Consolidation of dual MAPK inhibitor therapy by allograft in histiocytic sarcoma: A report of two cases Free

Introduction: Histiocytic sarcoma (HS) is a high-risk histiocytic neoplasm often involving mutations in mitogen-activated protein kinase (MAPK) pathway genes, such as BRAF, KRAS and MEK. National database studies from the United States report a median overall survival of 6 months in HS, and multifocal disease appears a poor prognostic factor. The efficacy of BRAF and MEK inhibitors in multifocal HS remains unclear, with some patients achieving prolonged remission on treatment and others experiencing progression shortly after initiation. We report 2 patients treated with dabrafenib and trametinib to complete metabolic remission (CMR) then consolidated with allograft. Both remain alive and in remission at 16- and 6-months post-transplant respectively. Inhibitors were continued throughout transplant (except on days of chemotherapy) and have not yet been withdrawn.

Case A: A 44-year-old male presented with a neck lump, dry cough, weight loss and night sweats. A diagnosis of HS was confirmed by supraclavicular lymph node biopsy demonstrating large cells positive for CD163, CD4, BCL6 and Cyclin D1. Next-generation sequencing (NGS) identified BRAF^V600Eand MAP2K1 c.370C>T (p.Pro124Ser) variants. Fluorine-18-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) revealed hepatic and splenic foci, large volume supradiaphragmatic disease and a single subdiaphragmatic node. DA 3+10 was commenced but disease progressed by day 16 of cycle 1. Dabrafenib (150mg twice daily) and trametinib (2mg daily) were initiated, achieving CMR by day 59 of treatment. No adverse drug reactions (ADRs) occurred. To consolidate this response, matched unrelated donor allograft was planned. A 14-month delay in donor matching occurred, throughout which inhibitors were continued and disease remained stable. Transplant proceeded using fludarabine 150mg/m² and melphalan 140mg/m² with post-grafting cyclophosphamide, mycophenolate mofetil and tacrolimus for graft-versus-host disease (GvHD) prophylaxis. Recovery was uneventful, with neutrophil engraftment achieved on day 13 and platelet engraftment on day 12. Tacrolimus was tapered from day 68 and withdrawn by day 128. 100% Donor chimerism was achieved in myeloid cells and T cells by 3 months post-transplant. No significant post-transplant infection or GvHD has occurred to date. He remains well on dabrafenib and trametinib in CMR at 16-months post-transplant.

Case B: A 44-year-old male presented with abdominal pain, weight loss and night sweats. CT revealed multiple hepatic and splenic lesions with upper abdominal lymphadenopathy. Liver biopsy confirmed a diagnosis of HS, revealing large cells positive for CD4, CD14, CD163, S100 and CD1a. NGS confirmed BRAF^V600E and KRAS c.68T>G (p.Leu23Arg) variants. FDG PET/CT demonstrated hepatic and splenic foci as well as supra- and infradiaphragmatic lymphadenopathy. CHOP14 was given to partial response but active disease remained after 5 cycles. Dabrafenib (150mg twice daily) and trametinib (2mg daily) were initiated, achieving CMR after 2 weeks. To consolidate this response, allograft from a haploidentical donor was performed using fludarabine 150mg/m² and melphalan 140mg/m² with post-grafting cyclophosphamide and ciclosporin for GvHD prophylaxis. Trametinib was temporarily withdrawn during transplant due to an ADR (grade 3 pan-colitis with gastrointestinal bleeding) then restarted. Neutrophil engraftment was achieved on day 22 and platelet engraftment on day 30. Ciclosporin was withdrawn by day 100. 100% Donor chimerism was achieved in myeloid cells and T cells by 6 months post-transplant. Recovery was complicated by Mycobacterium Tuberculosis infection at 2 months post-transplant, which was initially mistaken for relapse and treated with an abrupt withdrawal of immunosuppression. Antimycobacterial therapy was started instead when lymph node biopsy showed acid-fast bacilli, and FDG PET/CT demonstrated a good response after an initial paradoxical reaction. No significant GvHD has occurred to date. He remains well on dabrafenib and trametinib in CMR at 6-months post-transplant.

Discussion:These 2 cases suggest that allograft is feasible on dual MAPK inhibitor therapy and may have potential efficacy as consolidation for high-risk visceral HS. Withdrawal of inhibitors and longer follow up are required to determine the durability of remission with this approach.