When monoclonal gammopathy‐associated chronic neutrophilic leukemia is a reactive process distinct from a clonal myeloproliferative neoplasm: Lessons from mistakes

Chronic neutrophilic leukemia (CNL) is a BCR::ABL1-negative myeloproliferative neoplasm (MPN) characterized by sustained peripheral blood (PB) neutrophilia (white cell count ≥ 25×109/L, with ≥80% neutrophils), bone marrow (BM) hypercellularity due to granulocyte proliferation without excess of blast or dysplasia. Somatic mutations CSF3R gene, encoding the colony stimulating factor (G-CSF) receptor protein, are detected in >60% cases and have significantly helped confirm CNL diagnosis. Two classes been described (cytoplasmic domain truncations membrane proximal threonine mutation as T618I T640N), but all result hyperactivation down-stream Janus Kinase (JAK) signaling.[1, 2] Furthermore, could sensitize tyrosine kinase inhibitors, such ruxolitinib dasatinib. In absence myeloid clonality mutation, diagnosis remains challenging. According World Health Organization (WHO) classification, presence plasma disorders (PCDs) should be investigate avoid misdiagnosis.[3] fact, numerous case studies reported co-existence multiple myeloma/monoclonal gammopathy unknown significance (MGUS).[4] cases, related G-CSF secretion from abnormal cells (PCs), confusion regarding shared between MPN PCD.[5-7] Here, we report an asymptomatic 56-year-old sub-Saharian African woman, relevant medical history, who was referred explore serum monoclonal IgA Lambda component (7.7 g/L) associated hyperleucocytosis at 27.9 G/L (81%) monocytosis (9%). BM aspirate showed granular hyperplasia (84%) significant dysplasia nor small percentage dystrophic PC (1%). karyotype revealed germline t(12;18)(q?24.3;q12) metaphases BCR::ABL rearrangement fluorescence situ hybridization (FISH). biopsy granulocytic fibrosis. Whole body tomodensitometry did not detect any abnormality. A MGUS retained, explanation about neutrophilia. Three years later, patient developed fatigue, pain, splenomegaly, increased (58.5G/L; neutrophils 88%). Serum stable 7.3 g/L, unchanged. FISH reveal PDGFRA, PDGFRB, FGFR1 rearrangement. Sequencing 32 genes recurrently mutated malignancies only two rare single-nucleotide polymorphisms (SNP) on (p.R583H p.T640I), predicted nondeleterious. Genetic analysis nonhematopoietic tissues (nail hair) confirmed origin SNP p.T640I. Clonogenic assay performed using purified PB CD34+ progenitors, previously described.[8] G-CSF, spontaneous growth colony-forming unit (CFU-G) progenitors observed, CFU-G partially reduced JAK inhibition ruxolitinib. Based these results, pathogenic variant retained this time. Treatment dasatinib were sequentially administered efficacy. Due leukocytosis persistent systemic symptoms, received allogeneic hematopoietic stem transplantation (AHSCT) his human leukocyte antigen (HLA)-identical healthy brother after sequential conditioning (clofarabine-cytarabine followed busulfan-fludarabine-ATG [anti-thymocyte globulin]). At day 20 AHSCT, (85.6 G/L) mainly composed reoccurred, receiving stimulation. hyperplasia, chimerism surprisingly that originated donor (95% XY), arguing for extrinsic stimulation, present T640I (conversely R583H SNP). ELISA huge levels 18300 pg/mL (N < 40). still (8 3% PC. Overexpression CSF3 mRNA CD138+ Quantitative Reverse transcription polymerase chain reaction (RTq-PCR), favor production recipient (Figure 1). finally revised reactive PCD (MGUS), subsequently bortezomib-dexamethasone (BD). After three cycles 21-days regimen, drastic reduction 9.9 observed 32% spleen size decreased (2.7 g/L; 66% reduction). Concomitantly, 37% level BD 2). Unfortunately, treatment discontinued adverse event. Five months reappeared (58 G/L), daratumumab-dexamethasone efficacy S1). Afterward, started 3rd line therapy carfilzomib-cyclophosphamide-dexamethasone. first cycle, neutrophil normalized severe thrombocytopenia S2). graft-donor myelodysplastic syndrome (MDS) (12%), male monosomy 7 TET2 Q1545* (VAF 46%) ETV6 R418K 45%) mutations. Of note, graft samples prior transplantation. Patient concomitantly carfilzomib-dexamethasone azacitidine. 18 azacitidine, progressed acute died 4 later. Overall, AHSCT lambda originating PC, overexpression high response PC-targeted strongly argue induced This confirms clinicians rule out when detected.[3] our patient, position (T640, named T617) misleading, reproduced phenotype while being negative SNP, which supports nonpathogenic role.[8, 9]. Results clonogenic assays also misleading probably extremely levels. dosage most powerful tool make prompt avoid, inefficient (as ruxolitinib), morbidity, donor-cell MDS. The hypothesis concomitant inspired “monoclonal gammopathy-associated CNL” entity.[6] It currently clear whether clonally related, phenocopy suggests nonclonal relationship case. Our presented MDS, condition AHSCT.[10] Thus, hypothesize continuous exposition may promote development bona fide clonal disease, explain previous reports. Finally, describes correlated neutrophils, size, component, level.[11, 12] These results suggest efficient limit risk evolution into malignancy decreasing production. CW, CC, MD, SKH, CB, JR, CCL, JMM, AD, JL, SDB patient. VS cytological analysis. SC cytogenetic CM AR supervised molecular IP assay. ND CW RTqPCR SB, NB, BC dosage. collected data interpreted results. wrote manuscript. VS, SC, AR, IP, ND, All authors approved no conflict interest. specific funding work. Institutional review board authorized report. provided informed consent genetic publication clinical data. 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