Antiphospholipid syndrome during chronic myelomonocytic leukemia.
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Biomedical subjects
Publications and source records attributed to A Broustet.
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Iatrogenic third degree atrioventricular block due to alpha interferon is rare. The authors present a case which occurred with low dosage, regressed when treatment was withdrawn and reappeared when treatment was reintroduced. The physiopathological mechanism of disease of the conduction pathways and its general cardiotoxicity is not yet understood. The secondary effects of this increasingly widely used anti-tumoral and anti-infectious drug should be recognised in order to prevent them. Initial cardiological investigation and follow-up are indicated to ensure this prevention.
PURPOSE: In a first prospective nonrandomized trial, 107 patients with Stage III and IV "low-grade" lymphomas have been treated with a combination of chemotherapy and low-dose total body irradiation (LD-TBI). This study shows that this scheme of LD-TBI was very well tolerated, gave a high response rate (83%), and extended RFS. It incited us to start a pilot study on localized follicular lymphomas. METHODS AND MATERIALS: From January 1986 through October 1994, 34 patients with previously untreated localized low-grade non-Hodgkin's lymphomas have been included in a prospective trial with LD-TBI followed by radical involved field radiotherapy (IF-RT). Patients received two courses of whole body irradiation of 0.75 Gy in 5 fractions and 1 week separated by a rest period of 2 weeks. After 1 month, patients were reevaluated, and received 40 Gy in 20 fractions, and 4 weeks on initially pathological lymph node areas. Eight patients have been excluded from the study: 4 after histologic review (2 centrocytic, 1 lymphocytic, 1 centroblastic) and 4 patients with Stage IV because of bone-marrow involvement. The remaining 26 patients were 11 men and 15 women, 50 years old median age (mean: 50.2; range: 35-73.5) with clinical Stage I (10 pts), II1 (8 pts), and II2 (8 pts). All patients received the planned treatment. RESULTS: Clinical tolerance was excellent, and the hematological follow-up shows a mean nadir value of 3.9.10(9)/l (2.1-8.1) for leucocytes, 13.4 g/l (10.8-15.4) for hemoglobin, and 124.10(9)/l (46-216) for platelets, with a median delay of 3.2 months. Of 26 patients, 24 achieved complete remission (CR) after the LD-TBI that was before the IF-RT. All patients, except one, were in complete remission after IF-RT. Nineteen patients remain alive without any evidence of disease, with a median follow-up of 56.2 months. Five patients relapsed; 3 of them died. CONCLUSION: As delivered, this schedule of LD-TBI give a very high rate of CR in localized follicular non-Hodgkin's lymphoma, with a very good tolerance. It remains to prove that this immediate efficacy has an impact on long-term disease-free survival in such patients, and to understand how the LD-TBI works (direct and/or indirect induction of apoptosis; relationship with t(14;18) translocation and overexpression of bcl-2). These will be the two aims of a new EORTC prospective randomized trial comparing LD-TBI followed by IF-RT vs. IF-RT alone.
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The aim of the study was to analyze the factors influencing peripheral blood progenitor cell (PBPC) collection after high-dose cyclophosphamide (HDCYC) (7 g/m2) and hematopoietic recovery after autologous transplantation of HDCYC-mobilized PBPC (ABPCT) in 116 patients with aggressive multiple myeloma (MM). Following HDCYC 74 patients received hematopoietic growth factors (HGF), either G-CSF (n = 19) or GM-CSF (n = 55). All the patients were subsequently planned to undergo ABPCT. PBPC collection was possible for 106 patients. The most important prognostic factor for collection of more than 25 x 10(4) CFU-GM cells/kg and 2 x 10(6) CD34+ cells/kg was the use of HGF (P = 0.002 and 0.009, respectively). Previous use of an alkylating agent, response to treatment before HDCYC, and interval between diagnosis and HDCYC were also significant factors (P = 0.004, 0.025 and 0.001, respectively). The number of CFU-GM cells infused was the most important parameter for rapid and complete hematological recovery after ABPCT (P < 0.0001). Thus the use of HGF post-HDCYC is the major factor which, associated with reduced time between diagnosis and HDCYC and the use of an alkylating agent, could increase the numbers of hematopoietic progenitors collected, and subsequently improve hematopoietic recovery following ABPCT in MM patients.
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Acute lymphoblastic leukemia (ALL) in the elderly is characterized by its poor prognosis. Forty patients with ALL, aged 55 years or older, and with good performance status (ECOG <3) were prospectively treated according to an age-adapted regimen: induction therapy was derived from the LALA87 protocol while the feasibility of treatment with interferon combined with chemotherapy was assessed during maintenance. Compared with younger adults treated according to the LALA87 protocol, elderly patients did not present with more adverse prognostic features, except for a lower incidence of T cell ALL (9 vs 31%, P=0.005). There were even less patients with a high leukocyte count (15 vs 38%, P=0.003), a characteristic associated with adverse prognosis while the incidence of Philadelphia-positive (Ph-positive) ALL was not significantly increased compared to younger adults (31 vs 20%, P=0.2). After completion of induction therapy, with or without salvage treatment, 85% (CI: 70-94%) obtained a complete response (CR) while treatment-related mortality during induction was 7.5% (CI: 2-20%). Median overall survival and disease-free survival were 14.3 months and 14 months, respectively, which, although inferior to results achieved in younger adults, compares favorably with available data in the elderly. Treatment with IFN proved feasible in most patients but had to be discontinued in eight patients because of toxicity. Age-adapted treatment improves the prognosis of ALL in the elderly even if, in most cases, a cure cannot be achieved.
PURPOSE: The aims of the current study were to evaluate in patients with high-risk multiple myeloma (MM) the feasibility and usefulness of high-dose chemotherapy or chemoradiotherapy followed by hematopoietic stem-cell support with autologous peripheral-blood progenitor cells (PBPC) harvested after high-dose cyclophosphamide (HDCYC). PATIENTS AND METHODS: Seventy-three patients with high-risk MM were entered onto the study. Before the procedure, all patients had received HDCYC to collect PBPC by leukapheresis. One patient died of infection after HDCYC. All other patients subsequently received high-dose melphalan (HDM) (140 mg/m2) either alone (n = 1) or associated with either busulfan (16 mg/kg; n = 4) or total-body irradiation (TBI) (8 to 15 Gy; n= 67). In addition, three of the latter patients received cyclophosphamide (120 mg/kg). Thereafter, PBPC were reinfused either alone in 61 patients or together with back-up bone marrow cells in 11 patients in whom the granulocyte-macrophage colony-forming unit (CFU-GM) cell content of the leukapheresis was low. RESULTS: One patient died of acute cardiac failure after reinfusion of PBPC; three patients did not respond after autologous blood progenitor cell transplantation (ABPCT), while the other 68 patients achieved either a complete response (CR; n = 32) or partial response (PR; n = 36). Thirty-six patients relapsed or progressed after a median response duration of 14.5 months (range, 3 to 43) and 19 of these subsequently died. Four other patients died while still responsive of lung cancer (n = 1) or infection (n = 3). The remaining 28 patients are currently alive and still responding with a median follow-up duration of 27 months (range, 6 to 66). The 3-year probability of survival was 66% +/- 12% (95% confidence interval [CI] after ABPCT and 77% +/- 51% (95% CI) from diagnosis. CONCLUSION: High-dose chemotherapy or chemoradiotherapy followed by autologous PBPC support in MM is feasible and efficient. Further studies are needed to confirm these encouraging, although preliminary, results and to compare this technique with other therapeutic strategies.
Autografting could become a promising treatment for patients with chronic myeloid leukemia (CML) who cannot undergo allogeneic bone marrow transplantation or failed to respond to recombinant alpha-interferon (IFN). In this review, we analyze the results which have been published for patients transplanted in chronic phase and which suggest that autografting could prolong survival, at least in some patients. We also discuss the different methods of purging whose clinical efficacy remains to be assessed.
A prospective randomized study was conducted comparing the efficacy and toxicity of two anthracyclines for the treatment of patients with acute myeloid leukemia (AML) between 55 and 75 years. A total of 220 patients were randomized to receive as induction chemotherapy cytosine arabinoside (Ara-C: 100 mg/m2/day; continuous infusion for 7 days) combined with either daunorubicin (DNR: 50 mg/m2/day, i.v. bolus for 3 days) (n=108) or idarubicin (IDA: 8 mg/m2/day, i.v. bolus for 5 days) (n=112). The complete remission (CR) rate was similar (P=0.296) after IDA (76/112; 68%) and DNR (66/108; 61%) (P=0.3). For patients aged 55-65, the CR rate was significantly higher after IDA (39/47; 83%) than after DNR (29/50; 58%) (P=0.007). Persistent leukemia was more frequent after DNR (26/108) than after IDA (13/112; P=0.015). Hematological and extra-hematological toxicities were similar. The CR patients were given a consolidation course of chemotherapy with Ara-C: 50 mg/m2/12 h, subcutaneously for 5 days, combined with either DNR:30 mg m2/day, i.v. bolus for 3 days or IDA:8 mg/m2/day i.v. bolus for 3 days according to the initial randomization, and then received a continuous maintenance treatment for 2 years. The survival and disease-free survival (DFS) were similar in both groups; there was no difference in the risk of relapse. However, there was a trend for a longer event-free survival (EFS) in the IDA group than for the DNR patients (P=0.07). Our results seem to indicate that IDA is probably more efficient than DNR for AML patients between 55 and 75 years, and confirm the data published in other studies comparing prospectively IDA and DNR in adults.
To improve the management of chronic myeloid leukemia (CML) in a single center, we have used interferon-alpha (IFN-alpha) to treat newly diagnosed Ph-positive CML patients and investigated the factors predictive of a major cytogenetic response. Eighty-one patients with a median age of 50.5 y (17-70) were given IFN-alpha (5 x 10(6)/sqm/day, s.c.). The median interval between diagnosis and IFN-alpha was 45 days (0-160). IFN-alpha doses were adjusted to maintain the white blood cell (WBC) count between 1.5 and 5 x 10(9)/l and the platelet count between 50 and 100 x 10(9)/l. At diagnosis, Sokal's criteria were used to classify patients into three groups: low (n = 39), intermediate (n = 32) and high risk (n = 10). A complete hematological response (CHR) was achieved in 66 cases (81.5%). Cytogenetic response was evaluated in these 66 responders. Thirty-six patients (44.4%) achieved a major cytogenetic response (MCR) (> or = 65% Ph-negative cells), 31 of them having a complete cytogenetic response. The 5-y transformation-free survival (TFS) of the 81 patients was 77 +/- 14% (95% CI) and was statistically influenced by the CHR rate at three months (p = 0.008) and the achievement of MCR or CCR (p < 0.0009 and p < 0.0005, respectively). Moreover, we found that the MCR or CCR were significantly influenced by the obtaining of CHR at three months (p < 0.001 and p < 0.0001, respectively). These results show that IFN-alpha can induce high rates of hematological and cytogenetic responses when administered in doses leading to myelosuppression. The achievement of CHR within three months could be useful to identify early those patients who will not respond to IFN-alpha and who need alternative treatments such as allogeneic or autologous stem cell transplantation.
In 204 adult patients with de novo acute myeloid leukemia (AML), we prospectively compared allogeneic bone marrow transplantation (alloBMT), autologous stem cell transplantation (ASCT) and chemotherapy (Chemo). 162 patients (79.4%) achieved a complete remission (CR). Of the 135 patients who were still in CR after consolidation, 96 patients were less than 46 years of age: 36 patients had an HLA-identical sibling donor and were allocated for alloBMT (group I); they were compared to the 60 other patients who did not have an HLA-identical sibling donor and were treated with either ASCT or chemotherapy (group II). The 3-year disease-free survival was higher for group I patients (66.5 +/- 16%) than for the 60 group II patients (42.4 +/- 13%) (P < 0.05). The actuarial risk of relapse at 3 years was significantly lower for group I patients (24 +/- 15%) than for the other 60 group II patients (56 +/- 13%; P < 0.009). By multivariate analysis, the disease-free survival and risk of relapse were influenced by the initial WBC count (P < 0.02 and P < 0.006), the number of chemotherapy courses for CR (P < 0.001 and P < 0.01) and the type of post-induction treatment (alloBMT vs no alloBMT; P < 0.1 and P < 0.02). The 99 patients who did not fulfill the inclusion criteria for alloBMT were given intensive chemotherapy including high-dose aracytine. When they were still in CR (n = 77), these patients were then randomized for either ASCT (n = 39) or Chemo (n = 38). We were unable to detect any statistical difference between ASCT and Chemo for either disease-free survival, risk of relapse or survival. These results indicate that alloBMT seems to produce results which are at least superior to those of other therapeutic modalities. The results of either ASCT or Chemo look similar.
In the present report, we describe two cases of rare extramedullary relapse (skin, muscle) after allogeneic bone marrow transplantation (BMT). As both patients were male and had received sex mismatched (non T-depleted) BMT, marrow samples were analysed with a Y-chromosome specific probe allowing the sensitive detection of host DNA. The proportion of host DNA remained low in all post BMT samples from these patients, even at the time of extramedullary relapse.
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We report minimal residual disease evaluation in 18 chronic myelocytic leukemia patients who achieved a durable complete cytogenetic conversion (CCC) under interferon alpha (IFN) therapy. Monitoring was performed every 3-6 months using bone marrow (BM) karyotypes and/or two-step reverse transcription polymerase chain reaction (RT-PCR) on peripheral blood samples. Median follow-up after first CCC was 47 months (range 15-69). All patients maintained complete hematological remission during follow-up. A median of five BM karyotypes were performed per patient (range: 3-11). The estimated chances of maintaining a major cytogenetic response (either CCC or less than 35% Ph positive metaphases were 93 +/- 13% (95% CI) at 36 months. One patient lost his cytogenetic response. A median of seven RT-PCR reactions were performed per patient (range: 1-11). A residual disease was detectable even in cases with long periods of CCC. However, in two patients, RT-PCRs were often negative; one, who had four successive negative RT-PCR was taken off IFN therapy and did not receive any other treatment; later in this case, RT-PCRs were again positive, but CCC was maintained for 39 months. Of the three who were taken off IFN and no longer treated, two maintained CCC (39+ and 33+ months); the third had a recurrence of 7% Ph-positive metaphases, and later returned to CCC. These results confirm that in most well-responding patients, the disease is not eradicated. However, it seems that the clonogenic potential of the residual leukemic clone is low. In patients taken off IFN therapy, IFN may have a particular remnant effect.
We report a case of peripheral neuropathy occurring after autologous blood stem cell transplantation (ABSCT) for multiple myeloma. The patient, free of neurological symptoms, was transplanted in partial remission, and achieved a complete remission after transplantation. A severe peripheral, symmetric, distal sensori-motor polyneuropathy appeared at day 25 and worsened progressively until commencement of corticosteroid therapy. A peripheral nerve biopsy showed endoneurial cellular infiltrates which were predominantly composed of T cells identified by immunocytochemistry. Ultrastructural examination showed acute axonal damage. Electrophysiologic studies performed before and during the treatment were consistent with a severe axonal degeneration and showed a marked improvement, concomitant with the favorable clinical outcome. This is the first report of peripheral neuropathy after ABSCT.
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BACKGROUND: Cases of adult T-cell leukemia/lymphoma (ATLL) resulting from human T-cell leukemia virus type I (HTLV-I) have been observed mainly in the southern part of Japan. Recently, the authors performed a second examination of cutaneous, muscle, and nerve biopsy specimens from a French white woman who died of ATLL in 1979. METHODS: A 67-year-old white woman had a lymphoma diagnosed on a lymph node biopsy. She then had acute pains and a thickened skin on both legs. Blood examination showed a leukocyte count of 16,000/ml with 75% leukemia T-cells. Biopsies were performed on the antero-external surface of the right leg. She died after 2 years of illness. RESULTS: Lymphomatous infiltrates of T-cell origin were seen in the dermis, between muscle fibers, and in a peripheral nerve. The recent ultrastructural examination of a few vacuoles located in the cytoplasm of certain lymphomatous cells showed rounded structures mixed with larger virus-like formations having a central nucleoid and spike material around the envelope. Polymerase chain reaction experiments performed on deparaffinized sections demonstrated the presence of a tax sequence homologous to that of HTLV-I. Other structural genes were not detected. CONCLUSIONS: These results contrast with other ultrastructural studies in which HTLV-I was detected only after cultivation of leukemia cells from patients with ATLL. This case probably resulted from an HTLV-I variant.