Myelodysplastic Syndromes with Hypocellular Marrow: Clinical Characteristics and Evaluation of Outcome
Authors: Santini Valeria , Gioia Daniela Maria , Masiera Elisa , Poloni Antonella , Ferrero Dario , Fragasso Alberto , Finelli Carlo , Salvi Flavia , Gaidano Gianluca , Oliva Esther Natalie , Catarini Massimo , Cametti Gianni , Bonferroni Margherita , Danise Paolo , Tassara Rodolfo , Allione Bernardino , Cilloni Daniela , Castelli Andrea , Centurioni Riccardo , Ciravegna Giorgio , Visani Giuseppe , Musto Pellegrino , Balleari Enrico , Boveri Emanuela , Ponzoni Maurilio , Gianelli Umberto , Della Porta Matteo Giovanni 
Published: October 2019

Abstract
Background. MDS may be characterized by hypocellular marrow, irrespective of their WHO classification or molecular characteristics. Their prognostic weight must still be completely evaluated. MDS with hypocellular marrow tend to be considered an aplastic anemia "overlap syndrome" or a pre-aplastic anemia stage. There are no strong specific therapy recommendations, and large studies analyzing the outcome of hypocellular MDS are lacking. While selective sensitivity to immunosuppressive therapy is suggested, evidence in this sense is controversial.
Aims. We wanted to evaluate the clinical characteristics, outcome and choice of therapy of patients with hypocellular MDS and compare them with normocellular MDS.
Methods. We analyzed 2559 MDS cases with complete clinical annotations and with evaluable bone trephine biopsy, enrolled in our Italian National Registry FISMonlus. In this cohort of patients, 438 had a bone marrow cellularity <= 30% and 2121 cellularity above 30%. We proceeded by comparing these two groups in terms of age, gender, WHO classification, IPSS-R categories, overall survival and first line therapies. As a validation cohort, 874 unselected MDS cases enrolled in Rete Ematologica Lombarda (REL) registry were analyzed. In this population, 108 patients had cellularity <= 30%.
Results. In FISM cohort median age was 72.5 yrs in the hypocellular group and 72,3 yrs in the normocellular group; M/F were 53.2%/46.8% for hypocellular MDS vs 62.6%/37.4% in normocellular MDS. IPSS-R risk categories were distributed as follows: Hypocellular MDS Very Low 15.5%, Low 35.1%, Intermediate 30.1%, High 11.3%, Very high 8%; Normocellular MDS Very Low 12.8%, Low 37.2%, intermediate 23.7%, High 15.5%, Very High 11.4%. Global median overall survival (OS) was 77 months for hypocellular MDS and 56 months for normocellular MDS. When OS was evaluated in the different IPSS-R risk groups, Lower risk MDS cases with hypocellular BM had a median OS of 125 mos while normocellular had a median OS of 74 mos (p< .001). Higher risk MDS with hypocellular BM had 19 mos median OS vs 20 mos OS in normocellular MDS. Regarding the first line therapy, the comparison of hypocellular MDS with normocellular ones yielded the following: watch and wait 33.8% vs 31.6% for IPSS-R lower risk, 12.1% vs 16% for higher risk cases; AML like chemotherapy and HSCT were chosen for< 1% of lower risk cases overall, and in 1.7% of higher risk hypocellular MDS, while higher risk MDS with normocellular marrow received it in 6.2% of the cases. Azacitidine was first line treatment for 36.2% of the higher risk MDS patients with hypocellular BM and 25% of normocellular BM. Immunosuppressive treatments were emploied for < 1% and 1.5% respectively in lower risk cases only. Erythroid stimulating agents were administered in 42.6% and 41.2% MDS IPSS-R lower risk, hypo- and normocellular, respectively. We then focused on the validation cohort (REL registry). Median age was 74 yrs in the hypocellular group IPSS-R risk categories were distributed as follows: Very Low risk 9 %, Low 36%, Intermediate 39%, High 17 %, Very high 9%. Global median overall survival (OS) was 79 months for hypocellular MDS and 64 months for normocellular MDS. The difference was significant in very low/low IPSS-R risk groups, cases with hypocellular BM having a median OS of 103 mos vs. 69 mos of normocellular cases (p=.011). No significant differences were present in higher disease risk categories. No significant difference was noticed on first line treatment of choice between hypocellular an normocellular MDS. Immunosuppressive treatments were used in a very low proportion of cases (2% and 3% respectively).
Conclusion. Our results are based on an unbiased analysis of "real life" MDS patients with hypocellular BM compared to normocellular ones. Clinical characteristics between the two groups were not significantly different in terms of age, gender, and distribution in the various IPSS-R risk categories. The outcome of the hypocellular marrow-MDS cases was better in comparison with that of normocellular MDS, with significantly longer OS in IPSS-R lower risk cases. The advantage in OS for hypoplastic MDS wasn't present for IPSS-R higher risk cases. Finally, the choice of first line therapy doesn't seem to be influenced by the BM cellularity, with a surprising very low proportion of patients receiving immunosuppressive agents, despite several guideline recommend of this treatment for hypoplastic MDS.

Disclosures
Santini: Novartis: Honoraria; Otsuka: Consultancy; Celgene: Honoraria, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Finelli:Novartis: Consultancy, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Gaidano:Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Morphosys: Honoraria; Roche: Consultancy, Honoraria. Oliva:Celgene: Consultancy, Other: Royalties, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; La Jolla: Consultancy; Sanofi: Consultancy, Speakers Bureau. Cilloni:celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.