Lars Möllgård

Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry

Acute myeloid leukemia (AML) is most common in the elderly, and most elderly are thought to be unfit for intensive treatment because of the risk of fatal toxicity. The Swedish Acute Leukemia Registry covers 98% of all patients with AML (nonacute promyelocytic leukemia) diagnosed in 1997 to 2005 (n = 2767), with a median follow-up of 5 years, and reports eligibility for intensive therapy, performance status (PS), complete remission rates, and survival. Outcomes were strongly age and PS dependent. Early death rates were always lower with intensive therapy than with palliation only. Long-term survivors were found among elderly given intensive treatment despite poor initial PS. Total survival of elderly AML patients was better in the geographic regions where most of them were given standard intensive therapy. This analysis provides unique real world data from a large, complete, and unselected AML population, both treated and untreated, and gives background to treatment decisions for the elderly. Standard intensive treatment improves early death rates and long-term survival compared with palliation. Most AML patients up to 80 years of age should be considered fit for intensive therapy, and new therapies must be compared with standard induction.

Continuing high early death rate in acute promyelocytic leukemia: a population-based report from the Swedish Adult Acute Leukemia Registry

Our knowledge about acute promyelocytic leukemia (APL) patients is mainly based on data from clinical trials, whereas population-based information is scarce. We studied APL patients diagnosed between 1997 and 2006 in the population-based Swedish Adult Acute Leukemia Registry. Of a total of 3897 acute leukemia cases, 3205 (82%) had non-APL acute myeloid leukemia (AML) and 105 (2.7%) had APL. The incidence of APL was 0.145 per 100 000 inhabitants per year. The median age at the time of diagnosis was 54 years; 62% were female and 38% male. Among younger APL patients, female sex predominated (89% of patients <40 years). Of the 105 APL patients, 30 (29%) died within 30 days (that is, early death (ED)) (median 4 days) and 28 (26%) within 14 days from diagnosis. In all, 41% of the EDs were due to hemorrhage; 35% of ED patients never received all-trans-retinoic acid treatment. ED rates increased with age but more clearly with poor performance status. ED was also associated with high white blood cells, lactate dehydrogenase, creatinine, C-reactive protein and low platelet count. Of non-ED patients, 97% achieved complete remission of which 16% subsequently relapsed. In total, 62% are still alive at 6.4 years median follow-up. We conclude that ED rates remain very high in an unselected APL population.

A randomized phase 3 study of tipifarnib compared with best supportive care, including hydroxyurea, in the treatment of newly diagnosed acute myeloid leukemia in patients 70 years or older

This phase 3, multicenter, open-label study evaluated the efficacy and safety of tipifarnib compared with best supportive care (BSC), including hydroxyurea, as first-line therapy in elderly patients (>or=70 years) with newly diagnosed, de novo, or secondary acute myeloid leukemia. A total of 457 patients were enrolled with 24% 80 years of age or older. Tipifarnib 600 mg orally twice a day was administered for the first 21 consecutive days, in 28-day cycles. The primary endpoint was overall survival. The median survival was 107 days for the tipifarnib arm and 109 days for the BSC arm. The hazard ratio (tipifarnib vs BSC) for overall survival was 1.02 (P value by stratified log-rank test, .843). The complete response rate for tipifarnib in this study (8%) was lower than that observed previously, but with a similar median duration of 8 months. The most frequent grade 3 or 4 adverse events were cytopenias in both arms, slightly more infections (39% vs 33%), and febrile neutropenia (16% vs 10%) seen in the tipifarnib arm. The results of this randomized study showed that tipifarnib treatment did not result in an increased survival compared with BSC, including hydroxyurea. This trial was registered at www.clinicaltrials.gov as #NCT00093990.

Effects of PRIMA-1 on chronic lymphocytic leukaemia cells with and without hemizygous p53 deletion

The tumour suppressor gene p53 is the most commonly mutated gene in solid tumours. Although less common in haematological malignancies, 10–15% of B‐cell chronic lymphocytic leukaemia (B‐CLL) cases carry a p53 mutation. Recently, the compound P53‐dependent reactivation and induction of massive apoptosis (PRIMA‐1) has been shown to induce cytotoxic effects and apoptosis in human tumour cells by restoration of the transcriptional activity of mutated p53. This is believed to be mediated by a change in the conformation of mutated p53 protein, restoring DNA binding and activation of p53 target genes. We studied the effects of PRIMA‐1 and commonly used anti‐leukaemic drugs on B‐CLL cells from 14 patients with and without hemizygous p53 deletion. Cells obtained from peripheral blood or bone marrow were exposed to PRIMA‐1 and fludarabine alone or in combination. PRIMA‐1 showed cytotoxic effects on B‐CLL cells from samples with and without hemizygous p53 deletion. Furthermore, conventional B‐CLL drugs were less effective in cell samples with hemizygous p53 deletion and the response depended on the size of the p53 deleted clone. Finally, we found evidence for synergistic and additive effects of PRIMA‐1 in combination with fludarabine.

Mutated and non-mutated TP53 as targets in the treatment of leukaemia

TP53 is mutated in 10–20% of cases of chronic lymphocytic leukaemia (CLL) and 3–8% of cases of acute myeloid leukaemia (AML). Recently, two classes of compounds that restore the function of p53 in tumours have been described. PRIMA‐1 (p53‐dependent reactivation and induction of massive apoptosis) restores the wild‐type conformation of mutant TP53, whereas RITA (reactivation of p53 and induction of tumour cell apoptosis) increases intracellular levels of p53. We evaluated the effects of RITA alone and in combination with PRIMA‐1 or conventional cytostatics on leukaemic cells isolated from AML and CLL patients. AML samples with −17, which are more resistant to daunorubicin and cytarabine compared with samples without −17, were effectively killed by PRIMA‐1. RITA, which stabilizes the function of wild‐type p53, induced apoptosis in AML cells. In contrast to that seen with PRIMA‐1, AML patient samples without −17 were significantly more sensitive to RITA. Similarly, RITA exerted dose‐dependent apoptosis and cytotoxicity in CLL cells, which was significantly more pronounced in samples without hemizygous TP53 deletion. Notably, a synergistic effect was observed in all CLL samples with RITA and fludarabine in combination. In both AML and CLL cells exposure to RITA resulted in induction of intracellular p53. We conclude that small molecules targeting p53 might be of clinical importance in the future for treating drug‐resistant leukaemia.

PRIMA-1 induces apoptosis in acute myeloid leukaemia cells with p53 gene deletion

The p53 tumour suppressor gene located on chromosome 17p13 is the most frequently mutated gene in human tumours. About 5–8% of cases with acute myeloid leukaemia (AML) carry the p53 mutation. Recently, the compound p53‐dependent reactivation and induction of massive apoptosis (PRIMA‐1) has been shown to induce cytotoxic effects and apoptosis in human tumour cells by restoration of the transcriptional activity of mutated p53. This is believed to be mediated by a change in the conformation of mutated p53 protein, restoring DNA binding and activation of p53 target genes. We studied the effects of PRIMA‐1 and commonly used antileukaemic drugs on AML cells from 62 patients. Cells were obtained from peripheral blood or bone marrow and were exposed to PRIMA‐1, cytarabine, daunorubicin, chlorodeoxyadenosine and fludarabine. This study showed that PRIMA‐1 had cytotoxic effects on AML cells. Conventional AML drugs were less effective in cells with hemizygous p53 deletion. Interestingly, our data indicated that PRIMA‐1 was more effective in this subgroup of patients compared with patients with normal chromosome 17. Our data suggest that the concept of restoration of p53 protein by PRIMA‐1 or a PRIMA‐1‐based new drug may increase the efficacy of AML treatment in patients with p53 mutations.

Increased remissions from one course for intermediate-dose cytosine arabinoside and idarubicin in elderly acute myeloid leukaemia when combined with cladribine. A randomized population-based phase II study

Summary.  Cladribine has single‐drug activity in acute myeloid leukaemia (AML), and may enhance the formation of the active metabolite (ara‐CTP) of cytosine arabinoside (ara‐C). To evaluate the feasibility of adding intermittent cladribine to intermediate‐dose ara‐C (1 g/m2/2 h) b.i.d. for 4 d with idarubicin (CCI), we performed a 2:1 randomized phase II trial in AML patients aged over 60 years. Primary endpoints were time to recovery from cytopenia and need for supportive care following the first course. Sixty‐three patients (median 71 years, range 60–84 years) were included, constituting 72% of all eligible patients. Toxicity was limited, with no differences between the treatment arms. The early toxic death rate was 11%. The median time to recovery from neutropenia and thrombocytopenia was 22 and 17 d from the start of course no. 1, respectively, and the requirement for platelet and red cell transfusions was four and eight units respectively. Patients had a median of 8 d with fever over 38°C, and 17 d with intravenous antibiotic treatment. The overall complete remission (CR) rate was 62%, with 51% CR from one course of CCI in comparison with 35% for the two‐drug therapy (P = 0·014). The median survival with a 2‐year follow‐up was 14 months, and the 2‐year survival was over 30%, with no differences between the treatment arms. Considering the median age and our population‐based approach, the overall results are encouraging.

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).

Hematopoietic stem cell transplantation rates and long-term survival in acute myeloid and lymphoblastic leukemia: Real-World Population-Based Data From the Swedish Acute Leukemia Registry 1997-2006.

Allogeneic stem cell transplantation (alloSCT) reduces relapse rates in acute leukemia, but outcome is hampered by toxicity. Population‐based data avoid patient selection and may therefore substitute for lack of randomized trials.

Characterization and prognostic features of secondary acute myeloid leukemia in a population-based setting: A report from the Swedish Acute Leukemia Registry

Patients with secondary acute myeloid leukemia (AML) often escape inclusion in clinical trials and thus, population‐based studies are crucial for its accurate characterization. In this first large population‐based study on secondary AML, we studied AML with an antecedent hematological disease (AHD‐AML) or therapy‐related AML (t‐AML) in the population‐based Swedish Acute Leukemia Registry. The study included 3,363 adult patients of which 2,474 (73.6%) had de novo AML, 630 (18.7%) AHD‐AML, and 259 (7.7%) t‐AML. Secondary AML differed significantly compared to de novo AML with respect to age, gender, and cytogenetic risk. Complete remission (CR) rates were significantly lower but early death rates similar in secondary AML. In a multivariable analysis, AHD‐AML (HR 1.51; 95% CI 1.26–1.79) and t‐AML (1.72; 1.38–2.15) were independent risk factors for poor survival. The negative impact of AHD‐AML and t‐AML on survival was highly age dependent with a considerable impact in younger patients, but without independent prognostic value in the elderly. Although patients with secondary leukemia did poorly with intensive treatment, early death rates and survival were significantly worse with palliative treatment. We conclude that secondary AML in a population‐based setting has a striking impact on survival in younger AML patients, whereas it lacks prognostic value among the elderly patients. Am. J. Hematol. 90:208–214, 2015.