Does Sustained Monocytosis Always Mean CMML? A Case of Ras-Associated Autoimmune Leukoproliferative Disorder

A healthy 59-year-old man with a negative family history was evaluated five years ago at another institution for massive symptomatic splenomegaly (30 cm on ultrasound). Findings included moderate thrombocytopenia (80-100 x 10⁹/L) and sustained absolute monocytosis (1.5-1.8 x 10⁹/L); normal cellularity in bone marrow biopsy; a negative polymerase chain reaction for BCR::ABL1 p210-p190 transcripts and JAK2V617F; and a negative autoimmune and infectious workup. PET-CT scans showed nonspecific ileal fluoro-2-deoxyglucose uptake, without hypermetabolic lymph nodes. Clinicians decided to pursue a watch-and-wait strategy and, due to the development of splenomegaly-related symptoms (abdominal discomfort, left upper abdomen pain, and early satiety) and progressive leukocytosis, the patient was referred one year ago for a laparoscopic splenectomy.

The pathological report demonstrated marked red pulp congestion (Figure: A) and sinusoidal histiocytosis in splenic hilar lymph nodes (Figure: B). The patient was referred to our department after splenectomy. Laboratory results were remarkable for marked leukocytosis and monocytosis and increased levels of polyclonal immunoglobulin G and immunoglobulin A. An abdominal ultrasound revealed a normal liver span with a single perihilar lymph node. A repeat bone marrow biopsy showed myeloid hyperplasia (M:E ratio of 10:1) with a slight increase in morphologically normal eosinophils and megakaryocytes with dysplastic nuclei, not meeting criteria for myelodysplasia (Figure: C).

Peripheral blood immunophenotyping revealed 16% monocytes (2.2 x 10⁹/L): 83.9% classical (CD14+, CD16-); 15.8% intermediate (CD14+, CD16+); and 0.3% nonclassical (CD14+ weak, CD16+) (Figure: D). The monocytes expressed CD2 weakly, and the expression of CD56 was not studied. The granulocytes had moderate atypical expression of CD14+ (Figure: E), with a slight increase in circulating CD10+ late-precursor B cells also observed (Figure: F). Bone marrow karyotyping revealed 45,X,-Y[13]/46,XY[7] in 13 out of 20 metaphases.

Given the suspicion for CMML and considering that the classical monocyte fraction was less than 94% (a cutoff value that has shown reproducible sensitivity and specificity for CMML diagnosis),²²  next-generation sequencing (NGS) panel testing for myeloid malignancies was performed. After NGS panel testing, the patient was started on hydroxyurea therapy with a good hematologic response. The patient was found to have a KRAS G12D mutation with a variant allele frequency of 45.7%. Germline testing (e.g., in skin-derived fibroblasts) was not performed; however, the patient had no family history, and the age at onset was unlikely to have a germline origin. This information led to a diagnosis of adult-onset RALD. The patient is currently asymptomatic, under observation, and without any treatment (hydroxyurea was stopped after white blood cell count decreased).

Because RALD is an extremely rare disease with unknown prevalence, we reviewed the literature and found 23 of 37 cases of RALD secondary to KRAS mutations, including nine due to mutations at codon 12, four of which were due to KRAS G12D (Table). This G12 position is located within the p-loop of the KRAS protein and participates in its GTPase function, provoking cellular responses such as proliferation, differentiation, and survival. When glycine is replaced at position 12 to aspartate, it leads to a negatively charged side group into the active site, causing a steric hindrance in GTP hydrolysis that impairs GTPase function and locks KRAS in its active state (GTP-bound).²³  This gain-of-function mutation causes a growth factor-independent activation of downstream pathways that increase cellular development and suppress T-cell death.¹  These actions explain the mechanisms for evident cytopenias, hepatosplenomegaly, lymphadenopathy, and concomitant autoimmune diseases in affected patients (Table).

RAS mutations are driver mutations in approximately 30% of cases of CMML.²⁴  However, the patient discussed here presented with features that were less likely to represent CMML: younger age; flow cytometry pattern (circulating activated monocytes and polyclonal CD10+ B cells); absence of TET2 or SRSF2 mutations; and a slow progression rate, in spite of having a myeloproliferative phenotype.^5,24,25  Hematologists should be alert to this nonmalignant condition with an indolent clinical course to avoid unnecessary treatments like hypomethylating agents or hematopoietic cell transplantation.

Management of patients with RALD depends on clinical manifestations. Autoimmune manifestations could require immunosuppressive agents or steroids, including mitogen-activated protein kinase inhibitors (such as trametinib) and mammalian target of rapamycin inhibitors (such as sirolimus and everolimus).^10,16  While RALD is largely thought to be an indolent disorder,¹⁵  cases evolving into myeloid malignancy have been described and are likely related to additional genetic alterations. Therefore, close monitoring of RALD patients is recommended.^4-6,15 

This case report emphasizes the heterogeneous phenotype of RALD and highlights the value of integrating NGS studies with assessment of clinical and genetic features. RALD should be considered in the differential diagnosis of leukocytosis with monocytosis, even in adult patients.

The authors indicated no relevant conflicts of interest.