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Outcome of adult acute lymphoblastic leukemia (ALL) with central nervous system (CNS) involvement is not clearly defined. We studied 104 patients presenting with CNS involvement at diagnosis among 1493 patients (7%) included into the LALA trials, and 109 patients presenting CNS disease at the time of first relapse among the 709 relapsing patients (15%). Eighty-seven patients (84%) with CNS leukemia at diagnosis achieved complete remission (CR). Fifty-three patients underwent stem cell transplantation (SCT): 25 allogeneic SCT, 28 autologous SCT, while 34 continued with chemotherapy alone. Seven-year overall survival (OS) and disease-free survival (DFS) were 34% and 35%, respectively. There were no significant differences in terms of CR, OS and DFS among patients with CNS involvement at diagnosis and those without CNS disease. There were also no differences among the two groups regarding T lineage ALL, B lineage ALL, and among those who underwent SCT. After a first relapse, 38 patients with CNS recurrence (35%) achieved a second CR. The median OS was 6.3 months. Outcome was similar to that of relapsing patients without CNS disease. CNS leukemia in adult ALL is uncommon at diagnosis as well as at the time of first relapse. With intensification therapy, patients with CNS leukemia at diagnosis have a similar outcome than those who did not present with CNS involvement. CNS leukemia at first relapse remains of similar poor prognosis than all other adult ALL in first relapse.

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.

Purpose We analyzed the benefits of a risk-adapted postremission strategy in adult lymphoblastic leukemia (ALL), and re-evaluated stem-cell transplantation (SCT) for high-risk ALL. Patients and Methods A total of 922 adult patients entered onto the trial according to risk groups: standard-risk ALL (group 1), high-risk ALL (group 2), Philadelphia chromosome-positive ALL (group 3), and CNS-positive ALL (group 4). All received a standard four-drug/4-week induction course. Patients from group 1 who achieved a complete remission (CR) after one course of induction therapy were randomly assigned between intensive and less intensive postremission chemotherapy, whereas those who achieved CR after salvage therapy were then included in group 2. Patients in groups 2, 3, and 4 with an HLA-identical sibling were assigned to allogeneic SCT. In groups 3 and 4, autologous SCT was offered to all other patients, whereas in group 2 they were randomly assigned between chemotherapy and autologous SCT. Results Overall, 771 patients achieved CR (84%). Median disease-free survival (DFS) was 17.5 months, with 3-year DFS at 37%. In group 1, the 3-year DFS rate was 41%, with no difference between arms of postremission randomization. In groups 2 and 4, the 3-year DFS rates were 38% and 44%, respectively. In group 2, autologous SCT and chemotherapy resulted in comparable median DFS. Patients with an HLA-matched sibling (groups 2 and 4) had improved DFS. Three-year DFS was 24% in group 3. Conclusion Allogeneic SCT improved DFS in high-risk ALL in the first CR. Autologous SCT did not confer a significant benefit over chemotherapy for high-risk ALL.

Summary. 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 acheived by salvage chemotherapy combining an intercalating agent with high-dose cytosine arabinoside, as used in acute myeloid leukaemia.

While the t(8;21) translocation is one of the most recurrent chromosomal abnormalities in acute myeloid leukemia, prognostic studies have been hampered by the relatively few number of patients reported. We thus performed a large retrospective study in 161 adults and children with t(8;21) acute myeloid leukemia, all prospectively enrolled in 6 different trials conducted in France between 1987 and 1998 (median follow-up 4.9 years). Prognostic studies were performed in the 154 patients who achieved a complete remission. Individual data were registered, including sex, age, blood and marrow counts, extramedullary disease, and cytogenetics. The value of allogeneic stem cell transplantation versus chemotherapy as postremission therapy was evaluated according to the intent-to-treat principle. Estimated 5-year disease-free survival (DFS) and overall survival were 52% and 59%, respectively. Outcome was not significantly better in patients from the stem cell transplantation group (estimated 5-year DFS and survival, 56% vs 52% and 67% vs 57%; P =.55 and.64, respectively). White blood cell count (WBC) was the only identified prognostic factor. To further take into account the spontaneous differentiation potential of the leukemic clone, a WBC index was derived as the product of WBC by the ratio of marrow blast. This WBC index was a more powerful factor than the original WBC, allowing us to distinguish 3 subgroups of patients with different outcomes (low index, < 2.5; intermediate index, 2.5-20; high index, 20 or more). In multivariate analysis, the WBC index was the only prognostic factor for DFS (P =.003), complete remission duration (P =.002), and overall survival (P =.04).

PURPOSE: Bisphosphonates have been found to reduce the incidence of skeletal-related events (SREs) in patients with multiple myeloma. This is the first double-blind, randomized, placebo-controlled study to assess the efficacy of ibandronate, a third-generation amino-bisphosphonate, in preventing SREs in advanced-stage multiple myeloma patients. PATIENTS AND METHODS: Patients with multiple myeloma stage II or III were randomly assigned to receive either ibandronate 2 mg or placebo as a monthly intravenous (IV) bolus injection for 12 to 24 months in addition to conventional chemotherapy. SREs such as peripheral pathologic or vertebral fractures, hypercalcemia, severe bone pain, and bone radiotherapy or surgery were analyzed. Bone-turnover markers were also studied. Finally, post hoc analyses of bone morbidity and survival were performed. RESULTS: Ninety-nine patients per treatment group were assessable for efficacy analysis. The occurrence of SRE per patient year and the time to first SRE were not significantly different between the two treatment groups. In overall evaluation, no differences were found between the treatment groups regarding bone pain, analgesic drug use, quality of life, and median survival (33.1 v 28.2 months, respectively). Explorative post hoc analyses revealed that ibandronate patients with strongly suppressed bone-turnover markers (≥ 30% and ≥ 50% mean reduction of serum osteocalcin and urinary C-terminal telopeptides) developed significantly less bone morbidity. Ibandronate was tolerated well during as many as 25 therapy cycles. CONCLUSION: Monthly injections of ibandronate 2 mg IV neither reduced bone morbidity nor prolonged survival in the overall population of stage II/III multiple myeloma patients.

Introduction: Structural rearrangements of chromosome 3q have been described in approximately 2% of patients with acute myeloid leukemia. Breakpoints are mainly located in the 3q21 and 3q26 regions but may occur elsewhere on chromosome 3. To determine the relationship between these breakpoints and the hematological parameters, including outcome of these patients, we analysed data from newly diagnosed adult AML patients with 3q rearrangements referred to our institution over a 15-year period. Materials and methods: This retrospective study was conducted using data from 57 AML patients (median age: 64 years, range 19‐82) with 3q rearrangements. Cytogenetic analysis was performed using standard techniques (RHG banding, FISH). Data concerning AML patients with 3q abnormalities were compared for outcome with those from patients with normal karyotype and from patients with 5q deletion, treated according to the same intensive protocols for the same time period. Results: Patients with myeloid malignancy displaying 3q rearrangement were assigned to five subgroups, including those with: 3q21/q26 rearrangement; 3q21 alone, including t(1;3)(p36;q21); 3q26 alone, resulting in translocations involving multiple chromosome partners; t(3;5); 3q deletions. Among these patients, 37 were treated in AML chemotherapy trials. Complete remission was achieved in 43% (26/57) of cases. Five patients died early. Sixteen patients were resistant to induction chemotherapy. Median DFS and median OS were 4.5 and 8.8 months respectively. Relapse was observed in 34% of patients achieving CR. Comparison of the outcome of CR patients with that of patients presenting with normal karyotype (intermediate-risk) or complete/partial 5q deletion (high-risk) confirmed the very poor prognosis of patients carrying 3q chromosomal rearrangements. Conclusion: These data confirm that 3q rearrangements at q21 or q26 are recurring chromosomal abnormalities in AML. Appearing frequently in combination with monosomy 7 and an abnormal megakaryopoiesis, patients with these abnormalities have a particularly poor prognosis. The Hematology Journal (2002) 3, 21‐31. DOI: 10.1038/sj/thj/6200143

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 was0.5 x 10(9)/l and platelet count was30 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 count50 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 (p0.01 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.

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.

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.

In order to assess the place of HLA-identical allogeneic bone marrow transplantation (BMT) and to compare it to other post-induction therapies, we analyzed patient outcome in intention-to-treat based on the presence or not of an HLA-identical familial donor in young adults with de novo acute myeloid leukemia (AML) in first complete remission (CR). Between 1985 and 1998, 152 consecutive AML patients aged less than 41 years old, seen in our institution, were treated according to 3 different successive protocols (LYLAM85, LAM90, AML10). 144/152 patients entered our prospective study in which they were registered at time of diagnosis for presence or absence of HLA-identical donor and analyzed in intention-to-treat. In this study, 52 patients (36%), who had at least one identical sibling donor (group 1), were offered allogeneic BMT after CR achievement. The 92 patients without donor were allocated to group 2 and were assigned to receive chemotherapy or autologous transplantation as post-remission according to the protocol they were initially included in. Patients from both groups had similar disease characteristics at diagnosis. Karyotypes at diagnosis were defined as low risk (t(8;21) or t(15;17) or chromosome 16 abnormalities(, intermediate risk (normal karyotypes), or high risk (other abnormalities). Overall, 114/152 patients (75%) achieved a CR. Of the 144 eligible patients, 46/52 (88%) with a donor and 68/92 (74%) without a donor achieved a CR. The median follow-up duration of the 144 patients was 21.2 months. The relapse rate was higher in group 2 (56%) than in group 1 (31%). However, the overall survival was not different between patients with and without donor (median survival respectively at 16.7 months and 26.6 months with estimated survival at 5 years respectively at 32% and 34%). Thirty-four patients from group 1 (65%) were actually transplanted in first CR. The probability of 5-year survival for patients receiving effectively allogeneic BMT was 44% and was not significantly better than that of patients who did not. In univariate as in multivariate analysis, karyotypic status was the main prognostic factor for CR achievement (p = 0.002), CR duration (p < 0.0001), and overall survival (p < 0.0001). There were no significant differences between group 1 and group 2 when survivals were compared with adjustment for karyotypes.

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 de-escalating cell dose cohorts of CD34 + Thy1 + 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 + Thy1 + HSCs mobilized from peripheral blood with cyclosphosphamide and granulocyte-macrophage colony-stimulating factor to support a single transplant after high-dose melphalan 140 mg/m 2 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 × 10 6 CD34 + Thy1 + HSCs/kg provided prompt engraftment (absolute neutrophil count >0.5 × 10 9 /L day 10; platelet count >50 × 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 × 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.

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.

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.

A prospective study of the pharmacokinetics of itraconazole solution was performed in 11 patients who underwent allogeneic BMT (day of BMT = day 0) after a conditioning regimen including total body irradiation (TBI). Itraconazole solution (400 mg once a day) was given 7 days before BMT and continued up to the end of neutropenia unless another antifungal treatment was necessary. Blood samples were collected before itraconazole intake (Cmin) and 4 h later (Cmax) every other day for assays of itraconazole (ITRA) and its active metabolite hydroxy-itraconazole (OH-ITRA). The mean values of Cmin ITRA and OH-ITRA, respectively, were 287 +/- 109 ng/ml and 629 +/- 227 ng/ml at day -1 and 378 +/- 147 ng/ml and 725 +/- 242 ng/ml at day +1. The maximum Cmin values were observed at day +3. Six patients at day -1 (54%) and 8 at day +1 (72%) had satisfactory residual plasma concentrations of at least 250 ng/ml of unchanged ITRA. From day +1 to day +9, eight patients discontinued the itraconazole treatment, five of them had satisfactory plasma residual concentrations at this time. This work shows a good bioavailability of itraconazole oral solution during the early phase after allogeneic BMT, but more data are needed for the late phases.

With the aim of determining the ability of all-trans retinoic acid (ATRA) to improve prognosis in refractory and relapsed acute promyelocytic leukemia (APL), the data of 45 patients resistant to previous conventional chemotherapy or in first relapse were retrospectively reviewed. Thirty-seven patients presented with typical M3, five with variant form (M3v), and three with intermediate form. Seven patients died before any chemotherapy could be given. Thirty-five patients received one course of chemotherapy combining anthracyclines and cytarabine without (n = 22) or with ATRA (n = 13), according to different protocols. One elderly patient received only ATRA, and two patients received only low-dose cytarabine. Nine patients died within 4 weeks of relapse. A complete remission (CR) was achieved in 29 of the 38 patients retreated after first relapse or primary failure (76.3%, 95% CI: 60-89%). Among relapsed patients, four of five patients who had initially received ATRA therapy achieved a second CR when retreated by ATRA. The median second disease-free survival (DFS) was 23.3 months. Overall median survival was 7.8 months, with a 5-year survival rate of 29% (95% CI: 14-44%). Parameters found to be associated with decreased second CR rate were presence of hemorrhages and hemostatic disorder, and high levels of GGT at the time of relapse. Factors associated with short survival were WHO performance status1, high serum LDH levels, and coagulopathy at time of relapse. Use of ATRA at time of relapse (n = 14) was significantly associated with higher CR rates (p = 0.008), longer DFS (median not reached versus 7.9 months; p = 0.05), and longer survival after first relapse (median 32.3 months versus 4.4 months; p = 0.003). In the multivariate analysis, the only factor predictive of poor prognosis for overall survival was the absence of ATRA therapy at relapse. We conclude that ATRA is effective in the treatment of relapsed or refractory APL and appears superior to chemotherapy alone.

Sequential chemotherapy with vincristine, daunorubicin, cyclophosphamide, and prednisone doses was administered to 57 adult patients with acute lymphoblastic leukemia (ALL). Complete remission (CR) was achieved in 51 (89%, 95% confidence intervals, [CI] 78-96%). Among patients achieving CR, 62% were in CR after one sequence of chemotherapy, 23% after two sequences, and 5% after three sequences. Six patients (11%) had resistant disease. All patients experienced profound myelosuppression. Median time to recovery of neutrophils0.5 x 10(9)/1 was 22 days (range: 5-89 days), and of platelets100 x 10(9)/1 21 days (range: 0-45 days). Nonhematologic WHO grade 3 or more side effects consisted predominantly of hyperbilirubinemia (7%), mucositis (5%), nausea and vomiting (2%), and cutaneous toxicity (1%). Severe infectious complications occurred in only 14% of cases. One patient (2%, 95% CI 0-9%) died of therapy-related toxicity while in early CR. We concluded that sequential use of prednisone seemed at least as effective as continuous administration at the expense of a few adverse side effects.

PURPOSE To compare intensive chemotherapy and HLA-identical allogeneic bone marrow transplantation (BMT) as postinduction therapy in young adults with acute myeloid leukemia (AML). PATIENTS AND METHODS Seventy-eight consecutive AML patients younger than 40 years of age were treated according to a prospective protocol in which every patient in complete remission (CR) with an HLA-identical sibling was scheduled to receive BMT rather than intensive chemotherapy consolidation. To minimize comparison biases, the availability or not of an HLA-identical sibling donor was considered to be the equivalent of genetic randomization to the BMT or chemotherapy arm, respectively. RESULTS Fifty-eight patients (74%) achieved a CR. A donor was found for 27 patients (BMT arm), and 20 of these patients were actually transplanted in first CR. The 31 patients without a donor were allocated to the chemotherapy arm. Patients in the two arms had similar disease characteristics at diagnosis and previous responses to induction therapy. The cumulative risk of relapse was 43% +/- 24% in the BMT arm and 67% +/- 19% in the chemotherapy arm (P = .01). The 7-year leukemia-free survival (LFS) rate was 41% +/- 20% in the BMT arm and 27% +/- 16% in the chemotherapy arm, a difference that is not statistically significant between the two arms. The overall survival rates were 41% +/- 20% and 46% +/- 19%, respectively. CONCLUSION In this study, the availability of an HLA-identical sibling donor was not associated with a better survival rate because of both the impossibility of some patients with a donor to receive BMT and the more efficient salvage treatment of patients who relapsed after intensive consolidation chemotherapy than of patients who relapsed after BMT.

Among patients included in the multicentric trial ALL87, 95 patients were randomly allocated to purged ABMT arm for post-remission therapy. Immunological phenotyping performed in patients at diagnosis allowed to assigned 51 patients (54%) to the B lineage and 34 patients (36%) to the T lineage. Only 64 patients (67%) actually received ABMT mainly because of early relapses. Fifty-two patients were depleted according to the protocol: 25 B-ALL were depleted with CD10+CD19 mAbs, 19 T-ALL with CD2+CD5+CD7 mAbs and 8 patients received an Asta-Z purged BMT. Among the 12 remaining patients, 4 received Asta-Z purged BMT and 8 an unpurged one. Using an intention to treat analysis, overall survival and event free survival were similar to results observed in chemotherapy group. This study emphasizes the importance of a precise phenotyping at ALL diagnosis which allows specific immunologic bone marrow purging for ABMT.

PURPOSE In a prospective multicenter study, we analyzed the benefits of allogeneic bone marrow transplantation (BMT) in a nonselected group of adult patients with acute lymphoblastic leukemia (ALL) and, by a randomized trial, evaluated the effectiveness of autologous BMT over chemotherapy as postremission therapy in patients younger than 50 years who were not candidates for allogeneic BMT. PATIENTS AND METHODS After induction therapy that randomized patients to receive one of two anthracycline-containing regimens, either daunorubicin (DNR) or zorubicin (ZRB), patients were assigned to postremission treatment according to age and results of HLA typing. Patients younger than 40 years with an HLA-identical sibling (group 1) were scheduled to receive cyclophosphamide 60 mg/kg on days 1 and 2, total-body irradiation (TBI), and allogeneic BMT. Patients older than 50 years (group 2) received the chemotherapy arm composed of three monthly consolidation courses (DNR or ZRB, cytarabine, and asparaginase) followed by maintenance chemotherapy (modified L10 regimen). The remaining population (group 3) was randomly assigned to receive, after the three 1-month consolidation courses, either the chemotherapy arm or autologous BMT following a conditioning regimen similar to that of group 1. RESULTS Of the 572 assessable patients, 436 achieved complete remission (78% +/- 2% for DNR v 74% +/- 3% for ZRB; P = .3). The estimated 3-year disease-free survival (DFS) rate for the 116 patients included in group 1 was 43% +/- 5%. Both autologous BMT (95 patients) and chemotherapy (96 patients) produced comparable 3-year DFS rates (39% +/- 5% v 32% +/- 5%) and survival durations (49% +/- 5% v 42% +/- 5%). However, late relapses after 36 months were mainly observed in the chemotherapy arm. CONCLUSION This first interim analysis did not demonstrate a benefit of this autologous BMT procedure over classical maintenance chemotherapy in patients with ALL who received consolidation chemotherapy.

Thirty-four patients with acute myeloid leukemia (AML) in complete remission (CR), 30 of them aged over 60, received maintenance therapy scheduling four courses of low-dose cytarabine (LDA) 20 mg/m2/day in two subcutaneous injections for 3 weeks every 6 weeks. Each course was stopped when hematologic toxicity occurred, and doses of LDA were subsequently reduced by 50% for the following courses. During the first course of LDA, 15 patients needed blood and four patients platelet transfusions. Overall, 28 patients received four courses of LDA: 11 did not require any dose reduction, while 14 required one dose reduction and three neeeded two successive dose reductions. Two patients were hospitalized during maintenance. Median disease-free survival (DFS) is 308 days, with 16% of patients surviving at 5 years. Seven patients relapsed during the 168 days of maintenance, while ten of the 27 patients remaining at risk on day 169 relapsed during the 168 days following maintenance. We conclude that in AML in CR, the maximal dose of LDA tolerated by ambulatory patients is 10 mg/m2/day for 3 weeks. LDA seemed to delay relapse; however, precise assessment of the efficacy of this approach would require a randomized trial.

To help understanding host-tumor relationships in acute myelogenous leukemia (AML) and better define indications for interleukin 2 (IL-2) therapy in this disease, we studied the relationship between the susceptibility of leukemic cells of 44 AML patients to lysis by autologous (26 cases) and/or allogeneic (41 cases) lymphokine-activated killer (LAK) cells and characteristics of the leukemia. Lymphocytes were activated in the presence of 1000 u/ml recombinant IL-2 for 5 days. Lysis of AML cells was studied by 51 Cr release. Average lysis of AML cells by autologous LAK cells was 9 ± 13% and by allogeneic LAK cells 10 ± 9% with a significant correlation between lyses by both effectors ( p = 0.01). Autologous ( p = 0.005) and allogeneic ( p = 0.004) lyses were higher in patients with initial infection. Allogeneic lysis was correlated with initial WBC count ( p = 0.009), serum lactic-dehydrogenase level ( p = 0.05), and expression of CD13 ( p = 0.01). Autologous lysis was inversely correlated with expression of CD34 ( p = 0.003). Expression of adhesion molecules CD54 (ICAM-1) and CD58 (LFA-3) by the leukemic cells did not correlate with their lysis by LAK cells. Susceptibility of leukemic cells to lysis by LAK cells did not correlate with prognosis of the leukemia.

Surface markers were studied at first relapse in 66 cases of acute myeloid leukaemia (AML), using a panel of five monoclonal antibodies directed to CD13, CD14, CD15, CD33 and CD34 antigens. At time of relapse, there was increased expression of CD33 (P = 0.002) and CD34 (P = 0.0001), and decreased expression of CD13 (P = 0.004) and CD15 (P = 0.0001) antigens by comparison to initial diagnosis. There was no strict correlation with the FAB classification. However, CD13 and CD33 expression changes preferentially affected granulocytic leukaemias. At relapse, CD14 and CD34 were significantly more expressed in monocytic than in granulocytic AML (P = 0.01 and 0.003 respectively). In a multivariate analysis, CD34 expression was associated with a low CR rate (P = 0.001) and short survival (P = 0.05), whereas CD15 expression was associated with long survival (P = 0.0004). These results suggest that AML tends to relapse with a less differentiated phenotype than observed at diagnosis and that AML with less differentiated phenotype is of poor prognosis after first relapse, as also observed at diagnosis.

A murine monoclonal antibody against human lysozyme (AHL MoAb) was produced and tested on normal and leukemic monocytes using flow cytometry. The antibody gave a positive reactivity on normal monocytes permeabilized by saponin (82% to 98% of positive cells) and a negative reactivity on normal permeabilized neutrophils. This monocyte-specific reactivity had not been observed using a polyclonal antibody. Nevertheless, immunoblotting detected lysozyme in both monocyte and polymorphonuclear leukocyte (PMNL) lysates. The AHL MoAb, in the presence of lysozyme substrate (Micrococcus lysodeikticus cell walls), strongly inhibited the enzymatic activity. Flow cytometric analysis of leukemic cells isolated from patients suffering from different subtypes of acute myeloid leukemia (French-American-British [FAB] classification FAB M1–5) showed a highly significant positivity of FAB M5 for lysozyme compared with the other subtypes. The present results were consistent with the detection of a lysozyme epitope by AHL MoAb located near the catalytic site in monocytes. The same epitope was probably masked in PMNL granules.

To evaluate the clinical value of the expression of multidrug resistance P-glycoprotein (P-170) on the surface of acute nonlymphoblastic leukemia (ANLL) cells, we analyzed specimens from 150 newly diagnosed patients for staining with MRK16, a monoclonal antibody (MoAb) that binds to an external epitope of P-170. Other surface markers (CD13, CD14, CD15, and CD34) were studied by the same technique. A marker was considered positive when 20% or more cells were stained. Of 150 samples, 71 were P-170-positive. These cases did not differ from P-170-negative cases with regard to age, sex, initial white blood cell (WBC) counts, or French-American-British (FAB) type (except for M3 ANLL, which were more frequently negative). However, leukemias arising from previous myelodysplastic syndrome (MDS) and therapy- induced leukemias were more frequently P-170-positive. CD34 and P-170 expression were significantly associated. All patients were treated by intensive chemotherapy. Complete remission (CR) rates were significantly lower in P-170-positive (23/71, 32%) than in P-170- negative cases (64/79, 81%) (P less than 10(-5)). CD34 positivity was also associated with a low remission rate (P less than 10(-5)). Survival was shorter for P-170- and CD34-positive patients (P less than 10(-5)). The prognostic value of both markers was confirmed in multivariate analysis. CR duration was also shorter for P-170-positive cases, but the difference is less significant (P = .05). It is concluded that P-170 analysis may be an important tool for predicting the outcome of intensive chemotherapy in ANLL patients.

Intensive sequential chemotherapy with mitoxantrone, 12 mg/m2/d on days 1 through 3, etoposide, 200 mg/m2/d as a continuous infusion on days 8 through 10, and cytarabine, 500 mg/m2/d as a continuous infusion on days 1 through 3 and 8 through 10 was administered to 72 patients aged less than 60 years with previously treated acute myelogenous leukemia (AML). Forty patients had refractory AML (nonresponse to prior therapy, early first relapse, or multiple relapse) and 32 had late first relapse. Sixty-one percent of patients, with a 95% confidence interval (CI) ranging from 49% to 72%, achieved complete remission (CR), including 45% (CI: 30% to 62%) of refractory patients and 81% (CI: 64% to 93%) of late first relapse patients. Twenty-nine percent of patients (CI: 19% to 41%) did not respond to therapy and 10% (CI: 4% to 19%) died from therapy-related toxicity. Median duration of aplasia was 30 days. Nonhematologic WHO grade 3 or more toxicity included sepsis (57% of patients), vomiting (10%), mucositis (35%), diarrhea (7%), skin rash (6%), and hyperbilirubinemia (11%). Postinduction therapy was attempted in 36 of 44 CR patients: 16 of them received a second course of the same regimen, 7 received maintenance chemotherapy, 4 underwent autologous bone marrow transplantation (BMT), and 9 allogeneic BMT. At a median follow-up of 20 months, 23 of the 44 complete remitters have relapsed, 1 to 14 months after achievement of CR, including 19 of 31 patients not undergoing BMT. Median survival is 7 months with 16% (CI: 4% to 28%) projected survival at 47 months. Median disease-free survival is 6 months with 21% (CI: 3% to 39%) of CR patients projected to remain disease-free at 46 months. Twenty-six percent (CI: 13% to 43%) of the evaluable patients who did not receive transplantation had inversion of CR duration. Among patients younger than 50 years, there was no significant difference in disease-free survival between patients receiving postinduction chemotherapy and those receiving BMT. We conclude that this chemotherapy regimen is highly efficient and could be used as first-line therapy in young patients with AML.

In a cohort of 67 adult patients with newly diagnosed untreated acute promyelocytic leukemia (APL), the initial clinical and biological parameters were submitted to multivariate analysis for potential prognostic significance. Median age of the patients was 40 years and the hematologic characteristics of the patients were those regularly seen. Complete remission (CR) was achieved in 43 cases (64%). Fourteen patients died within 4 weeks of diagnosis, due to severe hemorrhage. Factors predictive of hemorrhagic death in the multivariate analysis were hyperuricemia (p = 0.001), splenomegaly (p = 0.009), anemia (p = 0.02), high serum levels of LDH (p = 0.02), increased prothrombin time (p = 0.04), and hypercreatininemia (p = 0.05). Pretreatment patient characteristics for poor prognosis and achieving CR were hyperuricemia (p = 0.0002), splenomegaly (p = 0.01), anemia (p = 0.02), and lymphadenopathy (p = 0.04). The median disease-free survival (DFS) was 15.6 months. Poor prognostic factors for DFS were hyperuricemia (p = 0.007), and splenomegaly (p = 0.03). Maintenance chemotherapy had no statistically significant impact on CR duration. Median survival duration was 10 months. Poor prognostic factors for survival were hyperuricemia (p = 0.0005), and elevated serum LDH levels (p = 0.01).

Thirty-nine patients with relapsed acute lymphoblastic leukemia (ALL) and four with primarily refractory ALL were treated with a regimen that included cytarabine 1 gm/m2 (2-hour infusion) twice daily days 1 to 5, mitoxantrone 12 mg/m2 daily days 1 to 5, prednisone 0.5 mg/kg daily days 1 to 5, and etoposide 200 mg/m2/day daily days 6 to 8. Of the 43 patients, 30 achieved a complete remission (CR), 28 out of the 39 relapsed patients and two among the four with refractory disease. Five patients died in aplasia. Eight patients were nonresponders. Nonhematologic side effects consisted predominantly of nausea, vomiting, and mucositis. One patient had transient cerebellar dysfunction. Recovery of blood counts occurred at a median of 24 days. The median time to CR was 38 days. As this regimen is highly effective in relapsed or refractory ALL, its use during earlier stage of the disease is warranted.

The GET-LALA (Groupe d‘Etude et de Traitement de la Leucemie Aigue Lymphoblastique de l’Adulte) group has performed a series of studies evaluating different aspects of remission induction and postremission treatment in adults with acute lymphoblastic leukemia (ALL). The LALA group was formed by interested hematologists, physicians, and statisticians in the beginning of the 1980s. The first working party was set up in 1982 with Professor Denis Fiere as chairman of the Steering Committee, and the first randomized trial involving multiple French centers was started in 1983. Since then several other trials have been opened to persons over 15 years of age. In recent years, clinical trials have been supplemented by systematic morphologic, immunophenotyping, cytogenetic, and molecular genetic studies leading to the identification of different risk groups of patients who may warrant individualized treatments. With the development of data managing and the establishment of a large network of collaborating physicians and biologists, the later trials became larger, and reporting was more reliable.

BACKGROUND. In adult acute lymphoblastic leukemia, treatment results generally are expressed in terms of overall survival or disease-free survival at 3 years. In this investigation, the authors attempted to express the results in terms of the proportion of long-term disease-free survivors and in terms of lifetime in patients who developed recurrent disease or died. METHODS. Univariate and multivariate analyses were used to assess the influence of different covariates on the 2 result criteria in 922 participants in the Adult Acute Lymphoblastic Leukemia-94 multicenter trial. RESULTS. The proportion of long-term survivors was 21.5% (95% confidence interval [95% CI], 18.1–25.4%) and was higher in women than in men. The proportion decreased with increasing age, white blood cell count, and lactate dehydrogenase level. The lowest proportion was observed in patients ages 44 years to 55 years (11.4%; 95% CI, 7–17.9%) and in patients with the t(9;22) BCR-ABL karyotype (13.4%; 95% CI, 8.8–19.8%), and the highest proportion was observed in patients with the t(4;11) MLL-AF4 karyotype (31.3%; 95% CI, 18.2–48.3%). The mean expected lifetime of patients who were not cured was 11.4 months (95% CI, 9.1–14.1 months). It was longer in men than in women and was shorter with increasing age, performance status, hemoglobin level, and white blood cell count. CONCLUSIONS. The results of this study highlighted and specified the importance of some classic prognostic factors in patients with acute lymphoblastic leukemia. Cancer 2007. © 2007 American Cancer Society.

Prospective multicentric molecular study for poor prognosis fusion transcripts at diagnosis in adult B-lineage ALL patients: the LALA 94 experience

Factors able to predict overall survival in adult patients with acute lymphoblastic leukaemia were assessed according to the period since initiation of the treatment using a Cox proportional hazards model. This period covers successively an initial period during the induction treatment and a consolidation period during the postinduction treatment. From 1994 to 2002, 922 patients with acute lymphoblastic leukaemia (excluding French-American-British L3 subtype) were enrolled in a multicentre protocol and followed, with a mean follow up of 58 months. A multivariate time-segmented analysis was performed on 658 patients. Analyses of the initial (before 100 d) and the late phases were realised after stratification on the type of induction treatment and on the different treatment strategies respectively. Age was the sole factor that influenced survival during the initial phase (hazard ratio 1.48 per 10-yr increase; P

Patients with T-cell acute lymphoblastic leukemias (T-ALLs) within the Leucémies Aiguës Lymphoblastiques de l'Adulte-94 (LALA-94) prospective trial were treated with a 4-drug per 4-week induction, with intermediate-dose cytarabine and mitoxantrone salvage treatment for patients not achieving complete remission (CR) in 1 course. Only the latter received allografts, if possible, thus providing an informative setting for assessing early response. Representative patients with T-ALL (91 patients) were classified into surface T-cell receptor (TCR)–expressing T-ALL patients (TCRαβ+ or TCRγδ+), pre-αβ T-ALL patients (cTCRβ+, TCR–), and immature (IM) cTCRβ–, TCR– T-ALL patients; 81 patients underwent genotyping for SIL-TAL1, CALM-AF10, HOX11, and HOX11L2. Overall, CR was obtained in 81 (89%) patients; relapse rate was 62% at 4 years and overall survival (OS) rate was 38%. CR rate was significantly lower in IM T-ALL patients after 1 course (45% vs 87%; P < .001) and after salvage (74% vs 97%; P = .002), with the latter inducing a higher rate of CR (9 [64%] of 14) than initial induction. Once CR was obtained, cumulative relapse rates were similar for IM, pre-αβ, and TCR+ T-ALL patients (P = .51), but were higher in HOX11L2 (83%) and SIL-TAL1 (82%) T-ALL patients compared with other genetic subgroups (48%; P = .05). This was associated with an inferior OS for HOX11L2 T-ALLs (13% vs 47% in HOX11L2-T-ALLs; P = .009). The majority of patients with HOX11 T-ALL underwent allografting, predominantly in second CR, but were not associated with a superior OS. Both TCR and genotypic stratification can therefore contribute to risk-adapted management of adult T-ALLs.

To reveal the relationship between hypodiploidy with 30 to 39 chromosomes and near-triploidy in acute lymphoblastic leukemia (ALL), we studied 24 patients presenting with one of these aneuploidies among 623 adults with ALL registered in the Leucemie Algue Lymphoblastique de l'Adulte (LALA) protocols. The 2 ploidy groups presented a striking similarity of their cytogenetic profiles: chromosomes 2, 3, 4, 7, 13, 15, 16, and 17, significantly monosomic in hypodiploidy 30 to 39, were also frequently disomic in near-triploidy, whereas those retained in pairs in hypo diploidy 30 to 39 were frequently tetrasomic in near-triploidy. DNA content data revealed the simultaneous presence of 2 aneuploid peaks in most tested cases (DNA indexes: 0.72-0.87/1.39-1.89) and a multiple correspondence analysis applied on cytogenetic profiles ascertained their strong relationship. We thus assumed that near-triploidy derives from the duplication of hypodiploidy with 30 to 39 chromosomes and that both aneuploid groups are 2 expressions of the same disease. These 24 patients presented with B-cell phenotype, low leukocytoses (median white blood cell count, 4.2 x 10(9)/L), and poor prognosis (complete remission, 57%; median disease-free-survival, 8 months; median survival, 10.4 months) comparable to that of Ph+ patients treated according to the same protocol. We suggest that hypodiploidy with 30 to 39 chromosomes or near-triploidy should be regarded as a new high-risk factor in the risk stratification of adult ALL protocols. (C) 2004 by The American Society of Hematology.

Acute myeloid leukemias (AMLs) carrying inv(16)/t(16;16) chromosomal abnormalities are associated with a good prognosis. However, studies of this AML subtype have been hampered by the few number of patients reported, frequently collectively considered with those with AML carrying the t(8;21) translocation. We performed a retrospective study in 110 patients with inv(16)/t(16;16) AML (median age, 34 years) prospectively enrolled in 6 trials conducted in France between 1987 and 1998, with the aim to investigate prognostic factors for complete remission (CR) achievement and outcome of CR patients in this AML subtype. CR rate was 93%. Bad-prognosis factors for CR achievement were higher white blood cell count (WBC) and lower platelet count (optimal cutpoints at 120 and 30 x 109/L, respectively). At 3 years, estimated overall survival, disease-free survival (DFS), and cumulative incidence of relapse were 58%, 48%, and 42%, respectively. In multivariate analysis, (1) advanced age (optimal cutpoint, 35 years) was the only factor for shorter DFS and (2) advanced age and low platelet count were the 2 factors for shorter survival of CR patients. Outcome of CR patients (1) was not influenced by WBC and cytogenetic findings and (2) was similar among patients allocated to receive allogeneic transplantation, high-dose, or intermediate-dose cytarabine. Interestingly, advanced age was associated with a trend for more frequent additional chromosome abnormalities and predictive of higher cumulative incidence of relapse rather than death in first CR. These results markedly contrast with those reported in patients with t(8;21) AML in whom WBC, and not age, was the main high-risk factor for relapse, DFS, and survival.

Purpose: To compare pediatric and adult therapeutic practices in the treatment of acute lymphoblastic leukemia (ALL) in adolescents. Patients and Methods: From June 1993 to September 1994, 77 and 100 adolescents (15 to 20 years of age) were enrolled in the pediatric FRALLE-93 and adult LALA-94 protocols, respectively. Among the different prognostic factors, we retrospectively analyzed the effect of the trial on achieving complete remission (CR) and event-free survival (EFS). Results: Patients were younger in the FRALLE-93 than in the LALA-94 protocol (median age, 15.9 v 17.9 years, respectively), but other characteristics were similar, including median WBC count (18 × 109 cells/L v 16 × 109 cells/L), B/T-lineage (54 of 23 v 72 of 28 patients), CD10-negative ALL (13% v 15%), and poor-risk cytogenetics (t(9;22), t(4;11), or hypodiploidy less than 45 chromosomes: 6% v 5%). The CR rate depended on WBC count (P = .005) and trial (94% v 83% in FRALLE-93 and LALA-94, respectively; P = .04). Univariate analysis showed that unfavorable prognostic factors for EFS were as follows: the trial (estimated 5-year EFS, 67% v 41% for FRALLE-93 and LALA-94, respectively; P < .0001), an increasing WBC count (P < .0001), poor-risk cytogenetics (P = .005), and T-lineage (P = .01). The trial and WBC count remained significant parameters for EFS in multivariate analysis (P < .0001 and P = .0004). Lineage subgroup analysis showed an advantage for the FRALLE-93 trial for CR achievement (98% v 81%; P = .002) and EFS (P = .0002) in B-lineage ALL and for EFS (P = .05) in T-lineage ALL. Age was not a significant prognostic factor in this population of adolescents. Conclusion: This study’s findings indicate that adolescents should be included in intensive pediatric protocols and that new trials should be designed, inspired by pediatric protocols, for the treatment of young adults with ALL.

Multiple myeloma is a malignant plasma cell disorder which still bears a dramatic prognosis. Renal insufficiency is a frequent and severe complication directly related to prognosis. The aim of our study was to establish whether an intermediate dose of intravenous melphalan, 25 mg/m2, could be safely and efficiently administered to patients with multiple myeloma and renal impairment.Between January 1990 and April 2000, 45 patients with multiple myeloma received a single intravenous dose of melphalan, 25 mg/m2. Survival was analysed, as well as the duration of response and potential toxicity. In addition, a melphalan pharmacokinetic study was performed.The overall median survival was 45 +/- 43 months after diagnosis. Based on the Cockcroft and Gault formula, 79% patients had renal impairment. For the 28 stage III patients, survival was no different whether renal insufficiency was present or not. Twenty-five out of 34 patients had leukopenia for an average of 13.8 +/- 12 days, and the most frequent adverse effect was infection. The pharmacokinetic study showed that the melphalan area under the curve was positively correlated to the degree of renal insufficiency. However, this was not clinically relevant since patients with the most altered renal function, including those undergoing dialysis, did not present more episodes of leukopenia.The present study shows that renal impairment is not a contraindication for aggressive myeloma chemotherapy, even for patients undergoing dialysis. Intravenous melphalan, 25 mg/m2, is associated with good survival and acceptable side-effects. A randomised trial seems needed to compare this melphalan dose with standard melphalan/prednisone or combination chemotherapies.

Introduction: All trans retinoic acid has shown a remarkable eAectiveness in acute promyelocytic leukemia. These results have encouraged studies of treatment with ATRA in other acute myeloid leukemia subtypes. Patients and methods: In order to evaluate toxicity and antileukemic eAcacy of all ATRA in patients with relapsed or refractory non promyelocytic AML, 95 patients (median age, 58 years; range, 20 to 80 years), with unclassified AML according to the FAB classification or secondary AML at diagnosis, or refractory or relapsing AML, received induction therapy with Idarubicin, 10 mg/m 2 /day, for 3 days and cytarabine, 1000 mg/m 2 /12 h, for 6 days, alone or combined, on a randomized basis, with ATRA, 45 mg/m 2 /day, from day 1 to complete remission. Patients in CR received maintenance therapy with 6 monthly courses combining Ida, 10 mg/m 2 /day, intravenously, on day 1 with Ara-C100 mg/m 2 /day, subcutaneously, from day 1 to day 5. Results: Results were evaluated after one induction course. Overall 54 patients (57%, 26 with ATRA and 28 without ATRA) achieved CR including five patients treated at time of initial diagnosis, seven previously resistant, 38 in first relapse and four in further relapse. Thirty patients (31%) had resistant disease and 11 (12%) died from toxicity. Median time for neutrophil recovery to 0.5610 9 /l and platelets to 20610 9 /l was 31 and 21 days respectively. Severe toxicity (WHO grade 53) included infections (37%), diarrhea (9%), bleeding (3%), vomiting (16%), hyperbilirubinemia (5%), mucositis (6%) and hypercreatininemia (2%). No ATRA syndrome was noted in the ATRA arm. Median overall survival for the entire cohort was 6.3 months and median disease-free survival was 4.7 months. There were no statistical diAerences in terms of CR, DFS, and OS between the two arms. Conclusion: We conclude that ATRA in combination with Ida and Ara-C can be administered safely to high-risk AML patients. However, in this setting, ATRA did not oAer any advantage when compared to chemotherapy alone. The Hematology Journal (2002) 3, 49‐55. DOI: 10.1038/sj/thj/6200141

In order to investigate the sensitivity of malignant target cells to lysis by LAK cells according to their clonogenic capacities and their position along the maturation pathway, we compared clonogenic and chromium release cytotoxicity assays performed on human hematopoietic cell lines using Effector: Target ratios of 1:1, 3:1, 6:1, 12:1, 24:1, 48:1 and 96:1, and studied the sensitivity of HL-60 and U937 human cell lines after exposure to different factors including GM-CSF, SCF, IFN, Retinoic acid (RA), DMSO, and TPA which are able to recruit cells into the cell cycle or to induce cell differentiation. There was a good correlation between the lysis of the target cells using 51Cr release and the growth inhibition in semisolid medium. The degree of inhibition was significantly higher using the colony growth assay (p = 0.006). Regarding the effects of culturing cell lines with proliferating and differentiating agents on the sensitivity of these cell lines to LAK cytolysis, a correlation was noted between the proliferative response of the U937 cell line and susceptibility to LAK cell lysis (p = 0.01), while results appeared close to significance with HL-60. The most significant effects were a decreased sensitivity of HL-60 to LAK lysis with RA (p0.001) and TPA (p0.001), and an increased susceptibility of U937 to LAK lysis with GM-CSF (p0.0001). In studies planned to investigate whether susceptibility of treated cells to LAK activity was a consequence of a downregulation of adhesion molecules expressed on target cell surface, the proportion of cells expressing adhesion molecules was not significantly changed, except for CD54 expression on HL-60 cells which showed a higher expression, after cells were treated with RA or DMSO. We conclude that clonogenic cells are more sensitive to LAK cell lysis and that cell line sensitivity to LAK cytolysis can be modulated by a variety of agents of potential therapeutic use. The poor correlation between adhesion molecules expression and sensitivity to LAK lysis suggests that molecules other than CD54, CD56, CD58, and CD106 may possibly be more central to the processes involved.

In order to potentially mobilize and harvest the Ph cells observed in most patients with chronic myeloid leukaemia (CML) during interferon-alpha (IF-alpha) therapy, G-CSF (filgrastim), 5 microg/kg/d, was administered subcutaneously together with IF-alpha to 30 CML patients in haematological remission but with various degrees of cytogenetic remission, after IF-alpha therapy. Peripheral blood stem cells (PBSC) were harvested using standard aphereses from day 5 of G-CSF Patients underwent one to four (median three) aphereses. Median total yields/kg were 7.6 (range 3.8-25) x 10(8) MNC, 3.4 (0-140) x 10(6) CD34+ cells, and 17 (1.1-107) x 10(4) CFU-GM. No patient had a significant increase in the percentage of Ph+ cells in the bone marrow under G-CSF therapy. The percentage of Ph+ cells in apheresis products tended to decrease between the first and the last apheresis (P = 0.05). 14 patients who were not responsive to IF-alpha were transplanted after conditioning with busulphan 16 mg/kg and melphalan 140 mg/m2. Median time to neutrophils > 0.5 x 10(9)/l was 20 d (16-114 d) and to platelets > 50 x 10(9)/l 18 d (12-149 d). Nine patients had a major cytogenetic response post graft, which correlated with the amount of Ph+ cells reinfused with the graft (P = 0.02). We conclude that this procedure is feasible, allowing the harvest of enough PBSC, some of them Ph- in patients who responded to IF-alpha, to allow autologous transplantation.

PURPOSE To evaluate the impact of granulocyte-macrophage colony-stimulating factor (GM-CSF) or placebo on the durations of intravenous (IV) antibiotic use, hospitalization, neutropenia, and fever, as well as remission rates, after high-dose melphalan (HDM) without stem-cell transplantation (SCT) in patients with multiple myeloma (MM). PATIENTS AND METHODS One hundred two patients with high-risk MM were randomized 2:1 in a prospective multicenter trial to receive 5 microg/kg/d GM-CSF (69 patients) or placebo (33 patients) starting the day after 140 mg/m2 IV melphalan for up to 21 days. RESULTS GM-CSF significantly reduced neutropenia after HDM (median, 23.5 v 29 days; P = .0468), with a trend to reduce the duration of hospitalization (median, 32 v 38 days; P = .0841). Nevertheless, GM-CSF did not significantly reduce infectious toxicity as regards the number of days with fever (median, 5 v 3; P = .359), the number of days with IV antibiotics (median, 22 v 27; P = .14), or early deaths, with an 11.5% treatment-related mortality rate in the GM-CSF group (eight of 69 v two of 32 patients in the placebo group; P = .686). There was no difference in response rates between the two groups of patients. CONCLUSION GM-CSF after HDM without SCT is feasible and significantly shortens neutropenia with a trend toward reduction of hospitalization duration, but does not significantly reduce the morbidity and mortality of such therapy. Thus, when intensive therapy is indicated, given that the mortality of HDM followed by SCT reported in the literature is less than 5% and patients are discharged at approximately day 15, despite the risk of contamination by clonogenic malignant cells, SCT appears to be preferable to GM-CSF after HDM.

Serum interleukin-6 (IL-6) levels were measured in 58 adult patients with newly diagnosed acute myelogenous leukemia (AML) using an ELISA method in order to find potential clinical correlations. Detectable average levels were 57 +/- 68 pg/ml and 52 patients (90%) had higher cytokine levels than normal donors. IL-6 levels (115 +/- 102 pg/ml versus 36 +/- 40 pg/ml, p = 0.0001) were higher in patients with fever of apparently non infectious origin, and higher levels were associated with higher percentage of blasts in the peripheral blood (R = 0.29, p = 0.04) and in the bone marrow (R = 0.39, p = 0.003), elevated serum LDH level (R = 0.36, p = 0.01), hyperbilirubinemia (R = 0.36, p = 0.008), elevated serum GGT level (R = 0.46, p = 0.003), and elevated serum GOT (R = 0.36, p = 0.008) and GPT levels (R = 0.44, p = 0.004). Highest IL-6 levels were observed in FAB M1 (86 +/- 112 pg/ml), M3 (73 +/- 69 pg/ml), and M6 (92 +/- 60 pg/ml) AML subtypes. Serum IL-6 levels in AML might be related to both non specific inflammatory reactions and the specific biology of the disease.

We describe a patient with AML with a monocytic component who developed a T-lymphoblastic lymphoma. Lymphoma was diagnosed 9 months following AML diagnosis. To our knowledge, this is the first report of phenotypically documented T-cell lymphoma following AML. The questions relating to the pathogenesis of the two malignancies are discussed.

In this study, we investigated the impact of recombinant interleukin-2 (rIL-2) after high dose chemotherapy and autologous bone marrow transplantation (ABMT) in 25 patients with refractory or relapsed Hodgkin's disease (HD) (11 patients) and non Hodgkin's lymphoma (NHL) (14 patients). 48% of patients had resistant disease, 84% achieved complete remission after ABMT. rIL-2 was started at a median of 54 days post-transplant and consisted of a first cycle of 5 days followed by 4 cycles of 2 days every other week. Patients received a mean of 160 x 10(6) IU/m2 rIL-2 and hematological toxicity was moderate and transient. None of the 5 evaluable patients with measurable disease responded to rIL-2. After a 5 year median follow-up, the probability of survival and DFS is 72% (HD: 73% and NHL: 70%, p = NS) and 45% (HD: 36% and NHL: 48%, p = NS) respectively. These somewhat encouraging results warrant further evaluation of rIL-2 after ABMT in controlled studies, especially in NHL patients stratified for previous chemosensitivity.

EMA 86 regimen, associating mitoxantrone, 12 mg/m2/day on days 1–3, etoposide, 200 mg/m2/day as a continuous infusion on days 8–10 and cytarabine, 500 mg/m2/day as a continuous infusion on days 1–3 and 8–10, was administered to 133 patients. 70 patients had refractory AML and 63 had late first relapse. 60% achieved complete remission (CR), including 44% of refractory patients and 76% late first relapse patients (p = 0.0002). 11% died from therapy-related toxicity. Median survival is 7 months, with 11% survival at 5 years. Median disease-free survival (DFS) is 8 months, with 20% DFS at 5 years.

Endothelial cell activation during allogeneic bone marrow transplantation, mainly in acute graft-versus-host disease (aGvHD) was studied in 23 recipients and 5 controls using anti-von Willebrand factor (vWF) antibody, antibodies to endothelial leukocyte adhesion molecule-1 (ELAM-1), vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), and anti-HLA-DQ antibody, by immunohistological staining of skin. vWF extravasation, ELAM-1 and VCAM-1 expression were present in most recipients with a cutaneous rash which was confirmed as an aGvHD by histological examination (documented aGvHD) (p = 0.005 for vWF extravasation and ELAM-1 expression and p = 0.03 for VCAM-1 expression in comparison with the controls). In recipients with a rash, the cases displaying vWF extravasation and ELAM-1 expression were significantly more numerous in those with a documented aGvHD than in those without histological features of aGvHD (p = 0.01). vWF extravasation and ELAM-1 occurred concomitantly (p

Two clones were observed at the initial phase of an acute myelogenous leukemia (AML): 46,XX,t(15;17) and 46,XX,t(8;21),t(15;17). Clinical, immunologic, and morphologic findings were in favor of expression of both chromosomal anomalies. Relapse occurred after 12 months of complete remission with typical acute promyelocytic leukemia (APL) syndrome when t(15;17) alone was then most predominant.

We investigated on the outcome of patients with AML 60 year old and older who received an autograft within EBMT. The population consisted of 193 patients from 60 to 74 years of age (median 63) autografted from 1/84 to 12/98. 147 patients were in CR1. The source of stem cells was peripheral blood (PB) in 128, bone marrow in 51, and a combination of both in 14. 97% of patients had successful engraftment, on leukocytes on day 14 (6-57), neutrophils on day 15 (7-71) and platelets on day 30 (9-894). In patients autografted in CR1, the transplant related mortality (TRM) was 15±4%, the relapse incidence (RI) 58±5%; the leukemia free survival (LFS) 36±5% and the overall survival 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 versus 63±6% in those receiving PB ( p =0.04). The dose in CFU-GM collected was available in only 59 patients, including 53 in CR1. Patients autografted in CR1 who received the higher doses (above median) had a lower RI (47±11% versus 79±9%, p =0.009). Finally, there was a significant improvement for patients transplanted after March 1996: for those in CR1, the RI was 41±8% versus 65±6% ( p =0.01), the LFS 53±8% versus 28±5% ( p =0.01) and the overall survival 72±7% versus 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 lower RI for marrow. In conclusion, the present survey indicates that ASCT is a potential therapeutic approach in patients with AML over 60 years of age and that results have improved recently.

The addition of high-dose methylprednisolone (120 mg given i.v. and repeated after a 4-h interval) to a conventional antiemetic regimen consisting of metoclopramide (0.5 mg/kg given as an i.v. bolus over 30 min followed by 1 mg/kg given as a continuous infusion over 24 h) and alprazolam (0.5 mg given p.o.) was evaluated in a randomized study of leukemic patients undergoing anthracycline-containing multiple-day chemotherapy. Double-blind analysis was done in 30 patients who completed a total of 40 treatment courses. Cumulative 3-day results revealed complete control of nausea in 66% of patients and complete control of emesis in 77% of cases. The addition of methylprednisolone significantly reduced the occurrence of nausea (p = 0.003) and emesis (P = 0.06). Moreover, antiemetic rescue with chlorpromazine was less frequently necessary in patients receiving corticosteroids (P = 0.02). No harmful side effect was observed, and the incidence of severe infectious episodes was similar in both arms. We conclude that high-dose methylprednisolone can improve the efficacy of metoclopramide and alprazolam in controlling nausea and emesis induced by anthracycline-containing multiple-day chemotherapy in patients with acute myeloblastic leukemia.

In order to compare the effects of interferon versus hydroxyurea for the treatment of chronic myelogenous leukaemia (CML), 58 CML patients, having received no previous treatment, were randomized into two treatment groups (hydroxyurea or interferon) for an open multicentre study from 1 May 1987 until 1 July 1990. Fifty patients were evaluable: 24 in the interferon group and 26 in the hydroxyurea group. Haematological response was obtained in 1624 interferon-treated patients and 2326 hydroxyurea patients. Failure to obtain haematological remissions occurred in eight of 24 interferon-treated patients and in three of 26 hydroxyurea patients. Four interferon-treated patient failures and one hydroxyurea-treated failure were due to drug intolerance. Progression occurred in one interferon-treated patient and in three patients given hydroxyurea. Fourteen of 16 patients in the interferon group and 1723 in the hydroxyurea group continue on study and show no progression.