who had IDH2/JAK2-mutated MPN-BP with the combination of ruxolitinib with enasidenib and
azacitidine resulted in sustained complete remission (both molecular and hematologic) and
MRD negativity for more than 2.5 years 11.
Targeting JAK/STAT and the epichaperome. The heat shock protein 90 (Hsp90) inhibitor PU-H71
in combination with ruxolitinib showed synergism in preclinical MPN models (more
potent inhibition of the JAK/STAT pathway than ruxolitinib only) 12. We are exploring the
combination in a phase 1b study for potential enhancement of the clinical efficacy of
ruxolitinib in patients with primary or secondary MF (NCT03935555) 13.
Combination targeting JAK and anti-apoptotic proteins. Navitoclax is an orally bioavailable
small-molecule, potent inhibitor of the anti-apoptotic proteins Bcl-2/Bcl-xL. In preclinical
studies, ABT-737 (the non-clinical analog of navitoclax) in combination with ruxolitinib
demonstrated synergism in apoptosis of leukocytes isolated from patients with primary MF
14. In the phase 2 clinical study assessing the efficacy of navitoclax as “add-on” to ruxolitinib
in patients with relapsed/refractory MF (NCT03222609), eligible patients were treated with
ruxolitinib alone for more than 12 weeks and had suboptimal response. At week 24, among
evaluable patients, 27% had ≥35% reduction in spleen volume (SVR35), palpable splenomegaly
resolved in 53% of the patients, and 30% of them had more than 50% improvement in TSS
15. The combination of ruxolitinib/navitoclax versus ruxolitinib/placebo is currently being
evaluated in patients who had not previously received JAK inhibitors (in the frontline setting)
in a pivotal randomized phase 3 study (TRANSFORM-I; NCT04472598).
Combination targeting JAK/STAT signaling and Human Double Minute 2 (HDM2)-mediated
pathways. KRT-232 (a potent, bioavailable inhibitor of HDM2, which is a key negative
regulator of p53) in combination with ruxolitinib is being assessed in a global, open-label phase
1b/2 study (NCT04485260) in patients with MF who had a suboptimal response to ruxolitinib
treatment after more than 18 weeks (patients who harbor TP53 mutations are excluded from
the study). The goals of the study are to determine the recommended phase 2 dose and the
rates of SVR35, TSS50, and the overall/progression free survivals 16.
Combination treatment of ruxolitinib with drugs targeting anemia. Luspatercept is an activin
receptor-ligand trap that enhances late-stage erythropoiesis and is currently assessed in
patients with MF because most patients develop anemia and many require red blood cell
(RBC) transfusions. Currently, there is no medication for anemic MF patients; therefore, there
is a great need for this cohort. The ongoing phase 2 study included a cohort of patients who
received ruxolitinib for a median of 73 weeks prior to treatment with the combination of
ruxolitinib and luspatercept and were RBC-transfusion dependent. Of these patients, 46%
(10/22) achieved 50% or higher reduction in RBC transfusions over 12 weeks and nearly 30%
of the patients receiving transfusions achieved RBC transfusion-independence for a long term
(12 consecutive weeks) 17. The phase 3 study of luspatercept vs. placebo in combination
with ruxolitinib in patients with MPN-associated MF who require RBC transfusions
(INDEPENDENCE trial) is planned.
In summary, building on the success of JAK inhibitors, several phase 3 trials are underway to
evaluate rational combinatorial strategies alongside JAK/STAT inhibition for MF, in order to
improve the management of our MF patients.
References:
1. Bose P and Verstovsek S. JAK inhibition for the treatment of myelofibrosis: Limitations and future
perspectives. HemaSphere 2020;4(4):e424.
2. Bose P, Masarova L, Verstovsek S. Novel Concepts of treatment for patients with myelofibrosis and
related neoplasms. Cancers (Basel), 2020;12(10):2891.
SCIENTIFIC PROGRAMME
SESSION I
OPTIMIZING
CYTOREDUCTION
SESSION II
MANAGEMENT OF CML
WITH TKI
SESSION III
MPN RISK
STRATIFICATION
INCLUDING VASCULAR
EVENTS
DEBATE 1
INTERFERON ALPHA
SHOULD BE FRONT LINE
THERAPY IN ALL ET/PV
PATIENTS
ROUNDTABLE 1
INFECTIONS IN
MYELOPROLIFERATIVE
DISORDERS, INCLUDING
CML
ROUNDTABLE 2
PREGNANCY AND
PARENTING
DEBATE 2
ALLOGENEIC STEM CELL
TRANSPLANTATION
SHOULD BE CONSIDERED
THIRD LINE OPTION IN
CHRONIC PHASE CML
SESSION IV
EVOLVING THERAPIES
IN MYELOFIBROSIS
SESSION V
MANAGEMENT OF
ADVANCED AND UNUSUAL
DISEASE (MPN AND CML)
SESSION VI
TREATMENT FREE
REMISSION IN CML
KEYNOTE LECTURE
SELECTED ABSTRACTS
FOR AN ORAL
PRESENTATION
SELECTED ABSTRACTS
FO R A POSTER
PRESENTATION
DISCLOSURES