Case presentation

In 2001, a Caucasian female (aged 77 years as of July 2026) was diagnosed with stage III IgG kappa MM. At the time of diagnosis, she exhibited a normal karyotype, low-risk gene array features, and a hyperdiploidy molecular subtype. She was treated according to the Total Therapy 2 approach, receiving induction chemotherapy with VAD (vincristine, doxorubicin (Adriamycin), dexamethasone), followed by two cycles of DCEP (dexamethasone, cyclophosphamide, etoposide, and cisplatin). She underwent ASCT in April 2002, followed by four cycles of consolidation therapy with VD-PACE (bortezomib, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide) from August 2002 to June 2003. Thereafter, she was started on maintenance therapy for three years with dexamethasone pulsing and interferon one million units three times a week (October 2003 to October 2004) and interferon only (2004-2006). She remained in remission from 2007.

On her regular follow-up of MM in February of 2025, her positron emission tomography-computed tomography (PET-CT) was negative for any fluorodeoxyglucose (18 F-FDG)-avid focal bone lesion, lytic bone lesions, or extramedullary relapse. Her serum immunoglobulin fixation studies showed no M-protein, and bone marrow was morphologically negative for any plasma cell myeloma. Flow cytometry minimal residual disease (MRD) analysis demonstrated 0.05% atypical plasma cells concerning for mild indolent relapse of MM. She was monitored until the subsequent visit. However, in the next routine visit, her white blood cell (WBC) count increased from 6.4 to 71.2 K/uL with ~62% neutrophils. Hemoglobin (12.1 g/dL) and platelets (201 K/uL) were within normal reference ranges. She denied any symptoms, and her physical examination was unremarkable. Given the absence of clinical signs and symptoms suggestive of infection, a leukemoid reaction secondary to infection was considered less likely in the differential diagnosis. Bone marrow aspirate and biopsy revealed a markedly hypercellular bone marrow with prominent granulocytic hyperplasia (see Figures 1A-1B, 2A-2B), concerning for involvement by an MPN.

Figure 1: Low-power (40× magnification) and high-power (1,000× magnification) views of the bone marrow aspirate.1A shows a hypercellular bone marrow spicule. 1B demonstrates granulocyte hyperplasia with all stages of maturation.

Figure 2: Low-power (40× magnification) and high-power (400× magnification) views of the bone marrow biopsy (hematoxylin and eosin stain).2A reveals hypercellular for age (~90% cellularity). 2B shows prominent granulocytic hyperplasia.

Flow myeloma MRD analysis was negative. Repeat PET-CT demonstrated diffuse uptake in the skeleton without lytic lesions; however, splenomegaly of ~15.0 cm in craniocaudal dimension was noted (see Figure 3).

Figure 3: PET-CT demonstrating splenomegaly (arrow).

Next-generation sequencing (NGS) showed mutations in CSF3R, ASXL1, DNMT3A, EZH2, SETBP1, and STAT3 genes (see Table 1).

Detected genomic alterations
MUTYH (?Germline) | SETBP1 | DNMT3A | EZH2 (2 mutations) | ASXL1
CSF3R | STAT3 | ABCG2 (?Germline) | CHEK1 | Autosomal chromosomes show 11p− (deletion of the WT1 gene) and 13q−

Chromosome analysis confirmed a normal female karyotype. The neutrophilia, CSF3R mutation, and absence of cytopenia and/or significant morphologic dyspoiesis were consistent with a diagnosis of CNL. Per the Mayo Clinic CNL risk model for survival, she was deemed a "high-risk" patient due to her WBC count and concurrent ASXL1 mutation at presentation. Considering the limited role of chemotherapy for this condition, she was started on hydroxyurea 500 mg BID for cytoreduction (started on Day 20 of the presentation). Within four weeks of treatment, her WBC count decreased to ~24K (see Table 2).

Day | -281 | 0 | 27 | 51 | 113 | 155 | 198
WBC count (in 1,000/uL); normal range: 3.60-9.50 | 6.38 | 71.18 | 69.57 | 24.31 | 18.55 | 20.76 | 22.45
RBC count (in 1,000,000/uL); normal range: 4.00-5.20 | 5.09 | 4.60 | 4.44 | 4.13 | 3.66 | 3.45 | 3.33
Platelet count (in 1,000/uL); normal range: 150-450 | 179 | 199 | 218 | 391 | 199 | 149 | 262

She tolerated hydroxyurea well, with her WBC count being 22.45 K/uL on the day of admission for allogeneic ASCT in June 2026 (Day 198 in Table 1). Her post-transplant course so far was complicated by neutropenic fevers, enteropathic Escherichia coli, as well as chemotherapy-induced diarrhea, and BK virus hemorrhagic cystitis.