Chronic bone marrow failure and transfusion patterns : epidemiological studies of blood transfusions and outcomes in patients with myelodysplastic syndromes

Sammanfattning: Myelodysplastic syndromes (MDS) encompass a diverse group of clonal hematological malignancies characterized by dysplasia and ineffective hematopoiesis with an increased risk of leukemic evolution. It is a disease of the elderly with a median age of nearly 75 years. Anemia is the most common cytopenia and a majority of the patients have a temporary or chronic need for red blood cell (RBC) transfusions, either during treatment or at loss of response to treatment. Recognizing the importance of RBC transfusions, the transfusion burden is likewise associated with a reduced overall and progression-free survival and with other unwanted effects, such as alloimmunization and impaired quality of life. This thesis aimed to expand the knowledge on transfusion patterns primarily in patients with MDS, but also to investigate transfusion patterns in hematological malignancies overall. Specific goals were to characterize transfusion patterns, identify clinical and patient-specific parameters associated with transfusion intensity and to investigate variables that might affect the efficacy of the RBC transfusion, such as RBC storage time and alloimmunization. In study I, we presented a nation-wide overview of transfusion patterns in patients diagnosed with a hematological malignancy of myeloid, lymphoid or plasma cell origin, during the first two years following diagnosis. Great variations in the transfusion patterns were observed between hematological diagnoses with regard to transfusion incidence, median number of transfused units and direct costs. Patients with acute leukemia and MDS received the highest cumulative number of transfusions and thereby accounted for the highest costs. Conversely, patients with chronic lymphoid leukemia, Hodgkin’s lymphoma or follicular lymphoma received the lowest cumulative number of transfusions. The transfusion incidence was highest immediately after diagnosis in patients with acute leukemia and in patients undergoing allogeneic stem cell transplantation. In study II, we aimed to identify clinical and patient-specific parameters associated with transfusion intensity of RBC and platelet transfusions, in patients with MDS. Independent predictors of RBC and platelet transfusion intensity were male sex and mutations in genes encoding histone modulation, signaling and transcriptional regulation. We observed that transfusion intensity was significantly associated with poor survival. In study III, we investigated if duration of RBC storage affected the hemoglobin increment following RBC transfusions in a cohort of MDS patients. A longer duration of RBC storage was associated with a smaller increment of the hemoglobin level after transfusion, per RBC unit, compared to units stored less than five days. The estimates proved stable when adjusting for age and sex and in five different sensitivity analyses. In study IV, we analyzed risk factors of alloimmunization and potential clinical changes following alloimmunization, such as transfusion requirements and the post-transfusion hemoglobin increment, in an MDS cohort. Female sex and a positive direct antiglobulin test were significantly associated with alloimmunization. Following alloimmunization, we observed an increase of the average transfusion intensity and estimated lower post-transfusion hemoglobin increments per RBC unit. In conclusion, characterization of transfusion patterns and identification of variables associated with transfusion intensity are of great importance and could guide therapeutic options and optimize transfusion therapy to patients with a chronic bone marrow failure due to MDS.