Predictors of Prognosis in Acute Myeloid Leukemia a Clinical and Epidemiological Study

AML is a malignant disorder characterized by clonal expansion of immature myeloid hematopoietic stem cells, myeloblasts, in bone marrow, blood and/or other tissue. Despite advances in treatment the majority of patients eventually die from this aggressive disease. We conducted a study including 9,729 AML patients diagnosed in Sweden 1973-2005 to define survival patterns over time. One-year relative survival ratios (RSRs) improved in all age groups. Improvement in 5-year RSRs was restricted to patients <80 years. The 5-year RSRs in the last calendar period were 0.65, 0.58, 0.36, 0.15, 0.05, and 0.01 for the age groups 0-18, 19-40, 41-60, 61-70, 71-80, and 80+ years, respectively. Intensification of induction and consolidation treatment, an increasing rate of allografted patients, a continuous improvement in supportive care measures, and a more precise risk stratification of patients are probably the most important factors contributing to the improvement. We also assessed the impact of socioeconomic status (SES) on survival in 9,165 patients with AML. Overall, higher white-collar workers had lower mortality compared to other SES groups (p=0.005). In AML patients, a consistently higher overall mortality was observed in blue-collar workers compared to higher white-collar workers in the last three calendar periods (hazard ratio [HR]=1.26; 95% confidence interval (CI) 1.05-1.51; HR=1.23; 1.05-1.45; HR=1.28; 1.041.57, respectively). Differences in comorbidities, management, and life-style factors are likely to explain these findings. We determined expression patterns of CD33 and CD15 in leukemic blasts from 129 patients with AML using flow cytometry (FC) and a standard panel of triple antibody combinations. Five patterns, corresponding to the consecutive stages of myeloid differentiation, were identified [I:CD33-/CD15(n=18), II: CD33+/CD15(n=43), III: CD33++/CD15 heterogeneous (n=10), IV: CD33+/CD15+ (n=50), V: CD33-/CD15+ (n=8)]. Patients with pattern II had the highest relapse rate and shortest median overall survival (OS; 8 months), but they were also the oldest (median age 72 years) and had a high frequency of unfavorable cytogenetics. Pattern V patients had a short OS (median 14 months) even though they were the youngest (median age 50 years) and had high remission rate. Age (p=0.004), cytogenetics (p=0.011), CD15 expression (p=0.031), and the immunophenotypic classification (p=0.024) were all independent significant predictors for OS. The presence of minimal residual disease (MRD) in AML patients in complete remission (CR) is a predictor of poor prognosis. We determined MRD status by FC in 45 AML patients ≤60 years old in first CR. MRD was determined after induction (MRD1; n=43) and/or at the end of post-remission chemotherapy (MRD2; n=31). Patients with detectable MRD at either time-point who underwent allogeneic or autologous stem cell transplantation (SCT) had significantly better 5-year relapse-free survival than patients not transplanted (MRD1: 83%, 54%, and 8%, respectively, p<0.0001; MRD2: 80%, 53%, and 0%, respectively, p=0.003). We identified 11,039 patients with myeloproliferative neoplasms (MPNs) from the Swedish Cancer Registry and major hematology units. Through record-linkage with the Cancer Registry patients who developed AML (n=271) and myelodysplastic syndromes (MDS; n=21) were identified. For each patient with a subsequent AML/MDS diagnosis (cases) two matched patients without AML/MDS (controls) were identified. After exclusions the final study population consisted of 162 cases (153 AML, 9 MDS) and 242 controls. 25% of patients with AML/MDS development were never exposed to cytotoxic agents. Compared to no hydroxyurea (HU) exposure the odds ratios (with 95% CIs) for 1-499 g, 500-999 g, >1000 g of HU were 1.22 (0.61-2.45), 1.41 (0.58-3.40), and 1.35 (0.55-3.32), respectively for AML/MDS development (not significant). In contrast, MPN patients who received radioactive phosphorus (P 32 ) >1000 MBq and alkylating agents >1 g had a 4.60-fold (2.159.85; p<0.0001) and 3.39-fold (1.08-10.59; p=0.036) increased risk of AML/MDS, respectively. Lower exposures to P 32 and alkylators were not associated with a significantly increased risk of AML/MDS. LIST OF PUBLICATIONS This thesis is based on the following papers, which are referred to in the text by their Roman numerals: I. Rangert Derolf Å, Kristinsson SY, Andersson T M-L, Landgren O, Dickman PW, Björkholm M. Improved patient survival for acute myeloid leukemia: a population-based study of 9729 patients diagnosed in Sweden between 1973 and 2005. Blood 2009;113(16):3666-72. II. Kristinsson SY, Rangert Derolf Å, Edgren G, Dickman PW, Björkholm M. Socioeconomic differences in patient survival are increasing for acute myeloid leukemia and multiple myeloma in Sweden. J Clin Oncol 2009;27(12):207380. III. Rangert Derolf Å, Björklund E, Mazur J, Björkholm M, Porwit A. Expression patterns of CD33 and CD15 predict outcome in patients with acute myeloid leukemia. Leuk Lymphoma 2008; 49(7):1279-91. IV. Laane E, Rangert Derolf Å, Björklund E, Mazur J, Everaus H, Söderhäll S, Björkholm M, Porwit-MacDonald A. The effect of allogeneic stem cell transplantation on outcome in younger acute myeloid leukemia patients with minimal residual disease detected by flow cytometry at the end of postremission chemotherapy. Haematologica 2006; 91(6):833-36. V. Björkholm M, Rangert Derolf Å, Hultcrantz M, Kristinsson SY, Ekstrand C, Andreasson B, Birgegård G, Linder O, Malm C, Markevärn B, Nilsson L, Samuelsson J, Granath F, Landgren O. Treatment related risk factors for transformation to acute myeloid leukemia and myelodysplastic syndromes in chronic myeloproliferative neoplasms – a population-based nested casecontrol study. Manuscript to be submitted.