The patient’s story began four months earlier with persistent watery diarrhea and recurrent abdominal discomfort that failed to respond to standard therapy for gastritis and duodenitis. Initial blood counts at a local hospital revealed a subtle but telling anomaly: an absolute monocyte count of 1.54 × 10⁹ per liter, above the normal threshold, together with a low platelet count of 66 × 10⁹ per liter. By the time he reached the referral center, his hemoglobin had fallen from 147 to 100 grams per liter, his platelets had dropped further to 62 × 10⁹ per liter, and his monocyte count had climbed to 1.93 × 10⁹ per liter. His spleen was enlarged, and his alkaline phosphatase — an enzyme normally kept below 125 units per liter — had skyrocketed to 1,145.3 units per liter, a biochemical red flag for infiltrative disease in bone and liver.

Imaging deepened the mystery. Contrast-enhanced computed tomography showed a spleen roughly 13 centimeters long studded with mildly enlarged retroperitoneal lymph nodes. Positron emission tomography using fluorodeoxyglucose revealed a gastric wall burning with metabolic activity at a maximum standardized uptake value of 19.1 — a figure more typical of aggressive lymphoma than of chronic indigestion — along with diffusely increased uptake in the spleen and mild hypermetabolism in mediastinal and abdominal nodes. Yet endoscopic biopsies of the stomach and duodenum showed only chronic active gastritis and ulcers, with no infiltrative lesions. The mismatch between spectacular metabolic signals and bland biopsy results pointed the team toward the bone marrow.

What they found there was extraordinary. The marrow biopsy showed dense, multifocal infiltrates of atypical mast cells consuming roughly half of the marrow cellularity, accompanied by grade MF-2 to MF-3 reticulin fibrosis. The aspirate smears told a more nuanced story: atypical mast cells made up 18.5 percent of nucleated cells, just under the 20 percent threshold that the current WHO classification requires for a diagnosis of mast cell leukemia. Because an adequate aspirate was available, the biopsy burden alone could not override that criterion, so the team classified the disease as advanced systemic mastocytosis rather than the leukemic variant. The mast cells displayed the classic aberrant phenotype — bright CD117 with inappropriate CD25 expression — and were positive for tryptase on immunohistochemistry.

Next-generation sequencing locked in the molecular diagnosis. The panel detected the KIT D816V mutation, the pathogenic engine of more than 90 percent of adult systemic mastocytosis cases, at a variant allele frequency of 12.1 percent. But the sequencing revealed far more than a mast-cell clone. A frameshift mutation in TET2 at 64.9 percent variant allele frequency marked a founding epigenetic clone, compounded by a deletion of TET2 exons 3 through 11 — evidence of biallelic inactivation. A SRSF2 p.Pro95Arg splice-factor mutation at 44.6 percent and two independent RUNX1 mutations completed a mutational triad that is a hallmark of CMML. A CEBPA nonsense mutation rounded out the profile. Together with sustained absolute monocytosis lasting more than three months and a flow-cytometric finding that 98 percent of the patient’s monocytes were of the classical CD14-positive, CD16-negative subset, the molecular data satisfied WHO and International Consensus Classification criteria for CMML-1 of the proliferative subtype.

Then came the third clone. Serum free light-chain testing showed lambda light chains elevated to 2,274.69 milligrams per liter against a kappa of just 28.98, crushing the kappa/lambda ratio to 0.0127 — roughly fiftyfold below the lower limit of normal. Immunofixation of serum and urine confirmed a monoclonal lambda component. Flow cytometry identified a lambda-restricted plasma-cell population, and fluorescence in situ hybridization on enriched CD138-positive cells revealed the t(11;14)(q13;q32) translocation fusing the immunoglobulin heavy-chain locus to CCND1, the cyclin D1 gene. Bone marrow biopsy showed at least 20 percent CD138-positive plasma-cell infiltration. Yet the team stopped short of calling it multiple myeloma: no myeloma-defining event was documented, since plasma cells remained below 60 percent, the involved/uninvolved light-chain ratio was about 78.5 rather than above 100, and PET-CT showed no focal bone lesions. They classified it conservatively as a t(11;14)-positive plasma-cell neoplasm under surveillance.

The biology behind this triple concurrency is what makes the case scientifically rich. Systemic mastocytosis with an associated hematologic neoplasm is itself not rare — roughly 30 to 40 percent of systemic mastocytosis patients harbor a second blood cancer, and CMML accounts for about a quarter to a third of those associations. The prevailing model holds that KIT D816V, TET2, and RUNX1 mutations arise in an early hematopoietic progenitor with multilineage potential, which then branches into mast-cell-dominant and monocyte-dominant subclones. This patient’s mutation profile — KIT D816V alongside TET2, SRSF2, and RUNX1 — fits that shared-ancestor model precisely. The plasma-cell disorder, however, is almost certainly an independent B-lineage event. Only isolated case reports have ever linked systemic mastocytosis with plasma-cell dyscrasias, and none have documented all three diseases simultaneously. Mechanistically, mast cells can secrete interleukin-6 and stem cell factor, cytokines known to support myeloma cell survival, and can engage CD40-CD154 signaling that promotes lymphoplasmacytic proliferation — possible, if speculative, links between the clones.

Treatment was tailored to the two clinically active components. The team initiated avapritinib, a potent and selective inhibitor of KIT D816V that overcomes the imatinib resistance conferred by that mutation, combined with azacitidine, a hypomethylating agent directed at the CMML clone and its TET2/SRSF2/RUNX1 signature. Venetoclax, which has shown activity in t(11;14)-positive myeloma, was deliberately withheld because the plasma-cell neoplasm had no documented myeloma-defining event and was not the immediate threat. After three cycles, the results were encouraging: the frequency of watery diarrhea decreased substantially, hemoglobin and platelet counts improved, the absolute monocyte count declined, and the alkaline phosphatase began trending downward. The authors note that overlapping myelosuppression from both drugs — azacitidine’s anemia, neutropenia, and thrombocytopenia, and avapritinib’s thrombocytopenia, bleeding risk, and cognitive effects — demanded careful monitoring. Serial light-chain measurements were unavailable during follow-up, so the plasma-cell clone’s response could not be formally assessed.

Beyond its rarity, the case is a pointed argument for diagnostic integration. No single abnormality in this patient could explain the full picture: the mast-cell disease accounted for the diarrhea and the alkaline phosphatase but not the monocytosis; the CMML explained the monocytes and cytopenias but not the lambda light chains; the plasma-cell clone explained neither the mast-cell burden nor the gastric hypermetabolism. Only by weaving together morphology, multiparameter flow cytometry, immunohistochemistry, FISH cytogenetics, and targeted sequencing could the team assemble three coherent diagnoses from one confusing clinical presentation. For clinicians, the lesson is that when a patient’s findings exceed what one hematologic disease can produce, the marrow — examined with every modern tool — may be hiding more than one answer.

Subject of Research: Coexistence of systemic mastocytosis, chronic myelomonocytic leukemia, and a t(11;14)-positive plasma-cell neoplasm in one patient

Article Title: Case Report: Coexistence of advanced systemic mastocytosis, chronic myelomonocytic Leukemia, and t(11;14)-positive plasma-cell neoplasm: a rare triple-clonal hematologic case

Article References: Yin, J., Luo, J., Huang, L., Wang, L., Zhong, M., Li, M., & Huang, S. (2026). Case Report: Coexistence of advanced systemic mastocytosis, chronic myelomonocytic Leukemia, and t(11;14)-positive plasma-cell neoplasm: a rare triple-clonal hematologic case. Frontiers in Oncology, 16, Article 1982665. https://doi.org/10.3389/fonc.2026.1982665

Image Credits: AI Generated

DOI: 10.3389/fonc.2026.1982665

Keywords: systemic mastocytosis, chronic myelomonocytic leukemia, plasma-cell neoplasm, KIT D816V, TET2, SRSF2, RUNX1, t(11;14), avapritinib, azacitidine, bone marrow diagnostics, SM-AHN