Treatment with rituximab, dexamethasone, high-dose cytarabine, and oxaliplatin (R-DHAOx) produces a strong long-term antitumor effect in previously treated patients with follicular non-Hodgkin's lymphoma.

BACKGROUND: We explored the addition of rituximab to high-dose cytarabine (ara-C), oxaliplatin (L-OHP), and dexamethasone [R-DHAOx], in resistant and relapsed patients with CD20-positive follicular non-Hodgkin's lymphoma. METHODS: Twenty-two patients were included; they were treated previously with one to five chemotherapy regimens, including 13 patients who had also received rituximab. R-DHAOx consisted of rituximab, 375mg/m(2), day 1; dexamethasone, 40mg/d, days one to four; L-OHP, 130mg/m(2), day 1; and ara-C, 2000mg/m(2) every 12 h, day 2. Courses were repeated every 21 days for eight courses. RESULTS: Twenty-one patients (95%) achieved a complete response and one had a partial response. Responses were obtained in patients with and without resistance to prior treatment, either alone or combined with rituximab. The median follow-up time was 58.3 months (range, 8.7-92.6 months). Progression-free survival reached a plateau at 84% at 38.2 months. Only two of the 21 complete responders have relapsed. Tumor molecular markers disappeared in all 10 complete responders whose markers were found before treatment. Peripheral neuropathy related to the cumulative dose of L-OHP, and myelosuppression were the most prominent toxic effects. CONCLUSIONS: R-DHAOx is highly active for salvage treatment of patients with follicular non-Hodgkin's lymphoma, and it produces long-term antitumor efficacy.

Cytotoxic synergism of methioninase in combination with 5-fluorouracil and folinic acid.

Potentiation of the cytotoxic activity of 5-fluorouracil (FUra) by folinic acid (5-HCO-H4folate) is due to elevation of the methylene tetrahydrofolate (CH2-H4folate) level, which increases the stability of the ternary complex of thymidylate synthase (TS), fluorodeoxyuridine monophosphate, and CH2-H4folate that inactivates the TS. Methionine deprivation results in the production of tetrahydrofolate (H4folate) and, subsequently, CH2-H4folate from methyl tetrahydrofolate, as a consequence of the induction of methionine synthesis. We hypothesized that the efficacy of FUra could be augmented by the combination of high-concentration 5-HCO-H4folate and recombinant methioninase (rMETase), a methionine-cleaving enzyme. Studies in vitro were performed with the cell line CCRF-CEM. Cytotoxic synergism of FUra + rMETase and FUra + 5-HCO-H4folate + rMETase was demonstrated with the combination index throughout a broad concentration range of FUra and rMETase. A subcytotoxic concentration of rMETase reduced the IC50 of FUra by a factor of 3.6, and by a factor of 7.5, in the absence and in the presence of 5-HCO-H4folate, respectively. 5-HCO-H4folate increased the intracellular concentrations of CH2-H4folate and H4folate from their baseline levels. Concentrations of folates were not changed by exposure to rMETase. Levels of free TS in cells treated with FUra + 5-HCO-H4folate and with FUra + rMETase were lower than those in cells exposed to FUra alone. The decrease of TS was still more pronounced in cells treated with FUra + 5-HCO-H4folate + rMETase. The synergism described in this study will be a basis for further exploration of combinations of fluoropyrimidines, folates, and rMETase.

Dexamethasone, high-dose cytarabine, and oxaliplatin (DHAOx) as salvage treatment for patients with initially refractory or relapsed non-Hodgkin's lymphoma.

BACKGROUND: Dexamethasone. cytarabine (ara-C), and cisplatin (DHAP) can be used effectively to treat patients with non-Hodgkin's lymphoma (NHL). We hypothesized that substitution of cisplatin by oxaliplatin (L-OHP) could result in less toxicity and greater efficacy. L-OHP is active in patients with lymphoma. It produces mild myelosuppression and is devoid of renal toxicity. We report on a phase II study of dexamethasone, high-dose ara-C, and L-OHP (DHAOx) used to treat patients with NHL who were previously treated with chemotherapy. PATIENTS AND METHODS: Fifteen patients were given DHAOx. They had failed to achieve a CR with initial chemotherapy or had recurrent disease. DHAOx consisted of dexamethasone, 40 mg/day (days 1 to 4): L-OHP, 130 mg/m2 (day 1); and ara-C, 2,000 mg/m2 every 12 h (day 2). Treatment was repeated every 21 days. RESULTS: Patients received a median of four courses of DHAOx. Myelosuppression and transient sensory peripheral neuropathy were the most prominent toxic effects. Serum creatinine levels did not increase in patients with normal renal function, nor in patients who had renal impairment before DHAOx. The median follow-up time from the start of DHAOx treatment was 17 months. Eight patients (53%) achieved a CR, and three patients (20%) had a PR. Responses were achieved by patients with lymphomas of various histologies that included mainly the follicular subtype, and by patients with and without resistance to prior chemotherapy. None of the eight responders have relapsed from CR at 4+. 6+, 14+, 15+, 19+, 20+, 24+, and 24+ months. They had various types of therapy after DHAOx. Disappearance of molecular markers was observed in all four patients who achieved a CR and whose tumor cells carried molecular abnormalities. CONCLUSION: DHAOx possesses characteristics of toxicity which compare favorably to those reported with DHAP, and it is useful as a salvage treatment for patients with NHL. Larger studies are required to establish the therapeutic potential of the regimen.

Long-term outcome after allogeneic hematopoietic stem cell transplantation for advanced stage acute myeloblastic leukemia: a retrospective study of 379 patients reported to the Société Française de Greffe de Moelle (SFGM).

To assess the place of allogeneic hematopoietic stem cell transplantation (HSCT) in the advanced stage of acute myeloid leukemia (AML), we retrospectively analyzed 379 consecutive patients who underwent allogeneic HSCT for advanced AML. The median follow-up of the entire cohort was 7.5 years. Sixty-nine patients (18%) were transplanted with primary resistant disease. Three hundred and ten (82%) were relapsed patients, 94 (30%) of whom were in untreated relapse, 67 (22%) in refractory relapse and 149 (48%) in 2nd or 3rd complete remission at time of transplantation. The 5-year probabilities of overall survival (OS), disease-free survival (DFS), and transplant-related mortality (TRM) were 22 +/- 4%, 20 +/- 4%, 45 +/- 6%, respectively. In multivariate analysis, we demonstrated the favorable impact on OS, DFS and TRM of two factors over which we have no control (age <15 years, complete remission achievement) and three factors over which we have some control (female donor, acute and chronic graft-versus-host disease). The results of this study suggest that the graft-versus-leukemia effect is important in advanced AML and that new HSCT modalities are needed for some patients with this indication.

Large scale recovery and characterization of stromal cell-associated primitive haemopoietic progenitor cells from filter-retained human bone marrow.

Bone marrow aspirates are composed of two cellular compartments, an abundant buffy coat suspension and a minor particulate fraction. The particulate fraction is routinely removed by filtration prior to transplantation in order to reduce the risk of embolism. This study shows that the filter-retained fraction includes many multicellular complexes, previously defined as haematons. A haematon is a finely arborized stromal-web which is tightly packed with haemopoietic progenitor cells and differentiated postmitotic cells. Comparison of the pooled buffy coat and the filter-retained materials from healthy donors showed that the haematon fraction contained 8-40 x 10(6) CD34+ cells, 20-115 x 10(3) high proliferative potential colony-forming cells (HPP-CFC) and 0.49-2.67 x 10(6) granulocyte-macrophage colony-forming unit (GM-CFU) which constituted 24+/-8% (10-36; n=8) of the total GM-CFU population harvested. Similar, but more variable recoveries of GM-CFU were obtained from the haematon fractions from patients with breast cancer (21+/-13%; n=10), Hodgkin's disease (33+/-19%; n=4), non-Hodgkin's lymphoma (21+/-18; n=7), but the recovery was lower from patients with acute myelogenous leukaemia (AML) (13+/-13%; n=6). The haematon fraction was enriched in CD34+ cells (2.5-fold), long-term culture initiating cells (LTC-IC/CAFC, week 5) (3.5-fold), HPP-CFC (2.8-fold) and GM-CFU (2.3-fold) over the buffy coat. Purified CD34+ cells expanded exponentially and produced 800 to 4000-fold more nucleated cells, 300 to 3500-fold more GM-CFU and 10 to 80-fold more HPP-CFC in stroma-free suspension culture with interleukin-1 (IL-1beta), IL-3, IL-6, GM-CSF and stem cell factor (SCF), than did the starting cell input. The haematon fraction produced significantly more progenitor cells than the buffy coat in long-term liquid culture (LTC). This was due to the higher frequency of LTC-IC/CAFC and to the presence of the whole spectrum of native, stroma cell-associated CAFC in haematons. Thus, the haematon includes the most productive haematogenous compartment in human BM. This simple enrichment strategy, using filter-retained haematons, provides a rational source of BM cells for large scale experimental and/or clinical studies on haemopoietic stem cells and on critical accessory stromal cells.

Longitudinal melanonychia induced by hydroxyurea: four case reports and review of the literature.

Although the occurrence of skin lesions during long-term hydroxyurea therapy is well known, longitudinal melanonychia (LM) are more rarely described. In the present paper, we report four cases of LM associated with skin lesions induced by long-term daily hydroxyurea therapy (4 to 10 years), characterized by two uncommon aspects: late onset (2.5 to 5 years) and predominance of toenail involvement in three cases.

Cardiac localization of non-Hodgkin's lymphoma: two case reports and review of the literature.

Secondary non-Hodgkin's lymphoma of the heart (SNHLH) are more frequent than primitive non-Hodgkin's lymphoma and represent the third most common malignant tumour of the heart in autopsy studies. Cardiac involvement usually occurs as a late manifestation in patients with disseminated disease. Initial cardiac lymphoma, defined as cardiac involvement at initial diagnosis with concomitant extracardiac localizations, have nevertheless been reported in approximately 42 cases. The present paper concerns two patients with non-Hodgkin's B-cell lymphoma where cardiac involvement occurring 3 and 6 years after initial diagnosis constituted the unique site of relapse. These cases differ from previous reports of the literature by the predominance of extranodal localizations at initial diagnosis and the late onset of cardiac involvement. Clinical and radiological findings were otherwise in accordance with those usually described in such patients. Transthoracic echocardiography revealed the cardiac tumour in the first case, but in the second case transoesophageal echocardiography and magnetic resonance imaging (MRI) were required to demonstrate its presence. As in most reports, the site of tumour involvement was the right cardiac cavity and histology showed high grade B-cell non-Hodgkin's lymphoma. Polychemotherapy, associated with radiotherapy in the second case, led to partial or complete remission of the cardiac tumour without recurrence within the months of follow-up, although both patients died of their disease within one year.

Evaluation of carboplatin as a single agent in highly refractory acute myeloid leukemia.

Thirteen patients (pts) with highly refractory acute myeloid leukemia (AML) 10 pts with de novo AML and 3 with blast crisis of chronic myeloid leukemia were treated with carboplatin (CP) 150 mg/m2/day through continuous IV infusion for 7 consecutive days. Seven of them received CP at least as third or more line therapy after a median duration of the disease of 26 weeks. None achieved a complete remission but a good hematologic response, with disappearance of circulating blast cells along with correction of bone marrow failure, persisting for 3 months was obtained in one patient and correction of hyperbasophilemia was observed in another with blast crisis of chronic myelogenous. Myelosuppression was the most consistent toxic effect. Two deaths occurred, one from renal acute failure and the other from sepsis. Median survival after CP was 8 weeks (range 4 days-11 months) and the majority of patients were able to return home. When used as a single agent and with the dose-schedule used in this study, CP does not appear effective in refractory AML. Other studies are necessary to assess its role at an higher dose or in combination with other agents in earlier phases of the disease.

[Treatment of high malignancy lymphoma with intensive short-term chemotherapy using the MACOP-B regimen]. / Traitement des lymphomes de grande malignité par chimiothérapie courte et intensive de type MACOP-B.

We present our results of a MACOP-B regimen in a series of 46 patients with high-grade NHL. The complete remission rate was 74% for patients with advanced stage disease. The excellent tolerance allowed this regimen to be given on an outpatient basis in the majority of cases. The median follow-up for the living patients is 28 months. Although some patients received additional treatment that could influence the results, the predicted DFS (disease-free survival) at 45 months of 57% compares favorably with the best results published so far with more toxic regimens.

Acute myelomonocytic leukemia in a XYY man.

A case of acute myeloid leukemia (M4) in a 29-year-old male with a 47,XYY karyotype is reported. This aneuploidy was found in both bone marrow cells and mitogen-stimulated lymphocytes. Monosomy 7 correlated with myelodysplastic features. The possible role of XYY in increasing the risk of leukemia is discussed.

Cyclosporin A as a modifier agent in the salvage treatment of acute leukemia (AL).

Sixteen adult patients with relapsed (7 patients) or refractory (9 patients) acute leukemia received mitoxantrone (10 mg/m2 per day for 3 days) and etoposide (200 mg/m2 per day for 3 days) with escalating dose of cyclosporin A (CsA) from a loading dose of 2 mg to 6.5 mg/kg per 2 h followed by 3 days continuous infusion of 5-15 mg/kg per day. The major toxicities were stomatitis and prolonged aplasia, occurring for 15 mg/kg per day of CsA. Transient conjugated hyperbilirubinemia occurred in all patients, and was CsA dose-dependent (r = 0.7). Adequate serum levels of CsA (> 1 microgram/ml) were obtained in 3/6 patients treated with 10 mg/kg per day and 4/4 patients with 15 mg/kg per day. The pharmacokinetic of mitoxantrone showed an unusual increase of carboxylic metabolites, parallel to CsA levels. We observed six responses (two complete and four partial remissions), and eight resistances. Two patients died at days 3 and 8 from sepsis. Before treatment, 7/16 patients tested for P-gp with C219 were positive (> 10% positive cells). 3/6 responders were P-gp-positive. At time of leukemic regrowth, cells expressing P-gp before therapy reverted to P-gp-negative cells.

Treatment of chronic myelogenous leukemia in blast crisis and in accelerated phase with high- or intermediate-dose cytosine arabinoside and amsacrine.

Twenty-two patients (mean age 41 years) in blast crisis or accelerated phase (AP) of chronic myelogenous leukemia (CML) were treated with cytosine arabinoside (Ara-C) 500 mg/m2 [intermediate dose] or 1000 mg/m2 [high dose] twice a day for 6 days and amsacrine (AMSA) 120 mg/m2 for 3 days. Twenty-one cases were of myeloid type and one was a lymphoid BC. The mean duration of aplasia (neutrophils < 0.5 x 10(9)/l) was 21.5 days. Four patients (18%) died of infection during aplasia and minor toxicities were noted for the remainders. Nine patients (41%) achieved a complete remission (CR) and 4 (18%) a partial response. Various additional therapies were proposed after induction treatment including allogeneic bone marrow transplantation (2 patients), Ara-C and AMSA maintenance or other regimens with or without alpha-interferon (9 patients). Median survival for the entire cohort was 20 weeks (wks), significantly superior for complete responders (37 wks) than for others (7 wks) (p = 0.008). In this study, age, sex, initial platelet or basophil counts, interval between diagnosis of CML and blast crisis were not predictive of response. Although inducing a high CR rate and associated with acceptable toxicity, this regimen did not improve the survival of patients with BC or CML, strengthening the need for alternate approaches to be defined.

[Intra-alveolar hemorrhage during treatments of acute leukemia]. / Hémorragies intra-alvéolaires au cours des traitements des leucémies aiguës.

Intra-alveolar haemorrhages represent frequent and severe complications in acute leukaemia treated with chemotherapy. Thrombocytopenia with or without associated haemostasis disorder in association with infectious or toxic lesions of the alveolar membrane (related to radio- or chemotherapy) represent the major promoting factors. Presence of intra-alveolar haemorrhage is mainly suspected on X-ray chest roentgenogram and can be confirmed by bronchoalveolar fluid examination demonstrating an excess of siderophages. Prevention of this complication is based upon reduction of risk factors. Platelet transfusions and careful introduction of steroids are proposed in certain cases.