JOHN MASCARENHAS (NEW YORK)
EVOLVING THERAPIES FOR MYELOFIBROSIS;
NON-JAK INHIBITOR APPROACHES
Although JAK inhibitor therapy has clearly benefitted many patients with myelofibrosis (MF),
it has become clear that none of the currently tested JAK inhibitors convincingly alter the
natural history of this chronic and progressive clonal hematologic malignancy. Current clinical
investigation in MF is focused on salvaging either suboptimal spleen/symptom response or
loss/worsening of initial response. More recently, paradigm shifting prospective evaluation of
JAK inhibitor based combination therapy in JAK inhibitor naïve patients has paved the wave to
testing rational combination strategies earlier in the disease course to optimize outcomes.
However, novel targeted agents are also being evaluated with innovative end points in those
patients who have failed prior JAK inhibitor therapy. Such approaches include the pan BET
inhibitor CPI-0610 in cohort 1 monotherapy arm of the MANIFEST study which allows for clear
assessment of the activity of this agent alone and in contrast to the arm 2 and 3 in combination
with ruxolitinib as second and first line therapy, respectively. Epigenetic therapeutics such as
the LSD1 inhibitor bomedemstat has also been tested in the setting of ruxolitinib failure and
dosing is uniquely guided by the platelet count. Correcting bone marrow microenvironmental
abnormalities with anti-fibrotic approaches targeting pathologic TGFβ signaling is being
evaluated in a phase 1b trial of the TGFβ 1/3 trap AVID200. Induction of p53 pathway killing
of MF cells with a selective MDM2 antagonist such as KRT-232 capitalizes on the differential
expression of MDM2 in CD34+ MPN cells compared to normal CD34+ cells. Tagraxofusp, a
CD123-targeted agent approved for BPDCN, with rationale for MF has been tested in a phase
1/2 study after ruxolitinib failure. Lastly, with an aim to extend survival beyond the reported
15 month median survival after ruxolitinib failure, imetelstat exploits constitutive expression
of telomerase in MPN stem cells and has demonstrated on-target pharmacodynamic activity
which links outcome measures such as spleen, symptom, bone marrow fibrosis reduction and
survival. These agents and others will also ultimately be tested in JAK inhibitor strategies as
drug development is naturally structured in this way, but novel-novel drug combinations and
triplet therapies with complementary mechanisms of action and non-overlapping toxicities
are on the horizon.
References:
Yacoub et al. Blood (2020) 136 (Supplement 1): 23–24.
Mascarenhas et al. Blood (2020) 136 (Supplement 1): 6–8.
Pemmaraju et al. Blood (2020) 136 (Supplement 1): 39–40
Mascarenhas et al. Blood (2020) 136 (Supplement 1): 33–34.
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