Inge Høgh Dufva

Clonal Ph-negative hematopoiesis in CML after therapy with imatinib mesylate is frequently characterized by trisomy 8.

Clonal Ph-negative hematopoiesis in CML after therapy with imatinib mesylate is frequently characterized by trisomy 8

Epidemiologic study on survival of chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia patients with BCR-ABL T315I mutation

The BCR-ABL T315I mutation represents a major mechanism of resistance to tyrosine kinase inhibitors (TKIs). The objectives of this retrospective observational study were to estimate overall and progression-free survival for chronic myeloid leukemia in chronic-phase (CP), accelerated-phase (AP), or blastic-phase (BP) and Philadelphia chromosome-positive (Ph)(+) acute lymphoblastic leukemia (ALL) patients with T315I mutation. Medical records of 222 patients from 9 countries were reviewed; data were analyzed using log-rank tests and Cox proportional hazard models. Median age at T315I mutation detection was 54 years; 57% cases were men. Median time between TKI treatment initiation and T315I mutation detection was 29.2, 15.4, 5.8, and 9.1 months, respectively, for CP, AP, BP, and Ph(+) ALL patients. After T315I mutation detection, second-generation TKIs were used in 56% of cases, hydroxyurea in 39%, imatinib in 35%, cytarabine in 26%, MK-0457 in 11%, stem cell transplantation in 17%, and interferon-alpha in 6% of cases. Median overall survival from T315I mutation detection was 22.4, 28.4, 4.0, and 4.9 months, and median progression-free survival was 11.5, 22.2, 1.8, and 2.5 months, respectively, for CP, AP, BP, and Ph(+) ALL patients. These results confirm that survival of patients harboring a T315I mutation is dependent on disease phase at the time of mutation detection.

Epidemiology and Clinical Significance of Secondary and Therapy-Related Acute Myeloid Leukemia: A National Population-Based Cohort Study

PURPOSE Secondary and therapy-related acute myeloid leukemia (sAML and tAML, respectively) remain therapeutic challenges. Still, it is unclear whether their inferior outcome compared with de novo acute myeloid leukemia (AML) varies as a result of previous hematologic disease or can be explained by differences in karyotype and/or age. PATIENTS AND METHODS In a Danish national population-based study of 3,055 unselected patients with AML diagnosed from 2000 to 2013, we compared the frequencies and characteristics of tAML, myelodysplastic syndrome (MDS) -sAML, and non-MDS-sAML (chronic myelomonocytic leukemia and myeloproliferative neoplasia) versus de novo AML. Limited to intensive therapy patients, we compared chance of complete remission by logistic regression analysis and used a pseudo-value approach to compare relative risk (RR) of death at 90 days, 1 year, and 3 years, overall and stratified by age and karyotype. Results were given crude and adjusted with 95% CIs. RESULTS Overall, frequencies of sAML and tAML were 19.8% and 6.6%, respectively. sAML, but not tAML, was associated with low likelihood of receiving intensive treatment. Among intensive therapy patients (n = 1,567), antecedent myeloid disorder or prior cytotoxic exposure was associated with decreased complete remission rates and inferior survival (3-year adjusted RR for MDS-sAML, non-MDS-sAML, and tAML: RR, 1.14; 95% CI, 1.02 to 1.32; RR, 1.27; 95% CI, 1.16 to 1.34; and RR, 1.16; 95% CI, 1.03 to 1.32, respectively) compared with de novo AML. Among patients ≥ 60 years old and patients with adverse karyotype, previous MDS or tAML did not impact overall outcomes, whereas non-MDS-sAML was associated with inferior survival across age and cytogenetic risk groups (adverse risk cytogenetics: 1-year adjusted RR, 1.47; 95% CI, 1.23 to 1.76; patients ≥ 60 years old: 1-year adjusted RR, 1.31; 95% CI, 1.06 to 1.61). CONCLUSION Our results support that de novo AML, sAML, and tAML are biologically and prognostically distinct subtypes of AML. Patients with non-MDS-sAML have dismal outcomes, independent of age and cytogenetics. Previous myeloid disorder, age, and cytogenetics are crucial determinants of outcomes and should be integrated in treatment recommendations for these patients.

Allogeneic stem cell transplantation for patients harboring T315I BCR-ABL mutated leukemias

T315I(+) Philadelphia chromosome-positive leukemias are inherently resistant to all licensed tyrosine kinase inhibitors, and therapeutic options remain limited. We report the outcome of allogeneic stem cell transplantation in 64 patients with documented BCR-ABL(T315I) mutations. Median follow-up was 52 months from mutation detection and 26 months from transplantation. At transplantation, 51.5% of patients with chronic myeloid leukemia were in the chronic phase and 4.5% were in advanced phases. Median overall survival after transplantation was 10.3 months (range 5.7 months to not reached [ie, still alive]) for those with chronic myeloid leukemia in the blast phase and 7.4 months (range 1.4 months to not reached [ie, still alive]) for those with Philadelphia chromosome-positive acute lymphoblastic leukemia but has not yet been reached for those in the chronic and accelerated phases of chronic myeloid leukemia. The occurrence of chronic GVHD had a positive impact on overall survival (P = .047). Transplant-related mortality rates were low. Multivariate analysis identified only blast phase at transplantation (hazard ratio 3.68, P = .0011) and unrelated stem cell donor (hazard ratio 2.98, P = .011) as unfavorable factors. We conclude that allogeneic stem cell transplantation represents a valuable therapeutic tool for eligible patients with BCR-ABL(T315I) mutation, a tool that may or may not be replaced by third-generation tyrosine kinase inhibitors.

Clinical effect of increasing doses of lenalidomide in high-risk myelodysplastic syndrome and acute myeloid leukemia with chromosome 5 abnormalities

Background Patients with chromosome 5 abnormalities and high-risk myelodysplastic syndromes or acute myeloid leukemia have a poor outcome. We hypothesized that increasing doses of lenalidomide may benefit this group of patients by inhibiting the tumor clone, as assessed by fluorescence in situ hybridization for del(5q31). Design and Methods Twenty-eight patients at diagnosis or with relapsed disease and not eligible for standard therapy (16 with acute myeloid leukemia, 12 with intermediate-risk 2 or high-risk myelodysplastic syndrome) were enrolled in this prospective phase II multicenter trial and treated with lenalidomide up to 30 mg daily for 16 weeks. Three patients had isolated del(5q), six had del(5q) plus one additional aberration, 14 had del(5q) and a complex karyotype, four had monosomy 5, and one had del(5q) identified by fluorescence in situ hybridization only. Results Major and minor cytogenetic responses, assessed by fluorescence in situ hybridization, were achieved in 5/26 (19%) and 2/26 (8%) patients, respectively, who received one or more dose of lenalidomide, while two patients achieved only a bone marrow response. Nine of all 26 patients (35%) and nine of the ten who completed the 16 weeks of trial responded to treatment. Using the International Working Group criteria for acute myeloid leukemia and myelodysplastic syndrome the overall response rate in treated patients with acute myeloid leukemia was 20% (3/15), while that for patients with myelodysplastic syndrome was 36% (4/11). Seven patients stopped therapy due to progressive disease and nine because of complications, most of which were disease-related. Response rates were similar in patients with isolated del(5q) and in those with additional aberrations. Interestingly, patients with TP53 mutations responded less well than those without mutations (2/13 versus 5/9, respectively; P=0.047). No responses were observed among 11 cases with deleterious TP53 mutations. Conclusions Our data support a role for higher doses of lenalidomide in poor prognosis patients with myelodysplastic syndrome and acute myeloid leukemia with deletion 5q. (Clinicaltrials.gov identifier NCT00761449).

Comorbidity and performance status in acute myeloid leukemia patients: a nation-wide population-based cohort study

As the world population ages, the comorbidity burden in acute myeloid leukemia (AML) patients increases. Evidence on how to integrate comorbidity measures into clinical decision-making is sparse. We determined the prognostic impact of comorbidity and World Health Organization Performance Status (PS) on achievement of complete remission and mortality in all Danish AML patients treated between 2000 and 2012 overall and stratified by age. Comorbidity was measured using a modified version of the Charlson Comorbidity Index, with separate adjustment for pre-leukemic conditions. Of 2792 patients, 1467 (52.5%) were allocated to intensive therapy. Of these patients, 76% did not have any comorbidities, 19% had one comorbid disease and 6% had two or more comorbidities. Low complete remission rates were associated with poor PS but not with comorbidity. Surprisingly, among all intensive therapy patients, presence of comorbidity was not associated with an increased short-term mortality (adjusted 90 day mortality rate (MR)=1.06 (95% confidence interval (CI)=0.76–1.48)) and, if any, only a slight increase in long-term mortality (91 day–3 year adjusted MR=1.18 (95%CI=0.97–1.44). Poor PS was strongly associated with an increased short- and long-term mortality (adjusted 90 day MR, PS⩾2=3.43 (95%CI=2.30–5.13); adjusted 91 day–3 year MR=1.35 (95%CI=1.06–1.74)). We propose that more patients with comorbidity may benefit from intensive chemotherapy.

The Danish National Acute Leukemia Registry

Aim of database The main aim of the Danish National Acute Leukemia Registry (DNLR) was to obtain information about the epidemiology of the hematologic cancers acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and myelodysplastic syndrome (MDS). Study population The registry was established in January 2000 by the Danish Acute Leukemia Group and has been expanded over the years. It includes adult AML patients diagnosed in Denmark since 2000, ALL patients diagnosed since 2005, and MDS patients diagnosed since 2010. The coverage of leukemia patients exceeds 99%, and the coverage of MDS patients is currently 90%. Main variables and descriptive data Approximately, 250 AML patients, 25 ALL patients, and 230 MDS patients are registered in the DNLR every year. In January 2015, the registry included detailed patient characteristics, disease characteristics, treatment characteristics, and outcome data on more than 3,500 AML, 300 ALL, and 1,100 MDS patients. Many of the included prognostic variables have been found to be of high quality including positive predictive values and completeness exceeding 90%. These variables have been used in prognostic observational studies in the last few years. To ensure this high coverage, completeness, and quality of data, linkage to the Danish Civil Registration System and the Danish National Registry of Patients, and several programmed data entry checks are used. Conclusion The completeness and positive predictive values of the leukemia data have been found to be high. In recent years, the DNLR has shown to be an important high-quality resource for clinical prognostic research.

Durable complete remission after azacitidine treatment in a patient with erythroleukaemia.

To the Editor: In August 2010, a 79-yr-old man was diagnosed with AEL. The patient was well preserved and besides hypertension had no significant intercurrent diseases. The patient was admitted to hospital after a GI haemorrhage; endoscopy found no cause, but blood samples showed mild pancytopenia with haemoglobin of 11.3 g/dL, leucocytes of 1.5 9 10/L with neutrophils of 0.35 9 10/L and platelets of 36 9 10/L. A bone marrow biopsy and aspirate was performed. The bone marrow sample showed 22% myeloblast cells and >50% erythroid precursors. Thus, the AML was classified as FAB M6 and, according to the 2008 WHO classification, as erythroleukaemia, which is the most common subtype of AEL. Azacitidine treatment was started with 100 mg/m subcutaneously on days 1–5 every 4 wk (to avoid treatment during weekends). Prophylactic antibiotics were administered during the first three courses, where neutrophils were below 0.5 9 10/L. Besides injection-related erythema and slight pain, the patient had no side effects. Currently, the patient has been treated for 18 months and received a total of 18 azacitidine treatment series, the last 16 courses at a 20% dose reduction, owing to slight myelosupression following the first two courses. Following treatment the peripheral blood counts increased as shown in the figure. In December 2010, after five courses of therapy, a bone marrow sampling was performed, showing no erythroblasts and a reduction in myeloblasts to 15% compatible with RAEB-2. In October 2011, following course 12, a bone marrow sample showed further improvement, that is, the BM demonstrated persisting multilineage dysplasia with a reduction of blasts to <5%, which is compatible with complete remission according to Cheson criteria (1). The patient has so far lived 18 months after diagnosis and is still in complete remission with a good quality of life, capable of travelling, with no hospital admissions, and the patient only received one unit of blood so far. To our knowledge, this is the first report describing activity of azacitidine in AEL, which generally is considered to have a poor prognosis. Our finding needs confirmation in a larger cohort of AEL patients preferentially treated in a prospective multicenter trial of patients, who are not candidates for intensive chemotherapy and/or allogeneic stem cell transplantation. Epigenetic treatment with 5-azacitidine, a DNA methyltransferase inhibitor, is approved as first-line treatment for patients with advanced MDS and MDS/AML with <30% blasts, who are not candidates for allogeneic stem cell transplantation. First-line treatment with azacitidine was established after Fenaux et al. published the results of a large multicenter study in 2009. In the study, 358 patients with IPSS Int-2 and high-risk MDS, MDS/AML with <30% blasts (previous RAEB-t) and advanced, non-proliferative CMML-2 were included. The patients were randomized to receive either azacitidine or conventional care (best supportive care alone, best supportive care and low-dose cytarabine or intensive chemotherapy), which was selected before randomization. Azacitidine was given subcutaneously as 75 mg/ m/d for 7 d every 28 d. The results for the primary outcome, overall survival, showed a significant longer median overall survival in the azacitidine group of 24.5 months, compared with 15 months in the conventional care group (P = 0.0001) (2). There are only a few publications describing azacitidine treatment in patients with AML (either de novo or following MDS) with more than 30% blasts and specifically no reports regarding azacitidine in patients with erythroleukaemia (3, 4). Acute erythroid leukaemia (AEL) represents <5% of all cases of AML. AEL are acute leukaemias that are characterized by a predominant erythroid population. There are two subtypes: