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Bromodomain and extraterminal domain proteins (BET) are epigenetic modulators that bind to acetylated histones and non-histone proteins and regulate the production of proinflammatory cytokines in response to Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signalling pathway activation.1 Proinflammatory cytokines have been shown to contribute to myelofibrosis (MF) etiology by supporting the development of bone marrow fibrosis and other symptoms.2 BET inhibitors, like CPI-0610 have shown promising preclinical efficacy for MF as single agents and in combination with JAK inhibitors, like ruxolitinib (rux).2 In an attempt to clinically validate these results the MANIFEST study was established. This ongoing phase II trial investigates the efficacy of CPI-0610 with or without rux in patients with refractory or intolerant MF.
During the 61st American Society of Hematology (ASH) Annual Meeting & Exposition (2019), John Mascarenhas presented an oral abstract1 on the interim results of MANIFEST. This article is based on data presented at ASH and may supersede the data in the published abstract.
Table 1. Key baseline characteristics from the MANIFEST phase II trial1
ASXL, additional sex comb-like gene; DIPSS, dynamic international prognostic scoring system; ECOG, eastern cooperative oncology group; ET, essential thrombocytopenia; MF, myelofibrosis; PV; polycythemia vera; rux, ruxolitinib; TSS, total symptom score |
||||
Characteristics |
CPI-0610 monotherapy (n = 36) |
CPI-0610 + rux (n = 54) |
Overall (n = 90) |
|
---|---|---|---|---|
Median age (years) |
69 |
69 |
69 |
|
Males |
21% |
32% |
53% |
|
ECOG ≤ 1 > 1 |
91.7% 8.3% |
92.6% 5.6% |
92.2% 6.7% |
|
DIPSS Intermediate High |
55.6% 30.6% |
64.8% 22.2% |
61.1% 25.6% |
|
MF subtype Primary MF Post-PV MF Post-ET MF |
63.9% 19.4% 11.1% |
66.7% 16.7% 16.7% |
65.6% 17.8% 14.4% |
|
Mutations ≥ 3 mutations High molecular risk ASXL |
38.9% 52.8% 41.7% |
68.5% 64.8% 55.6% |
56.7% 60.0% 50.0% |
|
Hemoglobin (g/dl) < 10 g/dl |
72.2% |
74.1% |
73.3% |
|
Median TSS (n) |
22.0 |
19.5 |
21.0 |
Table 2. Best responses from the MANIFEST phase II trial1
PGIC, patient global impression of change; rux, ruxolitinib; SVR35, spleen volume response of 35% reduction from baseline at 24 weeks; TD, transfusion dependent; TI, transfusion independent; TSS, total symptom score |
||||
Best responses |
CPI-0610 + rux
|
CPI-0610 monotherapy
|
||
---|---|---|---|---|
TD patients |
TI patients |
TD patients |
TI patients |
|
SVR35 response (%, n/N) |
29% (5/17) |
0% (0/15) |
25% (1/4) |
0% (0/9) |
TD to TI conversion (n/N) |
6/14 |
- |
0/4 |
- |
TSS ≥ 50% response (%, n/N) |
76.5% (13/17) |
43% (6/14) |
50% (1/2) |
62.5% (5/8) |
PGIC (%, n/N) |
89% (16/18) |
93.3% (14/15) |
100% (4/4) |
91% (10/11) |
Table 3. Hemoglobin and bone marrow fibrosis improvements in the MANIFEST trial1
BMF, bone marrow fibrosis; Hgb, hemoglobin; rux, ruxolitinib; TD, transfusion dependent; TI, transfusion independent |
||
|
CPI-0610 + rux
|
CPI-0610 monotherapy
|
---|---|---|
BMF improvement (%, n/N) |
43.5% (10/23) |
22.2% (2/9) |
BMF improvement 1.5 g/dl increase of Hgb (%, n/N) |
17.4% (4/23) |
22.2% (2/9) |
BMF improvement TD to TI conversion (%, n/N) |
36.4% (4/11) |
0% (0/2) |
Hgb increase by ≥ 1.5 g/dl (%, n/N) |
13% (2/15) |
55% (6/11) |
Table 4. Key adverse events combined from both treatment arms of the MANIFEST trial1
AEs, adverse events; URT, upper respiratory tract |
||
Adverse events |
All grade (n = 90)
|
Grade ≥ 3 (n = 90) |
---|---|---|
Hematological AEs (%, n/N) |
|
|
Thrombocytopenia Anemia |
23.3% 8.9% |
10.0% 6.7% |
Non-hematological AEs (%, n/N) |
|
|
Diarrhea Nausea Vomiting Cough Fatigue URT infection |
32.2% 22.2% 14.4% 16.7% 14.4% 14.4% |
4.4% 1.1% 1.1% - 3.3% - |
The interim results of the MANIFEST phase II trial indicate that the BET inhibitor CPI-0610 both with and without rux has antitumor activity in patients with refractory or intolerant advanced MF. Improvements in hemoglobin levels and BMF were observed with both treatments with a trend for better efficacy when rux and CPI-0610 were used in combination. TD patients seem to benefit the most from the combination treatment with CPI-0610 and rux leading to both objective and subjective patient-reported responses. Moreover, the combination treatment seemed more effective in converting patients with TD to TI. Both treatments were well tolerated with asymptomatic thrombocytopenia being the most common hematological side effect. Building upon these promising early data, the trial has now increased its sample size to further validate the synergistic efficacy of CPI-0610 with rux in TD patients and is also investigating a separate cohort of rux naïve MF patients (Arm 3). Preliminary data from Arm 3 of this trial were presented by Prof Harrison at ASH 2019 here.
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