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Autologous stem cell transplantation after first remission induction treatment in multiple myeloma: a report of the French Registry on autologous transplantation in multiple myeloma.

Eighteen French centers reported 133 autologous stem cell transplantations performed after first remission induction in multiple myeloma. The source of stem cell was marrow (81 cases), blood (51 cases) or marrow plus blood (1 case). The immediate outcome after transplantation was 49 (37%) complete remissions (CRs) (13 maintained, 36 achieved), 61 (46%) partial remissions, 17 failures and 5 toxic deaths. With a median follow-up of 35 months, the median remission duration was 33 months, the median time to treatment failure was 22 months. The median survival was 46 months overall, 54 months for the 103 patients responding to primary treatment, and 30 months for the 30 nonresponders. In univariate analysis, the outcome was influenced by age, Ig isotype, initial beta 2 microglobulin level, response to initial chemotherapy, plasma cell marrow involvement at the time of harvest, albumin and beta 2 microglobulin level at the time of transplantation, and CR achievement after transplantation. In multivariate analysis, the most important prognostic factor was the quality of response after transplantation. The conditioning regimen and the source of stem cell had no significant impact on immediate and long-term results. Maintenance therapy with interferon alpha did not appear to prolong remission duration or survival. Autologous stem cell transplantation is an effective consolidation for patients responding to primary treatment and a salvage therapy for some nonresponding patients. This approach has to be compared to conventional chemotherapy in prospective randomized studies. The critical impact of CR achievement on survival implies new strategies to increase the CR rate.

Adult↗

[Transient dysfibrinogenemia and cerebral thrombosis following remission induction therapy for acute lymphoblastic leukemia].

A 38-year-old female with acute lymphoblastic leukemia developed monoplegia of the left upper extremity following chemotherapy for remission induction consisting of vincristine, prednisolone, cyclophosphamide, adriamycin and methotrexate. Hemorrhagic infarction due to thrombosis of the right cortical vein was diagnosed by brain images using computed tomography and magnetic resonance imaging in addition to the clinical course. At this time, a plasma level of fibrinogen measured by the thrombin time method had decreased to 84 mg/dl, while its antigenicity was 276 mg/dl. There was no evidence of activation of the blood coagulation and fibrinolysis system nor of abnormal liver function. A mixing test with normal plasma disclosed the absence of an inhibitory factor against fibrin polymerization in her plasma. Fibrinogen levels as assessed by the thrombin time method recovered to the antigenicity level one and half months later. The discrepancy between the activity and antigenicity of fibrinogen indicated the occurrence of acquired dysfibrinogenemia, probably induced by antileukemic agents. Thus, it is suggested that dysfibrinogenemia is a possible cause of cerebral thrombosis in this patient.

Adult↗

The effect of short-course high-dose methylprednisolone on peripheral blood CD34+ progenitor cells of children with acute leukemia during remission induction therapy.

This study was undertaken to determine the effect of short-course high-dose methylprednisolone (HDMP) treatment on peripheral blood (PB) CD34+ progenitor cells during remission induction treatment in 11 children with newly diagnosed acute leukemia (7 with ALL, 4 with AML) whose bone marrow (BM) cells expressed fewer than 5% CD34 at the time of diagnosis. All children who had no infection were given HDMP as a single daily oral dose of 30 mg/kg for the first four days of induction therapy. The number of CD34+ progenitor cells were determined by flow cytometry before and after four days of HDMP treatment. While the number of PB blast cells significantly decreased after only a four-day course of HDMP treatment, the number of PB CD34+ progenitor cells increased in all patients. In addition, after four days of HDMP treatment polymorphonuclear leukocytes (PMN) and mononuclear cells (MNC) increased significantly (p < 0.05). We suggest that the potential beneficial effects of HDMP in the induction treatment of acute leukemia may occur partly by the stimulation of PB CD34+ hematopoietic progenitor cells in a short period of time.

Adolescent↗

Granulocyte-macrophage colony stimulating factor treatment of febrile neutropenia following remission induction chemotherapy for acute leukemia.

Recombinant human granulocyte macrophage colony stimulating factor (GM-CSF) was given for 2-6 days in 10 patients with febrile neutropenias following remission induction chemotherapy for acute leukemia (6 acute lymphoblastic and 4 acute myeloid leukemias) in which, broad spectrum and targeted antibiotherapy was ineffective. In 7 patients, the addition of GM-CSF helped overcome the serious infectious complications, leading to an accelerated neutrophil recovery averaging 18.4 days, significantly faster than in a historic group of 9 similar patients in whom GM-CSF was not given Side-effects of GM-CSF treatment were minor and reversible. GM-CSF treatment did not have any significant effect on the achievement of complete remission status.

Adolescent↗

Etoposide in remission induction of adult acute myeloid leukemia.

96 consecutive acute myelogenous leukemia (AML) patients were analyzed retrospectively with regard to the regimen used for remission induction. 35 patients received daunorubicin for 3 days, cytosine arabinoside and 6-thioguanine for 7 days. 61 were treated with the same regimen but 6-thioguanine was replaced by etoposide. Complete remission was achieved in 57 and 72% of patients, respectively (p = 0.06). In leukemias with monocytic phenotype (M4-M5), the remission rate was significantly higher with the etoposide-containing regimen (p = 0.02). Our findings suggest that the replacement of thioguanine by etoposide could be useful in induction therapy of AML.

Adult↗

Continuous intravenous administration of daunorubicin and cytarabine for remission induction of poor risk acute myelogenous leukaemias and myelodysplastic syndromes.

Seventeen consecutively admitted poor risk acute myeloid leukaemia (AML) patients and 4 patients with myelodysplastic syndrome (MDS) were treated with a remission-induction regimen consisting of a 7-day continuous intravenous infusion of conventional doses of cytarabine and of three 24-h constant rate infusions of daunorubicin administered intermittently on days 1, 3 and 5. The diagnoses were: relapsed primary AML in 6 patients, secondary AML in 11 patients (9 untreated, 2 relapsed) and MDS in 4 patients. The median age was 50 yr. Five of 6 patients with relapsed primary AML, 3 of 11 patients with secondary AML and 2 of 4 patients with MDS achieved complete remission (CR). The overall CR rate was 48% with a median remission duration of 5 months (range: 0.25-20 months). Few acute toxic side effects were observed thanks to the constant rate of infusion of daunorubicin.

Acute Disease↗

Remission induction by granulocyte colony-stimulating factor in hypoplastic acute myelogenous leukemia complicated by infection. A case report and review of the literature.

A patient with hypoplastic acute myelogenous leukemia (AML) who achieved remission with granulocyte colony-stimulating factor (G-CSF) alone is reported. The 59-year-old male patient received antibiotics and G-CSF but not any antileukemic drugs because of ongoing pneumonia. After 2-week administration of G-CSF, he achieved complete remission and his pneumonia improved. Since leukemia relapsed after 3 months, he received G-CSF again for 5 weeks, but failed to be in remission this time. He underwent antileukemic chemotherapy and achieved second remission. When he suffered from a second relapse after 7 months, intensive chemotherapy was commenced but was stopped on the 2nd day since his general condition became very poor due to septicemia. He began to receive G-CSF again and achieved third complete remission after 3 weeks. In vitro studies showed that G-CSF did not stimulate proliferation of the patient's blast cells although they expressed G-CSF receptor on their surface. Moreover, G-CSF induced differentiation of the blast cells into segmented neutrophils in vitro. According to the literature, in all of the 12 patients with AML who were reported to achieve remission by G-CSF the course was complicated by infection, and 7 of the patients were diagnosed as hypoplastic acute leukemia. It is suggested that not G-CSF alone but G-CSF with infection could induce remission, which might be related to a differentiation effect of G-CSF in this case. G-CSF is not only safe but also useful for remission induction therapy in hypoplastic acute leukemia.

Cell Count↗

Oral acyclovir prophylaxis against herpes simplex virus in non-Hodgkin lymphoma and acute lymphoblastic leukaemia patients receiving remission induction chemotherapy. A randomised double blind, placebo controlled trial.

Forty-one patients receiving remission induction chemotherapy with vincristine, adriamycin and prednisolone (VAP) for high grade lymphoma or acute lymphoblastic leukaemia were entered into a double blind, placebo controlled trial of oral acyclovir prophylaxis against herpes simplex virus (HSV) infection. The dose of acyclovir was 200 mg four times daily for the duration of chemotherapy (six weeks). Of the 40 evaluable patients, 20 were randomised to each arm. Prophylactic oral acyclovir significantly reduced the incidence of clinical HSV infection from 60% on placebo to 5% acyclovir (P less than 0.001), and the incidence of viral isolates from 70% on placebo to 5% on acyclovir (P less than 0.001).

Acyclovir↗

Features affecting outcome during remission induction of acute myeloid leukaemia in 619 adult patients.

Six hundred and nineteen patients with de novo acute myeloid leukaemia, entered into the Medical Research Council's eighth trial of therapy have been studied. All patients were treated with the same remission induction regimen. Pretreatment variables comprising age, clinical status, haematological status and a detailed marrow cytology and cytochemistry score have been analysed. Poorer remission rates have been found in older patients, in those with lower Karnofsky scores and in patients with a platelet count of less than 25 X 10(9)/l. Leukaemias showing evidence of cytoplasmic maturation along the granulocyte and monocyte lines, as evidenced by granules, Auer rods, a high percentage of Sudan black positive blast cells and morphological and cytochemical abnormalities of neutrophils were associated with a higher remission rate. Marrow eosinophilia was a good prognostic feature. Nuclear features of immaturity, i.e. increasing numbers and prominence of nucleoli were associated with a low remission rate. Abnormalities of the erythroid series, notably Periodic acid-Schiff positivity which was present in 133 cases (22% of the total), was associated with a low remission rate. Patient age and pretreatment Karnofsky score were the most useful predictors of treatment outcome.

Adolescent↗

Remission induction therapy of untreated acute myeloid leukemia using a non-cytarabine-containing regimen of idarubicin, etoposide, and carboplatin.

BACKGROUND: The safety and efficacy of idarubicin, etoposide, and carboplatin as remission induction therapy for patients younger than 60 years with untreated acute myeloid leukemia was studied as an alternative to standard regimens based on cytarabine plus anthracycline. METHODS: Eligible patients received idarubicin (36-40 mg/m2), etoposide (500 mg/m2), and carboplatin (1000-1500 mg/m2) over 5 days. Those who achieved complete remission received a single course of cytarabine 1.5 gm/m2 every 12 hours for a total of 12 doses. D-xylose absorption was studied as a marker for cytotoxic therapy-induced gut mucosal damage. Cytogenetic and immunophenotyping studies were performed at the time of diagnosis and examined for prognostic importance. RESULTS: Remission was achieved in 29 (67%) of 43 patients with a single induction course. The median leukemia free and overall survival times were 15.4 months (95% CI 6.5-24.2) and 12.5 months (95% CI 5.9-19.1), respectively. Induction mortality was 14%. Karyotype (normal, simple, or complex vs. very complex) was the strongest predictor of remission (79% vs. 25%, P=0.01), leukemia free survival (odds ratio [OR] 19.3, 95% CI 2.7-138.9), and overall survival (OR 5.4, 95% CI 2.1-13.9). Dose-limiting gut mucosal toxicity was greatest during Weeks 2 and 3. Bloodstream infections occurred in 49% of patients at a median of 12 days. Grade 3-4 diarrhea, nausea, stomatitis, esophagitis/dysphagia, and vomiting developed in 33%, 26%, 23%, 9%, and 2% of cases, respectively, at a median of 17, 16, 11, 15.5, and 21 days, respectively. CONCLUSIONS: This regimen was active in adults younger than 60 years with untreated acute myeloid leukemia and normal, simple, or complex karyotypes. Remission duration was confounded by karyotype. Mucosal toxicity limited the tolerability of this regimen. These adverse effects might be overcome by increasing the intensity of postremission therapy and modifying the dosing schedule.

Acute Disease↗

First and second complete remissions in a HIV positive patient following remission induction therapy for acute non-lymphoblastic leukaemia.

A small number of patients positive for the human immunodeficiency virus (HIV) have been reported as developing acute non-lymphoblastic leukaemia (ANLL) and none has achieved remission despite attempts at treatment. We report on a 34-year-old HIV positive heterosexual intravenous drug user who presented with ANLL (FAB classification M5, Monoblastic) and entered remission following one cycle of cytosine arabinoside and daunorubicin according to the 7-3 protocol of the Australian Leukaemia Study Group (ALSG). This was followed by consolidation of 5-2 as per ALSG and one cycle of maintenance with low dose cytosine arabinoside. Ten months after remission, he relapsed but achieved a second remission with the ALSG 7-3-7 protocol (7-3 plus etoposide) followed by consolidation with 5-2-5. He remained HIV positive but showed little progression towards the acquired immunodeficiency syndrome despite the intense immunosuppression. The duration of his second remission was five months. The patient died of septicaemia during the third attempt at remission induction 18 months after diagnosis. We conclude that HIV seropositivity is not an absolute contraindication to aggressive chemotherapy in those patients who develop ANLL.

Adult↗

[Clinical evaluation of cases of remission induction failure in acute myelogenous leukemia].

Among 73 patients who were admitted to our hospital between 1972 and 1983, 9 died before starting chemotherapy, 29 achieved complete remission (CR) with an initial regimen of induction chemotherapy, while the remaining 35 patients failed to achieve CR with this initial regimen. Patients with high initial WBC counts (greater than 100,000/cmm), old age, temperature (greater than 38 degrees C) and antecedent hematological disorders, were more prone to failure of remission induction therapy. Comparing CR patients and non-CR patients, there seemed to be no difference in sex distribution, initial platelet counts, initial LDH, percentage of blasts in the blood and bone marrow, the incidence of DIC and the regimen used for remission induction. According to Preisler's criteria, remission induction failure cases were further subdivided into various types and the numbers of each type were as follows: Type I (absolute drug resistance) 1, Type II (relative drug resistance) 16, Type III (regeneration failure) 0, Type IV (hypoplastic death) 6 and Type V (early death) 11. Among 18 M1 cases, 8 were Type II or Type V. Four out of 7 M2 cases belonged to Type II and all 3 M3 cases were Type V. Six out of the 35 remission induction failure patients entered CR with the 2nd chemotherapy regimen and 19 patients died during induction treatment with the initial induction regimen. Causes of death were infection (5 cases), bleeding (6 cases), infection and bleeding (3 cases) and organ failure (5 cases).

Adolescent↗

[Adams-Stokes attack due to complete atrioventricular block in a patient with acute promyelocytic leukemia during remission induction therapy using all-trans retinoic acid].

We describe a case of Adams-Stokes syncope due to complete atrioventricular block which occurred in a leukemic patient receiving all-trans retinoic acid (ATRA). Remission induction therapy was performed for a 46-year-old Japanese man with acute promyelocytic leukemia using ATRA (45 mg/m2), enocitabine (170 mg/m2, 5 days), and mitoxantrone (4 mg/m2, 3 days). On the 25th day of chemotherapy, syncope suddenly occurred. Electrocardiography revealed a complete atrioventricular block, and a temporary pacemaker was inserted on the following day. The block was persistent and the cardiac rhythm was dependent on the pacemaker. ATRA was discontinued on the 29th day because the arrhythmia was believed to be an adverse reaction to the ATRA regimen. The normal sinus rhythm was restored 15 days thereafter, and the patient eventually reached remission. He subsequently received 4 courses of consolidation therapy without any cardiovascular complications. Although ATRA sometimes induces arrhythmias, to the best of our knowledge this is the first report in the literature of such a critical ATRA-related arrhythmia.

Antineoplastic Combined Chemotherapy Protocols↗

The efficiency of strict reverse isolation and antimicrobial decontamination in remission induction therapy of acute leukemia.

The efficiency of strict reverse isolation and antimicrobial decontamination in remission induction therapy of acute leukemia was studied retrospectively in 47 patients who were treated with a standardized aggressive chemotherapy of daunorubicin and cytosine arabinoside. Twenty-two patients were treated in strict reverse isolation with antimicrobial decontamination and 25 patients in the open ward without any measures against infections. In the patients in isolation the incidence of new infections per patient was 0.77 compared to 1.42 in the control group. The rate of complete remissions was 77% in the patients in isolation vs. 56% in the control patients.

Acute Disease↗

High-dose Ara-C for remission induction and consolidation of previously untreated adults with ALL or lymphoblastic lymphoma.

Thirty-two patients with untreated ALL (n = 26) or lymphoblastic lymphoma (n = 6) between 17 and 65 years of age were treated with a short remission induction course with VP16-213, amsacrine, intermediate dose Ara-C for 6 days, prednisone and intrathecal methotrexate, followed by a consolidation course with vincristine, amsacrine, high dose Ara-C for 4 days, prednisone and intrathecal methotrexate. After subsequent cranial irradiation, no further maintenance was planned. However, some patients underwent an allogenic (n = 5) or autologous (n = 5) bone marrow transplantation after the consolidation treatment. Twenty-three of 32 patients (72%) achieved a complete remission. Ten of 13 patients with T-ALL or lymphoma, six of eight patients with pre-B or common ALL, and seven of 11 patients with B-ALL or Burkitt's lymphoma achieved a complete remission. The median duration of remission was 24 months. Overall survival for the whole group was 35% at 5 years. The disease-free survival was 45% at 5 years. Long-term survival for patients with B or T-ALL was approximately 60%, compared with 15% for those with common or pre B-ALL. Short term intensive courses including intermediate or high dose Ara-C during remission and consolidation treatment lead to results comparable to those obtained with long-term maintenance regimens. Our regimen may be sufficient for patients with T or B-ALL. Larger randomized studies are needed to investigate the relative importance of our observations.

Adolescent↗

Intensified remission induction therapy for acute nonlymphocytic leukemia (ANLL). Treatment report on 60 patients.

Sixty patients with ANLL were given intensified remission induction therapy consisting of thioguanine, cytosine arabinoside and daunorubicin (TAD). The mean age of patients was 47.6 years (range 18 to 74 years). Basing on leukemic cell kinetic data time sequencing of drugs was different from the original TAD protocol. Complete remission (CR) waa achieved in 43/60 patients (72%) with 10 CR in 15 patients over 60 years of age. Seventy-nine percent of the CR were induced by one cycle vs thirty percent reported from the original TAD regimen. The major cause of induction failure--in ten of the 60 patients--was thrombocytopenia refractory to platelet transfusions. Persisting leukemia after two induction cycles was documented in only two patients. Median remission duration by life table analysis is 10 months with 17 patients in continuous CR for 1+ to 22+ months.

Acute Disease↗

[Cytological findings of the cerebrospinal fluid at diagnosis of acute lymphocytic leukemia in children--effect of remission induction chemotherapy].

Cytological examination of the cerebrospinal fluid (CSF) was performed in 88 children with acute lymphocytic leukemia at the time of initial diagnosis (54 cases), during (day 1-15, 17 cases) or after (day 37-58, 17 cases) the remission induction chemotherapy. Leukemic cells were found on cytological examination in 23 cases (42.6%), 5 cases (29.4%) and 2 cases (11.8%), respectively, and the incidence of central nervous system (CNS) leukemia had a tendency to decrease during the induction chemotherapy. The follow-up study of 15 cases of CNS leukemia at diagnosis revealed that the leukemic cells in CSF had decreased within 2 weeks and then disappeared after the induction chemotherapy. These findings indicate the therapeutic effect of induction chemotherapy including prednisolone on subclinical CNS leukemia at diagnosis.

Adolescent↗

Comparison of autologous bone marrow transplantation and peripheral blood stem cell transplantation after first remission induction treatment in multiple myeloma.

The optimal source of stem cells is a controversial issue in the field of autologous stem cell transplantation. A comparison of autologous bone marrow transplantation (BMT) and peripheral blood stem cell transplantation (PBSCT) after first remission induction treatment in multiple myeloma was made by a retrospective analysis of 132 transplants performed in 18 French Centers from 1984 to 1991 (81 autologous BMT, 51 PBSCT). The two groups differed in the median age (PBSCT 49 years; autologous BMT 55 years, P < 0.001), the duration of chemotherapy prior to transplantation, the interval between stem cell collection and transplantation, and in the conditioning regimen (more total body irradiation and higher doses of irradiation in the PBSCT group). The median time to neutrophil recovery was shorter in the PBSCT group (13 days vs. 20 days, P < 0.001), but the median time to platelet recovery did not differ significantly between PBSCT (26 days) and autologous BMT (22 days). There was no significant difference between the two groups regarding overall response rate (PBSCT 84%, autologous BMT 82%) and complete remission rate (PBSCT 37%, autologous BMT 36%). The actuarial relapse-free survival, time to treatment failure and overall survival were not significantly different. A case controlled study comparing 43 autologous BMT and 43 PBSCT matched for age and status at the time of transplantation did not show any advantage of PBSCT over autologous BMT in terms of immediate outcome, relapse-free survival, overall survival and time to treatment failure. Thus, in this retrospective analysis, the only significant benefit for PBSCT was reduced time to neutrophil recovery.

Adult↗