Determinants of lenalidomide response with or without erythropoiesis-stimulating agents in myelodysplastic syndromes: the HOVON89 trial.

A randomized phase-II study was performed in low/int-1 risk MDS (IPSS) to study efficacy and safety of lenalidomide without (arm A) or with (arm B) ESA/G-CSF. In arm B, patients without erythroid response (HI-E) after 4 cycles received ESA; G-CSF was added if no HI-E was obtained by cycle 9. HI-E served as primary endpoint. Flow cytometry and next-generation sequencing were performed to identify predictors of response. The final evaluation comprised 184 patients; 84% non-del(5q), 16% isolated del(5q); median follow-up: 70.7 months. In arm A and B, 39 and 41% of patients achieved HI-E; median time-to-HI-E: 3.2 months for both arms, median duration of-HI-E: 9.8 months. HI-E was significantly lower in non-del(5q) vs. del(5q): 32% vs. 80%. The same accounted for transfusion independency-at-week 24 (16% vs. 67%), but similar in both arms. Apart from presence of del(5q), high percentages of bone marrow lymphocytes and progenitor B-cells, a low number of mutations, absence of ring sideroblasts, and SF3B1 mutations predicted HI-E. In conclusion, lenalidomide induced HI-E in patients with non-del(5q) and del(5q) MDS without additional effect of ESA/G-CSF. The identified predictors of response may guide application of lenalidomide in lower-risk MDS in the era of precision medicine. (EudraCT 2008-002195-10).

Changing prognosis in paroxysmal nocturnal haemoglobinuria disease subcategories: an analysis of the International PNH Registry.

BACKGROUND: Paroxysmal nocturnal haemoglobinuria (PNH) is a rare disease. Although much progress has been made in the understanding of the pathophysiology of the disease, far less is known with respect to the clinical outcomes of patients with PNH. Few retrospective studies provide survival estimates, and even fewer have explored the clinical heterogeneity of the disease. Haemolytic and aplastic anaemia (AA) forms of the disease have been recognised as main disease categories, with the haemolytic form being associated with the worst prognosis by the largest studied cohort some years ago. AIMS: To describe mortality and causes of death in PNH overall and by PNH classification and to evaluate risk factors associated with mortality. METHODS: We analysed data of 2356 patients enrolled in the International PNH Registry with multivariate analyses, using time-dependent covariates. Patients were classified into haemolytic, AA/PNH syndrome or intermediate PNH. RESULTS: Overall, 122 (5.2%) patients died after enrolment, the incidence according to subcategories being 5.1, 11.7, 2.0 and 4.8% for patients with haemolytic PNH, AA-PNH, intermediate and insufficient data respectively. Older age and decreased performance status also affected survival in multivariate analysis. Improved outcome of patients with haemolytic PNH suggests that eculizumab treatment in PNH may be associated with improved survival. CONCLUSION: A detailed analysis of clinical presentations and causes of death in patients with PNH, overall and by disease subcategories, provide evidence that in the current era, patients with haemolytic PNH are no longer those who harbour the worst prognosis. This finding differs sharply from what has been previously reported.

Neutrophil activation and nucleosomes as markers of systemic inflammation in paroxysmal nocturnal hemoglobinuria: effects of eculizumab.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by complement-mediated hemolysis and a high risk of life-threatening venous and arterial thrombosis. Uncontrolled complement activation and the release of cell-free heme may result in systemic inflammation, neutrophil activation, and the release of procoagulant neutrophilic proteases. Eculizumab, an antibody to complement factor C5, inhibits hemolysis and reduces thrombotic risk. OBJECTIVES: To study neutrophil activation and nucleosome levels in relation to thrombosis in PNH patients before and during treatment with eculizumab. PATIENTS/METHODS: In 51 untreated PNH patients, including 20 patients before and after commencing eculizumab treatment, we have assessed neutrophil activation by measuring elastase-α1 -antitrypsin (EA) complexes and circulating nucleosomes, as established markers for systemic inflammation and cell death. RESULTS: Nucleosomes (median; range; 95% confidence interval [CI]), but not EA complexes, were higher in PNH patients with a history of thrombosis (16; 7-264; 0.3-94 U mL(-1) , n = 12) than in those without (6; 6-35; 7-11 U mL(-1) , n = 39) or controls (8; 6-23; 7-12 U mL(-1) , n = 17). EA complexes, but not nucleosomes, decreased promptly and markedly upon eculizumab treatment. EA complexes (estimated marginal means; 95% CI) remained low at ≥ 12 weeks (50; 34-67) compared with baseline (12; -6 to 29). CONCLUSIONS: The increased nucleosome levels in PNH patients with a history of thrombosis suggest systemic inflammation and/or cell death. Neutrophil activation markers did not differ between patients with and without a history of thrombosis and healthy controls. Interestingly, basal neutrophil activation in PNH patients significantly decreases on treatment with eculizumab, indicating that neutrophil activation is C5a driven.

Alterations in markers of coagulation and fibrinolysis in patients with Paroxysmal Nocturnal Hemoglobinuria before and during treatment with eculizumab.

BACKGROUND: Paroxysmal Nocturnal Hemoglobinuria is characterized by complement-mediated hemolysis and an increased thrombosis risk. Eculizumab, an antibody to complement factor C5, reduces thrombotic risk via unknown mechanisms. Clinical observations suggest that eculizumab has an immediate effect. OBJECTIVES: A better understanding of the mechanism via which eculizumab reduces thrombotic risk by studying its pharmacodynamic effect on coagulation and fibrinolysis. METHODS: We measured microparticles (MP), tissue factor (TF) activity, prothrombin fragment 1+2 (F1+2), D-dimer and simultaneously thrombin and plasmin generation in 55 PNH patients. In 20 patients, parameters were compared before and during eculizumab treatment (at 1 and 2hours, 1, 4 and≥12weeks after commencement). RESULTS: Patients with a history of thrombosis had elevated D-dimers (p=0.02) but not MP. Among patients on anticoagulants, those with thrombosis had higher F1+2 concentrations (p=0.003). TF activity was undetectable in plasma MP. Unexpectedly, thrombin peak height and thrombin potential were significantly lower in PNH patients than in healthy controls. Fibrinolysis parameters were normal. During eculizumab treatment D-dimer levels significantly decreased after 1hour (p=0.008) and remained decreased at≥12weeks (p=0.03). F1+2 (p=0.03) and thrombin peak height (p=0.02) in patients not on anticoagulants significantly decreased at≥week 12. MP remained unchanged. CONCLUSIONS: Eculizumab induces an immediate decrease of D-dimer levels but not of other markers. The decrease in thrombin peak height and F1+2 suggests that eculizumab reduces thrombin generation. Elevated D-dimer levels in untreated PNH patients with a history of thrombosis suggest possible value in predicting thrombotic risk.

High numbers of mobilized CD34+ cells collected in AML in first remission are associated with high relapse risk irrespective of treatment with autologous peripheral blood SCT or autologous BMT.

The faster hematopoietic recovery after autologous peripheral blood SCT (APBSCT) in patients with AML may be offset by an increased relapse risk as compared with autologous BMT (ABMT). The EORTC and GIMEMA Leukemia Groups conducted a trial (AML-10) in which they compared, as second randomization, APBSCT and ABMT in first CR patients without an HLA compatible donor. A total of 292 patients were randomized. The 5-year DFS rate was 41% in the APBSCT arm and 46% in the ABMT arm with a hazard ratio (HR) of 1.17; 95% confidence interval=0.85-1.59; P=0.34. The 5-year cumulative relapse incidence was 56% vs 49% (P=0.26), and the 5-year OS 50% and 55% (P=0.6) in the APBSCT and ABMT groups, respectively. APBSCT was associated with significantly faster recovery of neutrophils and platelets, shorter duration of hospitalization, reduced need of transfusion packed RBC and less days of intravenous antibiotics. In both treatment groups, higher numbers of mobilized CD34+ cells were associated with a significantly higher relapse risk irrespective of the treatment given after the mobilization. Randomization between APBSCT and ABMT did not result in significantly different outcomes in terms of DFS, OS and relapse incidence.

Clofarabine in combination with a standard remission induction regimen (cytosine arabinoside and idarubicin) in patients with previously untreated intermediate and bad-risk acute myelogenous leukemia (AML) or high-risk myelodysplastic syndrome (HR-MDS): phase I results of an ongoing phase I/II study of the leukemia groups of EORTC and GIMEMA (EORTC GIMEMA 06061/AML-14A trial).

This study aims to determine the maximum tolerated dose (MTD) of clofarabine combined with the EORTC-GIMEMA 3 + 10 induction regimen (idarubicin + cytosine arabinoside) in adults with untreated acute myelogenous leukemia or high-risk myelodysplastic syndrome. In this phase I trial, 25 patients (median age 56 years) received 5 days of clofarabine as 1-h infusion (arm A) or push injection (arm B) at the dose level of 5 × 10 or 5 × 15 mg/m(2)/day in an algorithmic dose escalation 3 + 3 design. A consolidation course (intermediate dose cytosine arabinoside, idarubicin) was planned for patients in complete remission (CR). Primary endpoint was safety and tolerance as measured by dose limiting toxicity (DLT); secondary endpoints were response rate, other grade III/IV toxicities, and hematological recovery after induction and consolidation. Five DLTs were observed (in arm A: one DLT at 10 mg/m(2)/day, three at 15 mg/m(2)/day; in arm B: one DLT at 15 mg/m(2)/day). Three patients receiving 15 mg/m(2)/day were withdrawn due to adverse events not classified as DLT. Prolonged hypoplasia was observed in five patients. CR + complete remission with incomplete recovery were achieved in 21 patients (11/12 (92 %) receiving clofarabine 10 mg/m(2)/day; 10/13 (77 %) receiving clofarabine 15 mg/m(2)/day). Clofarabine, 5 × 10 mg/m(2)/day, resulted in one DLT and no early treatment withdrawals. MTD of clofarabine combined with cytosine arabinoside and idarubicin is 5 × 10 mg/m(2)/day.

Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome.

BACKGROUND: Atypical hemolytic-uremic syndrome is a genetic, life-threatening, chronic disease of complement-mediated thrombotic microangiopathy. Plasma exchange or infusion may transiently maintain normal levels of hematologic measures but does not treat the underlying systemic disease. METHODS: We conducted two prospective phase 2 trials in which patients with atypical hemolytic-uremic syndrome who were 12 years of age or older received eculizumab for 26 weeks and during long-term extension phases. Patients with low platelet counts and renal damage (in trial 1) and those with renal damage but no decrease in the platelet count of more than 25% for at least 8 weeks during plasma exchange or infusion (in trial 2) were recruited. The primary end points included a change in the platelet count (in trial 1) and thrombotic microangiopathy event-free status (no decrease in the platelet count of >25%, no plasma exchange or infusion, and no initiation of dialysis) (in trial 2). RESULTS: A total of 37 patients (17 in trial 1 and 20 in trial 2) received eculizumab for a median of 64 and 62 weeks, respectively. Eculizumab resulted in increases in the platelet count; in trial 1, the mean increase in the count from baseline to week 26 was 73×10(9) per liter (P<0.001). In trial 2, 80% of the patients had thrombotic microangiopathy event-free status. Eculizumab was associated with significant improvement in all secondary end points, with continuous, time-dependent increases in the estimated glomerular filtration rate (GFR). In trial 1, dialysis was discontinued in 4 of 5 patients. Earlier intervention with eculizumab was associated with significantly greater improvement in the estimated GFR. Eculizumab was also associated with improvement in health-related quality of life. No cumulative toxicity of therapy or serious infection-related adverse events, including meningococcal infections, were observed through the extension period. CONCLUSIONS: Eculizumab inhibited complement-mediated thrombotic microangiopathy and was associated with significant time-dependent improvement in renal function in patients with atypical hemolytic-uremic syndrome. (Funded by Alexion Pharmaceuticals; C08-002 ClinicalTrials.gov numbers, NCT00844545 [adults] and NCT00844844 [adolescents]; C08-003 ClinicalTrials.gov numbers, NCT00838513 [adults] and NCT00844428 [adolescents]).

Mechanisms and clinical implications of thrombosis in paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired disease characterized by a clone of blood cells lacking glycosyl phosphatidylinositol (GPI)-anchored proteins at the cell membrane. Deficiency of the GPI-anchored complement inhibitors CD55 and CD59 on erythrocytes leads to intravascular hemolysis upon complement activation. Apart from hemolysis, another prominent feature is a highly increased risk of thrombosis. Thrombosis in PNH results in high morbidity and mortality. Often, thrombosis occurs at unusual locations, with the Budd­Chiari syndrome being the most frequent manifestation. Primary prophylaxis with vitamin K antagonists reduces the risk but does not completely prevent thrombosis. Eculizumab, a mAb against complement factor C5, effectively reduces intravascular hemolysis and also thrombotic risk. Therefore, eculizumab treatment has dramatically improved the prognosis of PNH. The mechanism of thrombosis in PNH is still unknown, but the highly beneficial effect of eculizumab on thrombotic risk suggests a major role for complement activation. Additionally, a deficiency of GPI-anchored proteins involved in hemostasis may be implicated.

Need for early recognition and therapeutic guidelines of congenital sideroblastic anaemia.

We present a patient with iron overload, who was initially diagnosed with hereditary haemochromatosis. Family analysis, however, established that the iron overload was secondary to congenital sideroblastic anaemia. The patient died of a hepatocellular carcinoma, likely a complication of iron overload, despite phlebotomies. Increased awareness, as well as development of evidence-based clinical guidelines, is required for timely diagnosis and adequate treatment.

Intensified chemotherapy inspired by a pediatric regimen combined with allogeneic transplantation in adult patients with acute lymphoblastic leukemia up to the age of 40.

Event-free survival (EFS) at 5 years in pediatric acute lymphoblastic leukemia (ALL) is >80%. Outcome in adult ALL is still unsatisfactory, which is due to less cumulative dosing of chemotherapy and less strict adherence to timing of successive cycles. In the present phase II trial, we evaluated a pediatric regimen in adult patients with ALL under the age of 40. Treatment was according to the pediatric FRALLE approach for high-risk ALL patients and characterized by increased dosages of asparaginase, steroids, methotrexate and vincristin. However, allogeneic stem cell transplantation was offered to standard risk patients with a sibling donor and to all high-risk patients in contrast to the pediatric protocol. Feasibility was defined by achieving complete remission (CR) and completion of treatment within a strict timeframe in at least 60% of patients. In all, 54 patients were included with a median age of 26. CR was achieved in 49 patients (91%), of whom 33 completed treatment as scheduled (61%). Side effects primarily consisted of infections and occurred in 40% of patients. With a median follow-up of 32 months, EFS estimated 66% at 24 months and overall survival 72%. These data show that a dose-intensive pediatric regimen is feasible in adult ALL patients up to the age of 40.

Non-infusional vs intravenous consolidation chemotherapy in elderly patients with acute myeloid leukemia: final results of the EORTC-GIMEMA AML-13 randomized phase III trial.

In this trial, acute myeloid leukemia patients (pts) aged 61-80 years received MICE (mitoxantrone, etoposide and cytarabine) induction chemotherapy in combination with different schedules of granulocyte colony-stimulating factor administration. Pts in complete remission were subsequently randomized for two cycles of consolidation therapy: mini-ICE regimen (idarubicin, etoposide and cytarabine) given according to either an intravenous (i.v.) or a 'non-infusional' schedule. Among the 346 pts randomized for the second step, 331 pts received consolidation-1 and 182 consolidation-2. A total of 290 events (255 relapses, 35 deaths in first CR) have been reported. The median follow-up was 4.4 years. No significant differences were detected in terms of disease-free survival (median 9 vs 10.4 months, P=0.15, hazard ratio (HR) =1.18, 95% confidence interval (CI) 0.94-1.49) - primary end point - and survival (median 15.7 vs 17.8 months, P=0.19, HR=1.17, 95% CI 0.92-1.50). In the 'non-infusional' arm grade 3-4 vomiting (10 vs 2%; P=0.001) and diarrhea (10 vs 4%; P=0.03) were higher than in the 'i.v.' arm, whereas time to platelet recovery >20 x 10(9)/l (median: 19 vs 23 days; P=0.02) and duration of hospitalization (mean: 15 vs 27 days; P<0.0001) was shorter. The 'non-infusional' consolidation regimen resulted in an antileukemic effect similar to the intravenous regimen, which was less myelosuppressive and associated with less hospitalization days.

Gemtuzumab ozogamicin (Mylotarg) as single-agent treatment for frail patients 61 years of age and older with acute myeloid leukemia: final results of AML-15B, a phase 2 study of the European Organisation for Research and Treatment of Cancer and Gruppo Italiano Malattie Ematologiche dell'Adulto Leukemia Groups.

The therapeutic activity and toxicity profile of gemtuzumab ozogamicin were assessed in 40 patients >60 years of age with acute myeloid leukemia (AML) who were not considered eligible for conventional chemotherapy because of advanced age or poor performance status. The drug was administered at the dose of 9 mg/m2 as a single 2-h i.v. infusion on days 1 and 15. Patients who achieved a complete remission (CR/CRp) were to receive a consolidation with two additional injections of the immunotoxin at the same dose. The overall CR/CRp rate was 17% (95% CI, 8-32%). The CR/CRp rate in patients 61-75 years old was 33% (6/18), and 5% (1/22) in patients older than 75 years. Induction death occurred in seven patients (17%), all aged above 75 years. Overall survival was significantly longer in patients aged 61-75 years than in older individuals (P=0.05), and in CD33+ cases than in CD33- cases (P=0.05). We conclude that the dose/schedule of gemtuzumab ozogamicin used in this trial is too toxic in the age group over 75 years. For these patients, additional studies with reduced doses of the immunotoxin are warranted.

The presence of an HLA-identical sibling donor has no impact on outcome of patients with high-risk MDS or secondary AML (sAML) treated with intensive chemotherapy followed by transplantation: results of a prospective study of the EORTC, EBMT, SAKK and GIMEMA Leukemia Groups (EORTC study 06921).

This report used the framework of a large European study to investigate the outcome of patients with and without an HLA-identical sibling donor on an intention-to-treat basis. After a common remission-induction and consolidation course, patients with an HLA-identical sibling donor were scheduled for allogeneic transplantation and patients lacking a donor for autologous transplantation. In all, 159 patients alive at 8 weeks from the start of treatment were included in the present analysis. In total, 52 patients had a donor, 65 patients did not have a donor and in 42 patients the availability of a donor was not assessed. Out of 52 patients, 36 (69%) with a donor underwent allogeneic transplantation (28 in CR1). Out of 65 patients, 33 (49%) received an autograft (27 in CR1). The actuarial survival rates at 4 years were 33.3% (s.e. = 6.7%) for patients with a donor and 39.0% (s.e. = 6.5%) for patients without a donor (P = 0.18). Event-free survival rates were 23.1% (s.e. = 6.2%) and 21.5% (s.e. = 5.3%), respectively (P = 0.66). Correction for alternative donor transplants did not substantially alter the survival of the group without a donor. Also, the survival in the various cytogenetic risk groups was not significantly different when comparing the donor vs the no-donor group. This analysis shows that patients with high-risk myelodysplastic syndrome and secondary acute myeloid leukemia may benefit from both allogeneic and autologous transplantation. We were unable to demonstrate a survival advantage for patients with a donor compared to patients without a donor.

Chemotherapy only compared to chemotherapy followed by transplantation in high risk myelodysplastic syndrome and secondary acute myeloid leukemia; two parallel studies adjusted for various prognostic factors.

Comparisons of the effectiveness of chemotherapy and transplantation in AML in first complete remission (CR) have focused almost exclusively on patients with de novo disease. Here we used Cox modelling to compare these strategies in patients with MDS and s-AML treated by the Leukemia Group of the EORTC or at the MD Anderson Cancer Center. All patients were aged 15-60. The 184 EORTC patients received conventional dose ara-C + idarubicin + etoposide for remission induction, and after one consolidation course, were scheduled to receive an allograft, or an autograft if a sibling donor was unavailable. The 215 MDA patients received various high-dose ara-C containing induction regimens, and in CR, continued to receive these regimens at reduced dose for 6-12 months. CR rates were 54% EORTC and 63% MDA (P = 0.09). Sixty-five of the 100 EORTC patients who entered CR received a transplant in first CR. Disease-free survival in patients achieving CR was superior in the EORTC cohort, the 4-years DFS rates were 28.9% (s.e. = 4.8%) EORTC vs 17.3% (s.e. = 3.7%) MDA (P = 0.017). Survival from CR was not significantly different in the EORTC and MDA groups, as was survival from start of treatment. After accounting for prognostic factors the conclusions were unchanged. Despite various problems with the analysis discussed below, the data suggest that neither transplantation nor chemotherapy, as currently practised, can be unequivocally recommended for these patients in first CR and that questions as to the superior modality may be less important than the need to improve results with both.

Intensive chemotherapy followed by allogeneic or autologous stem cell transplantation for patients with myelodysplastic syndromes (MDSs) and acute myeloid leukemia following MDS.

This study investigated the feasibility of allogeneic (alloSCT) and autologous stem cell transplantation (ASCT) as postconsolidation therapy for patients with myelodysplastic syndromes (MDSs) or acute myeloid leukemia after MDS. Patients with a histocompatible sibling were candidates for alloSCT and the remaining patients for ASCT. Remission-induction therapy consisted of 1 or 2 courses with idarubicin, cytarabine, and etoposide, followed by one intensive consolidation course with cytarabine and mitoxantrone. Initially, bone marrow cells were used for ASCT. Subsequently, mobilized blood stem cells were used in an attempt to shorten posttransplantation hypoplasia. With a median follow-up of 3.6 years the 184 evaluable patients showed a 4-year survival rate of 26% and a median survival of 13 months. The remission-induction chemotherapy induced complete remission (CR) in 100 patients (54%). The 4-year disease-free survival (DFS) rate was 29% and the median DFS was 12 months. Twenty-eight of 39 patients (72%) with a donor were allografted in CR-1, including 2 patients who underwent transplantation in CR-1 without a consolidation course. Thirty-six of 59 patients (61%) without a donor received ASCT in CR-1. The 4-year DFS rates in the group of patients with or without a donor were 31% and 27%, respectively. The 4-year survival rates from CR were 36% and 33%, respectively. This large prospective study shows the feasibility of both alloSCT and ASCT. This treatment approach leads to a relatively high remission rate, and the majority of patients in remission received the SCT in CR-1. The ongoing study investigates whether this approach is better than treatment with chemotherapy only.

Cyclosporin increases cellular idarubicin and idarubicinol concentrations in relapsed or refractory AML mainly due to reduced systemic clearance.

The feasibility of adding both the multidrug resistance modulator cyclosporin (CsA) and granulocyte colony-stimulating factor (G-CSF) to a standard salvage regimen of idarubicin (IDA) and cytarabine was evaluated in patients with resistant or relapsed acute myeloid leukemia and myelodysplastic syndrome. Three patients received IDA 12 mg/m2/day, the next four patients 9 mg/m2/day. The dose of CsA was 16 mg/kg/day. Six patients showed Pgp expression and none MRP1 expression. Grade III or IV toxicity (CTC-NCIC criteria) was registered in six patients for gastrointestinal, two patients for cardiovascular and one patient for neurological complications. Three patients died in hypoplasia and three patients showed leukemic regrowth. Three control patients were treated with IDA 12 mg/m2/day and cytarabine, but no CsA and G-CSF. The plasma IDA and idarubicinol (ida-ol) area under the curve's of patients treated with IDA 12 mg/m2 plus CsA were higher (P< 0.05) than in controls. Cellular IDA concentrations were almost similar, but cellular ida-ol concentrations were significantly higher (P < 0.05) in the presence of CsA than in controls. We conclude that the toxicity either with IDA 12 or 9 mg/m2/day was too high. The modulating effect of CsA was mainly based on changes in plasma kinetics of IDA and ida-ol, although ida-ol cellular clearance was delayed in the presence of CsA.

Long-term follow-up confirms the benefit of all-trans retinoic acid in acute promyelocytic leukemia. European APL group.

First results of a randomized trial (APL91 trial) and other randomized or non-randomized studies have shown that ATRA followed by chemotherapy significantly increased event-free survival (EFS) and survival, and decreased the incidence of relapse by comparison to chemotherapy alone in newly diagnosed APL. We present here long-term follow-up of the APL91 trial. In this trial, 101 patients had been randomized between ATRA followed by three courses of daunorubicin-AraC chemotherapy (ATRA group) and the same chemotherapy alone (chemotherapy group). Results were reanalyzed 73 months after closing of patient entry. Updated results of APL 91 trial found a Kaplan-Meier estimate of EFS and relapse rate at 4 years of 63% and 31% in the ATRA group, as compared to 17% and 78% in the chemotherapy group (P= 10(-4) and relative risk 2.95, P= 10(-4) and relative risk 3.68, respectively). Kaplan-Meier survival at 4 years was 76% in the ATRA group and 49% in the chemotherapy group (P= 0.026, relative risk 2.7). In the chemotherapy group, seven of the 27 relapses occurred after 18 months, but no relapse was seen after 43 months. In the ATRA group, four of the 17 relapses occurred after 18 months, including two late relapses (at 58 and 74 months). In the chemotherapy group, 23 of the 25 patients who relapsed achieved a second CR with ATRA, and the Kaplan-Meier estimate of second relapse was 40% at 30 months. In the ATRA group, the 10 patients who relapsed and were retreated with ATRA achieved a second CR. In conclusion, long-term results of APL91 trial confirm the superiority of the combination of ATRA and chemotherapy over chemotherapy alone in newly diagnosed APL, and that ATRA should be incorporated in the front-line treatment of APL.

Cost analysis of autologous peripheral stem cell transplantation versus autologous bone marrow transplantation for patients with non Hodgkin's lymphoma and acute lymphoblastic leukaemia.

We evaluated the costs of unpurged autologous stem cell transplantation in a non-randomised study of 54 consecutive patients with lymphoproliferative malignancies who have been transplanted at the Nijmegen University Hospital between July 1992 and March 1998. Thirty-five patients were transplanted with autologous peripheral stem cells (APSCT): 30 had non Hodgkin's lymphoma (NHL) and 5 acute lymphoblastic leukaemia (ALL). Nineteen patients were transplanted with autologous bone marrow stem cells (ABMT): 17 had NHL and 2 ALL. The number of progenitor cells (CFU-GM, BFU-E) and nucleated cells was significantly higher in peripheral blood transplants. The duration of cytopenia was shorter after APSCT. The leucocyte recovery to 0.5 x 10(9)/L was 13 days for recipients of peripheral stem cells compared to 20 days for bone marrow recipients (P <0.001). The platelet recoveries to 20 x 10(9)/L were 13 and 29 days, respectively (P = 0.001). This resulted in significantly shorter admission duration 24 days after APSCT versus 30 days (P = 0.003) after ABMT. Furthermore, a statistically significant difference between both groups was observed for antimicrobial costs (mean: fl 2,939 vs fl 4,888; P = 0.008), platelet transfusions (median: 3 vs 7 units; P = 0.01) and erythrocyte transfusions (median: 6 vs 10 units; P = 0.03). The mean overall costs were lower in patients transplanted with stem cells from peripheral blood: fl 34,178 versus fl 43,469 (P = 0.007). This study suggests that the APSCT results in significant cost savings due to shorter hospital stay and less costs of supportive care, despite higher mobilisation costs. The costs of blood transfusions and antimicrobials for patients with ALL were significantly higher when compared to patients with NHL.