Introduction: The use of histone deacetylase inhibitors has shown promising results in the prevention of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplant (HCT) (Choi et al, Lancet Oncology, 2014). In this protocol, we will build on prior experience by adding panobinostat to tacrolimus and sirolimus for GVHD prevention (Pidala et al, Haematologica, 2012 and idem, 2015). Panobinostat has been proven to be tolerable in our prior study of GVHD treatment in addition to glucocorticoids (Perez et al, ASH 2014 Abstract), in myelodysplastic syndrome (MDS) maintenance (Bug et al, ASH 2015 Abstract), and in early post-HCT epigenetic therapy (panobinostat and decitibine) followed by donor lymphocyte infusion (Cornelissen et al, ASH 2016 Abstract). We hypothesize that panobinostat added to tacrolimus-sirolimus may abolish GVHD while sparing the graft-versus-leukemia effect by enhancing T regulatory cell development and modulating antigen presentation.

Methods: This is a phase II Simon's minimax two-stage design; the null hypothesis will be rejected if the number of patients with grade II-IV aGVHD is 12 or less among 38 evaluable patients (≤31.6% incidence rate at day 100). To date, we have enrolled 27 patients with hematological malignancies (3 with AML, 3 with ALL, 3 with MPN, 6 with MDS, and 1 each with CML, chronic neutropenia, PTCL, and BPCDN) and a median age of 56 years (range, 29-72 years). These patients have been followed for at least 100 days after an HLA-compatible unrelated-donor (n=19) or related-donor (n=6) HCT. The conditioning regimen was BU/FLU AUC 5300 for 4 days (16 patients), BU/FLU AUC 3500 for 4 days (1 patient), or fludarabine/melphalan 140 mg/m2 (10 patients). All participants received G-mobilized peripheral blood stem cells. Panobinostat at 5 mg orally 3 times/week was initiated on day -5 or -6 and continued for 26 weeks; panobinostat stopping criteria included GVHD requiring corticosteroids (1 mg/kg) or toxicity. Tacrolimus was given starting on day -3, with taper recommended from day +50, and sirolimus was started on day -1 with taper recommended from day +365.

Results: Engraftment occurred at a median of 14.5 days (range, 12-18 days) for ANC over 500/µL and median of 15.5 days (range, 10-27 days) for platelets over 20,000/µL. Sinusoidal obstruction syndrome was seen in 1 patient (resolved). Among 27 patients, 7 completed panobinostat treatment as planned at day 100. The other 20 patients stopped panobinostat due to GVHD treated with 1 mg/kg corticosteroids (n=4), myelosuppression possible related to panobinostat (n=8), mucositis (n=2), QTCF prolongation (n=1), comorbidities (n=5), patient refusal (n=1), peripheral edema/renal failure possible related to panobinostat (n=1), rash/angioedema (n=1) definitively related to panobinostat), and facial erythema possible related to panobinostat (n=1). Among 27 evaluable patients, aGVHD was seen in 6 of 27 patients (22%), with 5 patients having grade II (4 responded to corticosteroids; 1 resolved with no corticosteroids) and 1 having grade III GVHD (Jakafi stopped pre-HCT resolved with re-initiation). We did not observe an increase in infection risk. None of the 27 patients died within 100 days, and 7 relapsed at 3-8 months (3 with AML FLT3+, 1 with AML DNMT3A and IDH1 mutations, 1 with ALL, 1 with MPN and 1 with MDS-complex cytogenetics).

Conclusions: The combination of tacrolimus-sirolimus-panobinostat seems to be an effective strategy to reduce aGVHD in myeloablated unrelated-donor or related-donor transplant with a 22% incidence of aGVHD compared with 43% reported with tacrolimus-sirolimus in our previous study. Follow-up and accrual completion are required, and correlative studies are planned that will compare results with control patients receiving tacrolimus-sirolimus only.


Kharfan-Dabaja: Alexion Pharmaceuticals: Speakers Bureau; Incyte: Speakers Bureau; Seattle Genetics: Speakers Bureau.

Author notes


Asterisk with author names denotes non-ASH members.