Background: Chronic Myeloid Leukemia (CML) constitutes a myeloproliferative neoplasm pathognomonically defined by the BCR-ABL1 fusion oncogene. Tyrosine kinase inhibitor (TKI) administration (including imatinib, dasatinib, and nilotinib) has substantially altered the natural history and prognosis of CML in the chronic phase (CML-CP). Although transient, dose-dependent myelosuppression represents a common and predictable toxicity1, severe, prolonged, idiosyncratic bone marrow aplasia (BMA) remains an exceedingly rare and potentially morbid hematological sequela. This BMA is posited to originate from a TKI-mediated, T-cell driven immune attack upon the host’s hematopoietic stem cell pool.2 This report delineates this critical adverse event, explicates the diagnostic challenge, and demonstrates a successful non-transplant therapeutic intervention utilizing established protocols for severe aplastic anemia (SAA).
Methods: We report a case of a 57-year-old female patient diagnosed with CML-CP upon whom first-line dasatinib therapy was instituted. Within a period of three months following the initiation of treatment, a precipitous decline in peripheral blood cell counts was observed, reaching nadir levels consistent with the diagnostic criteria for severe aplastic anemia (absolute neutrophil count < 0.5 × 109/L; platelet count < 20 × 109/L). Despite the immediate cessation of the causative TKI, the cytopenia’s remained refractory and persistent. Subsequent bone marrow trephine examination confirmed marked hypocellularity (estimated < 10%) with striking tri-lineage hypoplasia; the absence of blast proliferation ruled out progression to blastic crisis. Although Parvovirus B19 IgM seropositivity was documented, the observed refractoriness to intravenous immunoglobulin (IVIg) administration, coupled with negative PNH testing and the definitive temporal association with dasatinib exposure, provided strong clinical evidence supporting a primary TKI-induced, immune- mediated aplastic anemia etiology.3 The prolonged and severe thrombocytopenia led to the development of a major complication, specifically intracranial hemorrhage. Furthermore, the requirement for numerous transfusion events resulted in the development of multiple HLA antibodies, thereby precluding definitive therapeutic intervention via Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) due to the critical absence of suitably matched donors.
Results: Given the diagnosis of refractory SAA and HSCT ineligibility, a second-line therapeutic strategy was initiated, consistent with the accepted regimen for non-transplant candidates. The patient was commenced upon immunosuppressive therapy (IST) using cyclosporin in combination with eltrombopag, a thrombopoietin receptor agonist (TPO-R).4 Hematological efficacy was demonstrably achieved within an eight-week timeframe subsequent to the commencement of the combination regimen, characterized by the resolution of severe thrombocytopenia and the establishment of stable hematopoietic recovery across all cellular lineages.
Discussion
The introduction of Tyrosine Kinase Inhibitors (TKIs) such as dasatinib has revolutionized the management of Chronic Myeloid Leukemia in the chronic phase (CML-CP). While transient, dose-dependent myelosuppression is a well-documented and manageable side effect of TKI therapy, this case highlights a distinct and far more perilous entity: severe, idiosyncratic bone marrow aplasia (BMA). Unlike common cytopenias that typically resolve upon dose reduction or temporary interruption, the aplasia described in this report was profound, persistent, and refractory to TKI withdrawal, suggesting an etiology beyond direct cytotoxicity. The pathophysiology of this rare complication is hypothesized to be immune-mediated, involving a T-cell-driven attack on the hematopoietic stem cell pool. This hypothesis is strongly supported by the clinical course observed in this patient. The failure of the bone marrow to recover following the immediate cessation of dasatinib, combined with the subsequent dramatic response to immunosuppressive therapy (IST), mirrors the behavior of acquired Severe Aplastic Anemia (SAA) rather than reversible drug toxicity.
A significant aspect of this case was the diagnostic challenge posed by concurrent clinical findings. The detection of Parvovirus B19 IgM initially suggested a viral etiology; however, the lack of response to Intravenous Immunoglobulin (IVIg) and the definitive temporal correlation with dasatinib initiation pointed away from a viral cause. Furthermore, the exclusion of Paroxysmal Nocturnal Hemoglobinuria (PNH) and the absence of blast proliferation (ruling out blastic crisis) left TKI-induced immune dysregulation as the primary diagnosis.
Therapeutically, this case underscores the dilemma faced when Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)—often considered the definitive cure for marrow failure—is not viable. The development of multiple HLA antibodies due to repeated transfusions rendered this patient ineligible for HSCT. Consequently, the successful deployment of a non-transplant regimen comprising Cyclosporin (IST) and Eltrombopag (a Thrombopoietin Receptor Agonist) provides a crucial clinical precedent. The recovery of trilineage hematopoiesis within eight weeks of initiating this combination therapy aligns with data supporting the use of TPO-R agonists in refractory SAA, suggesting their utility extends to TKI-induced marrow failure.
Conclusion
This case report documents a rare but life-threatening instance of idiosyncratic dasatinib-induced bone marrow aplasia in a patient with CML-CP. It serves as a critical alert to clinicians that TKI-associated cytopenias may evolve into irreversible marrow failure that does not respond to simple drug withdrawal. The successful outcome achieved here validates a paradigm shift in managing such complications: when TKI withdrawal fails to restore hematopoiesis, the condition should be approached with the therapeutic rigor of Severe Aplastic Anemia. Specifically, the combination of Immunosuppressive Therapy and Eltrombopag represents a viable and effective salvage strategy for patients who are precluded from HSCT. Heightened vigilance, early differentiation between toxic and immune-mediated cytopenias, and prompt institution of SAA-directed therapies are essential to prevent mortality in this subset of CML patients.
Author of this article
Dr. Md. Mahmud-un-Nabi Tanmoy, MBBS, FCPS (Medicine), BCS (Health), MACP, Medicine Specialist, Shaheed Suhrawardy Medical College & Hospital
Reference
1. Dogra R, Dogra V, Shelke AR. Imatinib-Induced Bone Marrow Aplasia in Chronic Myelogenous Leukemia. Cureus. Published online May 27, 2024. doi:10.7759/CUREUS.61176
2. Amir M, Javed S. A Review on the Therapeutic Role of TKIs in Case of CML in Combination With Epigenetic Drugs. Front Genet. 2021;12:742802. doi:10.3389/FGENE.2021.742802/BIBTEX
3. Feld J, Steinberg A, El Jamal SM, Shapira I. Unexpected pancytopenia: Dasatinib induced aplastic anemia in chronic myeloid leukemia. J Oncol Pharm Pract. 2022;28(1):232-236. doi:10.1177/10781552211026375
4. Kamijo K, Shimomura Y, Yamashita D, Ishikawa T. A Case of Tyrosine Kinase Inhibitor-Induced Bone Marrow Aplasia That Was Successfully Treated with Allogeneic Hematopoietic Stem Cell Transplantation. Case Rep Oncol. 2021;14(2):1139-1143. doi:10.1159/000517442
5. Olnes MJ, Scheinberg P, Calvo KR, et al. Eltrombopag and improved hematopoiesis in refractory aplastic anemia. N Engl J Med. 2012;367(1):11-19. doi:10.1056/NEJMOA1200931