Variables Associated with Outcomes in Patients with Chronic Neutrophilic Leukemia with CSF3RT618I : A Multi-Centre Retrospective Study

Background Chronic neutrophilic leukaemia (CNL) is a rare, progressive myelo-proliferative neoplasm with poor prognosis. However, there were limited data on outcome prediction in CNL.

Objectives To explore the co-variates associated with transformation-free survival (TFS) and survival in patients with CNL with CSF3R^T618I.

Methods Data of adults with CNL from 30 medical centres throughout China were retrospectively interrogated. Diagnosis was based on the 2022 International Consensus Classification criteria and we focused only on those harboring CSF3R^T618I. TFS was defined as an interval from diagnosis to blasts ≥ 20% in blood or bone marrow or last follow-up. Survival was defined as an interval from diagnosis to death from any cause or last follow-up. TFS and survival were calculated by the Kaplan-Meier method. The X-tile plots wa used to determine optimal cut-off value continuous co-variates. Cox regression model was utilized to identify co-variates associated with outcomes.

Results A total of 94 patients were enrolled. 72 (77%) patients were male. Median age at diagnosis was 60 years (IQR, 48-69). 36 (38%) patients had ≥ 1 comorbidity(ies). 56 (60%) patients had palpable splenomegaly. In 85 patients tested ASXL1 and SETBP1 mutations, 39 (46%) had an ASXL1 mutation; 40 (47%), a SETBP1 mutation; 25 (29%), concurrent ASXL1 and SETBP1 mutations. With a median follow-up of 29 months (IQR, 14-48), 23 patients received ruxolitinib or combined with hydroxyurea, interferon, decitabine or azacitidine, 17 (74%) of them had hematologic improvement.

19 of 89 subjects with a known outcome developed AML (n = 17), ALL (n = 1) or chronic myelomono-cytic leukemia (n = 1) at a median of 24 months (IQR, 16-42). 15 subjects receiving a transplant in the first (n = 13) or second chronic phase (n = 2). 52 (55%) subjects died of progressive refractory neutrophilic leukocytosis (n = 14), AML (n = 12), infection and/or haemorrhage (n = 16), cardiac death (n = 2), spleen rupture (n = 1) and unknown causes (n = 7). Median TFS and survival were 60 months (95%CI, 24-76) and 34 months (24-44), respectively. 4-year probabilities of TFS and survival were 59% (42-77%) and 36% (24-47%).

In multi-variable analyses platelet ≤ 112×10E+9/L (HR = 6.5 [2.2, 19.6]; p = 0.001) was significantly-associated with poor TFS; age ≥ 64 years (HR = 3.0 [1.6, 5.4]; p < 0.001), WBC count ≥ 47×10E+9/L (HR = 1.9 [1.1, 3.4]; p = 0.024), hemoglobin concentration ≤ 119 g/L (HR = 2.1 [1.1, 3.9]; p = 0.018), poor survival. When censored at transplant, besides older age and anemia, splenomegaly ≥ 8 cm under the left costal margin (HR = 2.2 [1.0, 4.6]; p = 0.039) instead of high WBC count was identified as another adverse predictor for survival. In addition, harboring ASXL1 mutation (HR = 6.4 [2.0, 20.9]; p = 0.002) was significantly-associated with poor TFS in the 83 subjects with available data of gene mutations and known outcome including death causes.

Based on the number of adverse clinical prognostic co-variates for survival (age ≥ 64 years, WBC count ≥ 47×10E+9/L and hemoglobin concentration ≤ 119 g/L), all 94 patients were classified into the low- (0; n = 18; 19%), intermediate- (1; n = 29; 31%) and high-risk (2-3; n = 47; 50%) cohorts with significant difference in survival with 4-year survival rates of 65% (30-100%), 56% (34-78%) and 9% (0-21%, p < 0.001), respectively. HRs with the low-risk cohort as reference were 3.2 (1.0, 11.0; p = 0.069) and 9.4 (2.8, 31.4; p < 0.001; p-value for trend < 0.001).

Among 29 patients with targeted DNA sequencing, 22 (76%) were detected to have ≥ 1 mutation(s) besides CSF3R mutation. The most common mutation was ASXL1 (n = 17, 59%), followed by SETBP1 (n = 10, 34%), SRSF2 (n = 7, 24%) and U2AF1 (n = 6, 21%). ASXL1 mutation showed significant co-occurrence with SETBP1 mutation (n = 9, OR = 11.4, p = 0.019). Compared with wild type ASXL1, those harbored ASXL1 mutation was associated with shorter survival (31 [22-40] vs. not reached, p = 0.052) and TFS (30 [19-41] vs. 60 [8-100], p = 0.088) when censored at transplant.

Conclusions

Older age, higher WBC count, anaemia, low platelet count, splenomegaly, and ASXL1 co-mutation were correlated with worse outcomes in patients with CNL harboring CSF3R^T618I.