7  Novel Insights and Emerging Therapies in Immune-Mediated Cytopenias

7.1 Session Overview

Day 1, 4:15–4:45 p.m.

Cole organizes the session as six case-based vignettes that progress from PF4 biology to precision B-cell targeting [slide p.4]: triple-positive antiphospholipid syndrome (APS) as a newly recognized PF4-dependent immunothrombotic disorder, immune checkpoint inhibitor (ICI)–induced ITP with rechallenge decisions, rilzabrutinib 74-week data in warm AIHA, the BAFF-R antagonist ianalumab in heavily pretreated ITP (VAYHIT3), a 5-year real-world rituximab-versus-TPO-RA comparison, and precision IGHV1-69–targeted CAR-T for immune TTP. The unifying arc: mechanism-based targeting of specific immune effector pathways — from anti-PF4 Fc-silenced antibodies to idiotope-restricted CAR-T — is replacing empiric broad immunosuppression [slide pp.3, 49].

7.2 Speaker Spotlight

  • Michael A. Cole, MD, DPhil — Johns Hopkins School of Medicine, Baltimore [slide p.1]. Research focuses on platelet factor 4 (PF4) biology, the molecular mechanisms of vaccine-induced immune thrombocytopenia and thrombosis (VITT) and heparin-induced thrombocytopenia (HIT), and B-cell–targeting strategies for refractory cytopenias.

7.3 What’s New in 2025–2026

7.3.1 APS Joins the PF4 Immunothrombotic Family (Abstract 1773)

Case 1 frames a 34-year-old woman with triple-positive APS (lupus anticoagulant, high-titer anticardiolipin, anti-β2GPI IgG) who develops a small-vessel ischemic stroke despite therapeutic warfarin — a scenario highlighting why anticoagulation alone may be insufficient when the upstream “immunothrombotic firestorm” is not disrupted [slide pp.5, 9].

  • Shared pathogenesis with HIT and VITT. Sarkar et al. (Abstract 1773) position APS as the newest member of the PF4 immunothrombotic family alongside HIT and VITT, with high-titer IgG anti-PF4 antibodies driving FcγRIIA-mediated platelet activation, NETosis, and downstream thrombin generation through a common effector pathway [slide p.6].
  • Experimental evidence for PF4 dependency. Dynamic light scattering shows APS IgG converts DNA–PF4–β2GPI into ultra-large pathogenic complexes; microfluidic NET and thrombosis assays demonstrate 5–10-fold increased platelet binding when PF4 is present; and in hPF4 transgenic versus PF4-knockout mice, APS IgG produces massive thrombus only when PF4 is present. Anti-PF4 monoclonals (G4KKO, RTO, 1E12) abolish thrombus formation [slide p.7].
  • “Block without burning” — Fc-modified anti-PF4 antibodies. Unmodified IgG (e.g., KKO) clusters its Fc regions on the PF4/NET scaffold and plugs into FcγRIIA, pouring fuel on the fire. Fc-silenced variants (e.g., G4KKO switched to IgG4) retain high-affinity binding and provide steric hindrance against pathogenic autoantibodies without triggering the platelet activation cascade — the first mechanism-based therapeutic approach for APS, complementing (not replacing) anticoagulation [slide pp.8, 9].
PF4 as a Unifying Antigen

HIT, VITT, and now APS all converge on high-titer IgG anti-PF4 antibodies, FcγRIIA-mediated platelet activation, and a NETosis-driven prothrombotic firestorm [slide p.6]. This reframing suggests a shared therapeutic target — Fc-silenced anti-PF4 antibodies — that complements anticoagulation by interrupting the upstream immune trigger rather than only the downstream thrombin cascade.

7.3.2 Immune Checkpoint Inhibitor–Induced ITP (Abstract 2343)

Leaf et al. report the largest multicenter characterization of ICI-induced ITP to date, anchored on a case of a 67-year-old man with metastatic melanoma who develops platelets 28 × 10⁹/L after three cycles of ipilimumab/nivolumab [slide pp.10, 11].

  • Incidence ~0.25% (roughly 1 in 400 ICI-treated patients) — clinically uncommon but not negligible [slide pp.12–13, 26].
  • Onset timing: median 8 weeks after ICI initiation (IQR 4–18) and median 3 weeks after the last ICI dose (IQR 2–4) [slide p.15].
  • Severity: median platelet nadir 41 × 10⁹/L; ~43% mild, ~27% moderate, ~14% severe, ~16% very severe [slide p.16].
  • Independent risk factors (adjusted): combination ICI therapy (OR 1.83), additional irAEs (OR 2.07), stage 4 cancer (OR 2.15), and baseline platelets <150 × 10⁹/L (OR 2.96) [slide p.17].
  • Treatment: glucocorticoids, IVIG, and TPO-RAs (mostly romiplostim) dominate, with overall response ~75.2% at 180 days and median time to recovery 2.3 weeks (IQR 1.0–5.3) [slide pp.18–19].
  • Rechallenge: of 76 rechallenged patients, 23 (30%) developed recurrent ICI-ITP; transition from combination to single-agent ICI sharply reduced recurrence (2/15 vs. 13/15 who stayed on combination), and 73.9% recovered from recurrent episodes [slide pp.20, 22].
  • Mortality: independent association with ICI-ITP severity — adjusted HR 2.96 for severe/very severe disease (Model 3) vs. no ICI-ITP [slide pp.23, 26].
Clinical Pearl: ICI-ITP Rechallenge

After ICI-ITP recovery, the preferred strategy is de-escalation to single-agent ICI rather than resuming combination therapy — approximately 70% tolerate rechallenge, most recurrent episodes are mild-to-moderate, and combo-to-mono switching dramatically reduces the recurrence rate [slide pp.22, 26].

7.3.3 Rilzabrutinib in Warm AIHA: LUMINA 74-Week Data and LUMINA-3 (Abstracts 2459, 8126)

Case 3 centers on a 68-year-old woman with 7-year primary wAIHA refractory to rituximab, mycophenolate (intolerance), and cyclosporine, too comorbid for splenectomy [slide p.27]. Fattizzo et al. (Abstract 2459) present the LUMINA Phase 2b Part B 74-week follow-up and the Phase 3 LUMINA-3 design (Abstract 8126) [slide pp.27, 33].

  • Comparative landscape in wAIHA (second-line and beyond): rituximab (anti-CD20, ORR 70–90%, ~2 weeks to response, ~20 months duration); fostamatinib (SYK inhibitor, ORR ~45–50%); danazol (ORR 60–80%); azathioprine (ORR 50–70%, 60% relapse after taper); cyclophosphamide (ORR 50–100% with high-dose but significant toxicity); mycophenolate (ORR 25–70%, ~5 months to response) [slide p.28].
  • Rilzabrutinib dual mechanism: as a BTK inhibitor, it simultaneously blocks B-cell antigen receptor signaling (reducing pathogenic autoantibody production) and FcγR signaling in splenic macrophages (inhibiting phagocytosis of opsonized RBCs) — distinct from SYK inhibitors, which only interrupt the macrophage arm [slide p.29].
  • LUMINA Phase 2b Part B design: primary/SLE-associated wAIHA, Hb <10 g/dL, relapsed/refractory to corticosteroids; oral rilzabrutinib 400 mg BID for 24 weeks (Part A, N=22) with a 64% response rate (60% had ≥3 prior lines, 60% on corticosteroids, 27% transfused in prior year); 15 responders entered Part B for an additional 52 weeks [slide p.30].
  • Durable hemoglobin response at Week 74: median baseline Hb 8.2 g/dL (range 5.8–11.4) rose to median 11.7 g/dL (range 6.6–14.7) at week 74 in responders [slide p.31].
  • Hemolytic markers (week 74 vs. baseline): LDH –37%, reticulocytes –63%, total bilirubin –62% [slide p.32].
  • Patient-reported outcomes: median FACIT-Fatigue score improved from 34 to 44.4, with median change of 5.0 (IQR 2–11) at week 74 — clinically meaningful [slide p.33].
  • LUMINA-3 (NCT07086976): global Phase 3, ~90 adults with primary wAIHA, 2:1 randomization to oral rilzabrutinib vs. placebo for 24 weeks followed by open-label extension and ≥52-week LTE; FDA Breakthrough Therapy designation (February 2026), U.S. orphan designation, Japan MHLW orphan designation for wAIHA, and active Japan enrollment [slide p.34].
Rilzabrutinib Is Approved for ITP, Not Yet for AIHA

Rilzabrutinib is FDA-approved for adult chronic ITP. In wAIHA, it currently has FDA Breakthrough Therapy designation based on LUMINA Phase 2b; Phase 3 LUMINA-3 is ongoing [slide p.34]. Until LUMINA-3 reads out, use in wAIHA remains investigational.

7.3.4 Ianalumab (BAFF-R Antagonist) in Heavily Pretreated ITP (Abstract 8745)

Case 4 — a 55-year-old woman with chronic ITP refractory to steroids, rituximab (relapsed at 6 months), and romiplostim after 6 prior lines and 3 bleeding hospitalizations — motivates the rationale for BAFF-R blockade [slide p.35].

  • Post-rituximab relapse biology. After B-cell depletion, BAFF surges and drives autoreactive B-cell reconstitution. Belimumab neutralizes soluble BAFF only; ianalumab is a monoclonal antibody that depletes BAFF-R⁺ B cells via enhanced ADCC and blocks the BAFF/BAFF-R survival signal needed for repopulation [slide pp.35, 37]. BAFF-R is highly expressed on transitional, mature, and activated B cells, making it an attractive node for durable depletion [slide p.38].
  • VAYHIT3 design. Single-arm Phase 2 in adults with primary ITP previously treated with corticosteroids (±IVIG) and a TPO-RA, no prior splenectomy, platelets <30 × 10⁹/L; four doses of ianalumab 9 mg/kg IV q4w, with an optional second course [slide p.39].
  • Baseline characteristics (N=41): median age 55, median platelet count 8 × 10⁹/L, median ITP duration 4 years, median 6 prior lines of therapy (59% had ≥6), 46% prior rituximab; 20% Asian [slide p.40].
  • Efficacy: 44% (18/41) confirmed response; 24% (10/41) stable response at 6 months, of whom 90% were complete responses. Median time to confirmed response 1.3 months among responders [slide p.41].
  • Safety: No opportunistic infections; any infection 36.6%; only 1 grade ≥3 event (C. difficile). Common events were URI, oral herpes, UTI, COVID-19 [slide p.42].
  • Watch for VAYHIT-1 (first-line ITP with corticosteroids) and VAYHIT-2 (NEJM, December 2025, with TPO-RA overlap; failure-free treatment 30% placebo vs. 51–54% ianalumab) for positioning in the treatment algorithm [slide p.43].

7.3.5 Rituximab vs. TPO-RAs in Second-Line ITP: 5-Year Real-World Data (Abstract 12848)

With no head-to-head randomized trial and conditional ASH guideline support for either option, Zahid et al. performed a 5-year TriNetX propensity-matched comparison in second-line ITP — directly relevant to resource-constrained settings where rituximab and eltrombopag dominate the formulary [slide pp.44, 45].

  • Design: 1,439 matched patients per arm [slide p.45].
  • Survival: rituximab 76.8% vs. TPO-RA 69.7% (HR 0.735, p<0.001) [slide p.45].
  • Platelets <10 × 10⁹/L: rituximab 22.0% vs. TPO-RA 34.5% (HR 0.585, p<0.001) [slide p.45].
  • GI bleeding: 5.3% vs. 6.1% (OR 0.855); ICH equivalent [slide p.45].
  • PE/DVT: lower with rituximab (PE HR 1.324 favoring rituximab, p<0.01) [slide p.45].
  • Major bleeding: no difference; hospitalization slightly higher with rituximab (59.6% vs. 55.1%) [slide p.45].
  • Caveats: retrospective, coding-dependent, residual confounding [slide p.45].
A Counterpoint in the “TPO-RA First” Era

These real-world data challenge the increasingly common sequencing of TPO-RA before rituximab. The 7-percentage-point survival advantage and lower thrombosis signal with rituximab are particularly meaningful in resource-constrained settings where rituximab is cheaper and more broadly available than chronic TPO-RA dosing [slide p.45]. The caveats — confounding by indication, coding artifacts — prevent replacing the randomized evidence base, but rituximab should not be dismissed as “old school” in second-line ITP.

7.3.6 Precision CAR-T for Immune TTP: IGHV1-69 Targeting (Abstract 14087)

Case 6 — a 42-year-old woman with 4 iTTP episodes over 6 years, persistently undetectable ADAMTS13 despite 3 rituximab courses and chronic mycophenolate — introduces the Ruella Lab (Penn) IGHV1-69–directed CAR-T approach (Cohen et al., Abstract 14087) [slide p.46].

  • Problem with CD19 CAR-T in chronic autoimmunity. Anti-CD19 CAR-T produces complete B-cell aplasia lasting years, wide cytokine release, and infection risk — a major concern for decades-long disease management [slide pp.46, 47].
  • Idiotope-restricted targeting. The B-cell receptor IGHV repertoire is highly diverse; prior work showed IGHV4-34 (9G4 idiotype) CAR-T selectively eliminates autoreactive B cells in SLE while sparing total B cells [slide pp.48, 49].
  • iTTP rationale. Anti-ADAMTS13 neutralizing autoantibodies display highly restricted IGHV usage — 32 of 33 inhibitory clones (Ostertag et al., Transfusion 2016) were IGHV1-69⁺, making IGHV1-69 an attractive idiotope target [slide p.50].
  • Preclinical data. In an NSG mouse model using IGHV1-69⁺ Nalm6 cells, CART1-69 reduced anti-ADAMTS13 IgG comparably to CART19 [slide p.51]. In iTTP patient PBMC co-culture, CART1-69 spared normal B cells and total IgG while preferentially eliminating autoreactive clones — preserving ~97% of the B-cell repertoire with no B-cell aplasia [slide pp.52, 53].
  • Limitations. All data remain preclinical; foundational IGHV1-69 dominance rests on a limited patient series; IGHV1-69 is also used by some broadly neutralizing antibodies (e.g., anti-influenza); no patient has yet been treated with an idiotope-specific CAR-T for any autoimmune disease [slide p.53].

7.4 Clinical Pearls

Cole’s five take-home points translate the six cases into a single slide [slide p.54]:

  1. PF4 is a unifying mechanism across APS, HIT, and VITT, and Fc-silenced anti-PF4 antibodies are an emerging therapeutic target that complements anticoagulation without fueling FcγRIIA-driven platelet activation [Abstract 1773].
  2. ICI-ITP is ~1 in 400 ICI-treated patients but carries an independent mortality association (adjusted HR 2.96 for severe disease); ~70% tolerate rechallenge, and switching from combination to single-agent ICI dramatically reduces recurrence [Abstract 2343].
  3. Rilzabrutinib delivers sustained hemoglobin responses at 74 weeks in wAIHA with a drug-free remission signal; Phase 3 LUMINA-3 is enrolling globally including Japan, with FDA Breakthrough Therapy designation [Abstracts 2459, 8126].
  4. Ianalumab (BAFF-R) — dual deplete + block repopulation — achieved 44% confirmed response in ITP after a median 6 prior lines, with no opportunistic infections in VAYHIT3 [Abstract 8745].
  5. Rituximab outperformed TPO-RAs on 5-year survival (76.8% vs. 69.7%) and severe thrombocytopenia in a 1,439-per-arm real-world match — particularly meaningful for resource-constrained settings [Abstract 12848].
  6. Precision IGHV1-69 CAR-T for iTTP is a compelling concept that preserves ~97% of the B-cell repertoire, but all data remain preclinical and the idiotope evidence base is narrow [Abstract 14087].
Clinical Pearl: When PF4 Antibodies Should Cross Your Mind

Anti-PF4 antibody testing is reflexively ordered for HIT and VITT. The APS-as-PF4-family concept should prompt clinicians to think mechanistically when a triple-positive APS patient thromboses on adequate anticoagulation — not to order a HIT panel, but to recognize that the upstream immunothrombotic firestorm may be driving the recurrence and that anti-PF4 therapeutics (if they advance clinically) could become complementary to anticoagulation [slide p.9].

Clinical Pearl: Rechallenge After ICI-ITP

For ICI-ITP that has resolved with steroids ± IVIG ± romiplostim, single-agent ICI rechallenge is the preferred strategy rather than permanent discontinuation or resumption of combination therapy — recurrence risk drops roughly sixfold (2/15 vs. 13/15), and most recurrences are mild to moderate [slide pp.20, 22].

7.5 Key References

  1. Sarkar et al. Antiphospholipid syndrome (APS) is the newest member of the PF4 immunothrombotic family: mechanistic and therapeutic insights. ASH 2025 Abstract 1773 [slide pp.5–9].
  2. Leaf et al. Immune thrombocytopenia in patients treated with immune checkpoint inhibitors. ASH 2025 Abstract 2343 [slide pp.10–26].
  3. Fattizzo et al. Long-term efficacy and safety of rilzabrutinib, an oral Bruton tyrosine kinase inhibitor, in patients with warm autoimmune hemolytic anemia (wAIHA) in the LUMINA Phase 2b Part B study: a 74-week follow-up. ASH 2025 Abstract 2459 [slide pp.27–33].
  4. LUMINA-3 (rilzabrutinib Phase 3 in primary wAIHA), ASH 2025 Abstract 8126 / ClinicalTrials.gov NCT07086976 [slide p.34].
  5. Choi et al. Secondary analysis results from VAYHIT3, a Phase 2 study of ianalumab in primary immune thrombocytopenia previously treated with at least two lines of therapy. ASH 2025 Abstract 8745 [slide pp.35–43].
  6. Zahid et al. Rituximab beats the odds in ITP? A 5-year national showdown against TPO-RAs. ASH 2025 Abstract 12848 [slide pp.44–45].
  7. Cohen et al. (Ruella Lab, Penn). Precision targeting of autoantibody-producing IGHV1-69⁺ B cells in immune-mediated thrombotic thrombocytopenic purpura (iTTP) using chimeric antigen receptor T cells. ASH 2025 Abstract 14087 [slide pp.46–53].
  8. Cohen IJ, et al. Chimeric antigen receptor T cells against the IGHV4-34 B-cell receptor specifically eliminate neoplastic and autoimmune B cells. Sci Transl Med. 2026;18 [slide p.49].
  9. Ostertag et al. ADAMTS13 autoantibodies cloned from patients with acquired thrombotic thrombocytopenic purpura: structural and functional characterization in vitro. Transfusion. 2016 [slide p.50].
  10. Mackay F, Schneider P. Cracking the BAFF code. Nat Rev Immunol. 2009;9(7):491–502 [slide p.38].
  11. Panch et al. Management of refractory immune thrombocytopenia. Hematology Am Soc Hematol Educ Program. 2025 [slide p.36].