Journal Club – CAD

Jalink M, Berentsen S, Castillo JJ, Treon SP, Cruijsen M, Fattizzo B, Cassin R, Fotiou D, Kastritis E, De Haas M, Oosten LEM, Frederiksen H, Patriarca A, D’Sa S, Vos JMI. Effect of ibrutinib treatment on hemolytic anemia and acrocyanosis in cold agglutinin disease/cold agglutinin syndrome. Blood. 2021 Nov 18;138(20):2002-2005.

Clinical Question

In patients with cold agglutinin disease (CAD) or cold agglutinin syndrome (CAS), are the disease findings of anemia, hemolysis, and acrocyanosis improved by treatment with the BTK inhibitor ibrutinib?

Background

Cold agglutinin disease (CAD) is a primary clonal B cell disorder that accounts for ~15-30% of all autoimmune hemolytic anemias, most commonly involving the production of monoclonal IgM kappa antibodies with temperature-dependent binding of I antigen on red blood cells.¹ In contrast, cold agglutinin syndrome (CAS) occurs secondary to another process, typically autoimmune diseases, B cell lymphomas, or infections (commonly EBV, mycoplasma, SARS-CoV-2). These IgM antibodies are capable of fixing complement via activation of the classical pathway, resulting in erythrocyte opsonization and extravascular (and in severe cases, intravascular) destruction.

Diagnostic criteria for CAD/CAS involve the presence of a chronic hemolytic anemia, a monospecific DAT strongly positive for C3d, and cold agglutinin titer ≥64 at 4oC. The exclusion of an underlying trigger is necessary for diagnosis of CAD specifically as it differentiates primary from secondary disease. Clinically, ~20-50% of patients will demonstrate circulatory symptoms (acrocyanosis, Raynaud’s, pain/numbness, and/or risk of vessel occlusion) in the extremities related to impaired temperature-dependent passage through capillaries.²

Current therapies aim to reduce hemolysis by eliminating the pathogenic B cell clone, or address mechanisms of erythrocyte destruction. The most common first line regimen of rituximab +/- bendamustine is a commonly used treatment for various indolent B cell lymphomas. However, there is not clear consensus recommendation for subsequent lines of therapy. Sutimlimab inhibits the classical complement pathway (inhibition of C1s to prevent assembly of the C3 convertase), and has been shown in prospective studies to rapidly and durably improve anemia (Hb increases of >1-2g/dL), though it does not improve circulatory symptoms as these are not mediated by the complement pathway.³ Bortezomib and other proteasome inhibitors can also be considered in subsequent line therapy, as a single cycle in relapsed or refractory CAD patients had an overall response rate (ORR) of 33% and a median response of >16 months.⁴ More recently, Bruton’s Tyrosine Kinase (BTK) inhibitors have become a subject of study given their success in managing multiple clonal B cell malignancies. In this study, Jalink et al conducted a retrospective study of 15 patients with CAD/CAS who received the first generation BTK inhibitor, ibrutinib.

Guidelines

Standard practice for cold agglutinin disease involves treatment of patients with symptomatic anemia, fatigue, circulatory symptoms such as acrocyanosis, or those who can be expected to benefit from therapy.

First line therapy for cold agglutinin disease involves rituximab +/- bendamustine depending on fitness.⁵ Subsequent lines of therapy broaden to include complement inhibitors, proteasome inhibitors, cytotoxic chemotherapy, and/or immunosuppressive agents.

Study Design

• Multinational retrospective study
• Setting: Ten centers (Italy, Denmark, Greece, Norway, the Netherlands, United Kingdom, United States)
• N = 15:
  • 4 patients with primary CAD
  • 11 patients with CAS
    • 5 with Waldenström macroglobulinemia
    • 5 with CLL
    • 1 with SLL
• Follow-up period: April 2014 until February 2021
• Primary efficacy outcome: Improvements in anemia, hemolysis, and acrocyanosis measured at diagnosis, 1, 3, 6, and 12 months post treatment, and at late date of follow-up
  • Hemoglobin response graded as none, partial response (PR; Hb 10-12 or ≥2g/dL increase), or complete response (CR; Hb >12 g/dL)
  • Acrocyanosis scored as stable, better, or resolved
• Secondary outcomes:
  • Effect of MYD88^L265P mutation, where known, on efficacy
  • Safety and tolerability of ibrutinib monotherapy

Populations

Inclusion Criteria:

• Patients with confirmed cAIHA based on presence of anemia, elevated hemolysis markers (increased reticulocytes, lactate dehydrogenase, and bilirubin, with a decreased haptoglobin) and/or severe acrocyanosis, as well as positive direct antiglobulin test (DAT)

Baseline Characteristics:

• 15 patients enrolled
  • 8 patients were male, 7 patients were female
  • Median age 68 (55 – 85)
  • 11 were transfusion dependent
  • 9 reported symptoms of acrocyanosis
  • 2 patients had treatment indication of refractory acrocyanosis only, without significant hemolytic anemia
• Underlying disease
  • Primary CAD (4 patients)
  • CLL (5 patients)
  • SLL (1 patients)
  • LPL/WM (5 patients)
• MYD88^L265P mutation status
  • Positive (3 patients)
  • Negative (4 patients)
  • Not determined (8 patients)
• Median total IgM 5.7mg/dL (0.3 – 66.2)
• Median prior lines of therapy 3 (0-5)
  • Prior treatments of steroids, IVIG, rituximab, fludarabine, chlorambucil-obinutuzumab, MMF, bendamustine, bortezomib, cyclophosphamide, darbepoetin, ixazomib, and plasmapheresis
• Median hemoglobin 8.2 (5.0 – 11.9)
• Duration of ibrutinib treatment at time of data collection 12 months (3 – 82)
  • Two patients discontinued therapy; one died from metastatic melanoma present before ibrutinib initiation, and one switched to treatment of Richter’s transformation (found to have been present pre-ibrutinib)

Interventions

• All patients received ibrutinib 420mg daily
• One patient received C1 inhibitor, single dose of vincristine, and plasmapheresis within 2 weeks of starting ibrutinib

Outcomes

Primary outcome:

• 13/13 patients with cAIHA showed improvement in Hb, with 12 CR and 1 PR
• 12/13 with baseline cAIHA showed improvement in hemolysis markers (1 not evaluated due to missing data)
• 9/9 patients with acrocyanosis reported clinical improvement, 8 within 30 days and 1 after 3 months
• 6/9 patients with acrocyanosis reported complete resolution

Secondary outcome:

• MYD88^L265P status did not impact responsiveness to ibrutinib

Safety:

• 5 total grade 1 adverse events in 4 patients
  • 3 reported bruising
  • 1 reported diarrhea
  • 1 reported rash
• 1 grade 3 event occurred (neutropenia) requiring G-CSF

Commentary

In this retrospective multinational study, Jalink et al performed a retrospective analysis of 13 patients with either primary cold agglutinin disease or cold agglutinin syndrome treated with ibrutinib monotherapy. Regardless of underlying pathology, all 13 of the patients with cAIHA demonstrated treatment response, with all but one patient achieving a CR (Hb >12), and all 11 previously transfusion dependent patients became transfusion independent. All 9 patients with acrocyanosis reported subjective improvement in symptoms (8 within the first month) with 6 of 9 achieving complete resolution of symptoms. Notably, there was no apparent difference in MYD88 mutational status, and no new safety signals; only one patient had grade 3 neutropenia, a known adverse effect of ibrutinib therapy.

The primary limitation of the study is the small sample size of only 15 patients and retrospective design. While these results are encouraging, and suggest a potential role for BTK inhibition particularly in later lines of therapy, a more thorough evaluation in a randomized control setting will be necessary. Other therapies for CAD such as the complement inhibitor sutimlimab are associated with significant hemoglobin increase, though are less effective at managing acrocyanotic symptoms as these symptoms are not complement-mediated. A key area of future investigation will be duration of efficacy; while the median duration of treatment in this study was 12 months, ibrutinib has been shown to be tolerable for many for over a decade in trials of CLL/SLL and so may provide a chemotherapy-free option for therapy able to address both hemolytic and circulatory symptoms.

In summary, Jalink et al demonstrate a promising signal for the use of the BTK inhibitor ibrutinib in the treatment of CAD/CAS. All the patients in this small study with cAIHA had improvement in their anemia/reduction in hemolysis with 12 patients demonstrating a CR and 1 PR, and all with acrocyanosis reported improvement with 2/3rds noting complete resolution of symptoms. This study raises the potential role of BTKi in the treatment of CAD/CAS.

References

1. Sigbjørn Berentsen; Diagnosis and management of cold agglutinin disease. Hematology Am Soc Hematol Educ Program 2025; 2025 (1): 295–304. doi: https://doi.org/10.1182/hematology.2025000718 ↩︎
2. Berentsen S, Barcellini W, D’Sa S, et al. Cold agglutinin disease revisited: a multinational, observational study of 232 patients. Blood. 2020;136(4): 480-488. ↩︎
3. Röth A, Barcellini W, D’Sa S, et al. Sutimlimab in cold agglutinin disease. N Engl J Med. 2021;384(14):1323-1334. ↩︎
4. Rossi G, Gramegna D, Paoloni F, et al. Short course of bortezomib in anemic patients with relapsed cold agglutinin disease: a phase 2 prospective GIMEMA study. Blood. 2018;132(5):547-550 ↩︎
5. Jäger U, Barcellini W, Broome CM, Gertz MA, Hill A, Hill QA, Jilma B, Kuter DJ, Michel M, Montillo M, Röth A, Zeerleder SS, Berentsen S. Diagnosis and treatment of autoimmune hemolytic anemia in adults: Recommendations from the First International Consensus Meeting. Blood Rev. 2020 May;41:100648. doi: 10.1016/j.blre.2019.100648. Epub 2019 Dec 5. PMID: 31839434. ↩︎

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