In 2015, a previously healthy 26-year-old woman presented with general malaise and headaches. Laboratory evaluation was notable for a total white blood cell (WBC) count of 121.2 × 109/L (reference range (RR) 4.0–11.0 × 109/L) with 3% basophils, 4% eosinophils and 1% circulating myeloblasts. The hemoglobin (Hgb) level was 11.9 g/dL (RR 11.4–15.0 g/dL). An abdominal ultrasound showed a mildly enlarged spleen measuring 14 cm in craniocaudal length, with the EUTOS long-term survival (ETLS) score of 0.86 indicative of low risk. BM biopsy specimen showed a 100% cellular marrow with marked myeloid hyperplasia (myeloid: erythroid (M: E) ratio of 20:1), eosinophilia (10%), basophilia (3%), and < 5% myeloblasts. Both chromosomal and fluorescence in situ hybridization analysis revealed the presence of Ph chromosome in 94% of cells. Chromosomal analysis also identified a common chromosomal polymorphism, inv9 (p12q13), present in all metaphase cells without clinical significance.RT-qPCR for the BCR::ABL1 fusion transcript p210 was 158.015%. Based on these findings, the patient was diagnosed with CP-CML. Her complex treatment course and molecular responses are depicted in Fig.. Initially treated with hydroxyurea for 4 days, she was then started on nilotinib. After 9 months of therapy, BCR::ABL1 was 12.882% and nilotinib was discontinued due to complete blood count (CBC) showing pancytopenia with WBC of 2.3 × 109/L, absolute neutrophil count (ANC) of 1.6 × 109/L (RR 1.8–7.8 × 109/L), Hgb of 8.8 g/dL, and platelet count of 59 × 109/L (RR 143–382 × 109/L). BM biopsy revealed TKI-related aplasia. BCR::ABL1 kinase domain mutation analysis was negative. After 2 months off therapy and improvement of her CBC, our patient was started on dasatinib at 100 mg daily. Her BCR::ABL1 nadired at 4.4% after 4 months, but dasatinib was stopped due to transfusion-dependent anemia and thrombocytopenia. Despite her counts recovering off therapy, her BCR::ABL1 IS continued to rise, reaching 60–88%. The patient and providers determined that a reduced dose of dasatinib likely would not be sufficient to control the disease, as they were unable to proceed with the full dose. Consequently, she was switched to imatinib 400 mg daily after six months without TKIs. Over the next 26 months, she was intermittently adherent with imatinib. Despite achieving a major molecular response, she was switched to bosutinib given insufferable gastrointestinal upset. She was treated with bosutinib for 7 months before switching to omacetaxine due to inadequate response. Again, mutation analysis was unrevealing. She was evaluated for allogeneic stem cell transplantation (HSCT) and had a fully human leukocyte antigen matched unrelated donor available, but never proceeded forward due to fear. After 2 weeks of omacetaxine therapy, patient suffered a mandibular fracture requiring multiple surgeries. She was lost to follow-up for 1 year but once she reestablished care, she was switched to reduced dose nilotinib for 1.5 years. In 4/2022, she displayed new-onset pancytopenia (Hb 8.8 g/dL, ANC 1.2 × 109/L, platelets 22 × 109/L), normal WBC 4.2 × 109/L), raising concerns of drug toxicity. Nilotinib was promptly discontinued, and a BM examination was performed. The BM aspirate smears were hemodiluted but showed a predominance of erythroid cells, without dysplasia or an increase in myeloblasts or pronormoblasts. Iron staining revealed the presence of storage iron without ringed sideroblasts. The BM core biopsy demonstrated a hypercellular marrow (90%) with a substantial increase in erythroid cells with a reversed M:E ratio of 1:10. Both erythroid and myeloid cells displayed a full range of maturation. Megakaryocytes were present in normal numbers with unremarkable morphology. Immunohistochemistry (IHC) analysis highlighted the proliferation of maturing erythroid cells (90% of marrow cellularity) via CD71 staining and erythroid precursors (10% of erythroid cells) via E-cadherin staining. TP53 showed a wild-type pattern in erythroid cells. CD61 staining highlighted megakaryocytes with variable morphology. CD34-positive blasts were not increased, and reticulin staining revealed grade 2/3 reticulin fibrosis (not shown). CML transformation to pure erythroid leukemia (PEL) was ruled out due to the absence of elevated proerythroblasts, the lack of morphological dysplasia, and the absence of TP53 mutation by IHC. Surprisingly, chromosomal analysis revealed the presence of t(9;22) (q34;q11.2) in 19 out of 20 metaphase cells, along with the previously detected chromosomal polymorphism variant inv9 (p12q13). The IS BCR:ABL1 level was 20.7%. Comprehensive NGS performed by FoundationOne confirmed the BCR::ABL1 fusion transcript (p210) without detection of any other pathogenic variants. The diagnosis of the erythroid variant of CML was confirmed based on the disease-defining Ph chromosome. The patient continues to decline HSCT and is sporadically adherent to a reduced dose of asciminib, currently experiencing transfusion-dependent anemia.