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18 Chronic neutrophilic leukaemia

A 72‐year‐old man was referred for assessment of chronic asymptomatic neutrophilia. The initial blood tests had been triggered by a clinical diagnosis of gout. He had shown a chronic unexplained persistent neutrophilia and the most recent full blood count showed Hb 130 g/l, WBC 115 × 10⁹/l, neutrophils 92 × 10⁹/l and platelets 132 × 10⁹/l. The blood film showed neutrophilia with minimal dysplasia, minimal left shift and no excess of blast cells. The neutrophils showed normal or increased granulation and some were vacuolated (all images ×100 objective). A bone marrow aspirate showed myeloid hyperplasia with no excess of blasts, eosinophils or basophils. Molecular analysis did not show BCR‐ABL1. Two mutations in CSF3R were identified: T618I in exon 12 and E778X in exon 17. These findings are in keeping with a diagnosis of chronic neutrophilic leukaemia (CNL).

Chronic neutrophilic leukaemia is a rare myeloid disorder characterised by a chronic neutrophilia with mature neutrophils, often splenomegaly and the absence of a reactive trigger. Serum LDH and vitamin B12 levels are typically high and G‐CSF levels are low. The diagnosis was largely one of exclusion until a strong association with mutations in the CSF3R gene was demonstrated. This is important in that mutations in CSF3R identify this as a clonal rather than reactive disorder and this is a defining feature in the 2016 WHO classification (Bain et al. 2017). In addition, there should be peripheral blood leucocytosis ≥25 × 10⁹/l with at least 80% being mature neutrophils or band cells and <10% being neutrophil precursors with no monocytosis. The type of CSF3R mutation appears to influence prognosis, being worse in the majority of patients who have this mutation (Szuber et al. 2018). Mutations in CSF3R are not essential for diagnosis but when absent the situation should be carefully reviewed and a leukaemoid reaction should be considered. In addition to CSF3R, mutations in ASXL1, SETBP1, SRSF2 and rarely JAK2 have been reported. Traditionally, CNL has been treated with chemotherapy, interferon or hypomethylating agents but responses have often been partial and not sustained. Without effective disease control many patients ultimately progress to blast crisis. More recently, the use of the JAK inhibitor ruxolitinib has been explored as CNL shows aberrant activation of the JAK/STAT pathway (Szuber et al. 2020).

References

1 Bain BJ, Brunning RD, Orazi A and Thiele J (2017) Chronic neutrophilic leukaemia. In Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri S, Stein H and Thiele J (Eds) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised 4th Edn. IARC Press, Lyon, pp. 37–38.

2 Szuber N, Finke CM, Lasho TL, Elliott MA. Hanson CA, Pardanani A and Tefferi A (2018) CSF3R‐mutated chronic neutrophilic leukemia: long‐term outcome in 19 consecutive patients and risk model for survival. Blood Cancer J, 8, 21.

3 Szuber N, Elliott M and Tefferi A (2020) Chronic neutrophilic leukaemia: 2020 update on diagnosis, molecular genetics, prognosis and management. Am J Haematol, 95, 212–224.

MCQ

1 Increased neutrophil granulation (‘toxic’ granulation) is a usual feature of:Chronic myeloid leukaemia, BCR‐ABL1‐positiveChronic neutrophilic leukaemiaG‐CSF (filgrastim) therapyLeukaemoid reaction to multiple myelomaSepsisFor answers and discussion, see page 206.