Evaluating Platelet- vs Immune-Directed Therapies in Immune Thrombocytopenia

Immune thrombocytopenia (ITP) is a disease that, a generation ago, left oncologists cycling patients through cyclophosphamide, dapsone, and splenectomy with modest results, but now has 5 FDA-approved second-line and beyond options with distinct mechanisms of action and no cross-resistance between them. This leads to greater nuance in matching a drug to a patient, particularly when that patient carries even a modest thrombotic history.

In a virtual Case-Based Roundtable event for hematologist/oncologists across the West Coast, Amit R. Mehta, MD, a hematologist-oncologist in private practice in the Durham, North Carolina, area and adjunct faculty at Duke University, reviewed evolving ITP pathophysiology and second-line trial data, then moderated discussion of a case built around a patient whose remote, provoked deep vein thrombosis (DVT) complicated an otherwise straightforward treatment decision.

CASE SUMMARY

John, a 70-year-old man with a history of provoked DVT 4 years ago following orthopedic surgery (following 6 months of apixaban), hypertension, hyperlipidemia, type 2 diabetes (A1c 6.8%), presents to clinic today to discuss next-line treatment options for ITP diagnosed 14 months ago. He had received prior dexamethasone and rituximab (Rituxan) for chronic ITP. ​

• ​BMI: 32
• Platelet count: 26 x 10⁹/L​​
• Current medication list: lisinopril, atorvastatin, metformin, baby aspirin​
• Social history: lives with spouse; reports becoming increasingly more sedentary due to profound fatigue—he no longer golfs each week.​

EVENT RECAP

Mehta reviewed current guidelines and acknowledged that they offer limited help here. The American Society of Hematology's (ASH) 2019 ITP guideline, still the most recent formal version, predates fostamatinib (Tavalisse), avatrombopag (Doptelet), and rilzabrutinib (Wayrilz) entirely.¹ He said a revision has been in progress with no fixed publication date.

In its absence, Mehta walked participants through what has changed since: a large body of recent work has identified specific coagulation-cascade changes: upregulated prothrombin, plasminogen activator inhibitor 1 (PAI-1), and P-selectin, which make ITP an inherently prothrombotic state rather than a purely bleeding-risk one.² Separately, researchers have traced ITP's inflammatory biology to a specific cytokine cluster called the NLRP3 inflammasome, with Bruton tyrosine kinase (BTK) acting as a direct positive regulator, the mechanistic rationale behind rilzabrutinib, the newest approved agent.^3,4

Polling the room on first treatment choice for John, the majority, 73.3%, chose eltrombopag (Promacta), a thrombopoietin receptor agonist (TPO-RA), with the remainder split between avatrombopag and fostamatinib; nobody chose rilzabrutinib or splenectomy. Mehta called the choice reasonable given the DVT was provoked, treated, and 4 years remote, but flagged the tradeoff directly: TPO-RAs are highly effective at raising platelet counts but do not address ITP's underlying pathophysiology, and come with an increased risk of thrombotic events. For a patient with ongoing thrombotic risk factors such as atrial fibrillation, unprovoked prior clots, or thrombophilia, Mehta said he now defaults away from TPO-RAs.

The phase 3 FIT1 (NCT02076399) and FIT2 (NCT02076412) trials established fostamatinib, an oral spleen tyrosine kinase (SYK) inhibitor that blocks macrophage-mediated platelet phagocytosis, in a heavily pretreated population with a median of 3 prior therapies; the pooled overall response rate was 43% vs 14% with placebo, though the formal stable response end point was 18% vs 2%.⁵ The phase 3 LUNA 3 trial (NCT04562766), the largest randomized ITP trial to date at 202 patients, established rilzabrutinib in a similarly pretreated population with a of median 4 prior therapies: 64% of patients responded within the first 3 months, and 23% achieved a durable platelet response vs 0% with placebo (P < .0001).⁶ Neither drug carries a signal for thromboembolism in trial data, and rilzabrutinib's more selective BTK binding, unlike ibrutinib (Imbruvica), spares the TEC kinase pathway that governs platelet aggregation, so bleeding risk is not increased.

When Mehta revisited the case later in the session, eltrombopag support dropped to 40%, while fostamatinib rose to 20% and rilzabrutinib, which had drawn zero votes initially, rose to 26.7%. Xingyue He, MD, of Legacy Cancer Institute, described a recent case that crystallized the shift for her: a 46-year-old with atrial fibrillation and chronic ITP whose platelet count dropped to 15 x 10⁹/L, prompting her to hold anticoagulation and treat with steroids rather than reach for a TPO-RA. “Knowing the mechanism behind it, I think the 2 alternatives, fostamatinib and rilzabrutinib, will be better options than a TPO agonist,” she said. Ahmad Fora, MD, of Vista Oncology, raised a more practical issue about TPO-RAs: eltrombopag's empty-stomach dosing requirement is unpopular with younger, active patients, on top of joint aches some experience.

The discussion also touched whether splenectomy still has a place. Ashok Bapat, MD, who recalls treating patients with splenectomies over his career, noted about 70% of patients who achieved remission stayed in remission. Mehta said he now reserves it for later lines given permanent immunocompromise and, increasingly, difficulty finding surgeons willing to operate on thrombocytopenic patients. Participants also discussed whether fatigue alone, independent of platelet count, should ever drive treatment escalation. Mehta said he now takes this issue more seriously than he once did as his understanding of the disease has evolved.

Christopher DiSimone, MD, of Eisenhower Medical Groups, asked whether rilzabrutinib carries the same dose-titration flexibility as the TPO-RAs. Mehta answered that rilzabrutinib is given at a single fixed dose with no adjustment or up-titration for inadequate response the way eltrombopag, romiplastin (Nplate), or fostamatinib allow. Mehta expressed that it simplifies a regimen for a patient like John who is already managing several chronic-disease medications. He also reiterated the larger point underlying the sequencing discussion: because these 5 mechanisms do not appear to share cross-resistance, a patient who fails one option can reasonably try another without that failure predicting a worse response.

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DISCLOSURES: There were no known relevant disclosures.

REFERENCES

1. Neunert C, Terrell DR, Arnold DM, et al. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv. 2019;3(23):3829-3866. doi:10.1182/bloodadvances.2019000966

2. Garabet L, Ghanima W, Monceyron Jonassen C, et al. Effect of thrombopoietin receptor agonists on markers of coagulation and P-selectin in patients with immune thrombocytopenia. Platelets. 2019;30(2):206-212. doi:10.1080/09537104.2017.1394451\

3. Qiao J, Liu Y, Li X, et al. Elevated expression of NLRP3 in patients with immune thrombocytopenia. Immunol Res. 2016;64(2):431-437. doi:10.1007/s12026-015-8686-5

4. Singh A, Uzun G, Bakchoul T. Primary immune thrombocytopenia: novel insights into pathophysiology and disease management. J Clin Med. 2021;10(4):789. Published 2021 Feb 16. doi:10.3390/jcm10040789

5. Bussel J, Arnold DM, Grossbard E, et al. Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: Results of two phase 3, randomized, placebo-controlled trials. Am J Hematol. 2018;93(7):921-930. doi:10.1002/ajh.25125

6. Kuter DJ, Ghanima W, Cooper N, et al. Safety and efficacy of rilzabrutinib vs placebo in adults with immune thrombocytopenia: the phase 3 LUNA3 study. Blood. 2025;145(24):2914-2926. doi:10.1182/blood.2024027336