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Myeloproliferative neoplasms (MPNs) are characterized by excessive proliferation of hematopoietic cells and comprise essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), including prefibrotic myelofibrosis (pre-MF). MPNs are associated with an increased risk of thrombohemorrhagic events, reduced life expectancy, and may transform into secondary acute myeloid leukemia (sAML). The majority of MPNs are driven by somatic mutations in JAK2, CALR, or MPL, and thus, increasing knowledge on the complex molecular landscape in MPN has led to more personalized prediction of outcomes and improved clinical decision-making. However, the predictive role of somatic mutations regarding response and resistance to cytoreductive therapy remains uncertain.
The MPN Hub is pleased to summarize the key findings from a recent study by Knudsen and colleagues1 published in Blood Advances, investigating the role of somatic mutations in patients with MPN enrolled in the DALIAH trial (NCT01387763), treated with cytoreductive therapy (interferon-α [IFN-α] vs hydroxyurea [HU]).
The DALIAH trial was an investigator-initiated, open label, randomized controlled, phase III trial. Eligible patients were aged ≥18 years with a diagnosis of ET, PV, pre-MF or PMF based on the World Health Organization (WHO) 2008 criteria. Patients aged >60 years were randomly allocated (1:1:1) to receive HU, IFNα-2a, or IFNα-2b, whereas patients aged ≤60 years were randomly allocated (1:1) to receive IFNα-2a, or IFNα-2b. Treatment dose was modified based on efficacy and toxicity according to predefined dose levels.
The median age was 62 years (range, 20–88), and 55% of the enrolled patients were male. The clinical baseline characteristics are summarized in Table 1.
Table 1. Clinical baseline characteristics by treatment*
ET, essential thrombocythemia; Hb, hemoglobin; Hu, hydroxyurea; IFN-α, interferon-α; LDH, lactate dehydrogenase; PV, polycythemia vera; PMF, primary myelofibrosis; Pre-MF, prefibrotic myelofibrosis; vol, volume: WBC, white blood cell. |
||||
Characteristics, % (unless stated otherwise) |
HU |
IFNα-2a |
IFNα-2b |
Total |
---|---|---|---|---|
Patient related variable |
||||
Median age, range |
68 (60–80) |
60 (21–88) |
58 (20–81) |
62 (20–88) |
≤60 years |
0 |
55 |
55 |
45 |
>60 years |
100 |
45 |
45 |
55 |
History of major thrombosis |
16 |
25 |
15 |
19 |
History of stroke |
8 |
12 |
5 |
8 |
MPN subtype |
||||
ET |
24 |
37 |
40 |
36 |
PV |
55 |
41 |
41 |
44 |
Pre-MF |
3 |
11 |
7 |
8 |
PMF |
18 |
11 |
11 |
12 |
Phenotype driver mutation |
||||
JAK2† |
84 |
80 |
80 |
74 |
CALR |
16 |
14 |
17 |
14 |
MPL‡ |
3 |
6 |
6 |
5 |
Triple negative |
3 |
5 |
12 |
8 |
Median Hb (mmol/L), range |
9.3 |
9.0 |
8.9 |
9.0 |
Median hematocrit (vol %), range |
45 |
45 |
43 |
44 |
Median WBC (× 109/L), range |
9.9 |
8.9 |
9.5 |
9.4 |
Median platelets (× 109/L), range |
664 |
712 |
615 |
667 |
Median LDH (unit/L) |
242 |
232 |
224 |
229 |
Disease-related symptoms§ |
50 |
62 |
49 |
54 |
Previous treatment |
||||
HU |
11 |
12 |
9 |
10 |
Phlebotomy |
45 |
41 |
48 |
45 |
Somatic mutations in 34 genes were detected in 191 patients (95%) at baseline and MPN phenotypic driver mutations were present in 92% of patients (Table 2).
Table 2. Somatic mutations at baseline by disease subtype*
ET, essential thrombocythemia; PV, polycythemia vera; PMF, primary myelofibrosis; Pre-MF, prefibrotic myelofibrosis. |
||||||
Mutations, % |
ET |
PV |
Pre-MF |
PMF |
Total |
p value† |
---|---|---|---|---|---|---|
Patients with no mutations |
13 |
2 |
0 |
0 |
5 |
0.026 |
Patients with mutations |
||||||
Triple negative |
18 |
2 |
6 |
4 |
8 |
0.007 |
Driver mutations |
||||||
JAK2 |
50 |
97 |
69 |
56 |
74 |
<0.001 |
JAK2-UPD |
0 |
54 |
6 |
28 |
28 |
<0.001 |
CALR |
22 |
0 |
25 |
36 |
14 |
<0.001 |
MPL |
11 |
0 |
6 |
4 |
5 |
0.004 |
Concomitant mutations |
||||||
TET2 |
19 |
26 |
31 |
28 |
24 |
0.61 |
DNMT3A |
15 |
17 |
25 |
12 |
16 |
0.75 |
ASXL1 |
6 |
10 |
19 |
16 |
10 |
0.20 |
NGS was performed in 135 patients at 24 months, and driver mutations were still detectable in all patients.
CHR in patients with/without treatment-emergent mutations: Significantly more patients treated with IFNα and without treatment-emergent mutations, achieved CHR (51%, 35/68 vs 22%, 4/18; p = 0.034) compared to patients treated with HU without treatment-emergent mutations, respectively.
This study elucidated the association between mutation-specific responses to IFNα and HU at 24 months in patients with MPN. Distinct molecular responses were observed with IFNα in JAK2- and CALR-mutated patients with MPN. The study also demonstrated that DNMT3A-mutated clones/subclones emerged during treatment with IFNα in patients who did not achieve CHR. The findings from this study show treatment- and mutation-specific patterns of responses in patients with MPN treated with IFNα and HU, which may have clinical implications in the future.
References
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