CTIT is a common and clinically consequential hematologic toxicity in patients with solid tumors. Chemotherapy, radiotherapy, and targeted agents can all suppress the bone marrow’s ability to produce platelets, the small cell fragments that form clots and prevent hemorrhage. When platelet counts fall below safe thresholds, oncologists are frequently forced to postpone or reduce doses of anti-cancer drugs, compromising the very treatment meant to control the tumor. In severe cases, spontaneous bleeding can become life-threatening. Platelet transfusions and standard TPO-RA monotherapy help many patients, but a subset remains refractory, with counts that stay dangerously low despite every conventional measure.

The research team, led by Lin-Ya Wang and Fei-Fei Tang of the Peking University Institute of Hematology, set out to test whether adding ATRA to continued TPO-RA therapy could break through this resistance. Their rationale rests on platelet biology: TPO-RAs such as eltrombopag and romiplostim stimulate thrombopoietin receptors on megakaryocytes, the large bone marrow cells that shed platelets into the bloodstream, while ATRA is thought to promote megakaryocyte maturation and platelet production through complementary pathways, including retinoid signaling and effects on the bone marrow microenvironment. Combining the two agents, the investigators reasoned, might attack the problem from two directions at once.

The study retrospectively analyzed 28 patients with refractory CTIT, defined as grade 2 or worse thrombocytopenia according to the CTCAE v5.0 criteria despite prior TPO-RA therapy. All patients were treated at Peking University People’s Hospital between August 2023 and May 2025. Each received oral ATRA at a dose of 25 milligrams per square meter of body surface area daily for six weeks, alongside continued TPO-RA treatment. The severity of the starting condition was sobering: the median baseline platelet count was just 13 × 10⁹ per liter, with individual values ranging from a perilous 2 × 10⁹ to 69 × 10⁹ per liter. Counts at that level leave patients exposed to serious bleeding risk and effectively rule out continued cancer therapy.

The results were unambiguous. Platelet counts climbed steadily from baseline after treatment began, with median elevations of +17 × 10⁹ per liter by day 14 (P = 3.05 × 10⁻⁵), +36 × 10⁹ per liter by day 28 (P = 9.54 × 10⁻⁷), and +59 × 10⁹ per liter by day 42 (P = 7.45 × 10⁻⁹). By the end of the observation window, the median patient had gained nearly five times their starting platelet count. Twelve patients, or 42.9 percent, achieved a complete response, defined as recovery to normal platelet levels, while another seven patients, 25.0 percent, achieved a partial response. The overall response rate stood at 67.9 percent, meaning roughly two of every three patients who had failed standard therapy regained usable platelet counts. The median time to complete response was 31 days, with responses occurring as early as 12 days and as late as 40 days after starting the combination.

Safety data were equally encouraging. ATRA is not a benign molecule; it carries known risks of liver enzyme elevation, headache, and, in the setting of acute promyelocytic leukemia, a potentially dangerous complication called differentiation syndrome. Yet in this population, the combination was well tolerated. Only four patients, 14.3 percent, developed elevated liver enzymes, three of them grade 1 and one grade 2, and three patients, 10.7 percent, experienced mild, grade 1 nausea. Critically, no grade 3 or higher adverse events were recorded, no thrombotic events occurred, and no patient developed differentiation syndrome. For a drug that stimulates platelet production, the absence of clotting complications is a particularly important signal, since raising platelet counts in cancer patients could theoretically tip the balance toward thrombosis.

The study also uncovered intriguing patterns in who responded best. Within the female cohort, patients with tumors of the female reproductive system responded significantly more poorly than those with other cancers: their overall response rate was 57.1 percent compared with 100.0 percent for non-FRS tumors (P = 0.038), and none of the FRS tumor patients achieved a complete response versus 70.0 percent of the others (P = 0.008). The authors also noted trends toward inferior complete response rates among patients with a history of radiotherapy (P = 0.057) and those treated with paclitaxel (P = 0.054), neither of which reached statistical significance in this small sample. These signals suggest that the biology of refractory CTIT may differ depending on the tumor type and prior treatment exposures, and that certain patient groups may need alternative or intensified strategies.

One of the most mechanistically revealing findings involved the bone marrow itself. Patients whose baseline bone marrow biopsies showed higher megakaryocyte counts, at least five per high-powered field, exhibited a trend toward higher overall response rates compared with those with lower counts, 76.5 percent versus 54.5 percent, though the difference did not reach statistical significance (P = 0.41). The observation makes biological sense: megakaryocytes are the cellular factories of platelets, and a marrow that retains a reasonable supply of these cells is more likely to respond to drugs that push them into overdrive. Conversely, patients whose marrows have been devastated by chemotherapy or radiotherapy may lack the raw cellular substrate needed for any platelet-boosting strategy to succeed. If confirmed in larger cohorts, megakaryocyte counts could help clinicians identify which refractory patients are most likely to benefit from the ATRA-plus-TPO-RA combination before committing to six weeks of therapy.

The study’s design demands careful interpretation. As a retrospective, single-center analysis of 28 patients, it cannot rule out selection bias, and without a randomized control group it is impossible to say with certainty how many patients would have recovered on continued TPO-RA monotherapy alone. The authors themselves frame the work as hypothesis-generating. Nevertheless, the magnitude and tempo of the platelet recoveries, the near-complete absence of serious toxicity, and the internal consistency of the response kinetics give the findings considerable weight. A prospective randomized trial will be needed before the combination can be recommended as standard of care, but for a population with essentially no good options, the bar for moving forward is low.

The broader significance extends beyond one drug pairing. CTIT is becoming an increasingly visible problem as cancer therapy grows more intensive and as patients live longer with advanced disease, and refractory cases consume transfusion resources while delaying tumor-directed treatment. The Peking University study suggests that rational combinations of agents targeting different nodes of thrombopoiesis, in this case retinoid-driven megakaryocyte maturation layered on top of thrombopoietin receptor stimulation, can rescue patients who were previously written off. It also revives interest in ATRA, a decades-old leukemia drug, as a repurposed agent in supportive oncology. If larger trials confirm these results, a cheap oral vitamin A derivative could become a standard partner for platelet-boosting drugs, keeping cancer treatment on schedule for thousands of patients whose platelets, and whose therapies, currently run out of road.

Subject of Research: Combination therapy with all-trans retinoic acid and thrombopoietin receptor agonists for refractory cancer therapy-induced thrombocytopenia

Article Title: All-trans retinoic acid combined with thrombopoietin receptor agonists for refractory cancer therapy-induced thrombocytopenia: a retrospective single-center study

Article References: Wang, L.-Y., Gao, H.-T., Fu, Q., Xu, L.-P., Zhang, X.-H., Huang, X.-J., & Tang, F.-F. (2026). All-trans retinoic acid combined with thrombopoietin receptor agonists for refractory cancer therapy-induced thrombocytopenia: a retrospective single-center study. Annals of Hematology. https://doi.org/10.1007/s00277-026-07287-4

Image Credits: AI Generated

DOI: 10.1007/s00277-026-07287-4

Keywords: all-trans retinoic acid, thrombopoietin receptor agonists, cancer therapy-induced thrombocytopenia, platelets, megakaryocytes, solid tumors, hematology, chemotherapy toxicity, Peking University, retrospective study, thrombopoiesis, drug safety

Thrombocytopenia is a frequent consequence of systemic cancer treatment. Platelets, also known as thrombocytes, are small blood components that gather at sites of vascular injury and initiate clot formation. When their numbers fall substantially, patients may develop bruising, nosebleeds, mucosal bleeding or, in severe cases, potentially life-threatening hemorrhage. In oncology, the problem has consequences beyond bleeding itself. Low platelet counts can force clinicians to delay a treatment cycle, reduce drug doses or interrupt an effective regimen. Such modifications may be particularly consequential for breast cancer patients receiving intensive therapies or ADCs, which link targeted antibodies to cytotoxic payloads and deliver those compounds to tumor cells. The study’s authors describe cancer therapy-induced thrombocytopenia, or CTIT, as a complication that can compromise treatment intensity and potentially affect outcomes.

The trial enrolled patients whose platelet counts fell below 50 × 10⁹ per liter during the first cycle of anticancer therapy. This threshold represents severe thrombocytopenia in many clinical contexts and identified patients who had already demonstrated a significant vulnerability to treatment-related platelet suppression. Between September 2022 and May 2025, 67 breast cancer patients entered the study. One participant withdrew informed consent before randomization, leaving 66 patients who were assigned in equal proportions to receive either hetrombopag or subcutaneous recombinant human thrombopoietin, commonly abbreviated rhTPO. Treatment continued until platelet counts rose above 100 × 10⁹ per liter, a period the researchers defined as the thrombocytopenia treatment phase, or TTP. This design allowed the investigators to compare the experimental oral agent with an established biological approach to stimulating platelet recovery.

Hetrombopag belongs to a class of medicines known as thrombopoietin receptor agonists, or TPO-RAs. These drugs imitate or enhance the activity of thrombopoietin, the principal hormone responsible for regulating platelet production. Thrombopoietin binds to the c-Mpl receptor on hematopoietic stem and progenitor cells in the bone marrow, triggering signaling pathways that promote the development of megakaryocytes. These unusually large marrow cells extend cytoplasmic projections into blood vessels and release thousands of platelets into circulation. By activating the same receptor pathway, hetrombopag is intended to increase megakaryocyte maturation and platelet output rather than directly supplying platelets from outside the body. Its oral formulation also distinguishes it from injectable treatments and may offer practical advantages for patients already managing complex cancer-care schedules.

The central feature of the study was its secondary prevention phase, or SPP. After the initial thrombocytopenia treatment period, every participant who proceeded according to the protocol received hetrombopag as a self-controlled intervention during the next anticancer cycle. The drug was administered for 14 days beginning on the first day of Cycle 2. This approach was designed to test whether platelet stimulation could prevent a repeat decline after a patient had already experienced severe CTIT. Rather than comparing separate prevention and control groups, the investigators followed the same patients into the subsequent treatment cycle, allowing each individual’s earlier experience to provide context for the prevention assessment. The primary endpoint was the proportion of patients who responded during this prevention phase, while platelet-related measures and safety outcomes were also recorded.

Of the 66 randomized patients, six discontinued participation during the secondary prevention phase. The remaining 60 patients formed the per-protocol set used for the primary analysis. Among them, 51 met the study’s criteria for response, producing the reported rate of 85.0%. The response was especially notable among patients treated with ADCs: 42 of 47 patients in that subgroup responded, corresponding to 89.4%. ADC-based regimens included therapies such as trastuzumab emtansine, known as T-DM1, and trastuzumab deruxtecan, or T-DXd, although the supplied report does not provide a separate response figure for every individual drug regimen. These treatments can cause clinically meaningful marrow suppression, and the high response rate in this group suggests that hetrombopag may be particularly relevant where ADC-associated platelet decline threatens continued dosing.

The initial treatment phase also produced favorable comparative results. During the TTP, the response rate was 87.9%, or 29 of 33 patients, among those assigned to hetrombopag. In the rhTPO group, 27 of 33 patients responded, for a rate of 81.8%. These results indicate a numerical advantage for hetrombopag, although the trial was not presented as a definitive superiority study and the difference should not be interpreted as proof that one treatment is more effective in all clinical settings. The investigation was exploratory, and the sample size was limited. In addition, the prevention phase did not retain a parallel untreated or alternative-treatment control group, which makes it difficult to separate the drug’s effect from other influences, including changes in treatment exposure, natural recovery of marrow function and individual differences in susceptibility to CTIT.

Safety findings were reassuring within the limits of the study. The investigators reported that no treatment-emergent severe adverse events occurred. This is clinically important because drugs that stimulate platelet production must be evaluated not only for their ability to raise platelet counts but also for possible complications associated with excessive or poorly controlled platelet production. In cancer patients, concerns can include thrombotic events, interactions with anticancer therapy and abnormal blood-count changes. However, the abstract provides no detailed breakdown of all adverse events, their duration, laboratory abnormalities or longer-term follow-up. It therefore supports the conclusion that hetrombopag was well tolerated in this study population, but it does not establish the complete safety profile required for routine use across broader breast cancer populations or other malignancies.

The findings arrive as oncologists seek strategies that can maintain the planned intensity of modern cancer treatment. Unlike chemotherapy-induced thrombocytopenia, which specifically refers to platelet suppression caused by cytotoxic chemotherapy, CTIT encompasses a wider range of anticancer treatments, including targeted agents and ADCs. These therapies can affect platelet production through direct toxicity to marrow progenitors, altered megakaryocyte development or broader effects on the bone marrow environment. A preventive intervention given at the start of a new treatment cycle could, in principle, keep platelet counts above thresholds needed for treatment delivery and reduce the likelihood of delays. Yet the clinical value of preventing low counts ultimately depends on whether it reduces interruptions, preserves dose intensity, lowers bleeding complications or improves patient outcomes. The present trial primarily demonstrates platelet response, not these longer-term endpoints.

The researchers conclude that hetrombopag may be a promising strategy for both managing established CTIT and preventing its recurrence in breast cancer, particularly among patients receiving ADCs. Their results provide a signal for larger, controlled trials that can evaluate different cancer regimens, dosing schedules and patient risk groups while measuring treatment delays, dose reductions, transfusion requirements, bleeding, thrombosis and cancer-control outcomes. Such studies will also need to clarify which patients benefit most, how long prevention should continue and whether platelet stimulation remains effective across repeated cycles. For now, the phase II findings suggest that an oral agent acting on the body’s own platelet-production machinery could become a useful component of supportive oncology care, but the evidence remains preliminary and should be interpreted as a foundation for further validation rather than a change in standard treatment.

Subject of Research: Secondary prevention and treatment of cancer therapy-induced thrombocytopenia in breast cancer patients using hetrombopag.

Article Title: Secondary prevention of cancer therapy-induced thrombocytopenia with hetrombopag in breast cancer: a multicenter, randomized, exploratory phase II trial

Article References: Sun H, Lv H, Chen W, et al. BMC Medicine (2026).

Image Credits: AI Generated

DOI: 10.1186/s12916-026-05156-5

Keywords: Cancer therapy-induced thrombocytopenia; secondary prevention; breast cancer; hetrombopag; recombinant human thrombopoietin; antibody-drug conjugates; platelet counts; thrombopoietin receptor agonists.