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Inhibiting the Janus kinase (JAK) pathway is considered the hallmark in treating myelofibrosis (MF); however, treatment discontinuation due to adverse events has been a concern. After JAK failure, therapeutic options are limited and there is an ongoing effort for therapies beyond JAK inhibitors (JAKi). Several non-JAK inhibitor therapies are in clinical development and have demonstrated acceptable safety and attenuation of splenomegaly and other key symptoms.
During the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition, updates from clinical trials investigating non-JAKi were presented; and we provide a combined summary of these talks.
The MPN Hub have published an editorial theme on treatment options beyond JAK inhibition, which can be found here.
Bomedemstat is a lysine-specific-demethylase (LSD-1) inhibitor that has been investigated as a monotherapy in a trial (NCT03136185), which included patients with relapsed/refractory (R/R) MF, and outcomes from 86 patients were previously summarized on the MPN Hub during the 26th Congress of the European Hematology Association (EHA 2021), including study design and patient characteristics. At the 63rd ASH Annual Meeting and Exposition, Harinder Gill presented updated results from 89 patients. The latest findings were similar to those reported during EHA 2021; good level of tolerability, improvements on symptoms and anemia, and the mutant allele frequency for driver and high molecular risk (HMR) mutations, such as ASXL1, were stable or decreased in 81% of patients.
Bomedemstat is also currently under investigation for essential thrombocythemia (ET) and polycythemia vera (PV). For findings from patients with ET, read our summary here.
Tagraxofusp is a novel CD123-targeted therapy investigated in a phase I/II trial (NCT02268253) for patients with chronic myelomonocytic leukemia or MF, with high CD123 expression who have poor prognosis. Study design, patient characteristics, and data from 32 patients in the MF cohort (dose escalation stage, n = 4; and Stage 2, n = 28) were previously summarized on our hub. Since last update, an additional seven patients were included in the analysis, as reported at the 63rd ASH Annual Meeting and Exposition.
Pelabresib is a potent bromodomain and extra-terminal (BET) protein inhibitor that is currently investigated in the phase II MANIFEST trial (NCT02158858) in patients with MF in three arms; Arm 1 evaluates pelabresib monotherapy in patients who were resistant/intolerant or ineligible for JAKi treatment, which was divided into transfusion dependent (TD) and transfusion independent (TI) cohorts.
This update, at the 63rd ASH Annual Meeting and Exposition, provided results from Arm 1 with 36 patients treated in the TD cohort and 50 in the TI cohort (vs 16 and 27 patients, respectively, reported in the EHA 2020 update)
The phase III MANIFEST-2 trial investigating pelabresib + ruxolitinib versus placebo + ruxolitinib in JAKi-naïve patients with MF is currently ongoing (NCT04603495).
AVID200 is a novel, highly specific TGF-β 1/3 inhibitor investigated in a phase Ib trial for patients with MF (NCT03895112). AVID200 has been investigated as a potential therapy due to multiple molecular avenues by which upregulation of TGF-β 1/3 promotes BMF. Notable mechanisms include inhibition of normal megakaryocyte formation and, therefore, platelet production.
Eligibility criteria for this study included:
AVID200 was administered intravenously at three dosing levels on Day 1 of a 21-day cycle, and the response was assessed at Cycle 7.
Figure 1. Dose escalation*
DLTs, dose limiting toxicities.
*Adapted from Mascarenhas et al.4
†Dose level 3A (1,100 mg/m2) was not used in the study due to drug supply shortage (was switched from A to B lot).
Baseline characteristics for all patients treated in the dose escalation (n = 9) and the dose expansion stage (n = 12) are summarized in Table 1.
Table 1. Patient characteristics*
CALR, calreticulin; DIPSS, Dynamic International Prognostic Scoring System; HMR, high molecular risk; TSS, total symptom score. |
|
Characteristic |
N = 21 |
---|---|
Median age, years (range) |
73 (51–81) |
Prior ruxolitinib treatment, % |
90.0 |
DIPSS, % |
|
Intermediate-2 |
66.7 |
High-risk |
33.3 |
JAK2 V617F, % |
71.4 |
CALR, % |
19.0 |
TSS, median (range) |
14 (3–39) |
Patients with HMR mutation, % |
50 |
Selinexor is a small, oral, selective inhibitor of nuclear export that blocks the karyopherin protein exportin1 (XPO1) that is currently being evaluated in the phase II ESSENTIAL study (NCT03627403) for patients with JAKi R/R MF.
12 patients were eligible for the analysis (Table 2).
Table 2. Patient characteristics*
CALR, calreticulin; HMR, high molecular risk; JAKi, Janus kinase inhibitor; MPL, myeloproliferative leukemia virus. |
|
Characteristic |
N = 12 |
---|---|
Median age, years (range) |
68 (43–80) |
Median duration of JAKi therapy, months (range) |
22 (0.5–96) |
Resistance to JAKi, % |
92 |
Median spleen volume, cm3 (range) |
1,454 (835–5,792) |
Driver mutations, % |
|
JAK2 |
58.3 |
CALR |
33.3 |
MPL |
8.3 |
≥1 HMR mutation, % |
67 |
Median treatment duration was 11 months (2.8 – 28.8).
Grade ≥3 TEAEs are summarized in Table 3. 10 patients had a dose reduction due to fatigue, anemia, thrombocytopenia, abdominal pain and, most commonly, weight loss.
Table 3. Grade ≥3 TEAEs*
TEAEs, treatment-emergent adverse events. |
|
Grade ≥3 TEAEs, % |
N = 12 |
---|---|
Hematologic |
|
Anemia |
33 |
Thrombocytopenia |
17 |
Nonhematologic |
|
Weight loss |
8 |
Fatigue |
33 |
Dyspnea and hypoxia |
17 |
Hypertension |
17 |
Dizziness |
17 |
Flu-like symptoms |
17 |
Sepsis |
8 |
In summary, selinexor produced clinical responses in patients with JAKi-refractory MF. Long term use of selinexor appeared to be safe with manageable side effects. Further two studies will investigate selinexor in combination with ruxolitinib in patients with JAKi naïve MF (NCT04562389) and as a monotherapy in patients with previously treated MF (NCT04562870).
Sotatercept is a first-in-class, fusion protein composed of the extracellular domain of the human activin receptor and the Fc region of human IgG1, and traps ligands of the TGF-β superfamily that inhibit terminal erythropoiesis. Final results from a phase II trial investigating the safety and efficacy of sotatercept in anemic patients with MF (NCT01712308), were presented at the 63rd ASH Annual Meeting and Exposition.
Patients recruited in this study had primary or secondary MF and anemia, and sotatercept was given either as a monotherapy or in combination with ruxolitinib (Figure 2 and Table 4).
Figure 2. Study cohorts*
MF, myelofibrosis; SC, subcutaneously.
*Adapted from Bose et al.6
Table 4. Patient characteristics by treatment cohort*
CALR, calreticulin; DIPSS, Dynamic International Prognostic Scoring System; Hgb, hemoglobin; MPL, myeloproliferative leukemia virus. |
||
Characteristic |
Sotatercept alone |
Sotatercept + ruxolitinib |
---|---|---|
Median age, years (range) |
67 (47–84) |
71 (48–84) |
Median baseline Hgb, g/dL (range) |
7.4 (4.7–9.3) |
7.4 (4.6–9.1) |
Mutation, n |
||
JAK2 |
22 |
15 |
CALR |
4 |
4 |
MPL |
6 |
2 |
Triple-negative |
1 |
0 |
DIPSS, n |
||
Intermediate-1 |
2 |
0 |
Intermediate-2 |
27 |
20 |
High-risk |
5 |
1 |
Splenomegaly present, n |
19 |
12 |
Previously treated, n |
28 |
21 |
The overall response rate (ORR) for the monotherapy cohort (n = 27, evaluable patients) was 30% with a median duration of response (DoR) of 23.3 months (range, 3.9–68.4), whereas the ORR for the combination cohort (n = 19, evaluable patients) was 32% with a median DoR of 19.9 months (range, 3.7–56.8). Type of response was anemia and TI in the monotherapy cohort, and anemia only in the combination cohort. Four patients in the monotherapy cohort and three in the combination cohort required multiple dose holds for hemoglobin levels ≥11.5 g/dL, and sotatercept resumed when hemoglobin was <11 g/dL.
Sotatercept was well tolerated, with a total of nine Grade ≥3 events possibly related to treatment, including pain/myalgia (n = 2) and hypertension (n = 7). All but two patients (in each cohort) discontinued treatment, with the most common reason being lack or loss of response in both the monotherapy (n = 14) and combination (n = 8) cohort.
References
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