Sutimlimab for Relapsed Cold Agglutinin Disease: Real‐Life Evidence of Sustained Response With Extended‐Interval Dosing

We read with great interest the article by Frey et al. [1], reporting real-world outcomes of sutimlimab in 10 patients with cold agglutinin disease (CAD) treated through a Managed Access Program. The efficacy and safety profile they describe closely reflect our compassionate-use experience, active at our institution since 2022 and continued, in the last year, under standard AIFA approval. CAD is a chronic complement-mediated autoimmune hemolytic anemia for which B-cell–directed therapies, particularly rituximab, represent the initial therapeutic approach [2]. However, many patients relapse and require multiple treatment lines, making complement inhibition an increasingly relevant strategy [3]. Sutimlimab, a selective C1s inhibitor, provides rapid and targeted blockade of the classical complement pathway and is now approved for relapsed or refractory CAD [4, 5]. We report on four patients with primary CAD treated with sutimlimab under compassionate use at the Hematology Unit of the Federico II University Medical School of Naples. Two patients exhibited a DAT positivity restricted to C3d and two showed combined C3d and IgM reactivity. All patients had long-standing, multi-refractory disease, with multiple prior therapies including repeated courses of rituximab and—in selected cases—anti-CD38 antibodies and phosphoinositide 3-kinase inhibitors. Responses to these treatments had been transient or incomplete, underscoring the need for a mechanism of action independent of B-cell depletion. At baseline, patients had a median age of 68 years (range 38–81) and a median hemoglobin value of 7 g/dL (6.5–8.5 g/dL). All patients completed the recommended vaccination program prior to treatment and were monitored every 2 weeks with hemoglobin, reticulocytes, LDH, bilirubin, and haptoglobin. Three patients remain on therapy with sustained responses, whereas one 76-year-old patient died from postoperative complications following emergency cholecystectomy, unrelated to CAD or sutimlimab. The median treatment duration was 23 months (range 4–38), with three patients still on treatment. All patients initially received the standard induction schedule (Day 1, 8, 15, and then every 2 weeks) and hematologic improvement was rapid and clinically meaningful, typically within 1–2 weeks, achieving transfusion independence in all patients. Normalization of bilirubin and other hemolytic markers occurred early. After approximately 2 months of therapy and achievement of stable response according to trial-defined criteria (Hb > 10.5 g/dL with normalization of hemolytic indices), all patients were successfully transitioned to a maintenance regimen of one infusion every 4 weeks, without loss of efficacy (Figure 1A–C). Although this extended-interval schedule is off-label and not included in the approved dosing regimen, it was feasible and effective in our selected patients under close clinical and laboratory monitoring. This monthly schedule proved highly effective and well tolerated: no meningococcal or severe infectious complications occurred during treatment, and infusion tolerance remained excellent across all patients. Notably, two patients temporarily discontinued treatment for reasons unrelated to CAD—one due to transient drug unavailability and one due to hospitalization for acute cholecystitis. Both experienced biochemical relapses shortly after the monthly treatment was interrupted. Re-challenge with the standard induction schedule promptly restored hematologic remission, after which monthly maintenance was successfully resumed (Figure 1A,B). This reproducible pattern further supports the reversible and pharmacodynamically predictable nature of C1s inhibition and aligns with the relapse kinetics described by Frey et al. [1]. In conclusion, our compassionate-use experience, including off-label interval extension, supports and extends the findings of Frey et al. [1], providing real-life evidence that sutimlimab induces rapid, durable responses even in multi-refractory patients. Importantly, extension of the dosing interval should be individualized and cannot be generalized to all patients, as some may require shorter intervals to maintain disease control. Larger observational studies will be essential to better define long-term management strategies for patients with CAD. The authors have nothing to report. The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.