Triple Combination Therapy Shows Promise for Ruxolitinib-Resistant Myelofibrosis Patient
Key Insights
A 55-year-old Chinese woman with myelofibrosis (search) who became unresponsive to ruxolitinib after five years achieved durable response with venetoclax, azacytidine, and ruxolitinib combination therapy.
The patient experienced significant hematologic recovery and spleen size reduction after two treatment courses, with hemoglobin levels returning to normal and MPN10 score decreasing from 48 to 16 points.
This represents the first reported case of successful treatment using this triple combination in chronic-phase myelofibrosis (search) patients who failed ruxolitinib monotherapy.
A novel triple-drug combination has demonstrated promising results in treating a patient with myelofibrosis (search) who developed resistance to standard ruxolitinib therapy, according to a case report published in Frontiers in Oncology. The findings offer hope for patients in regions where newer JAK inhibitors remain unavailable.
The case involves a 55-year-old Chinese woman initially diagnosed with chronic-phase myelofibrosis (search) in April 2018. She was classified as intermediate-risk-2 according to IPSS, DIPSS, and DIPSS Plus scoring systems, with a MPN10 score of 22 points. The patient initially responded well to ruxolitinib 15mg twice daily, experiencing symptom improvement and spleen reduction that lasted over five years.
Treatment Failure and Disease Progression
By August 2023, the patient's condition deteriorated significantly. She developed poor appetite, left abdominal distension, and progressive cytopenias. Laboratory results showed a white blood cell count of 2.4×10⁹ cells/L, hemoglobin of 82g/L, and platelet count of 40×10⁹ cells/L. Her MPN10 score increased to 33 points, and imaging revealed enlarged spleen and liver dimensions.
Further evaluation in September 2023 confirmed disease progression with a MPN10 score reaching 48 points. Bone marrow analysis revealed complex chromosomal abnormalities and next-generation sequencing identified JAK2 (search) V617F mutation with 85% variant allele frequency, along with ARID2 and BCORL1 mutations. The patient's risk classification escalated to high-risk across multiple scoring systems.
Novel Triple Combination Approach
With standard second-line JAK inhibitors like fedratinib, pacritinib, and momelotinib unavailable in China, clinicians initiated an exploratory treatment combining venetoclax (100mg daily, days 1-7), azacytidine (100mg daily, days 1-7), and ruxolitinib (5mg daily continuously) on September 15, 2023.
The treatment rationale was based on venetoclax's role as a selective BCL-2 (search) inhibitor that induces apoptosis, while azacytidine synergistically inhibits pro-survival pathways, increasing myeloid malignancy cell dependence on BCL-2. Previous studies had shown effectiveness of venetoclax-azacytidine combinations in myelofibrosis (search) blast phase, with response rates of 42-80%.
Treatment Response and Complications
The patient experienced significant treatment-related toxicity, developing grade IV bone marrow suppression with granulocytopenia lasting seven days and platelet counts dropping below 20×10⁹ cells/L. Additional complications included pulmonary infection and herpes zoster, requiring supportive care including blood transfusions and antimicrobial therapy.
Despite initial toxicity, remarkable clinical improvement occurred by day 40 post-treatment. Complete blood count showed white blood cell count of 20.10×10⁹ cells/L, hemoglobin of 112g/L, and platelet count of 128×10⁹ cells/L. Imaging revealed normalized liver size and reduced spleen dimensions. The MPN10 score decreased dramatically from 48 to 16 points, indicating effective treatment response.
Sustained Clinical Benefit
Following a second treatment course in November 2023, the patient continued maintenance ruxolitinib therapy. Long-term follow-up at 12 months post-second course showed sustained hematologic parameters with white blood cell count of 22.56×10⁹ cells/L, hemoglobin of 109g/L, and platelet count of 118×10⁹ cells/L.
The authors noted that response evaluation timing may differ from acute leukemia patients, requiring assessment around six weeks post-treatment rather than the typical four-week timeframe. Consolidation therapy appeared beneficial for maintaining response and blood count stability.
Clinical Implications
This case represents the first reported successful use of venetoclax-azacytidine-ruxolitinib combination in chronic-phase myelofibrosis (search) patients who failed ruxolitinib monotherapy. The findings are particularly relevant for regions where newer JAK inhibitors remain inaccessible.
Previous studies have shown ruxolitinib discontinuation rates of 22.2%, 32.4%, and 40.8% at one, two, and three years respectively, with five-year discontinuation rates reaching 73.3%. The current case demonstrates a potential treatment strategy for this challenging patient population.
However, the authors acknowledge significant limitations, noting this represents a single case with multiple prior treatments, and the duration of response may not be generalizable. The patient's advanced age and poor chemotherapy tolerance resulted in prolonged bone marrow suppression, requiring careful monitoring and supportive care.
The researchers emphasize that further well-designed clinical trials are needed to confirm these preliminary findings and establish optimal dosing and scheduling for this combination in myelofibrosis (search) patients who have failed standard JAK inhibitor therapy.