A 73-year-old male was first diagnosed with PV (hemoglobin >18 g/dL, hematocrit >55%, JAK2 V617F positive) in 2016. He was managed with low-dose aspirin and phlebotomy; hydroxyurea was added later.

In 2019, routine CBC showed persistent lymphocytosis (lymphocytes ∼12  ×  10^9/L). Flow cytometry demonstrated CD5+, CD19+, CD23+, FMC7– B-cells comprising 68% of lymphocytes, confirming Rai stage I CLL. No active treatment was initiated.

In 2020, during evaluation for COVID-like respiratory symptoms, thoracic CT revealed a during evaluation for a COVID-19-suspected cough and dyspnea, thoracic CT revealed a 20 × 14 mm left upper lobe mass with mediastinal lymphadenopathy with mediastinal lymphadenopathy. Bronchoscopic biopsy confirmed adenocarcinoma. EGFR exon 21 L858R mutation was present; ALK and ROS1 were negative. PET–CT staged disease at IIIB. Standard chemoradiotherapy was declined by the patient. Erlotinib treatment was initiated in March 2020. Concurrent progression of CLL with B symptoms prompted introduction of chlorambucil 10 mg daily for 7 days in a 28-day cycle.

At 3-month follow-up, CT scan showed near-complete regression of primary lung lesion and mediastinal nodes. CBC normalized. JAK2 V617F mutation, positive in 2016, was undetectable via allele-specific PCR (<1% allele burden). The patient exhibited ECOG 1 and continued erlotinib and chlorambucil with no grade ≥2 toxicity.

• 2016: PV diagnosis (JAK2 V617F+) → aspirin/phlebotomy

• 2019: Rai stage IV CLL diagnosis+ chlorambucil

• 2020: NSCLC diagnosis (EGFR L858R+), start erlotinib

• 2021: Near-complete response, hematologic normalization, JAK2 negativity

Routine labs and molecular assays performed at a reference laboratory confirmed JAK2 mutation status. Flow cytometry was consistent with CLL immunophenotype. NSCLC diagnosis followed standard bronchoscopic sampling; molecular analysis used validated PCR panels and sequencing.

• Erlotinib: 150 mg PO daily as standard first-line for EGFR-mutant NSCLC[^3].

• Chlorambucil: 10 mg PO daily for 7/28 cycle for symptomatic Rai stage IV CLL, selected for low toxicity in elderly[^4].

• At 3 Months: Dramatic radiologic regression; normalization of hematologic parameters; JAK2 mutation undetectable.

• Continued stable on erlotinib + chlorambucil with no significant toxicity; quality of life maintained.

This case is unique in that:

• Sequential triple malignancy: PV, CLL, and EGFR-mutant NSCLC rarely occur together.

• Therapeutic synergy: Dual-targeted therapy produced durable responses in both solid and hematological malignancies.

• JAK2 loss: Post-treatment JAK2 negativity suggests clonal competition or epigenetic remission; parallels have been observed with interferon-alpha in MPN[5].

• Clinical implications: Supports feasibility of combinatorial targeted therapy in elderly with multiple malignancies.

Clonal hematopoiesis of indeterminate potential (CHIP) and aging likely predisposed this patient to multiple neoplasms[^6]. The “clonal competition hypothesis” posits that dominant clones (e.g., NSCLC with EGFR mutation) may suppress other clones (JAK2+) via shared niche or resource limitation.

Limitations include single-patient observation; further genomic investigation (e.g., NGS) could clarify clonal evolution mechanisms. We recommend longitudinal monitoring of allele burden and expanded studies on multi-targeted therapy interactions.

Conclusion Elderly patients with multiple sequential malignancies can benefit from tailored, low-toxicity targeted therapies. The unexpected disappearance of JAK2 mutation invites further investigation into clonal dynamics and epigenetic remission phenomena. This case enriches our understanding of cancer ecology in aging patients.