Autologous stem cell transplantation in adults with acute lymphoblastic leukemia in first complete remission: analysis of the LALA-85, -87 and -94 trials.

To evaluate the results of autologous stem cell transplantation (ASCT) in a large population of adults with acute lymphoblastic leukemia (ALL) in first complete remission (CR), we performed an individual data-based overview of the last three trials from the LALA group. Overall, 349 patients with ALL prospectively randomized in the consecutive LALA-85, -87, and -94 trials to receive either ASCT or chemotherapy as post-CR treatment were analyzed. Eligibility criteria were 15-50-year-old patients without sibling donors in both LALA-85/87 trials and 15-55-year-old patients with high-risk ALL and no sibling donors in the LALA-94 trial. Intent-to-treat analysis, which compared 175 patients from the ASCT arm to 174 patients from the chemotherapy arm, showed that ASCT was associated with a lower cumulative incidence of relapse (66 vs 78% at 10 years; P=0.05), without significant gain in disease-free or overall survival. Despite a possible lack of statistical power, a nested case-control analysis performed in 85 patient pairs adjusted for time to transplant and prognostic covariates confirmed these intent-to-treat results in patients actually transplanted. Of interest, the reduced relapse risk after ASCT translated in better disease-free survival in the 300 rapid responders who reached CR after the first induction course.

Adult T-biphenotypic acute leukaemia: clinical and biological features and outcome.

Biphenotypic acute leukaemia with T-lymphoid and myeloid markers is rare and poorly documented. In the Leucemie Aigue Lymphoblastique de l'Adulte (LALA) prospective trial (LALA 94) of treatment for adult acute lymphoblastic leukaemia (ALL), seven patients (0.86%) had T-biphenotypic forms. The clinical and biological characteristics and outcome of these seven patients are reported here. The patients' median age was 35 years. At diagnosis, all had a tumoural syndrome and five had a mediastinal mass. In all the cases, leukaemic cells expressed myeloid and lymphoid markers. Two patients (28%) entered complete remission (CR) after induction chemotherapy. Four of the five remaining and assessable patients entered CR after designed salvage chemotherapy with mitoxantrone and high-dose cytosine arabinoside. Three patients are currently in CR. Three patients died, from treatment toxicity in two cases and progressive disease in one case. One patient relapsed 6 months after allogeneic bone marrow transplantation and is still alive. Thus, biphenotypic T-acute leukaemia is clinically frequently associated with mediastinal involvement and the response to conventional chemotherapy used in ALL is poor. However, sustained CR can be achieved by salvage chemotherapy combining an intercalating agent with high-dose cytosine arabinoside, as used in acute myeloid leukaemia.

Anthracycline-related toxicity requiring cardiac transplantation in long-term disease-free survivors with acute promyelocytic leukemia.

We describe three cases of acute promyelocytic leukemia (APL) with long-term disease-free survival who developed congestive heart failure (CHF) requiring cardiac transplantation. All three patients presented late-onset cardiotoxicity. Cardiac failure occurred progressively after 31-month, 32-month, and 14-month intervals, respectively, following completion of first anthracycline therapy. Cumulative anthracycline doses were 585 mg of daunorubicin and 64 mg of mitoxantrone in case 1, 1779 mg of daunorubicin in case 2, and 825 mg of daunorubicin in case 3. The questions relating to the pathogenesis of cardiac failure are discussed. We also discuss the prophylactic measures required for such treatment-related side effects.

Influence of cigarette smoking on the presentation and course of acute myeloid leukemia.

BACKGROUND: It is known that cigarette smoking is associated with an approximately 50% increase in leukemia risk. In order to detect a possible influence of cigarette smoking on initial characteristics at the time of presentation and on the course of the disease, we conducted a retrospective study in 643 patients with newly diagnosed acute myeloid leukemia. PATIENTS AND METHODS: The study comprised 339 males and 304 females (median age 59 years, range 18-84 years). Two hundred and ninety-six patients (46%), smoking at least one cigarette per day for 6 months, were considered as smokers, while 347 patients (54%) were non-smokers. RESULTS: Cigarette smoking was significantly related to male gender (P <0.0001), professional occupancy (P = 0.002), presence of organomegaly (P = 0.01), and lower peripheral blood and bone marrow leukemic cell involvement (P = 0.007 and P = 0.0001, respectively). Leukemia of French-American-British (FAB) M1 subtype was more frequent in non-smokers (P = 0.005). Although not statistically significant, smokers tended to have lower leukocyte counts than non-smokers. No difference was noted in terms of complete remission rates between smokers and non-smokers (67% compared to 64%). However, a higher rate of severe pulmonary infection was observed in smokers during induction chemotherapy (P = 0.02). Cigarette smoking (>or=20 pack-years or smoking duration >or=30 years) was significantly associated with shorter disease-free survival (P = 0.03) and overall survival (OS; P = 0.02 and P = 0.004, respectively). Other characteristics associated with poor prognosis included mainly older age, unfavorable karyotype, secondary acute myeloid leukemia (AML) and elevated World Health Organization (WHO) performance status. Cigarette smoking was associated with shorter OS in younger adults, but did not significantly influence survival in patients >60 years old. Cigarette smoking worsened the poor OS in patients with unfavorable karyotype, but did not significantly influence the prognosis of other karyotypic risk groups. In a multivariate analysis, only karyotypic grouping and age remained of prognostic value for the occurrence of disease-free and overall survival. CONCLUSIONS: Cigarette smoking has a deleterious effect on survival in AML by shortening complete remission duration and subsequent survival. It was associated with severe infections during aplasia. Leukemogenic compounds favoring complex karyotypic abnormalities could also be involved.

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.

Treatment of acute lymphoblastic leukemia in the elderly: an evaluation of interferon alpha given as a single agent after complete remission.

Although interferon (IFN) has been used in elderly patients with acute lymphoblastic leukemia (ALL), the benefits from IFN therapy have not been properly assessed, especially as it was given combined with other cytotoxic drugs, which obscured the role of IFN if any. In 1997, we started a study aimed at improving our previous results in elderly patients with ALL and at assessing the therapeutic role of IFN in this disease. Fifty-eight patients with ALL, aged 55-81 years (median: 64.9 years), were randomly allocated to treatment with vindesine or vincristine during induction. After a first consolidation course, IFN was administered as a single agent for three months together with cranial radiotherapy. Chemotherapy was then resumed with a second consolidation course and maintenance. A complete remission (CR) was obtained in 58% of patients (CI: 45-71%), significantly less than in our previous study which included IFN combined with chemotherapy during maintenance (CR: 85%, CI:70-94%, p = 0.007). Overall survival (median: 289 vs 434 days in the previous study, p = 0.01) and disease-free survival (median: 146 vs 427 days, p = 0.009) were also inferior in the present study. In particular, the pattern of relapses over time suggested that the 3 month IFN treatment phase with no additional chemotherapy might have contributed to the comparatively poor outcome of this cohort. In addition, vindesine given during induction did not prove less neurotoxic than vincristine, did not improve the CR rate, and had no impact on survival. In conclusion, although similar to published studies in elderly patients with ALL, this study is inferior to our previous one. INF, given as a single drug, has a modest role if any in the treatment of older persons with ALL.

Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus.

During the past several decades, there has been a steady increase in the frequency of opportunistic invasive fungal infections (IFIs) in immunocompromised patients. However, there is substantial controversy concerning optimal diagnostic criteria for these IFIs. Therefore, members of the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group formed a consensus committee to develop standard definitions for IFIs for clinical research. On the basis of a review of literature and an international consensus, a set of research-oriented definitions for the IFIs most often seen and studied in immunocompromised patients with cancer is proposed. Three levels of probability are proposed: "proven," "probable," and "possible." The definitions are intended for use in the context of clinical and/or epidemiological research, not for clinical decision making.

Autologous transplantation in acute myeloid leukemia: peripheral blood stem cell harvest after mobilization in steady state by granulocyte colony-stimulating factor alone.

In order to determine whether granulocyte colony-stimulating factor (G-CSF) alone initiated during steady state was able to mobilize peripheral blood stem cells (PBSC) in acute myeloid leukemia (AML) and to assess predictive factors for engraftment after autologous PBSC transplantation, we studied 49 successive adult AML patients for whom autologous transplantation was planned between July 1994 and November 1998. G-CSF was used as priming agent and was initiated at least 4 weeks after the last day of chemotherapy, while neutrophil count was >0.5 x 10(9)/l and platelet count was >30 x 10(9)/l. A median of three aphereses was performed resulting in a median collection of 14.8 x 10(8) nucleated cells/kg containing 7.7 x 10(8) mononuclear cells/kg, 47.1 x 10(4) CFU-GM/kg, and 3.8 x 10(6) CD34+ cells/kg. A significant correlation was observed between nucleated cell, mononuclear cell, and CFU-GM yields, while no correlation was found with CD34+ cell yield. Recruitment was not significantly different in patients with CD34+ leukemic cells at the time of initial diagnosis when compared to that of those presenting with CD34- blastic cells. Thirty-three patients actually underwent transplantation. Reasons for not autografting were inadequate stem cell harvest (ten patients), early relapse (two patients), prolonged neutropenia (one patient), organ failure (two patients), or patient refusal (one patient). Median time to achieve a neutrophil count greater than 0.5 x 10(9)/l and platelet count >50 x 10(9)/l untransfused was 13 and 36 days, respectively. A predictive factor for a shorter period neutropenia and a shorter thrombopenia was a higher count of harvested nucleated cells (p < 0.01 and p = 0.02, respectively). A higher count of harvested cells was also a predictive factor for less red cell and platelet transfusions (p=0.03 and p=0.02, respectively). The number of CD34+ harvested PBSC was not predictive for engraftment. We conclude that PBSC mobilization with G-CSF alone initiated in steady state is a feasible, safe, and suitable procedure for harvesting cells in sight of autologous transplantation in adult acute myeloid leukemia.

Long-term follow-up of patients with newly diagnosed adult acute lymphoblastic leukemia: a single institution experience of 378 consecutive patients over a 21-year period.

Although the prospect of long-term leukemia-free survival (LFS) after treatment for adult acute lymphoblastic leukemia (ALL) is widely accepted, few studies have reported long-term survival data. Three hundred and seventy-eight ALL patients, referred to our hospital from 1978 to 1999, were reviewed for long-term follow-up data. The analysis included data on 351 patients treated by standard chemotherapy according to 11 different successive and/or concomitant regimens. Complete remission (CR) was achieved in 299 patients (79%). Initial performance status, LDH level, immunophenotype, age, and risk group (defined according to Hoelzer's criteria) at diagnosis were of significant prognostic value for CR achievement. Median leukemia-free survival (LFS) was 14 months with a 3-year, a 5-year, and an 8-year LFS at 30%, 26%, and 24%, respectively. LFS was better in T cell lineage ALL than in B cell lineage ALL (P = 0.05). Younger age was also a favorable prognostic factor for LFS (P = 0.001). Philadelphia-positive (Ph+) ALL displayed a poor outcome since median LFS was 7 months with only 13% of survival at 3 years. Median overall survival (OS) of the entire cohort was 18 months with a 3-year, a 5-year, and an 8-year OS at 32%, 24%, and 22% respectively. Favorable prognostic factors for OS were younger age (P < 0.0001), and T cell lineage ALL (P = 0.001). Among non-T cell lineage ALL, standard-risk ALL confirmed a significant better outcome than high-risk ALL (P = 0.0003). It was apparent from this analysis that hazard rates for death and relapse were greatest in the first year, decreased substantially between years 1 and 2, then decrease further between years 2 and 3. Rates of death and relapse were quite low after 3-4 years. All patients relapsing after 3 years of CR were B or non-B non-T cell lineage ALL. Long-term survivors (LTS), defined as survival in CR > or =3 years, represented 23% of evaluable patients. Eighty-three patients remain alive in initial CR at >3 years, while only three were LTS after a second CR. Overall, no significant improvement was shown in terms of CR achievement and survival duration over the years. However, regarding survival, a significant improvement was demonstrated in T cell lineage ALL (P = 0.03). Furthermore, patients (aged less than 50 years) transplanted while in first CR did significantly better than those receiving only chemotherapy as post-remission therapy (P < 0.0001). The 3-year OS, after allogeneic transplantation in first CR, was 74% in T cell lineage ALL, while it was less than 50% in B cell lineage ALL. This single center study on a large cohort of ALL patients reflects the degree to which ALL treatment remains unsuccessful in adults. Only T cell lineage ALL outcomes have improved over the years. The results suggest a time (3 years) at which it becomes reasonable to speak of potential cure, provided the patient is in CR.

Prognostic factors and treatment effects on survival in acute myeloid leukemia of M6 subtype: a retrospective study of 54 cases.

UNLABELLED: classification system of acute myeloid leukemia (AML) which designates it as M6 AML. This report describes the data of 54 patients with newly diagnosed M6 AML, consecutively seen in our hospital between May 1976 and May 1999. PATIENTS AND METHODS: There were 40 males and 14 females. Median age was 59 years. Pancytopenia was the most common feature at diagnosis. Twenty-six percent of cases presented with secondary AML. Karyotype was successfully performed in 35 cases. Eleven patients presented with normal karyotype, nine with simple karyotypic abnormalities, and fifteen with major karyotypic abnormalities. Fifty of the fifty-four patients received one or two courses of induction chemotherapy combining anthracyclines with cytarabine according to different successive protocols. One elderly patient only received low-dose cytarabine, and three patients died before any chemotherapy could be given. RESULTS: Complete remission (CR) was achieved in 29 cases (54%, 95% confidence interval (CI): 40%-67%). As post-remission therapy, four patients could be allografted, and two underwent autologous transplantation. All other treated patients received continuation chemotherapy. Twenty-one patients have relapsed (72%). Median time to relapse was six months. Among those patients, only eight achieved a second CR (38%). The median disease-free survival (DFS) was eight months (95% CI: 4-10 months) with a five-year survival rate of 17%. Median overall survival (OS) was nine months (95% CI: 5-12 months) with a five-year survival rate of 13%. In univariate analysis, poor prognostic factors for DFS were secondary AML (P = 0.05) and initial platelet count <50 x 109/l (P = 0.02). Poor prognostic factors for OS were age > or = 60 years (P = 0.005), secondary AML (P = 0.05), initial 'blastic' fever (P = 0.0004), and initial haemoglobin level < 90 g/l (P = 0.03). All factors, but haemoglobin level, remained significant in the multivariate analysis. Although it was not statistically significant, there was a trent for a better prognosis of M6 patients presenting with normal karyotype as compared to those displaying chromosomal abnormality. CONCLUSIONS: This retrospective analysis points to a somewhat heterogenous group of AML in terms of clinical and biological features, and outcome. Distinctive subgroups can be identified according to prognostic factors related to survival. A larger multicenter study with well-defined diagnostic criteria is warranted to further clarify treatment effects.

Acute lymphoblastic leukemia in the elderly: The Edouard Herriot Hospital experience.

Data on all patients with acute lymphoblastic leukemia (ALL) aged 60 or older, referred to our institution over a 18-year period, were studied to determine the incidence and range of clinical and biological subtypes, and the outcome of different therapeutic approaches. Sixty-nine ALL cases (median age: 68 years) were diagnosed between 1980 and 1998 (18% of all adult ALL seen during this period). Ten of them (14%) had a past history of previous malignancy. Karyotypic analysis was performed successfully in 42 cases. Ten patients were diagnosed as Philadelphia chromosome positive (Ph(+)) ALL. Immunophenotyping was performed in 63 cases. Fifty-six patients had B-cell lineage ALL. T lymphoid markers were observed only in 5 cases. Co-expression of myeloid markers was observed in 19% of tested cases. Five patients died before any chemotherapy could be given. All other patients received "curative" treatment according to different protocols used during the period of study. Overall complete remission (CR) rate of these patients was 62% (95% confidence interval (CI): 50-74%). Thirty-nine patients achieved CR after one course of chemotherapy and 4 patients after salvage therapy. Median disease-free survival (DFS) of the entire cohort was 8.3 months (95% CI: 5-12.8 months) and median overall survival was 7 months (95% CI: 6-10 months). In multivariate analysis, the presence of hemorrhage (P = 0.02) was a poor prognostic for CR achievement. Higher WHO performance status (P = 0.003) and the presence of hemorrhage (P = 0.01) at diagnosis were poor prognostics for overall survival. When patients were stratified into three groups according to the time of admission, survival appeared significantly longer for patients admitted between July 1992 and December 1998 (median overall survival at 10 months) than for patients admitted before July 1992 (P = 0.04). "Age-adapted" therapy appeared superior to "young adult-like" therapy in terms of CR rate (96% versus 60%; P = 0.007). However, "age-adapted" therapy did not show any advantage in terms of DFS or overall survival, making the difference in CR rates questionable. We conclude that the pejorative overall outcome in elderly ALL points to the need for new therapeutic trials taking into account the specific characteristics of ALL in this age group.

[Effectiveness of combined vancomycin and pefloxacine in gastrointestinal decontamination for preventing infections after chemotherapy-induced bone marrow aplasia. A randomized double-blind study]. / Intérêt d'associer la vancomycine à la péfloxacine en décontamination digestive pour la prévention des infections après chimiothérapie aplasiante. Etude randomisée en double insu.

OBJECTIVE: To test the value of the combination of pefloxacin and vancomycin as gastro-intestinal tract decontamination for the prevention of infections in patients with chemotherapy-induced neutropenia. PATIENTS AND METHODS: Oral pefloxacin plus vancomycin (48 patients), pefloxacin alone (51 patients), or placebo (52 patients) were administered in a randomized double-blind study. Evaluation was done by determining site and documentation of infections, organisms responsible for bacteriologically documented infections, organisms acquired in surveillance cultures and number of days with fever during aplasia. RESULTS: Patients receiving pefloxacin had significantly fewer episodes of bacteremia with enterobacteriacae. No differences were noted between patients treated by pefloxacin and those who received a combination of pefloxacin with vancomycin regarding gram-positive (Gram+) infections and infections with gram-negative (Gram-) organisms usually resistant to pefloxacin. However, placebo gave similar results. There was no induction of resistance to pefloxacin during the study. Tolerance of treatment was excellent. Only a prolonged aplasia has been observed in patients receiving pefloxacin. CONCLUSION: Thus, the combination of vancomycin with pefloxacin was not more efficacious than pefloxacin only for the prevention of Gram+ infections in the neutropenic patient. The systematic use of antibiotics as gastrointestinal tract decontamination for the prevention of infections in patients with aplasia may be questionable.

Feasibility and recent improvement of autologous stem cell transplantation for acute myelocytic leukaemia in patients over 60 years of age: importance of the source of stem cells.

A total of 193 patients with acute myelocytic leukaemia (AML) [147 in first complete remission (CR1)], ranging from 60 years to 75 years of age (median 63 years), were autografted between January 1984 and December 1998. The source of stem cells was peripheral blood (PB) in 128 patients, bone marrow in 51 patients and a combination of both in 14 patients. Total body irradiation (TBI) was used in 34 cases. Ninety-seven per cent of patients had successful engraftment of neutrophils on day 15 (range days 7-71) and of platelets on day 30 (range days 9-894). In patients autografted in CR1, the transplant-related mortality (TRM) was 15 +/- 4%, the relapse incidence (RI) was 58 +/- 5%, the leukaemia-free survival (LFS) was 36 +/- 5% and the overall survival was 47 +/- 5% at 3 years. The source and dose of stem cells were studied in particular; in patients transplanted in CR1, the RI was 44 +/- 11% in those receiving marrow compared with 63 +/- 6% in those receiving PB (P = 0.04). Patients autografted in CR1 who received higher granulocyte-macrophage colony-forming units (CFU-GM) doses (above the median) had a lower RI (47 +/- 11% vs. 79 +/- 9%, P = 0.009). There was a significant improvement in patients transplanted after March 1996; for those in CR1, the RI was 41 +/- 8% vs. 65 +/- 6% (P = 0.01), the LFS was 53 +/- 8% vs. 28 +/- 5% (P = 0.01) and the overall survival was 72 +/- 7% vs. 36 +/- 6% (P = 0.02). By multivariate analyses, significant factors for the outcome were the date of transplant with recent improvement and the source of stem cells, with a lower RI for marrow. Autologous stem cell transplantation (ASCT) is a potential therapeutic approach in patients with AML over 60 years of age; results have improved recently.

Transplantation with selected autologous peripheral blood CD34+Thy1+ hematopoietic stem cells (HSCs) in multiple myeloma: impact of HSC dose on engraftment, safety, and immune reconstitution.

OBJECTIVE: The aims of our study performed in myeloma were to evaluate the performance and the safety of Systemix's high-speed clinical cell sorter, to assess the safety and efficacy of deescalating cell dose cohorts of CD34+Thyl+ hematopoietic stem cells (HSCs) as autologous grafts by determining engraftment, and to assess the residual tumor cell contamination using polymerase chain reaction (PCR) amplification assays of patient-specific complementarity determining region III (CDR III) analysis for residual myeloma cells. MATERIALS AND METHODS: The clinical trial was performed in 31 multiple myeloma patients, using purified human CD34+Thyl+ HSCs mobilized from peripheral blood with cyclosphosphamide and granulocyte-macrophage colony-stimulating factor to support a single transplant after high-dose melphalan 140 mg/m2 alone (cohort 1) and with total body irradiation (TBI) (cohorts 2-5) after an HSC transplant cell dose de-escalation/escalation design. RESULTS: Twenty-three patients were transplanted. Engraftment data in the melphalan + TBI cohorts confirmed that HSC doses above the threshold dose of 0.8 x 10(6) CD34+Thy1+ HSCs/ kg provided prompt engraftment (absolute neutrophil count >0.5 x 10(9)/L day 10; platelet count >50 x 10(9)/L day 13). A higher rate of infections was observed in the early and late follow-up phases than usually reported after CD34+ selected or unselected autologous transplantation, which did not correlate with the CD34+Thy1+ HSC dose infused. Successful PCR for CDR III could only be performed in five patients on initial apheresis product and final CD34+Thy1+ HSC product and showed a median tumor log reduction >3.12. CONCLUSIONS: CD34+Thy1+ HSCs are markedly depleted or free of detectable tumor cells in multiple myeloma and are capable of producing fast and durable hematopoietic reconstitution at cell doses >0.8 x 10(6) CD34+Thy1+ HSCs/kg. The delayed immune reconstitution observed is not different from that described in unselected autologous bone marrow and peripheral blood mononucleated cells transplants in multiple myeloma and may be corrected by addition of T cells either to the graft or to the patient in the posttransplant phase.

Adult acute lymphocytic leukemia study testing chemotherapy and autologous and allogeneic transplantation. A follow-up report of the French protocol LALA 87.

The French protocol LALA 87 was designed to compare three different postinduction strategies in adult acute lymphocytic leukemia (ALL): chemotherapy, autologous transplantation, and allogeneic transplantation. This trial demonstrated a significant superiority of allogeneic bone marrow transplantation (BMT) in high-risk ALL patients. Similarly, there was a trend in favor of autologous BMT over chemotherapy in those same patients. Allogeneic BMT was not superior to autologous BMT or chemotherapy in less aggressive leukemia (standard-risk ALL). Further improvements are warranted in the treatment of adult ALL. The authors' current ongoing study is stratifying patients to allocate them to regimens with risk-adapted treatment intensity.

Late autologous transplantation in chronic myelogenous leukemia with peripheral blood progenitor cells mobilized by G-CSF and interferon-alpha.

In chronic myelogenous leukemia (CML), autologous stem cell transplantation could be a promising new approach for patients with no cytogenetic response after interferon alpha (IFN-alpha) therapy. We report data on 28 CML patients autotransplanted in chronic phase with peripheral blood progenitor cells mobilized with G-CSF (5 microg/kg/day x 5 days) given subcutaneously while continuing IFN-alpha therapy. At mobilization, 23 patients (82%) were in complete hematological remission (CHR), 16 (57%) achieved a minor cytogenetic response (mcr). We obtained, after stimulation, a median of 37.4 x 10(9)/l (6.9-108) white blood cells, 7.2 x 10(8)/kg (2.2-16.6) mononuclear cells, 39 x 10(4)/kg (4.8-403.5) CFU-GM and 4.2 x 10(6)/kg (0-58.6) CD34+ cells. Six patients received GM-CSF after transplantation. All patients engrafted, with no significant influence stemming from the Sokal index score and pretransplantation IFN-alpha therapy duration. The first cytogenetic evaluation after transplantation showed 11 (39%) major cytogenetic response (Mcr), and nine (32%) mcr with no significant correlation between these responses, the Sokal index score, and pretransplantation IFN-alpha therapy duration, although there was a significant impact from GM-CSF administration (P=0.01). After transplantation, 26 patients received IFN-alpha alone or associated with hydroxyurea. The median follow-up was 12 months after transplantation and 57 months after diagnosis. At the time of follow-up, nine patients were in CHR, six remained stable in chronic phase, three presented an mcr and one remained in Mcr. At the last follow-up, 22 patients were alive. We conclude that the results of this strategy are encouraging in poor IFN-alpha responders but that other prospective studies that try to maintain the cytogenetic responses obtained immediately after transplantation are needed.

Continuous-infusion carboplatin in combination with idarubicin or mitoxantrone for high-risk acute myeloid leukemia: a randomised phase II study.

Fifty-three patients of median age 66 years (39 patients > 60 yrs), including 5 with FAB unclassified or secondary acute myeloid leukemia (AML) at diagnosis, 14 with resistant AML, 19 in first and 15 in subsequent relapse, were treated with carboplatin (CBP), 200 mg/m2/day, as a continuous infusion, (days 3 to 7) with mitoxantrone (MIT) or idarubicin (IDA), (12 mg/m2/day) as an i.v. bolus, on days 1 to 3. Results were evaluated after one induction course. Overall, 15 patients (28% [95% confidence interval (CI), 17-42%], 8/28 with IDA and 7/25 with MIT) achieved complete remission (CR). There was no statistical difference between IDA and MIT arms. Fourty-nine percent (95% CI, 35-63%) had resistant disease (53% IDA versus 44% MIT respectively) and 23% (95% CI, 12-36%) died from toxicity (18% IDA versus 28% MIT). Median durations of neutrophils less than 0.5 x 10(9)/l and platelet counts less than 20 x 10(9)/l were 32 and 32 days respectively in the IDA arm and 31 and 26 days respectively in the MIT arm. Severe toxicity included infections (45%), diarrhea (21%), bleeding (9%), vomiting (7%), hyperbilirubinemia (6%), mucositis (4%) (no statistical difference was seen between both arms). Nephrotoxicity was observed in only one case in the IDA arm. Cardiac toxicity included reversible pulmonary oedema in one patient in the IDA arm. No severe ototoxicity was noted. CR patients received maintenance courses with 3 days of CBP and one day of IDA or MIT. Median survival was 2 months (range, 1-30+ months) and 2.5 months (range, 0.5-19.5 months), and median disease-free survival (DFS) 2 months (range, 1-30+ months) and 2.5 months (range, 1-14 months) in the IDA and MIT arms respectively. We conclude that CBP at a cumulative dosage of 1 g/m2 together with intercalating agents (IDA/MIT) has antileukemic efficacy in elderly patients.

Impact of cyclosporine and methylprednisolone dose used for prophylaxis and therapy of graft-versus-host disease on survival and relapse after allogeneic bone marrow transplantation.

In order to determine whether doses of cyclosporine and methylprednisolone used for prophylaxis and therapy of acute graft-versus-host disease (GVHD) have any influence on relapse and survival following allogeneic bone marrow transplantation (BMT), we studied 176 adult patients with hematologic malignancies, who underwent a first allogeneic transplant from an HLA-identical sibling donor. Two methods of management of acute GVHD used in two different centers were compared: group I included 62 patients who had 'standard' management of GVHD including prophylaxis with 1-3 mg/kg/day of cyclosporine and treatment with 2 mg/kg/day of methylprednisolone when acute GVHD developed; group II included 114 patients who received 'intensive' management of GVHD including prophylaxis with 5 mg/kg/day of cyclosporine and treatment with high-dose methylprednisolone (8-20 mg/kg/day for 3 days) at the onset of GVHD. The overall incidence of GVHD was the same in both groups. However, acute GVHD was more severe in group I than in group II (P < 0.0001), with consequently less resolution of GVHD after treatment in group I (61%) than in group II (80%) (P = 0.06). Overall survival and disease-free survival (DFS) did not differ between the two groups. However, actuarial risk of disease relapse was significantly higher in group II than in group I (36% vs 17%, P = 0.02). In a multivariate analysis taking into account known factors influencing GVHD and relapse, only type of GVHD management and age were significantly predictive for the occurrence of GVHD, while only type of GVHD management and pathology other than chronic myeloid leukemia (CML) were predictive for relapse. This study demonstrates that intensity of GVHD prophylaxis and therapy can influence the graft-versus-leukemia effect by decreasing severity of GVHD but at the price of increasing relapse rate post transplant.

Hypermethylation of calcitonin gene in adult acute leukemia at diagnosis and during complete remission.

Hypermethylation of the calcitonin gene has been described in various hematologic malignancies. In order to assess its frequency and potential usefulness as a marker for leukemic cells and to detect potential clinical correlations, 180 adult patients (aged > 15 years) with newly diagnosed acute leukemia including 133 cases of acute myeloid leukemia (AML) and 47 cases of acute lymphoblastic leukemia (ALL) were tested for its presence in leukemic blasts at diagnosis by Southern blot technique and polymerase chain reaction (PCR) using 3 sets of primers (P550, P566, P1400), amplifying the most frequent sites of hypermethylation upstream or within the gene. In AML, 92 patients (69%) had hypermethylation detected by Southern blot at diagnosis. This hypermethylation could be confirmed by PCR in 18 of 36 tested cases (50%). Hypermethylation was not significantly associated to any clinical or hematological characteristic of the disease. In ALL, 44 patients (94%) had hypermethylation detected by Southern blot at diagnosis. This hypermethylation could be confirmed by PCR in 33 of the 43 tested cases (77%). Sensitivity of PCR assessed by dilution was 1 to 0.1%. Hypermethylation was not either significantly related to any clinical or hematologic characteristics of the disease. Seven ALL cases which were positive by PCR at diagnosis and achieved cytological CR could be tested during CR. Five cases were negative and did not relapse after 3 to 27 months in CR. One case was positive at the beginning of CR and became negative after autologous transplant. However, he relapsed after 9 months in CR, 3 months after the last negative test. PCR for Bcr/Abl was also negative at this time. We conclude that hypermethylation of the calcitonine gene is frequent at diagnosis in adult acute leukemia, particularly in ALL.