 1977IU/L. CT scans were negative and BM showed relapse (see Fig. 1C and D). The patient complained of submental numbness, CSF sampling was negative×3 by cytology and flow (2–3mL each), MRI of the brain with focus on cranial nerves was negative for leptomeningeal involvement, his condition was concluded as numb chin syndrome (NCS). He received EPOCH-R with IT methotrexate 15mg (on day 1) and IT cytarabine 100mg (at least 72h after MTX) [3]. After the first cycle the patient׳s marrow showed 80% cellularity and a large area of necrotic tumor cells occupying 60–70% of the total marrow space consistent with bone marrow necrosis (BMN), the remaining 30–40% of marrow comprised of viable tumor cells, which were intermediate in cell size with round nuclei, indistinct nucleoli and scant amount of cytoplasm (see Fig. 1E and F). CD20 was strongly positive in both viable and necrotic tumor cells. Subsequent cycles were initiated at the first sign of hematological recovery (plts>75,000/µL, ANC>500/µL). Second CR was confirmed after second cycle (PET and BM). Aggressive prophylaxis with antibiotics, antifungals, antivirals, and against pneumocystis together with G-CSF were used. Fourth cycle was delayed by an episode of respiratory infection with parainfluenza 3, which was treated with IVIG (dose 500mg/kg). After 6 cycles (average 16.6 days, 15–20) the patient underwent 10/10 HLA matched unrelated donor transplant (CMV: R+/D−) with thiotepa/fludarabine/melphalan, posttransplant cyclophosphamide and sirolimus [4], which was tapered rapidly within 4 months. He remained asymptomatic and GVHD free at one year after his transplant: WBC 6.7×103/µL, HCT 37.9%, and platelets 260×103/µL. BM from the site where necrosis was present at relapse showed 40% cellular marrow with maturing adequate trilineage hematopoiesis and of the biopsy contained a necrotic area with many ghost outlines of intermediate-sized cells, which were positive for CD20, but negative for other markers (see Fig. 1G and H). The patient׳s counts and chimerism (>97% donor BM and blood) were stable. For profound hypogammaglobulinemia and frequent respiratory infections integument has received monthly IVIG. He is currently alive and well 2 years after his transplant. To our knowledge, this is the longest reported survival of BMN in setting of BL relapse.
    Discussion The optimal salvage strategy for BL patients with a partial remission or relapsed disease, is unknown. Combination salvage chemotherapy is usually attempted, but very few to no patients with BL achieve a meaningful response regardless of the chemotherapy agents used [1]. Autologous or allogeneic stem cell transplantation (ASCT or AlloSCT) represents a logical next step in consolidation of response; however, published data addressing high-dose therapy in BL are confounded by selection bias and the data is limited to subgroups of retrospective analyses [5–7], and case reports [8]. Chemosensitivity and disease status at the time of transplant determine the outcome. While clinical trial participation is warranted, due to time constrains this is very often not practical for patients and their physicians. Given the presence of BMN an AlloSCT was chosen for our patient. BMN is a rare and poorly understood complication of aggressive hematological malignancies with dismal survival ranging from 1 to 4 months. Retrospective data associated upto 15% of BMNs with lymphoma [10]. Different sites were used for BM biopsies and we cannot confirm whether BMN was present before salvage therapy. We however confirmed that BMN was persistent at least one year posttransplant proving the point that bone marrow can undergo remodeling, but is a prolonged process [9]. PET scan and MRI were not helpful in identifying the extent of the BMN. Associations with bone marrow fibrosis were seen, but historically these were limited to patients with underlying myeloproliferative neoplasms [9,10]. We did not see any increase reticulin. The finding of persistent BMN represents a therapeutic dilemma. Successful use of rituximab has been previously reported for PTLD related BMN [11]. Rituximab was discussed with the patient, but not used ldv as he remains clinically stable with normal counts and he requires IVIG replacement for frequent respiratory infections.