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ITP associated with MDS and CMML
similar platelet counts at diagnosis. First-line treatment consisted of glucocorticoids (98%) and intravenous immunoglobulins (56%). Patients with primary ITP were more likely to respond to intravenous immunoglobulins than were patients with MDS/CMML-associated ITP. Response rates to second-line ther- apies were not statistically different between patients with primary ITP or MDS/CMML-associated ITP. Four (10%) of the patients with MDS/CMML-associated ITP had multirefractory ITP whereas none of the primary ITP controls did so. After a median follow-up of 60 months, there was no difference in overall sur- vival between patients with MDS/CMML-associated ITP or primary ITP. Leukemia-free-survival was sig- nificantly better in patients with MDS/CMML-associated ITP than in those with MDS/CMML without ITP. In conclusion, it appears that patients with MDS/CMML-associated ITP have a particular phenotype, with more severe bleeding than patients with primary ITP, a higher likelihood of multirefractory disease, but a similar response to primary ITP therapy except for intravenous immunoglobulins. Finally, compared to MDS/CMML patients without ITP, they are less likely to progress to having acute myeloid leukemia.
Introduction
Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) are clonal hematopoietic stem cell disorders characterized by inef- fective and dysplastic hematopoiesis in the bone marrow leading to cytopenias and a risk of developing acute myeloid leukemia (AML).1 In 10 to 20% of cases, various systemic inflammatory or autoimmune diseases (SIAD) can be associated with MDS or CMML.2 The impact of these associated diseases on the survival and progression to acute leukemia of MDS/CMML patients remains con- troversial, but they can make therapy challenging. In addi- tion to the most frequently reported SIAD (vasculitis, neu- trophilic dermatoses, and polyarthritis), immune cytope- nias have been documented in 1 to 16% of cases.3-5 Immune thrombocytopenia (ITP) is an immune-mediated acquired disorder defined by a transient or persistent decrease in the peripheral blood platelet count to below 100 x 109/L for which other causes of isolated thrombocy- topenia have been excluded.6 ITP is characterized by autoimmune-mediated platelet destruction and impaired platelet production, which can lead to an increased risk of bleeding. Large studies analyzing the specific features, outcome and treatment of ITP in MDS/CMML are lack- ing. The aim of this study by the French Network of Dysimmune Disorders Associated with Hemopathies (MINHEMON) was to describe the clinical spectrum, ther- apeutic management and outcome of patients with ITP in the context of MDS/CMML in comparison to: (i) patients with primary ITP without MDS/CMML and (ii) patients with MDS/CMML without ITP.
Methods
Patients
We retrospectively collected data on patients with ITP associ- ated with MDS/CMML diagnosed since January 1999 at 16 French departments of internal medicine and hematology. Physicians were asked by MINHEMON, the Reference Center for Autoimmune Cytopenias in Adults (CERECAI) and the French Society of Internal Medicine (SNFMI) to report cases of ITP associated with MDS or CMML. Some patients with ITP and CMML (n=5) presented in this case series were described in a previous publication.7 Clinical, laboratory and immunological data at the time of diagnosis of MDS/CMML and ITP and during the follow-up were collected using a standardized form.
Patients were included if they fulfilled the following criteria: (i) age over 18 years; (ii) a diagnosis of ITP according to the inter- national criteria;6 platelet count <100 x 109/L on at least two sep- arate occasions and the exclusion of other causes of thrombocy- topenia; (iii) steroid-responsive thrombocytopenia (with response defined as any platelet count of at least 30 x 109/L and at least doubling of the baseline count, as described by Rodeghiero et al.6); (iv) a diagnosis of MDS or CMML, based on blood and bone marrow examinations, according to the 2016 World Health Organization classification;8 and (v) a maximum period of 10 years between the diagnoses of ITP and MDS/CMML.
The exclusion criteria were as follows: (i) patients with sec- ondary ITP not linked to MDS (e.g., cases related to malignancy, chronic viral infection, primary immune deficiency or drugs); and (ii) lack of response to steroids.
Patients were classified using the Revised International Prognostic Scoring System (IPSS-R) and separated into two sub- groups, low- and high-risk MDS, based on a cut-off IPSS-R score of 3.5 points.9 Secondary MDS refers to therapy-related MDS (occurring after chemotherapy or radiation therapy) or to MDS associated with another primary or acquired bone marrow dis- order.
Bleeding was graded according to the bleeding score previously reported by Khellaf et al.10 Severe bleeding was defined as intracra- nial hemorrhage, overt gastrointestinal bleeding, severe menstrual bleeding, or macroscopic hematuria.11 Multirefractory ITP was defined as severe chronic ITP not responding to rituximab, splenectomy or a thrombopoietin receptor agonist (TPO-RA).12
This study was conducted in compliance with the Helsinki Declaration, upon a database of patients treated according to standard care and, therefore, no ethics approval was necessary according to French law (https://www.legifrance.gouv.fr/eli/decret/ 2017/5/9/AFSP1706303D/jo/texte). The database was declared with registration number 2218061 v 0 to the Commission Nationale de l’Informatique et des Libertés (CNIL).
Criteria for immune thrombocytopenia response
Assessment of the response to ITP treatments was time-specific to each treatment, as described by Rodeghiero et al.6 Complete response was defined as any platelet count of at least 100 x 109/L. Partial response was defined as any platelet count between 30 and 100 x 109/L and at least doubling of the baseline count. No response was defined as any platelet count lower than 30 x 109/L or less than doubling of the baseline count. The definitions of par- tial response and complete response required concurrent resolu- tion of bleeding symptoms.
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