A phase I/II feasibility study of panobinostat alone and the combination of panobinostat and decitabine prior to donor lymphocyte infusion in recipients of allogeneic stem cell transplantation with poor and very poor risk AML

This study will explore the feasibility of post-transplant panobinostat
combined with decitabine after reduced intensity conditioning (RIC) alloHSCT in
patients with AMLor RAEB with IPSS >= 1.5 (AML/RAEB). While recent studies
showed that the allogeneic graft-versus-leukemia (GVL) effect is clearly
operational in (very) poor risk AML, relapse rates after alloHSCT in those
patients are still unacceptably high, with no curative options left. Based on
recent experience by others exploring the combination of panobinostat and
decitabine in AML patients and by different groups exploring post-transplant
chemotherapy including panobinostat, we here propose to study the combination
of panobinostat and decitabine after alloHSCT to be followed by donor
lymphocyte infusions to optimally profit from the allogeneic GVL-effect.
Feasibility in this study will be defined by the completion of protocol
treatment up to eligibility for a first dose of DLI in at least 70% of patients
starting protocol treatment, without dose limiting toxicity up to that point of
time.
Given recent findings showing favorable results of PNB alone, also the
feasibility and efficacy of PNB monotherapy will be investigated.

Primary objective:
Part I
- To asses the feasibility of addition of post-transplant panobinostat
combined with decitabine to a regimen of T-cell replete RIC alloHSCT in
patients with very poor risk AML/RAEB, and select the dose level for the phase
II part of the study.
Part II
-Assess the feasibility of addition of post-transplant panobinostat combined
with decitabine to a regimen of T-cell depleted RIC alloHSCT and DLI in
patients with (very) poor-risk AML
Part III
-Assess the feasibility of addition of post-transplant panobinostat to a
regimen of T-cell depleted RIC alloHSCT and DLI in patients with (very)
poor-risk AML


Secondary objectives:
-Assess efficacy in terms of complete remission rate, overall and progression
free survival.
-Assess toxicity

Multicenter, prospective phase I/II trial

During part I of the trial the combination of panobinostart en decitabine will
be tested at 4 dose levels, the first being panobinstat alone.

In part II, patients will be treated with T cell replete RIC alloHSCT, followed
by 2 cycles of panobinostat and decitabine (PNB/DAC), followed by DLI at 3
months after alloHSCT, followed by another 2 cycles of PNB/DAC and if no GvHD
a second DLI (and third DLI).


In part III, patients will be treated with T cell replete RIC alloHSCT,
followed by 2 cycles of panobinostat (PNB) followed by DLI at 3 months after
alloHSCT, followed by another 2 cycles of PNB and if no GvHD a second DLI (and
third DLI).

Although alloHSCT is standard care in (very) poor-risk AML/RAEB, the incidence
of relapse after alloHSCT is high, leaving patients without curative options.
In this protocol post-transplant panobinostat and azacitidine followed by donor
lymphocyte infusions is evaluated. The aim is to prevent early relapse prior to
DLI and to optimally profit from the allogeneic Graft versus Leukemia effect,
to improve outcome.
The risks associated with this procedure are opportunistic infections
associated with neutropenia and lymphopenia, that may occur after PNB/DAC, as
compared to standard alloHSCT.