Jonas Wallvik

Maintenance treatment with azacytidine for patients with high-risk myelodysplastic syndromes (MDS) or acute myeloid leukaemia following MDS in complete remission after induction chemotherapy

This prospective Phase II study is the first to assess the feasibility and efficacy of maintenance 5‐azacytidine for older patients with high‐risk myelodysplastic syndrome (MDS), chronic myelomonocytic leukaemia and MDS‐acute myeloid leukaemia syndromes in complete remission (CR) after induction chemotherapy. Sixty patients were enrolled and treated by standard induction chemotherapy. Patients that reached CR started maintenance therapy with subcutaneous azacytidine, 5/28 d until relapse. Promoter‐methylation status of CDKN2B (P15 ink4b), CDH1 and HIC1 was examined pre‐induction, in CR and 6, 12 and 24 months post CR. Twenty‐four (40%) patients achieved CR after induction chemotherapy and 23 started maintenance treatment with azacytidine. Median CR duration was 13·5 months, >24 months in 17% of the patients, and 18–30·5 months in the four patients with trisomy 8. CR duration was not associated with CDKN2B methylation status or karyotype. Median overall survival was 20 months. Hypermethylation of CDH1 was significantly associated with low CR rate, early relapse, and short overall survival (P = 0·003). 5‐azacytidine treatment, at a dose of 60 mg/m2 was well tolerated. Grade III‐IV thrombocytopenia and neutropenia occurred after 9·5 and 30% of the cycles, respectively, while haemoglobin levels increased during treatment. 5‐azacytidine treatment is safe, feasible and may be of benefit in a subset of patients.

Bleeding complications during warfarin treatment in primary healthcare centres compared with anticoagulation clinics.

Objectives. To examine determinants of bleeding complications during warfarin treatment in an unselected patient population and evaluate possible differences in safety between specialized anticoagulation clinics and primary healthcare centres. Design. Prospective cohort study. Data were collected with an admission form and medical records were scrutinized in order to pursue all adverse events. Differences between groups were estimated with a t-test and chi-squared test, and univariate and multivariate Cox regression analysis. Setting. All patients treated and monitored with oral anticoagulation in primary healthcare centres and specialized anticoagulation clinics in the Sundsvall and Skellefteå region (northern Sweden) during a five-year period. Subjects. A total of 2731 patients corresponding to 5044 treatment years. Main outcome measures. Bleedings were classified as fatal or major. Major bleedings were defined as an event causing admission, prolonged in-hospital care or death. Results. In total 195 major bleedings occurred corresponding to 3.9% per treatment year, including 34 fatal events (0.67% per treatment year). Patients monitored at the two specialized anticoagulation clinics combined had a major bleeding frequency of 4.1% as compared with 3.9% at primary healthcare units. The frequency of fatal haemorrhage was 0.57% and 0.76%, respectively. The rate of major and fatal bleeding was age related with an increase of 4% and 5%, respectively, per year. Conclusions. There was no difference in bleeding complications between patients monitored at primary healthcare centres and specialized anticoagulation clinics. Age was continuously and independently associated with bleeding risk. These study data indicate the need to exercise caution in treatment of the elderly.

Serum erythropoietin (EPO) levels correlate with survival and independently predict response to EPO treatment in patients with myelodysplastic syndromes

Abstract: Treatment with recombinant erythropoietin (EPO) can alleviate anaemia in patients with myelodysplastic syndromes (MDS). The present study, based on a long‐term follow‐up of 68 MDS patients (26RA, 16 RAS, 26 RAEB) treated with EPO alone, pinpoints pre‐treatment variables associated with response induction, response duration and overall survival. Response, defined as an increase in haemoglobin >15 g L−1 or eliminated erythrocyte transfusion requirements, was observed in 22 of 66 (33%) evaluable patients. The median response duration was 15 (range 3–64 +) months. Using univariate logistic regression models, responders displayed significantly lower baseline serum EPO levels (S‐EPO), more often normal bone marrow blast cell content (RA/RAS vs. RAEB), normal cytogenetics and no need for erythrocyte transfusion. In a multiple logistic regression model, S‐EPO (P = 0.009), marrow blast content (P = 0.031) and erythrocyte transfusion need (P = 0.024) remained associated with response induction. The probability of response for a patient with S‐EPO >50 U L−1, RA/RAS and no transfusion need was 0.79 (0.53–0.93, 95% CI). The median overall survival time from start of EPO treatment was 26 months, significantly longer for responders than for non‐responders (49 vs. 18 months, P = 0.018). Survival was also predicted by baseline S‐EPO; patients with S‐EPO > 50 U L−1 (n = 50) had a median survival of 17 months, as compared to 65 months for those with S‐EPO >50 U L−1 (n = 14, P = 0.024). The international prognostic scoring system (IPSS) for MDS predicted survival (P = 0.003) and progression to acute leukemia (P < 0.001) but not response to EPO treatment. Furthermore, in a logistic regression model with S‐EPO and IPSS, S‐EPO (but not IPSS) was again a significant predictor for response (P = 0.007). Our data facilitate the optimal selection of MDS patients suitable for EPO treatment and pinpoint S‐EPO as a powerful predictor of response and overall survival in MDS.

Quality of life, physical function and MRI T2* in elderly low‐risk MDS patients treated to a haemoglobin level of ≥120 g/L with darbepoetin alfa ± filgrastim or erythrocyte transfusions

Objective:  Anaemia in low‐risk myelodysplastic syndromes (MDS) is associated with reduced quality of life (QoL). Response to treatment with erythropoietin ± granulocyte colony‐stimulating factor (G‐CSF) is associated with improved QoL, but whether transfusion therapy with higher haemoglobin (Hb) target levels has similar effects is unknown. The objective for this prospective phase II Nordic multicentre trial was to assess QoL, response rate and physical function in elderly anaemic MDS patients treated to a target Hb level of >120 g/L.

Second malignancies following treatment of chronic myeloid leukaemia in the tyrosine kinase inhibitor era

Given that tyrosine kinase inhibitors (TKIs) have dramatically improved the survival of patients with chronic myeloid leukaemia (CML), we were interested in examining the possible risk of long‐term adverse events, such as the emergence of other neoplasms. Therefore, we studied the development of second malignancies in 868 patients diagnosed with CML between 2002 and 2011 using the Swedish CML register, cross‐linked to the Swedish Cancer register. With a median follow‐up of 3·7 (range 0–9·9) years, 65 (7·5%) patients developed 75 second malignancies (non‐haematological), 52 of which were of the invasive type. Compared to expected rates in the background population, the risk of second malignancies was higher in the CML cohort, with a standardized incidence ratio (SIR) of 1·52 (95% CI 1·13–1·99). The SIR before and after the second year following diagnosis of CML was 1·58 and 1·47, respectively. Among specific cancer types, gastrointestinal and nose and throat cancer were significantly increased. Founded on a population‐based material, our results indicate that CML patients treated in the TKI era are at an increased risk of developing a second malignancy, with indications that this risk may more likely be linked to CML itself rather than to the TKI treatment.

Long-term follow-up of 18 patients with myelodysplastic syndromes responding to recombinant erythropoietin treatment

The outcome of continued EPO therapy was studied in 18 responding MDS patients. The EPO dose was reduced in a stepwise fashion to find the lowest possible maintenance dose. Relapses of anemia were associated with either progressive disease or reduction of the administered EPO dose. In the latter group second responses to renewed EPO therapy were readily achieved. Long-term responses were seen in about a third of the patients. Thus, it seems safe to reduce the EPO dose among responding patients. This approach may have advantages both from a medical and a socio-economic perspective.

A sequential erythropoietin and GM-CSF schedule offers clinical benefits in the treatment of anaemia in myelodysplastic syndromes

In order to reduce anaemia in patients with myelodysplastic syndromes (MDS) a stepwise treatment protocol including erythropoietin (EP) and granulocyte-macrophage colony-stimulating factor (GM-CSF) was designed. Thirty-seven MDS patients (stages I-III) with symptomatic anaemia were first given EPO 10,000 U s.c. 3 times weekly for 6 weeks. Those not responding, i.e. increased their haemoglobin levels > 15 g/l, proceeded into the second phase of the study where GM-CSF (200 micrograms/d. s.c. on weeks 1-6) was combined with EPO (10,000 U s.c. 3 times weekly on weeks 5-14). Following the initial EPO treatment phase, 14 of the 37 patients (38%) responded with increased haemoglobin levels. Responders were significantly different from non-responders in that their pre-treatment values of s-EPO, s-LDH and bone marrow blast cell counts were lower, their baseline haemoglobin levels higher and their transfusion dependency less pronounced. Eighteen of the 23 non-responders proceeded into the second phase, 13 of those were evaluable having completed the entire schedule. Three of the 13 initially EPO resistant patients (23%) responded to the GM-CSF/EPO combination with increased haemoglobin levels, suggesting a positive synergy between the two cytokines. Thus, the overall response rate to the present protocol was 46% (17 of 37 cases), but only a limited subset of the patients did clearly benefit from the combined GM-CSF/EPO administration. Therefore, we believe this step-wise approach to multiple growth factor treatment in MDS, starting with EPO alone and reserving the combination for refractory cases, has considerable advantages, taking into account both medical and socio-economical aspects.

Oral cladribine for B‐cell chronic lymphocytic leukaemia: report of a phase II trial with a 3‐d, 3‐weekly schedule in untreated and pretreated patients, and a long‐term follow‐up of 126 previously untreated patients

Summary.  A phase II study was undertaken to evaluate the efficacy and toxicity of a new schedule of cladribine administration (10 mg/m2 orally daily for 3 d every 3 weeks) in 107 patients with B‐cell chronic lymphocytic leukaemia (CLL). To minimize toxicity, treatment withdrawal criteria were defined. The results of the 63 previously untreated patients were retrospectively compared with 63 from an earlier study using a 5‐d monthly schedule. The compiled data were analysed for prognostic factors for survival. No significant difference regarding response were seen in the two cohorts of the 126 previously untreated patients. The complete response (CR), nodular partial response (nPR) and partial response (PR) rates were 15%, 21% and 41%. Quality of response had no impact on survival. The 3‐ and 5‐year overall survival for previously untreated patients was 73% and 58%, respectively, with a median follow‐up of 54 months. Pretreatment haemoglobin < 11·0 g/dl and elevated beta‐2‐microglobulin had a negative influence on survival. Major infections occurred in 21% of patients in the 3‐d study compared with 35% in the 5‐d study. The overall response (OR) and CR rates in the 40 previously treated patients were 34% and 5% respectively. Median overall survival was 24 months and median progression‐free survival for responding patients was 14 months. Cladribine used as a single agent is an effective treatment with an acceptable safety profile for pretreated and untreated B‐CLL. The achievement of complete remission was not a prerequisite for long‐term survival.

Modulation of leukotriene signaling inhibiting cell growth in chronic myeloid leukemia

Abstract Although tyrosine kinase inhibitors (TKIs) have dramatically improved clinical outcome in chronic myeloid leukemia (CML), cure rarely occurs. This may be due to BCR-ABL-independent, aberrant signaling pathways, one of which leads to leukotriene (LT) formation. Well-recognized as inflammatory mediators, LT can also affect oncogenic mechanisms of several tumors. We have previously discovered elevated LT-synthesis and up-regulated cysteinyl-LT-inducing enzyme in CML. Here we report on dose-dependent inhibition of CML cell growth exerted by specific blockers of LT-signaling. Thus, the cysteinyl-LT1-receptor-antagonist montelukast significantly reduced the growth of K562, KCL22, and KU812 cells, as well as primary CD34+ blood cells from two CML patients. Adding montelukast to the TKI imatinib caused combined inhibition. No effect was seen on normal bone marrow cells. Similarly, growth inhibition was also observed with the 5-lipoxygenase (LO)-inhibitor BWA4C, the 5-LO-activating-protein-(FLAP)-inhibitor licofelone and the LTB4(BLT1)-receptor-antagonist LY293111. Thus, blocking of aberrant LT-signaling may provide an additional, novel therapeutic possibility in CML.