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Minimal residual disease (MRD), where leukemic cell levels are lower than the morphologic detection threshold, is the most important prognostic factor for acute lymphoblastic leukemia (ALL) relapse during first-line chemotherapy treatment and is standard of care in treatment monitoring and decision making. Limited data are available on the prognostic value of MRD response after relapse. We evaluated the relationship between MRD response and outcomes in blinatumomab-treated adults with relapsed/refractory (R/R) B-cell precursor ALL. Of 90 patients with complete remission (CR) or CR with partial hematologic recovery (CRh), 64 (71.1%) achieved a complete MRD response (no detectable individual rearrangements of immunoglobulin/T-cell receptor genes by polymerase chain reaction [PCR] at a minimum sensitivity level of 10(−4)). Eleven patients had MRD

Idarubicin (IDR) is a new anthracycline that can be administered orally. Oral IDR was given at a dose of 30 mg/m2 daily for 3 d in 20 patients aged 65 to 79 yr with previously untreated acute myeloid leukemia (AML). 5 patients whose marrow remained blastic at d 14 received a second course. 8 patients achieved complete remission (6 after one single course). There were: 1 early death, 4 deaths in aplasia, 7 failures. The hematologic toxicity was high. All but 1 patient had to stay in hospital and the duration of neutropenia was 12 to 34 d (median 19). Oral IDR is an effective therapy for AML in elderly patients but the total dose of 90 mg/m2 is too aggressive to be administered safely outside the hospital.

Acute lymphoblastic leukemia ( ALL) in the elderly is characterized by its ominous prognosis. On the other hand, imatinib has demonstrated remarkable, although transient, activity in relapsed and refractory Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL), which prompted us to assess the use of imatinib in previously untreated elderly patients. ALL patients aged 55 years or older were given steroids during 1 week. Ph+ve cases were then offered a chemotherapy-based induction followed by a consolidation phase with imatinib and steroids during 2 months. Patients in complete response (CR) after consolidation were given 10 maintenance blocks of alternating chemotherapy, including two additional 2-month blocks of imatinib. Thirty patients were included in this study and are compared with 21 historical controls. Out of 29 assessable patients, 21 (72%, confidence interval (CI): 53 - 87%) were in CR after induction chemotherapy vs 6/21 (29%, CI: 11 - 52%) in controls (P = 0.003). Five additional CRs were obtained after salvage with imatinib and four after salvage with additional chemotherapy in the control group. Overall survival ( OS) is 66% at 1 year vs 43% in the control group ( P = 0.005). The 1-year relapse-free survival is 58 vs 11% ( P = 0.0003). The use of imatinib in elderly patients with Ph+ ALL is very likely to improve outcome, including OS.

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.

We report a case of Sweet's syndrome associated with retinoic acid syndrome in a patient with acute promyelocytic leukemia treated with all- trans retinoic acid (ATRA). Sweet's syndrome appeared on day 6 of ATRA therapy for promyelocytic leukemia. It was associated with a mild retinoic acid syndrome, an inflammatory syndrome occurring in 25% of patients treated with ATRA and characterized by features of capillary leakage with systemic inflammatory signs. The ATRA therapy was discontinued for 11 days and treatment with corticosteroids improved the systemic and cutaneous signs. Only 11 cases of Sweet's syndrome associated with ATRA have been previously reported in the literature, involving only the skin in eight cases, the skin and muscles in two cases, and the lung, kidney, fascia, and muscles in one case. Sweet's syndrome was followed by retinoic acid syndrome in one of these cases. The previously reported cases are reviewed, and the mechanisms of Sweet's and retinoic acid syndromes and the link between them are discussed.

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.

Nilotinib (Tasigna) is a second-generation BCR-ABL kinase inhibitor, recently introduced and used for the treatment of chronic or accelerated phase CML patients, intolerant or resistant to imatinib. This treatment represents and important step forward for the disease control of such patients but can lead to side effects, sometimes serious, which can limit its optimal use. We propose here some guidelines that might be of help in daily practice, in order to manage properly these side effects.

Late first relapses in APL treated with all- trans -retinoic acid- and anthracycline- based chemotherapy: the European APL group experience (APL 91 and APL 93 trials)

Internal tandem duplications (ITDs) of the FLT3 gene have been observed in about 35% of APL cases. If FLT3-ITD is associated with a worse outcome in patients with acute myeloid leukemia (AML) in general, its prognostic value in acute promyelocytic leukemia (APL) is still a matter of debate. We investigated incidence, associated clinical features, and prognostic implication of FLT3-ITD, but also FLT3-D835 point mutation and N-Ras or K-Ras mutations in 119 APL patients, all prospectively enrolled in the two consecutive APL-93 and APL-2000 trials. Mutation incidences were 38, 20, and 4%, for FLT3-ITD, FLT3-D835, and Ras, respectively. The presence of FLT3-ITD was associated with high white blood cell count, high Sanz index, M3-variant subtype, and V/ S PML- RAR alpha isoforms. Complete remission (CR), induction death, and death in CR rates were not affected by FLT3 or Ras mutations, as well as cumulative incidence of relapse. However, a trend for a shorter overall survival (P = 0.09) was observed in FLT3-ITD patients, because of a very poor postrelapse survival (P = 0.02). This feature, which has been also reported in patients with AML in general, is suggestive of an underlying genetic instability in FLT3-ITD patients, leading to the acquisition of additional unknown bad-prognosis gene mutations at relapse.

Sickle cell anemia, a congenital hemolytic type of anemia due to a genetic defect in the beta chain of the globin molecule can cause severe disease. During pregnancy, the risk for preeclampsia and deep venous thrombosis is increased in patients with sickle cell anemia. Occlusion of placenta blood vessels with rigid deformed erythrocytes can cause repeated miscarriages and intra-uterine fetal death. Repeated blood transfusions can prevent these complications by reducing the concentration of abnormal hemoglobin S. We report on the evolution of five pregnancies in three patients with sickle cell anemia who received multiple blood transfusions during gestation, and discuss advantages and risks involved in the care of such cases.

Two new variant Philadelphia (Ph) chromosomes with an aberrant location of the BCR-ABL fusion gene on 9q34 of the derivative 9 are reported. One presented cytogenetically as a standard t(9;22)(q34;q11), whereas the other was classified as an ins(9;22)(q34;q11.1q11.2) using the combined interpretation of cytogenic, FISH, and molecular data. The mechanisms of the two rearrangements are presented. It is suggested that the insertion has occurred in a single event in the patient with ins(9;22). In the patient with t(9;22), both a translocation and an insertion, occurring either sequentially or simultaneously, can account for the location of the BCR-ABL fusion gene on the derivative 9. A possible poor prognostic impact of this aberrant location of the BCR-ABL is also suggested by the clinical data reported in such patients.

We report on a case of methotrexate (MTX) intoxication occurring in a 19-year-old man treated for a leukemia. Exchange-transfusion (ET) was performed in attempt to remove the MTX from the body. This exchange-transfusion was unable to decrease the MTX plasma concentration. This inefficacy of ET in MTX intoxication is in contradiction with previously reported recommendations. However, this result is easily explained by MTX pharmacokinetics parameters.

In a prospective study of 317 acute lymphoblastic leukemia (ALL) patients aged 15–40 years and in complete remission, 257 had a potential donor and one HLA typing analysis; A total of 116 patients were allocated to the allogeneic bone marrow transplantation (BMT) arm and 141 to a control group. In parallel, all patients without an identical donor were randomized to autologous BMT or classical chemotherapy. There is no difference in the two trials between the arms in overall survival. However, for highrisk ALL there is a better survival favoring the allogeneic BMT group. Autologous BMT has outcomes at least similar to classical chemotherapy. Classicial chemotherapy is effective in T-ALL.

The expression of a cell death-inducing gene, Bax, was investigated in 52 cases of Hodgkin's disease in parallel with Epstein-Barr virus and was compared with the immunodetection of other apoptosis-regulating proteins, Mcl-1, Bcl-2, and Bcl-x. Bax immunostaining was found in 92% of the cases, among them 28% with a strong signal in more than 75% of the Reed-Sternberg cells. Mcl-1 was positive in 80% of the cases, whereas Bcl-2 and Bcl-x were found in 53% and 88% of the cases, respectively. Of 48 (89%) Bax-positive tumors, 43 were found to express apoptosis-inhibiting proteins such as Mcl-1 or Bcl-2. With the exception of 1 case, all Bax-positive tumors also expressed either Bcl-2, Bcl-x, Mcl-1, or combinations of these anti-apoptotic proteins. No correlation was found between Bax expression and the presence of apoptotic cells as detected by morphology and the in situ 3' OH-DNA end-labeling technique. Our findings show that the apoptosis-inducing gene Bax expression is frequently expressed in Hodgkin's disease, providing a potential explanation for the good chemoresponses generally obtained for patients with this neoplastic disorder.

The authors report a patient with severe secondary progressive MS who responded to mitoxantrone but developed a fatal acute myeloblastic leukemia 15 months after completion of mitoxantrone therapy. Therapy-related acute leukemia (TRAL) in relation with mitoxantrone is rare; this patient was the first case among a cohort of 802 French MS patients treated with mitoxantrone. Nevertheless, this case stresses the need to further evaluate the long-term risk of TRAL in patients with MS who receive mitoxantrone.

Four consecutive children with myelodysplastic syndromes (MDS) underwent matched allogeneic bone marrow transplantation (BMT). Ages ranged from 3.2 to 6.3 years. Diagnosis was assessed according to FAB classification: refractory anemia-RA (n = 1), RA with excess of blasts (RAEB) (n = 1), and juvenile chronic myelogenous leukemia (JCML) (n = 2). Initial treatment included transfusions for all of them, splenectomy (n = 2) and chemotherapy (n = 1). Patients were all prepared with busulfan 21 mg/kg (480 mg/m2), cytosine arabinoside 24,000 mg/m2, melphalan 140 mg/m2. Graft-versus-host disease (GVHD) prophylaxis associated cyclosporine-methotrexate. Engraftment was prompt and complete in all children. Toxicity included severe mucositis (n = 3), moderate veno-occlusive disease (n = 2), acute GVHD (n = 3), chronic GVHD (n = 1). Sequelae have not yet been seen. All patients are alive and disease-free with a follow-up ranging from 7 to 35 months, with a Karnofsky score of 90-100%. Combined busulphan conditioning can offer an alternative to total body irradiation-based regimens in order to avoid late side-effects in children.

We report here two patients with polycythemia vera (PV) who developed secondary non-Hodgkin's lymphoma (NHL). Both cases were high grade B-cell NHL. Cytogenetic analysis of bone marrow and lymph node was performed in each case and showed numerous chromosomal abnormalities. Of interest, chromosomal abnormalities of the PV and of the NHL clones were different, suggesting the possible involvement of two different clones. A 11q23 breakpoint was common between the two cases and the putative role of this breakpoint in the pathogenesis of the NHLs is discussed.

The authors report a patient with severe secondary progressive MS who responded to mitoxantrone but developed a fatal acute myeloblastic leukemia 15 months after completion of mitoxantrone therapy. Therapy-related acute leukemia (TRAL) in relation with mitoxantrone is rare; this patient was the first case among a cohort of 802 French MS patients treated with mitoxantrone. Nevertheless, this case stresses the need to further evaluate the long-term risk of TRAL in patients with MS who receive mitoxantrone.

The authors report 7 cases of bone marrow necrosis during hematological malignant diseases:3 leukemia, 4 lymphoid malignancies. The main clinical features were bone pain and fever. The bone marrow aspiration and/or biopsy allow diagnosis. The prognosis was in all cases very poor.

The detection of Epstein-Barr virus (EBV) nucleic acids by in situ hybridization (ISH) with biotinylated BamHI-W probes was correlated with the expressions of EBV latent membrane protein (LMP) and EB nuclear antigen 2 (EBNA2), in 107 cases of Hodgkin's disease (HD) of different immunomorphologic subtypes. Epstein-Barr virus nucleic acids were present and restricted to the pathogenic cells in 4 of 40 (10%) cases of nodular sclerosis (NS) and 33 of 55 (60%) cases of mixed cellularity (MC), but were undetectable in other subtypes. Of the 37 cases positive for EBV nucleic acids, 35 (95%) showed the expression of LMP. Epstein-Barr virus nucleic acids and LMP were restricted to Reed-Sternberg cells and variants. Only 1 case (MC) showed LMP expression in the absence of EBV detection. The correlation was strengthened by the finding of LMP expression at first diagnosis in 6/7 EBV positive cases at relapse (14-126 months) (5/5 EBV negative cases at relapse were LMP negative at first diagnosis). EBNA2 was absent in all 13 (NS, 2; MC, 11) EBV+ and LMP+ cases tested. Both LMP and EBNA2 were expressed in control EBV-positive tissues and cell lines. EBV serology in MC HD was indicative of latent EBV infection, but neither serology nor clinical parameters correlated with the presence or the absence of EBV, over a short-term follow-up (median, 20 months). The findings, although not proving EBV as the etiologic agent of HD, suggest that: 1) LMP expression alone may be adequate for identifying EBV-associated HD, 2) the MC subtype has a stronger relation with EBV presence, and 3) the regulation of EBV genes in HD is different from other EBV-associated disorders. The clinical implications still remain to be discovered.

Idarubicin (IDR) is a new potent antileukemic agent and the only anthracycline derivative in current use that can be administered orally. We review here the French experience with oral and IV IDR.

There is general agreement about the use of a combination of cytosine arabinoside (Ara-C) and anthracycline as induction chemotherapy for patients with acute myeloid leukemia (AML). Cytosine arabinoside is usually given as a continuous infusion (100–200 mg/m2 per day) for 7–10 days. Daunorubicin (DNR) is the most commonly used anthracycline and is usually infused for 3 days (45–60 mg/m2 per day). Using such a combination, complete remission (CR) is achieved in 65%–80% of young adult patients but the CR rate is lower in elderly patients, varying from 40% to 70% [6]. This latter lower CR rate is due to a high proportion of patients who fail to enter remission either because they die during induction treatment (infection, cardial dysfunction, etc.) or their leukemic cells are not sensitive to chemotherapy [6]. In order to increase the CR rate in elderly patients, several therapeutic strategies have been proposed. Hematopoietic growth factors such as GM-CSF or G-CSF may shorten the duration of granulocytopenia following chemotherapy and decrease the number of early deaths [3]. New intercalating agents may be used instead of DNR for both increasing the antileukemic efficacy and decreasing the mortality due to cardiac toxicity. Idarubicin (IDA) (4-demethoxydaunorubicin) has been recently introduced as treatment for AML patients. Its safety and antileukemic activity have been reported in some phase I — phase II studies where IDA was used either alone [7] or in combination with Ara-C [1, 5, 8]. The preliminary results from some ongoing prospective studies indicate that IDA is at least as efficient as DNR for adult patients with AML [2, 10, 12, 13]. We report herein a prospective study comparing IDA and DNR in AML patients aged between 55 and 75 years. Our preliminary results are similar to those reported elsewhere in adult patients and confirm that IDA is at least as effective as DNR.

Microscopic intracellular detection of Epstein-Barr virus (EBV) messenger RNA in Reed-Sternberg cells of Hodgkin's disease (HD) was possible by in situ hybridization, in tissue sections prepared by a method termed modified acetone methyl benzoate xylene (ModAMeX). The ModAMeX method was initially developed for simultaneous optimal preservation of leucocyte differentiation antigens and morphology. Two biotinylated DNA probes, corresponding to the same BamHI-W (internal repeat) of the EBV genome were used. EBV mRNA was detected in neoplastic cells in 16 of 54 (30%) lymph node biopsy specimens from usual subtypes of HD (lymphocyte predominance, 0/5; nodular sclerosis, 4/22; mixed cellularity, 12/26; unclassified, 0/1). EBV mRNA was also detected in the lymph node biopsy of 1 additional human immunodeficiency virus (HIV)-related case of HD (mixed cellularity) and in 2 of 4 cases of B-cell lymphomas occurring in patients with acquired immunodeficiency syndrome (AIDS). In other non-Hodgkin's lymphomas, EBV mRNA was detected in only 1 of 41 cases. Cases of HD positive for EBV mRNA were immunostained by CD30 and CD15 antibodies. The hybridization signals were exclusively restricted to Reed-Sternberg cells and variants. When analyzed retrospectively, no statistically significant correlation emerged between hybridization findings, EBV serology, or disease outcome over the 3 years of the availability of ModAMeX technique. The findings support the contention of a direct role of EBV in the pathogenesis of HD, at least in some cases.

We have studied the plasma pharmacokinetics of idarubicin (4-demethoxy daunorubicin) in 11 elderly patients suffering from acute myeloblastic leukemia receiving orally 30 mg/m2 per day for 3 consecutive days. Idarubicin culminated in plasma 4 hr after administration and followed three similar time courses after the three administrations. Idarubicinol (13-dihydro-4-demethoxy daunorubicin) was the only fluorescent metabolite in plasma and no aglycone could be detected; idarubicinol concentration was always higher than that of unchanged idarubicin. Due to its protracted half-life (64 hr in this study), this metabolite progressively accumulated and the ratio of the areas under the curve (0-24) idarubicinol/idarubicin increased from day to day. By comparison to results obtained after i.v. administration of the drug in another study, the bioavailability of idarubicin alone can be estimated to about 21%, whereas the bioavailability of the sum idarubicin + idarubicinol is about 41%.

Background: APL is predominantly associated with low WBC counts. APL with very high WBC counts, i.e. >50 × 109/l, is rare, generally associated with severe coagulopathy and, before the ATRA era, was generally fatal due to early death or subsequent relapse. Methods: we report characteristics and outcome of APL with WBC >50 × 109/l enrolled in two consecutive multicenter trials (APL93 and APL2000) treated with ATRA-CT combinations. In both trials (Blood1999;94:1192, JCO2006;24:5703) pts with WBC >10×109/L received ATRA combined upfront to DNR+AraC followed by 2 consolidation DNR+AraC courses and, in APL93 trial, randomisation for maintenance to intermittent ATRA, continuous low dose CT (6MP+MTX), both treatments (ATRA+CT) or no treatment. In APL2000, they all received maintenance with ATRA +CT, high dose DXM during induction (to further prevent ATRA Sd), and CNS prophylaxis. Results: Of the 1031 pts included in both trials, 261 (25%), 65 (6.4%) and 14 (1.3%) pts had WBC >10×109/l, 50×109/l and 100×109/l, respectively (resp). As compared to pts with50×109/l were younger (48 vs. 44 vs. 40.5 years, p=0.002), had lower baseline plt counts (36 vs. 24.5 vs. 27×109/L, p=0.0002) fibrinogen level (1.8 vs. 1.3 vs. 1.2 g/L, p50×109/L, 6 of them due to ATRA Sd and 1 to bleeding. In pts with WBC > 50×109/l, ED was 6/33 (18%) in APL93 and only 2/32 (6%) in APL 2000 trial (p= 0.25). Thus in APL 2000 trial, the CR rate increased to 94% in pts with WBC>50×109/l (vs. 95% in other pts). 2 year incidence of relapse (CIR), EFS and overall survival (OS) were 31.3%, 17.3%, 8.7% (p50, 10–50, 50×109/l, only 6/38 (15.7%) of those who received combined maintenance (ATRA + CT) relapsed, vs. 12/16 (75%) of those with no or single maintenance (p 50×109/l: 15.7% (vs. 6.4% and 11% in pts with WBC>10–50 and 50×109/l pts, was positive in 5 (all relapsed), and negative in 28 (6 relapsed). The 19 relapses in pts with WBC> 50×109/l occurred after a median of 11 months, and included 2 CNS relapses (both in APL93 trial). 16 of those pts achieved CR2, most before the arsenic era. 2 y-OS after relapse was 62%. Conclusion: APL pts with WBC >50×109/l are rare, may achieve CR rates similar to pts with lower WBC with improved supportive care (including systematic DXM?). They have only a trend for higher risk of relapse with combined ATRA+CT maintenance, and possibly CNS prophylaxis.

ATRA combined to anthracycline based chemotherapy is the reference treatment of newly diagnosed APL and a role for maintenance treatment is supported by many studies, but some controversies remain, like the role of AraC. Methods: We performed a joint analysis of pts < 65 yrs included in studies LPA99 (Spanish PETHEMA) and APL 2000 (French -Belgian-Swiss APL group) to address some of those issues. In LPA99, pts received ATRA combined to Idarubicin (IDA) for induction, followed by 3 consolidation courses, 2 with IDA and 1 with mitoxantrone (MTZ, at cumulative dose of 50 mg/m2), and maintenance with intermittent ATRA and continuous 6MP + MTX during 2 years. Pts with high (WBC > 10000/mm3) and intermediate (WBC < 10000/mm3, platelets < 40000/mm3) Sanz score also received ATRA during consolidation courses and higher cumulative dose of IDA (100 mg/m2), vs low risk pts (no consolidation ATRA, cumulative IDA: 80 mg/m2). No AraC was administered in LPA99 trial. For APL 2000, we restricted the analysis to treatment groups that received AraC: pts with low or intermediate Sanz score received induction with ATRA and DNR (60 mg/m2/d x 3) + AraC (200 mg/m2/d x 7) followed by consolidation with a similar course and a final DNR (45 mg/m2/d x 3) + AraC (1 g/m2/12h x 8) course and the same maintenance as in LPA99. High risk patients received the same treatment, but with intrathecal CNS prophylaxis and, in pts < 60 years, AraC 2g/m2/12h x 8 during the last course. Median follow up was 30 and 22 months in LPA99 (412 pts) and APL 2000 (180 pts), respectively. Comparisons were adjusted on age, gender, WBC and platelet counts. Results: In low and intermediate risk patients (308 LPA99 pts, 97 APL 2000 pts), the CR rates, 2 year cumulative incidence of relapse (CIR), EFS and survival were 96% and 99% (p = 0.2), 2.5% and 6.9% (p = 0.05), 93% and 91% (p = 0.6), 95% and 97% (p = 0.3) in LPA99 and APL 2000 trials, respectively. In high risk patients (104 LPA99 pts, 83 APL 2000 pts), the CR rate, 2 year CIR, EFS and survival were 84% and 95% (p = 0.02), 16.0% and 3.3% (p = 0.06), 69.2% and 88.0% (p = 0.01), 82.4% and 91.2% (p = 0.04) in LPA 99 and APL 2000, respectively. Four relapses in high risk pts involved the CNS in LPA99, vs. none in APL 2000. Three and 5 pts in LPA99 and APL 2000 respectively, died in CR, from treatment toxicity. Conclusion: This analysis suggests than in pts with WBC < 10000/mm3, the current PETHEMA approach yields even fewer relapses than a classical ATRA + DNR + AraC regimen, while being less myelosuppressive. This may be due to the anthracyclines used (IDA and MTZ instead of DNR) and/or to the higher cumulative dose of anthracyclines used in LPA99 trial, and possibly also to consolidation ATRA for intermediate risk pts. On the other hand, in pts with high WBC counts, APL 2000 results yielded better EFS and survival and a strong trend for fewer relapses (including relapses involving the CNS), suggesting a beneficial role for AraC, possibly at high dose, in this subset of patients

The combination of ATRA and anthracycline based chemotherapy (CT) is established as the reference treatment of newly diagnosed APL. For CT, recent reports have suggested than an anthracycline alone may be as effective as anthracycline-AraC combinations, while being less myelosuppressive. We tried to confirm this hypothesis in a randomized trial. Patients and methods: In APL 2000 trial (started in July 2000) newly diagnosed APL patients (pts) < 60 years with WBC < 10,000/mm3 were randomized between a standard group A (induction : ATRA 45mg/m2/d until CR with DNR 60 mg/m2/dx3 and AraC 200mg/m2/dx7 started on day 3 ; first consolidation with the same CT course, second consolidation with DNR 45 mg/m2/dx3 and AraC 1g/m2/12h x4d ; maintenance : intermittent ATRA 15d every 3 months and continuous 6 MP + MTX, during two years) and Group B (same treatment as group A, but without AraC). Other pts were not randomized: pts aged < 60 with WBC > 10,000/mm3 (Group C) received the same treatment as Group A, but with AraC 2 g/m2/12h x4d during the second consolidation course. Pts aged > 60 with WBC < 10,000 (Group D) and >10,000/mm3 (Group E) received the same treatment as Group B and Group A, respectively. All pts with WBC > 10,000/mm3 received intrathecal MTX +AraC for CNS prophylaxis. Results: the first interim analysis was made at the reference date of September 1st 2003, after inclusion of 300 patients. Overall 289 (96.3 %) patients achieved CR, 9 (3 %) had early death (ED) and 2 had resistant leukemia. 19 patients relapsed, including 15 hematological relapses (Hem Rel) and 4 purely molecular relapses (Mol Rel) (ie treated before Hem rel). The randomized groups (pts < 60 years, WBC < 10,000) i.e. Group A (AraC +, 80 pts) and Group B (AraC -, 87 pts) were well balanced for all pretreatment characteristics. In Group A, 79 patients (98 %) achieved CR and one had early death (ED), as compared to 82 (94 %) CR, 3 ED, and 2 resistant leukemias in Group B (p = NS). The 2 year incidence of relapse, event free survival and survival was 3.8% vs. 11.9% (p = 0.021), 93.6% vs. 83.4% (p = 0.019), and 97.4% vs. 89.9% (p = 0.085) in Group A and B, respectively. Of the 11 relapses in group B, 9 were Hem Rel and 2 were Mol Rel, as compared to 1 and 1, respectively, for the 2 relapses in group A. For non randomized groups, the CR rate, 2 year relapse rate, EFS and survival were 97 %, 2.6%, 88.4%, and 91% for Group C (< 60 years, > 10 000 WBC, n = 70), 98 %, 11%, 79.4%, and 90.3% for Group D (> 60 years < 10 000 WBC, n = 47) and 87 %, 0%, 78.3%, and 78.3% for Group E (> 60 years, > 10 000 WBC, n = 16). Conclusion: Our results strongly support that, at least with the anthracycline used (DNR at a cumulative dose of 495mg/m2) AraC should not be omitted in consolidation chemotherapy of newly diagnosed APL, even in patients with WBC < 10,000/mm3. The low relapse rate in patients with WBC > 10 000/mm3 supports a role for high dose AraC (1 to 2 g/m2/12h) in this population at higher risk of relapse. Following this first interim analysis, Groups B and D (ie groups without AraC) were closed for inclusion. Updated results will be presented.

The authors report 7 cases of bone marrow necrosis during hematological malignant diseases: 3 leukemia, 4 lymphoid malignancies. The main clinical features were bone pain and fever. The bone marrow aspiration and/or biopsy allow diagnosis. The prognosis was in all cases very poor.

We report 18 cases of Castleman's disease (lymphoid angiofollicular hyperplasia). 11 had localized form, 4 multicentric form and 3 associated disease (A.I.D.S., cœliac disease). We propose to start a multicentric study for evaluation of incidence and pathogenesis of this singular disease.

Immunoperoxidase study can be performed either on fixed and paraffin embedded biopsy specimens or on frozen sections. Advantages and limits of these two methods, as well as the results obtained on normal and pathologic lymphoid tissue are presented. Immunoperoxidase on paraffin sections (PAP technic) is a simple method which allows a good morphologic analysis. However, most of the fixatives destroy proteic antigens particularly those linked to the cell membrane. Thus surface immunoglobulins (S.Ig) cannot be detected. In contrast cytoplasmic immunoglobulins remain antigenic enough to be demonstrated in routine paraffin embedded sections. In lymphomas synthesizing monotypic immunoglobulins, the percentage of labelled cells varies from 5 to 80%. Beside the background staining, which can be attenuated by trypsinisation, absorption of extracellular substances is often responsible for a false positive staining. Pathologists are mainly confronted with the passive uptake of extracellular immunoglobulins (IgG K and IgG L), as well as other serum proteins (lysozyme etc...). Immunoperoxidase on frozen sections allows the use of monoclonal antibodies. A large number of surface and cytoplasmic antigens can be detected. First, the localization of B and T lymphocytes, NK cells, interdigitating cells and dendritic reticulum cells within the normal lymph node is described. In the second part, the interest of monoclonal antibodies in differential diagnosis between lymphoma and pseudo-lymphoma, and in phenotyping of lymphomas is discussed. Now, it is possible to perform an in situ immunologic characterization of most lymphomas. B cell lymphomas have sIg associated with other antigens (Pan B+, HLA-DR+). Cells of chronic lymphoid leukaemia and centrocytic (cleaved-cell) lymphomas frequently express T65 (T 101+ or Leu 1+) antigen which is usually found on normal or neoplastic T lymphocytes. Monoclonal antibodies provide new evidence of the germinal centre origin of follicular lymphomas. Thus, monoclonal antibody directed against dentritic reticulum cells (CRD) revealed the same network of DRC in follicular lymphomas as in reactive germinal centres. This finding could account for the nodular pattern of these lymphomas, neoplastic cells being in some way, enclosed within the DRC network. On the other hand, neoplastic follicles are surrounded by a large amount of t lymphocytes. Some T lymphocytes are also found within the follicles where they are associated with NK cells. Lastly, as reactive benign follicles, neoplastic follicles are labelled by the anti-Calla antibody.(ABSTRACT TRUNCATED AT 400 WORDS)

Immunohistochemistry using monoclonal antibodies has been proved of diagnostic value in bone marrow pathology. Several monoclonal antibodies identifying antigens not denatured by fixation are now available. In anaplastic tumors infiltrating bone marrow these antibodies allow the distinction of large cell lymphomas which express the leucocyte common antigen (Dako-LC+) from undifferentiated carcinomas which are reactive with anti-cytokeratin antibodies (KL-1+, Dako-EMA+), neuroblastoma (NSE+) and rhabdomyosarcoma (desmin+). KL-1 and Dako-EMA antibodies are also considered to be powerful tools to disclose micrometastases from carcinoma, particularly breast carcinoma, which otherwise may be undiagnosed. The detection of residual or minimal bone marrow involvement in malignant lymphomas (particularly Burkitt type) remains difficult. However, in some cases, Dako-LC and MB2 (anti-B) antibodies are useful to detect bone marrow involvement in some lymphoproliferative disorders composed of small or medium-sized cells scattered among hematopoietic cells, and in some large cell lymphomas (i.e. centroblastic or immunoblastic types). These antibodies allow the detection of minimal or residual involvement by malignant cells, which can be confused with immature hematopoietic cells, on routine stainings. No anti-T antibody was found to react satisfactorily with T cell on decalcified biopsy specimens. In anaplastic large cell lymphomas (so-called malignant histiocytosis), malignant cells coexpress Ki-1 and EMA antigens. Antibodies recognizing these two antigens were found to be of value to demonstrate scarce neoplastic cell in bone marrow.

In France, more than 80% of children with Burkitt's lymphoma or Burkitt's leukemia (ALL3) are now cured with the LMB (B-cell non- Hodgkin's lymphoma and B-ALL) protocols of the Societe Francaise d'Oncologie Pediatrique, but so far, poor results have been obtained in the few adult studies available. We have analyzed the experience with LMB protocols in adult patients. This retrospective study involved 65 adult patients with small noncleaved cell lymphoma or ALL3 treated with the LMB protocols. They were 17 to 65 years old and not previously treated. Human immunodeficiency virus-infected patients were excluded. The diagnoses were made between September 1984 and August 1991. According to the Murphy classification, 12 patients (18%) had stage I or II disease, 25 (38%), stage III disease; 4 (6%), stage IV disease; and 24 (37%), ALL3 (> or = 25% blasts). According to the Ann Arbor classification, 9 patients had stage I disease; 8 patients, stage II; 5 patients, stage III; 21 patients, stage IV disease; and 22 patients, ALL (> or = 30% blasts). Twelve patients had central nervous system (CNS) involvement before treatment. Thirty-nine patients were treated according to the LMB 84 protocol scheme; 14 according to the LMB 86 protocol, and 12 patients received the LMB 84 induction courses followed by the LMB 86 consolidation courses. Three patients underwent bone marrow transplantation (BMT) while in second complete remission (CR) and 3 others had refractory disease. There were some protocol violations caused by empirical medical decisions: local irradiation was performed in 4 patients, 2 patients received prophylactic radiation to the brain that was not specified in the protocol, 13 patients underwent BMT in first CR, and methotrexate doses were modified in 10 patients. Fifty-eight patients (89%) achieved a CR. There were four (6%) primary induction treatment failures, and three (4%) early treatment-related deaths. Eight patients relapsed between 2 and 30 months after CR (median, 4.7 months). Forty-seven patients are alive in CR (45 first CR, 2 second CR) with a median follow-up of 57 months (24 to 93 months). There were five toxicity-related deaths among patients in CR including four BMT-related deaths and five deaths caused by refractory relapses. One patient died in CR at 62 months of rectal cancer. The 3- year overall survival rate is 74% (SE = 5). According to the stages in the Murphy classification, the 3-year survival rates are stages I and II, 100%; stage III, 80% (SE = 7); and stage IV and ALL, 57% (SE = 8). Seven of 12 patients with initial CNS disease are alive with a median survival of 56 months.(ABSTRACT TRUNCATED AT 400 WORDS)

The routine use of frontline ATRA and anthracycline-based chemotherapy has greatly improved the outcome of APL, particularly by reducing the incidence of relapses, notably early relapses. The incidence and characteristics of late relapses after this combined treatment, however, are not known. Methods: Between 1991 and 1997 (APL 91 and 93 trials) 630 newly diagnosed APL pts received ATRA combined to or followed by DNR-AraC chemotherapy (total of 3 courses), with or without (randomisation) maintenance treatment by continuous 6MP + MTX and/or intermittent ATRA (Blood1993; 82:3241–3249, Blood1999; 94:1192–1200). 582 (92.5%) pts achieved CR. 154 (26.4 %) had a first relapse, after 5 to 120 months. Results: 19 of the first relapses (i.e. 12.3% of the first relapses and 3.2% of pts who achieved CR) occurred more than 4 years after CR achievement (late relapses). Their median age was 45 (range 20–68), and M/F 7/12. Median time to relapse was 72 months (range 50–120). All late relapses involved the bone marrow only. t(15;17) and /or PML-RAR were seen in all cases at relapse. Pts were retreated with ATRA + anthracycline based chemotherapy (CT) (n = 14), ATRA alone (n =2), anthracycline based CT without ATRA (n=1), As2O3 (n =1), ATRA+ As2O3(n =1). 17 of them (89.4%) achieved CR2 and 2 had early death. CR2 pts were allografted (n = 3) autografted (n= 5), received consolidation and maintenance CT +/− ATRA (n = 7), and maintenance ATRA alone (n=2). 14 patients remained in CR2 after 5+ to 78+ months,2 (including 1 of the 2 pts salvaged and maintained with ATRA alone) relapsed after 9 and 22 months and died, and 1 patient developed secondary MDS and died. CR2 was already longer than CR1 in 5 cases. 3 year survival from relapse was 77% (median not reached). By comparison to patients who did not relapse and patients who relapsed < 4 years, patients with late relapse were not different for age and initial platelets. They were more often females and had lower initial WBC counts than patients who relapsed Conclusion: late relapse was seen in about 3% of APL treated with ATRA and chemotherapy. Initial characteristics of those patients were rather those of “low risk” APL (especially with WBC< 10000/mm3 and female predominance). Their prognosis was overall favourable, in spite of the fact that they generally occurred before As2O3 was available. Combined maintenance with low dose chemotherapy and ATRA during first line treatment may further reduce their incidence, as it does for earlier relapses.