SRDAN VERSTOVSEK (HOUSTON)
JAK INHIBITORS IN COMBINATION
Helen T. Chifotides, PhD; Srdan Verstovsek, MD, PhD
The University of Texas MD Anderson Cancer Center, Houston
Notwithstanding the major clinical benefits that myelofibrosis (MF) patients experience from
treatment with the JAK inhibitors ruxolitinib and fedratinib (in the US only), several rational
ruxolitinib-based combinations with novel agents have been in advanced clinical
development. The investigational drugs target alternate biological mechanisms beyond the
JAK/STAT pathway and concomitantly possibly boost the efficacy of JAK inhibitors, or bring
additional benefit to JAK inhibition, e.g., anemia benefit. Interest in the novel strategies stems
from preclinical evidence of combination synergism, the quest for disease-modifying agents
and therapeutic options for patients who show suboptimal response or resistance to
ruxolitinib, and the need to improve cytopenias 1,2.
Synergistic combinations targeting JAK/STAT and epigenetics.
Ruxolitinib and bromodomain and extraterminal (BET) protein inhibitors. CPI-0610 is a novel,
potent and selective BET protein inhibitor and epigenetic modifier that has shown efficacy in
combination with ruxolitinib in clinical studies. Patients with MF who had a suboptimal
response to ruxolitinib 3 or had not previously received a JAK inhibitor 4 were treated with
a combination of CPI-0610 and ruxolitinib in the ongoing global phase 2 study (MANIFEST;
NCT02158858); the first subgroup received CPI-0610 as an “add-on” to ruxolitinib 3. The
treated patients demonstrated reduction in splenomegaly, bone marrow fibrosis, and
improvement in anemia and total symptom score (TSS). Sixty-seven percent of the patients
who had not previously received JAK inhibitors demonstrated ≥35% spleen volume reduction
(SVR35, primary end point), and 57% of the patients achieved at least 50% improvement of
TSS with CPI-0610 and ruxolitinib treatment (the combination was initiated from the
beginning) at 24 weeks 3. The aforementioned improvement rates are higher than the
historical data reported for ruxolitinib in phase 3 trials. The global, pivotal, randomized,
double-blind phase 3 MANIFEST-2 trial (NCT04603495), assessing ruxolitinib/CPI-0610 versus
ruxolitinib/placebo in the frontline setting for JAK-inhibitor treatment-naïve patients with
primary and secondary MF, has been launched 5.
Ruxolitinib and hypomethylating agents. Ruxolitinib and decitabine showed synergistic
efficacy in the post-MPN AML mouse model 6. On the basis of the former preclinical studies,
phase 1 and 2 clinical trials were conducted by our team 7 and the Myeloproliferative
Neoplasms Research Consortium 8,9 in patients with accelerated-phase (AP) and blast-phase
(BP) MPN. Treatment with the combination of ruxolitinib and decitabine showed comparable
response rates with intensive chemotherapy but lower cytotoxicity, thus providing a viable
option for patients with AP- or BP-MPN.
Ruxolitinib and isocitrate dehydrogenase inhibitor (IDH). Preclinical studies demonstrated
synergism of enasidenib (IDH2 inhibitor) with ruxolitinib in patient-derived IDH2/JAK2-
mutated MPN and post-MPN AML cells 10. The aforementioned preclinical results provided
the background to design a phase 2 clinical study (NCT04281498) in which the combination of
ruxolitinib with enasidenib will be evaluated in patients who have MPN-AP/BP or chronic
phase MPN (blasts 4-9%) and also harbor the IDH2 mutation. Notably, treatment of a patient