Gunnar Öberg

A validated decision model for treating the anaemia of myelodysplastic syndromes with erythropoietin + granulocyte colony-stimulating factor: significant effects on quality of life

Summary. We have published previously a prototype of a decision model for anaemic patients with myelodysplastic syndromes (MDS), in which transfusion need and serum erythropoietin (S‐Epo) were used to define three groups with different probabilities of erythroid response to treatment with granulocyte colony‐stimulating factor (G‐CSF) + Epo. S‐Epo ≤ 500 U/l and a transfusion need of < 2 units/month predicted a high probability of response to treatment, S‐Epo > 500 U/l and ≥ 2 units/month for a poor response, whereas the presence of only one negative prognostic marker predicted an intermediate response. A total of 53 patients from a prospective study were included in our evaluation sample. Patients with good or intermediate probability of response were treated with G‐CSF + Epo. The overall response rate was 42% with 28·3% achieving a complete and 13·2% a partial response to treatment. The response rates were 61% and 14% in the good and intermediate predictive groups respectively. The model retained a significant predictive value in the evaluation sample (P < 0·001). Median duration of response was 23 months. Scores for global health and quality of life (QOL) were significantly lower in MDS patients than in a reference population, and fatigue and dyspnoea was significantly more prominent. Global QOL improved in patients responding to treatment (P = 0·01). The validated decision model defined a subgroup of patients with a response rate of 61% (95% confidence interval 48–74%) to treatment with G‐CSF + Epo. The majority of these patients have shown complete and durable responses.

Pharmacokinetics of high-dose busulphan in relation to age and chronopharmacology

SummaryBusulphan levels in plasma were measured in 27 patients during conditioning therapy (1 mg/kg×4 for 4 days) before bone marrow transplantation. The mean minimal concentration found in children aged <5 years (237 ng ml−1) was lower than that observed in adults or older children (607 and 573 ng ml−1, respectively). The AUC for the last dose was significantly lower in young children (2,315 h ng ml−1) than in adults or older children (6,134 and 5,937 h ng ml−1, respectively). The elimination half-life for the last dose in young children was shorter (2.05 h) than that in either adults (2.59 h) or older children (2.79 h). When the AUC was normalized for body surface area, the difference between young children and the other groups was smaller but remained statistically significant. The total body clearance was significantly higher in young children (7.3 ml min−1 kg−1) as compared with both older children and adults (3.02 and 2.7 ml min−1 kg−1, respectively). The plasma levels of busulphan showed circadian rhythmicity, especially in young children. The concentration measured during the night in some patients was up to 3-fold that observed during daytime. We conclude that the busulphan dosage for children must be reconsidered and that further studies are urgently needed to develop an optimal therapy.

High-dose therapy and autologous stem-cell transplantation in angioimmunoblastic lymphoma: complete remission at transplantation is the major determinant of Outcome-Lymphoma Working Party of the European Group for Blood and Marrow Transplantation.

Purpose Patients with angioimmunoblastic T-cell lymphoma (AITL) have poor prognoses with current conventional chemotherapy. The aim of this study was to evaluate the effect of high-dose therapy (HDT) followed by autologous stem-cell transplantation (ASCT) on patients with AITL. Patients and Methods We report a retrospective, multicenter study of 146 patients with AITL who received ASCT. The source of the stem cells was peripheral blood in 143 patients. The conditioning regimen varied, and 74% of the patients received carmustine and 1,3-bis(2-chloroethyl)-1-nitrosourea; etoposide; ara-C; and melphalan chemotherapy. Results After a median follow-up of 31 months (range, 3 to 174 months), 95 patients (65%) remained alive, and 51 patients (35%) died. Forty-two patients died as a result of disease progression, and nine died as a result of regimen-related toxicity. The cumulative incidence of nonrelapse mortality was 5% and 7% at 12 and 24 months, respectively. The actuarial overall survival (OS) was 67% at 24 m...

Influence of prophylactic anticonvulsant therapy on high-dose busulphan kinetics

The pharmacokinetics of high-dose busulphan was studied in 17 patients during conditioning prior to bone marrow transplantation using deuterium-labeled busulphan (d8-BU). About 50% of busulphan doses 1 and 16 was replaced with d8-BU. Patients were treated with phenytoin or diazepam as prophylactic anticonvulsant therapy. Patients who received phenytoin demonstrated significantly higher clearance (mean ±SD, 3.32±0.99 ml min−1 kg−1), a lower area under the concentration-time curve (AUC, 5,412±1,534 ng h ml−1; corrected for dose/kilogram) and a shorter elimination half-life (3.03±0.57 h) for the last dose of d8-BU (dose 16) as compared with the first dose (2.80±0.78 ml min−1 kg−1, 6,475±2,223 ng h ml−1 and 3.94±1.10 h, respectively). No difference in the above-mentioned pharmacokinetic parameters was seen in patients treated with diazepam. Moreover, a continuous decrease in the steady-state level of busulphan was observed in four of seven patients in the phenytoin-treated group, whereas in the diazepam group, such a decrease was seen in only one of eight patients. We conclude that phenytoin used as prophylactic anticonvulsant therapy alters busulphan pharmacokinetics and, most probably, its pharmacodynamics. For adequate prophylactic therapy, anticonvulsants with fewer enzyme-inductive properties than phenytoin should be used.

Post-transplant lymphoproliferative disease and other Epstein-Barr virus diseases in allogeneic haematopoietic stem cell transplantation after introduction of monitoring of viral load by polymerase chain reaction

The clinical value of monitoring of Epstein-Barr virus (EBV) viraemia by quantitative polymerase chain reaction during 1 y was evaluated. 39 recipients of allogeneic hematopoietic stem cell transplantation (SCT) were followed. More than 100 EBV genome equivalents (gEq)/ml in blood or plasma were found in 16/39 patients (41%) at 34 d (range 1–139) post-transplant. Seven of these 16 patients developed EBV disease; 3 post-transplant lymphoproliferative disease (PTLD), 1 myelitis, 1 encephalitis and 2 reactivations with fever. EBV diseases were only found in the high-risk group among recipients of mismatched related or unrelated donor grafts or in patients who underwent reduced-intensity conditioning. In this group, 3/20 (15%) developed PTLD. Conditioning with antithymocyte globulin was significantly associated with EBV disease (p<0.01). EBV load in plasma was more strongly associated with EBV disease than viral load in blood. A cut-off level of 1000 gEq/ml plasma distinguished EBV disease from asymptomatic viraemia, but not PTLD from other EBV diseases. Weekly monitoring of EBV load in plasma in high-risk patients in the first 3 months following SCT seems to be of value for prediction of EBV disease. Therapy for PTLD including rituximab was evaluated during 2 y and showed response in 4/6 cases.

Stimulation of NK cell, T cell, and monocyte functions by the novel immunomodulator Linomide after autologous bone marrow transplantation. A pilot study in patients with acute myeloid leukemia.

Immunostimulatory therapy is at present considered after autologous bone marrow transplantation (ABMT) in order to mimic the allogeneic graft-versus-leukemia effect and thereby reduce the relapse rate. In a pilot study, five adults with acute myeloid leukemia were treated with the new immunomodulator Linomide post-ABMT. Linomide (0.3 mg/kg/week orally) was given in cycles of three weeks followed by three weeks of rest for up to six months. During treatment periods cyclic increases of CD56+CD3- and CD16+ NK cells were observed in parallel with enhanced cytotoxic activity of patient cells against both the NK-sensitive K562 and NK-resistant Daudi cell lines. A cyclic increase of CD14+ monocytic cells was also recorded. The proliferative responses of patient cells to PHA and allogeneic cells (MLC) were enhanced during Linomide therapy. The in vitro production of TNF alpha, IFN gamma, and IL-1 followed the same cyclic increase during treatment periods. Side effects were generally mild, and no harmful effects on engraftment were seen. Linomide therapy after ABMT thus induces a broad immunostimulation that offers a potential benefit with regard to leukemia-free survival.

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.

Treatment of myelodysplastic syndromes with retinoic acid and 1α-hydroxy-vitamin D3 in combination with low-dose ara-C is not superior to ara-C alone. Results from a randomized study

Abstract: 63 evaluable patients with myelodysplastic syndromes (MDS) and 15 with acute myelogenous leukemia (AML) were randomized between low‐dose ara‐C (arm A) and low dose ara‐C in combination with 13‐cis‐retinoic acid (13‐CRA) and 1α‐hydroxy‐vitamin D3 (1α D3) (arm B). 69 patients were evaluable and 18 (26.1%) responded to therapy. The addition of 13‐CRA and 1α D3 had no positive influence on survival of the patients, remission rates or duration of remissions. 12/27 patients in arm A and 6/29 patients in arm B progressed from MDS to AML during the course of the study (p = 0.0527). Arm B gave significantly more side‐effects than arm A (p = 0.005). Therapeutic effects of 13‐CRA and 1α D3 on MDS is not supported by this study. However, an inhibiting effect on AML development in some MDS subgroups cannot be excluded.

Negative effect of DNA hypermethylation on the outcome of intensive chemotherapy in older patients with high-risk myelodysplastic syndromes and acute myeloid leukemia following Myelodysplastic syndrome

Purpose: Promoter hypermethylation of, for example, tumor-suppressor genes, is considered to be an important step in cancerogenesis and a negative risk factor for survival in patients with myelodysplastic syndromes (MDS); however, its role for response to therapy has not been determined. This study was designed to assess the effect of methylation status on the outcome of conventional induction chemotherapy. Experimental Design: Sixty patients with high-risk MDS or acute myeloid leukemia following MDS were treated with standard doses of daunorubicin and 1-β-d-arabinofuranosylcytosine. Standard prognostic variables and methylation status of the P15ink4b (P15), E-cadherin (CDH), and hypermethylated in cancer 1 (HIC) genes were analyzed before treatment. Results: Forty percent of the patients achieved complete remission (CR). CR rate was lower in patients with high WBC counts (P = 0.03) and high CD34 expression on bone marrow cells (P = 0.02). Whereas P15 status alone was not significantly associated with CR rate (P = 0.25), no patient with hypermethylation of all three genes achieved CR (P = 0.03). Moreover, patients with CDH methylation showed a significantly lower CR rate (P = 0.008), and CDH methylation retained its prognostic value also in the multivariate analysis. Hypermethylation was associated with increased CD34 expression, but not with other known predictive factors for response, such as cytogenetic profile. Conclusions: We show for the first time a significant effect of methylation status on the outcome of conventional chemotherapy in high-risk MDS and acute myelogenous leukemia following MDS. Provided confirmed in an independent study, our results should be used as a basis for therapeutic decision-making in this patient group.

No benefit from adding GM-CSF to induction chemotherapy in transforming myelodysplastic syndromes: better outcome in patients with less proliferative disease

In this prospective randomized multicenter trial 93 patients, median age 72 years, with RAEB-t (n=25) and myelodysplastic syndrome (MDS)-AML (n=68) were allocated to a standard induction chemotherapy regimen (TAD 2+7) with or without addition of granulocyte–macrophage-CSF (GM-CSF). The overall complete remission (CR) rate was 43% with no difference between the arms. Median survival times for all patients, CR patients, and non-CR patients were 280, 550, and 100 days, respectively, with no difference between the arms. Response rates were significantly better in patients with serum lactate dehydrogenase (S-LDH) levels ⩽9.5 μkat/l, bone marrow cellularity ⩽70%, and WBC counts <4.0 × 109/l, but S-LDH was the only variable independently associated with response by logistic regression analysis. Coxs regression analysis identified four significant prognostic factors for survival: bone marrow cellularity, S-LDH, cytogenetic risk group (International Prognostic Scoring System), and age. Only bone marrow cellularity (P=0.01) and S-LDH (P=0.0003) retained statistical significance in the log-rank test. Severe adverse events were significantly more common in the GM-TAD arm (P=0.01). Thus, addition of GM-CSF to chemotherapy showed no clinical benefit in terms of response but carried an increased risk for side effects. We present a clinically useful tool to predict response to chemotherapy and survival in elderly patients with transforming MDS, favoring patients with features of less proliferative disease.