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PubMed1994

In vitro all-trans retinoic acid (ATRA) sensitivity and cellular retinoic acid binding protein (CRABP) levels in relapse leukemic cells after remission induction by ATRA in acute promyelocytic leukemia.

The current treatment of acute promyelocytic leukemia (APL, also called AML3 subtype) is focused on differentiating agents such as the vitamin A derivative all-trans retinoic acid (ATRA). This agent is a novel and very promising therapy for this disease characterized cytogenetically by a translocation t(15;17)(q21;q22) involving the alpha retinoic acid receptor on chromosome 17 and the PML gene on chromosome 15. Clinical trials have demonstrated that ATRA followed by or combined with conventional chemotherapy may be more beneficial than chemotherapy for inducing complete remission. Unfortunately, ATRA as a single agent, does not appear able to maintain patients in remission (median 5 months), and when relapse occurs resistance to a second induction of ATRA therapy is observed in almost all cases. Recently our laboratory investigated whether specific features of the AML3 cells at relapse could explain the in vivo resistance observed. We have demonstrated that AML3 patients' cells (from four patients) at relapse show high levels of CRABP, a cytosolic retinoic acid binding protein and this protein was not detected prior to ATRA therapy. Relapse-AML3 cells (n = 12) showed reduced differentiation induction when compared with 'virgin'-AML3 cells. Results from this study suggest that CRABP could modulate ATRA cellular concentrations reaching the nucleus. This induced ATRA hypercatabolytic state should be monitored during consolidation therapy and at relapse by evaluating CRABP and RA metabolite levels, in order to detect ATRA resistance in patients with AML3.

Clinical Trials as Topic↗
PubMed2001

Improved efficiency of remission induction facilitates autologous BMT harvesting and improves overall survival in adults with AML: 108 patients treated at a single institution.

A hundred and eight patients less than 60 years old with de novo acute myeloid leukemia were treated between 1982 and 1994 by protocols including final intensification with a transplant using autologous bone marrow purged by mafosfamide in first remission in the absence of an HLA-matched sibling donor available for allograft. From 1989, we attempted to improve tumor control by using high-dose anthracyclines in induction, by increasing from one to two the number of consolidation courses pre-transplant and by introducing intermediate doses of cytarabine in the first consolidation course. The CR rate was 77% (33/43) before 1989 and 90% (59/65) after 1989 (P = 0.06). Forty-five out of the 59 patients (76%) who achieved CR after 1989 could undergo bone marrow grafting in CR1 vs 16/33 (48%) before 1989 (P = 0.01). In spite of the higher proportion of patients above 50 years after 1989 (32%) toxicity was mild and an adequate graft was obtained more frequently after one collection. The principal factor relating to improvement in graft feasibility was the post-1989 modification of induction and consolidation regimens. This improvement in graft feasibility was associated with a better disease-free survival (DFS) (48 +/- 7% vs 32 +/- 8%, P = 0.04) and overall survival (OS) (53 +/- 6% vs 30 +/- 7%, P = 0.007) at 5 years. By multivariate analysis four factors were associated with overall survival (OS): karyotype, white blood cell count at diagnosis, treatment regimen and bone marrow grafting in CR1. This global approach should be prospectively compared with intensive chemotherapy.

Acute Disease↗
PubMed2002

G-CSF administered in time-sequenced setting during remission induction and consolidation therapy of adult acute lymphoblastic leukemia has beneficial influence on early recovery and possibly improves long-term outcome: a randomized multicenter study.

Sixty-four untreated adult acute lymphoblastic leukemia (ALL) patients were randomized to receive chemotherapy alone, n = 31 or chemotherapy and granulocyte colony stimulating factor (G-CSF), n = 33. During induction patients received G-CSF for 5 days between four weekly Epirubicin+Vcr administrations, starting 36 h after each application and finishing 48 h before the next one with the intention to possibly generate a cell cycle dependent protection of normal hematopoietic progenitors and to stimulate granulopoiesis. The complete remission (CR) rate equaled 94% in the G-CSF group and 87% in controls. Patients who received G-CSF, if compared to the controls, had shorter granulocytopenia during induction and consolidation, displayed a lower infection rate, completed the induction-consolidation quicker and stayed shorter in hospital during induction, p < 0.001-0.04. Follow-up at 2 years revealed a rather higher probability of survival (59 vs. 27%, p = 0.04) and a lower relapse rate (32 vs. 60%) in G-CSF arm than in controls. The beneficial influence of G-CSF administered in time-sequenced fashion on survival needs further confirmation.

Adolescent↗
PubMed1978

[Leukaemias and lymphomas treatment by vindesine. Result of a phase II trial in terms of remission induction (author's transl)].

Vindesine is a derivative of vinblastine and of vincristine. A high proportion of remissions were obtained in acute lymphoid leukaemia (6 complete and 1 incomplete remissions in 15 patients), in blastic crisis of chronic myeloid leukaemia, and a few responses have been registered in lymphosarcoma and Hodgkin's disease. Permanent 48 h i.v. infusion may include a remission where i.v. pusch of the same dose has failed. The most remarkable characteristic of vindesine is the absence of cross-resistance with vincristine as documented in acute lymphoid leukaemia.

Adolescent↗
PubMedDate not supplied

Short-term remission induction and consolidation therapy for adult acute myelogenous leukemia.

One hundred and ninety two adults (median age 44 years) with de novo or secondary (n = 17) acute myelogenous leukemia (AML) were managed with a maximum of six intended courses with adriamycin 25 mg/m2/d for three days, plus cytarabine 200 mg/m2/d and 6-thioguanine 200 mg/m2/d for seven days (short-term therapy, STT). Twenty eight patients not in remission after the first course were given cytarabine 2 g/m2/bd for six days, a treatment that was highly toxic and gave a low CR rate. One hundred and twenty-six patients overall (66 per cent) achieved a complete remission (CR), 117/164 (71 per cent) after one to three standard courses (median 1), and 9/28 (32 per cent) after high-dose cytarabine. Median CR duration was 12 months. By multivariate analysis, younger age, blast count less than or equal to 50 x 10(9)/L, and de novo AML were associated with a better outcome (p less than 0.05). CR duration correlated favourably with FAB M3 morphology and total number (five or six) of cycles (p less than 0.05). In patients receiving five or six total courses, median CR length resulted 15.5 months and leukemia-free survival at 3 years 37 per cent. Therapy was curtailed in one fourth of CR patients because of unacceptable toxicity, and there were nine early deaths attributable to therapy-related complications among 126 CR cases. STT may be a worthwhile form of treatment for patients with de novo non-hyperleukocytic AML that are able to tolerate five or six consecutive induction-like chemotherapy courses.

Adolescent↗
PubMed1996

Feasibility and results of bone marrow transplantation after remission induction and intensification chemotherapy in de novo acute myeloid leukemia. Catalan Group for Bone Marrow Transplantation.

PURPOSE: To evaluate prospectively the feasibility and results of bone marrow transplantation (BMT) after induction and intensification chemotherapy (CT) in patients with de novo acute myeloid leukemia (AML). PATIENTS AND METHODS: A total of 159 patients less than 51 years of age were treated. Induction CT consisted of daunorubicin 60 mg/m2 for 3 days, cytarabine (ARA-C) 100mg/m2 for 7 days, and etoposide 100 mg/m2 for 3 days. The first intensification therapy included mitoxantrone 10 mg/m2 for 3 days and ARA-C 1.2 g/m2 every 12 hours for 4 days. Amsacrine (100 or 150 mg/m2 for 3 days) and ARA-C (1.2 g/m2 every 12 hours for 2 or 4 days) were given as the second intensification therapy. Depending on the availability of a human leukocyte antigen (HLA)-identical sibling, the intention of treatment after CT was allogeneic BMT (allo-BMT) or autologous BMT (ABMT). RESULTS: Complete remission (CR) was obtained in 120 patients (75%) and partial remission (PR) in 11 (7%), while 15 patients (10%) were refractory and 13 (8%) died during induction. There was a trend for better leukemia-free survival (LFS) at 4 years for patients assigned to the ABMT group (50% +/- 6%) compared with the allo-BMT group (31% +/- 7%) (P = .08). This difference in LFS reached statistical significance when considering only transplanted patients (63% +/- 3% at 4 years after ABMT and 38% +/- 11% after allo-BMT, P = .02). The favorable results in patients who received ABMT (no toxic deaths and 37% +/- 7% probability of relapse at 4 years) contrast with the poor outcome of allografted patients (11 patients with transplant-related mortality). CONCLUSION: Our study reflects the difficulties in the completion of a therapeutic strategy that include BMT and suggests that intensification before BMT may be useful in the setting of ABMT, but this approach was associated with a high mortality rate in allo-BMT patients.

Acute Disease↗
PubMed1999

Persistence of peripheral blood and bone marrow blasts during remission induction in adult acute lymphoblastic leukemia confers a poor prognosis depending on treatment intensity.

Our objectives were to evaluate the prognostic implications of persistence of peripheral blood blasts on day 7 (D7PBb) and of bone marrow blasts >5% on day 14 (D14Mb) after initiation of induction chemotherapy in adults with acute lymphoblastic leukemia (ALL) treated with two different chemotherapy regimens. Records of 365 consecutive newly diagnosed adult ALL patients treated with: (a) vincristine-, doxorubicin-, and dexamethasone-based chemotherapy (VAD, n = 219; 1984-1992); or (b) fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone, alternating with methotrexate/high-dose cytarabine (HCVAD, n = 146; 1993-1996), were analyzed. The complete remission (CR) rates were 73% with VAD and 91% with HCVAD (P<0.0001). Three-year event-free survival (EFS) rates were 23 and 40%, respectively (P = 0.00003). The impact of D7PBb and D14BMb on outcome varied with the induction regimen. Patients treated with VAD who had D7PBb had similar EFS rates compared with patients without D7PBb (P = 0.12), but EFS was inferior if they had persistent D14BMb compared with those patients without D14BMb (P = 0.00006). In HCVAD-treated patients, EFS was significantly worse in patients with persistent D7PBb (P = 0.003) but not in patients with D14BMb (P = 0.19). By multivariate analysis, D14BMb was an independent adverse feature for patients treated with VAD, whereas D7PBb was an independent adverse feature for EFS in HCVAD-treated patients. Early clearance of leukemia cells from blood and bone marrow is associated with improved outcome in adult ALL, but the prognostic significance of D7PBb and D14BMb clearance varies with treatment efficacy.

Adolescent↗
PubMed1976

Remission induction with L-asparaginase, vincristine, and prednisone in children with acute nonlymphoblastic leukemia.

Forty-five children with acute nonlymphoblastic leukemia in relapse received a total of 56 courses of L-asparaginase combined with vincristine and prednisone. The complete remission rate of 40% (12 of 30 trials) in patients resistant to vincristine and prednisone was almost identical to that in children still sensitive to vincristine and prednisone (42%, 11 of 26 trials). The complete remission rate of 38% (14 of 37 exposures) in those children who had not received L-asparaginase previously compared favorably with the complete remission rate in those children who had received prior L-asparaginase (47%, 9 of 19 exposures). Forty-seven of the 56 induction trials were in children with 1 or more remissions and 14 of these were in children with 3 or more prior remissions. Toxicity was minimal.

Acute Disease↗
PubMed1985

Homoharringtonine: an effective new drug for remission induction in refractory nonlymphoblastic leukemia.

Homoharringtonine (HHT) is a new plant alkaloid originally isolated in the People's Republic of China. Preliminary studies have suggested antitumor activity in several neoplastic diseases. We treated 49 patients with relapsed or resistant acute leukemia with escalating doses of homoharringtonine administered by continuous infusion. Three dose levels were examined: 5 mg/m2 for seven days, 7 mg/m2 for seven days, and 5 mg/m2 for nine days. Of 28 patients with acute nonlymphoblastic leukemia who received cumulative doses of 45 to 49 mg/m2, seven patients (25%) achieved complete remission. Four of these remissions occurred in a subset of ten patients previously resistant to two or more induction attempts with conventional chemotherapy. There were no remissions in three patients with secondary leukemia or in seven patients with acute lymphoblastic leukemia. Reversible hypotension, fluid retention, diarrhea, and tumor lysis syndrome were the major toxic effects of this treatment. Our results indicate that homoharringtonine is an effective new drug for the treatment of acute nonlymphoblastic leukemia and that this drug does not share cross-resistance with conventional antileukemic agents. The recommended dose is 5 mg/m2/d administered by continuous infusion for nine days.

Acute Disease↗
PubMed1986

Autoimmune thrombocytopenia and neutropenia after remission induction therapy for acute leukaemia.

Patients with acute leukaemia who are exposed to intensive chemotherapy, with or without radiotherapy, may remain thrombocytopenic or neutropenic in remission. The incidence of these prolonged cytopenias was examined retrospectively in 46 patients in remission and prospectively in 14 patients. The patients were tested for the presence of autoantibodies to platelets and neutrophils using a fluorescent antihuman globulin technique with paraformaldehyde-fixed cells. In the retrospective study nine patients (20%) had neutrophil autoantibodies and seven (15%) had platelet autoantibodies; only one of the former had neutropenia and one of the latter thrombocytopenia. In the prospective study three (21%) had neutrophil autoantibodies and seven (50%) had platelet autoantibodies. One of the patients with platelet autoantibodies had transient thrombocytopenia, and shortened platelet survival was demonstrated. None of the patients with neutrophil autoantibodies had neutropenia. The rare occurrence of cytopenias in association with these autoantibodies was possibly due to bone marrow compensation for antibody-mediated cell destruction, although other possible mechanisms are discussed.

Acute Disease↗
PubMed1984

Differentiation versus cytoreduction during remission induction in acute nonlymphoblastic leukemia treated with sequential high-dose ara-C and asparaginase.

Patients with acute nonlymphoblastic leukemia (ANLL) treated with sequential high-dose ara-C and asparaginase (HiDAC----ASNase) have occasionally exhibited an unusual morphologic picture during induction therapy with a transition period in which large numbers of blasts coexist with returning mature hemopoietic elements. In 2 of 11 adult patients with ANLL treated during a 6-month period using a new protocol of HiDAC----ASNase, the hypoplastic phase typically seen after intense induction never developed. Serial marrow examinations performed 7 to 35 days after treatment showed equal admixtures of blasts and mature elements. Despite these findings, both patients subsequently entered complete remission with morphologically normal bone marrow examinations. The possibility for diagnostic error in interpreting these transition marrows as failed inductions is great and could lead to cessation of supportive therapy or to an unnecessary further course of cytotoxic therapy. This phenomenon raises the biological question, does remission represent leukemia killed or leukemia matured?

Acute Disease↗
PubMed1988

Rebound peripheral blastosis with subsequent remission during remission induction in a patient with acute promyelocytic leukemia.

A patient with acute promyelocytic leukemia manifested peripheral blastosis with 50% peripheral blasts and an absolute blast count of 10,000/microliter 2 weeks after the start of induction chemotherapy. The subsequent disappearance of the peripheral and marrow blasts without further chemotherapy was noticed, and complete remission was achieved on day 25 of chemotherapy. The histologic and clinical implications of this phenomenon are discussed.

Adult↗
PubMed1992

Cost of complete remission induction in acute myeloblastic leukemia: evaluation of the cost-effectiveness of a new drug.

The use of new drugs in the treatment of AML could dramatically increase the cost of induction chemotherapy. To evaluate the cost-effectiveness of such new drugs, the overall cost to achieve complete remission (CR) with treatments including these drugs has to be compared to the cost of the daunorubicin-cytosine arabinoside (DNR-AraC) association, considered as the reference treatment. A retrospective analysis of charts from 15 patients treated with DNR-AraC was used to identify 228 items of cost, including general cost, diagnostic, supportive care, and chemotherapy. Eleven patients underwent CR after one course of chemotherapy for a cost of US$16,701 +/- 4451, and four patients achieved CR after two courses for a cost of US$37,130 +/- 4923. The chemotherapy represented only 1.4% of the total cost, supportive care 25% and general cost 56%. According to these data, the projective cost of a treatment with mitoxantrone instead of DNR was simulated in 40 untreated patients with AML. The better rate of CR obtained after one course of chemotherapy leads to a saving of 9% (US$1261) per patient, despite the higher cost of chemotherapy. Cost-effectiveness evaluation should be included in the clinical study of trials with new drugs.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1983

Daunorubicin, vincristine, and prednisone for remission induction in patients with acute lymphoblastic leukemia in relapse.

Patients with recurrent acute lymphoblastic leukemia were treated with daunorubicin (40 mg/m2/week X 4), vincristine (1.5 mg/m2/week X 4), and prednisone (40 mg/m2/day x 28). All of the patients had been treated with the same combination during the first induction treatment. Of 266 patients (221 children and 45 adults) treated in first relapse, 141 (53%) achieved complete remission (CR; 55% of the children and 44% of the adults). Of 61 patients who were re-treated with the same combination after the second relapse, 14 (23%) achieved CR. The difference between second and third CR was statistically significant (P less than 0.0005). The median durations of second and third CR were 8 and 6 weeks, respectively. No significant difference was observed when the duration of CR was compared with the initial wbc count, age at diagnosis, or duration of first CR.

Adolescent↗
PubMed1982

Causes of initial remission induction failure in acute myelogenous leukemia.

One-hundred and sixty-one of 378 previously untreated patients with acute myelogenous leukemia (AML) failed to enter complete remission with a combination of anthracycline, cytosine arabinoside, vincristine, and prednisone between 1973 and 1979. Thirty-six of the failing patients (22%) were considered chemotherapy failures. As in the past, the remainder failed largely because of death from infection. However, despite the routine use of prophylactic platelet transfusions, hemorrhage was a major cause of death in 33%. Thirty-seven percent of the fatal infections were due to fungi and the incidence of fungal infection was as high during the second week of treatment as later. Age greater than 50 yr predisposed to fatal infection but not chemotherapy failure, while the presence of an antecedent hematologic disorder increased the risk of both fatal fungal infection and resistance to chemotherapy. Patients with an initial white blood cell count of greater than or equal to 25000/microliter were more likely to die of hemorrhage at all times during treatment. Improvement in supportive care remains crucial if improved complete rates are to be forthcoming in previously untreated patients.

Adult↗