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“Arrested Development”: Understanding Acquired and Congenital Bone Marrow Failure Syndromes

December 13, 2022

Bone marrow failure syndromes are a group of disorders characterized by cytopenias that are caused by decreased or dysfunctional hematopoietic stem cells. Aplastic anemia (AA), paroxysmal nocturnal hemoglobinuria (PNH), and myelodysplastic syndrome fall under the umbrella of acquired bone marrow failure syndromes, whereas Diamond-Blackfan anemia (DBA), dyskeratosis congenita (DC), Schwachman-Diamond syndrome, and Fanconi anemia (FA) are examples of congenital bone marrow failure disorders. There were many exciting presentations in this field at #ASH22, with two dedicated oral sessions — Bone Marrow Failure: Acquired (session 508) and Bone Marrow Failure and Cancer Predisposition Syndromes: Congenital: From Biology to Therapeutics (session 509) on Saturday, December 10.

In the acquired bone marrow failure oral session, we learned from Dr. Emma Groarke from the National Institute of Health regarding the role of the JAK 1/2 inhibitor ruxolitinib in immune bone marrow failure such as AA. Ruxolitinib led to bone marrow recovery and improved peripheral blood counts in an immune bone marrow failure murine model. These exciting findings are leading the way to clinical trials with ruxolitinib in immune bone marrow failure syndromes.

Moving on from biology to clinical studies, there were several notable presentations on PNH. Dr. Rong Fu from Tianjin Medical University in China presented findings from the COMMODORE 3 trial of the novel complement C5 inhibitor crovalimab that demonstrated improvement in hemolysis control and transfusion dependence in patients with PNH who were naïve to C5 inhibitors. Furthermore, results of the APPLY-PNH trial studying the long-awaited oral complement factor B inhibitor iptacopan were unveiled during the Late-Breaking Abstract session by Dr. Regis Peffault De Latour of the Assistance Publique Hôpitaux de Paris. This study found that in patients with residual anemia, defined as hemoglobin (Hgb) less than 10 g/dL despite standard-of-care anti-C5 monoclonal antibody, single-agent iptacopan resulted in rise in Hgb greater than 12 g/dL, transfusion independence, and improvement in fatigue in almost all patients. We are excited to finally offer an oral treatment option to patients with PNH with inadequate response to anti-C5 monoclonal antibody therapy.

Lastly, the acquired bone marrow failure sessions closed out with remarkable studies on AA. Dr. Akiko Shimamura from Dana-Farber Cancer Institute presented the multicenter phase II ESCALATE trial that demonstrated safety and efficacy of eltrombopag in pediatric patients with relapsed/refractory severe AA. Additionally, Dr. Srilatha Dasari from the MetroHealth Medical Center presented a comprehensive review of immune-checkpoint inhibitor (ICI) –related AA, which occurred in 77 (0.15%) of 52,203 of patients treated with ICIs. She demonstrated that this adverse effect typically occurred within six months of ICI, and most patients responded to glucocorticoids, but a subset of patients had persistent cytopenias that resulted in a marked increase in mortality.

During the congenital bone marrow failure session, Dr. Richard Voit of Dana-Farber Cancer Institute presented a novel gene therapy approach to cure DBA, a disorder that involves mutations in 26 different ribosomal protein genes, the most notable of which is the erythroid-specific transcription factor GATA1. This approach salvaged impaired erythroid differentiation and will lead the way for the first-in-human gene therapy trials for DBA.

A focus on clonal hematopoiesis of indeterminate potential (CHIP) returns at #ASH22. This condition is characterized by a nonmalignant clonal proliferation of cells with acquired myeloid mutations, and increases in frequency with age. While CHIP increases the risk of cardiovascular events, it is associated with a reduced risk of Alzheimer’s disease. To learn more on “Clinical and Mechanistic Links between Clonal Hematopoiesis and Non-Hematological Disorders,” please check out the dedicated Poster Walk (a virtual-only event) on Wednesday, December 14 from 10:00 a.m. to 11:00 a.m. Further exploring the link between CHIP and cardiovascular health, Dr. Zoe McQuilten of Monash University in Melbourne, Australia, presented the results of the ASPREE trial, which assessed aspirin prophylaxis in older patients to lower cardiovascular events. The study demonstrated that CHIP with a variant allele frequency of greater than 10% was associated with increased cancer-related mortality rather than cardiovascular mortality. Moreover, aspirin did not provide clinical benefit in reducing cardiovascular events, including in those with JAK2 V617F mutations.

Keeping the focus on CHIP, Dr. Lachelle Weeks from the Dana-Farber Cancer Institute developed a prognostic model to risk-stratify patients with CHIP or clonal cytopenia of uncertain significance (CCUS) into low, intermediate, or high-risk categories with regard to development of myeloid neoplasms, by including variables such as genetic features, age, CCUS versus CHIP, red cell distribution width, and mean corpuscular volume. Her team derived this model from whole-genome sequencing of 193,743 healthy volunteers from the UK Biobank, which identified 1,337 instances (5.85%) of CHIP or CCUS. Remarkably, the high-risk group had five-year and 10-year rates of myeloid neoplasm development of 23.6 percent and 50.6 percent, respectively. We hope that future studies can direct us toward risk-adapted management options.

The alphabet soup of bone marrow failure and clonal hematopoiesis — AA, PNH, FA, DBA, CHIP, CCUS — is confusing, but the list is only to grow as we learn more about these entities. We are still in the infancy of understanding the pathogenesis, clinical significance, and effective surveillance and treatment options for these conditions, and we are very excited for new developments in this field.


Dr. Kumar and Dr. Jeong indicated no relevant conflicts of interest.

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