A randomized study of the efficacy of consolidation therapy in adult acute nonlymphocytic leukemia

The Eastern Cooperative Oncology Group conducted a randomized study to determine the efficacy of consolidation therapy in prolonging the duration of complete remission (CR) in adults with acute nonlymphocytic leukemia (ANLL). Induction chemotherapy with daunorubicin, cytosine arabinoside, and 6-thioguanine (DAT) yielded CR in 65% of 283 patients with ANLL, aged 16-69. For patients aged 60-69, the CR rate was 58%. Of 184 patients in CR, 146 patients were then randomized to receive either maintenance therapy with weekly cytosine arabinoside and 6-thioguanine alone (69 patients) or two courses of reduced doses of DAT 1 mo apart, before commencing the same maintenance program (77 patients). Consolidation therapy resulted in hematologic toxicity, but was not lethal in any of the eligible patients. Patients receiving consolidation plus maintenance therapy experienced a longer CR duration (40 wk) and disease-free survival at 2 yr (28%) than did those patients receiving maintenance therapy alone (34 wk and 14%, respectively). These differences are not statistically significant. These results suggest that approaches to consolidation therapy employing reduced doses of the induction therapy regimen can have, at best, only a small benefit. For consolidation therapy to provide substantial improvement in CR duration, intensive regimens with non-cross-resistant drugs will be required.     

A randomized comparison of postremission therapy in acute myelogenous leukemia: a Southeastern Cancer Study Group trial

The Southeastern Cancer Study Group conducted a post-remission induction randomized trial in adult acute myelogenous leukemia to assess the efficacy of alternate drug therapy during consolidation and of immunotherapy during maintenance. Of 508 evaluable patients entered into the study, 335 (66%) achieved a complete remission treated with a 7-day infusion of cytosine arabinoside at a dose of 100 mg/sq m/day and 3 days of daunorubicin at a dose of 45 mg/sq m/day. Those in remission were randomized to receive 3 courses of 1 of 3 consolidation regimens: (A) a continuous infusion of 5-azacytidine, 150 mg/sq m/day for 5 days; (B) 5-azacytidine plus beta-deoxythioguanosine, 300 mg/sq m/day for 5 days; or (C) cytosine arabinoside, 100 mg/sq m/day intravenously, and thioguanine, 100 mg/sq m orally every 12 hr, plus daunorubicin, 10 mg/sq m every 24 hr daily for 5 days. There was no difference in relapse rate among the 3 arms. Those completing consolidation and remaining in remission were randomized to 1 of 3 maintenance regimens: (D) chemotherapy, 5-day infusion of cytosine arabinoside and 2 days of daunorubicin (same doses as induction) given every 13 wk for 1 yr; (E) BCG given twice weekly for 1 mo and then monthly for 1 yr; or (F) the combination of regimens D and E. The median duration of remission was significantly better on regimen D (17.4 versus 9.4 and 9.5 mo), and median survival was 29 mo compared to 21 mo for the other regimens. Those given different drugs during consolidation than used for induction (regimens A and B) and subsequent chemotherapy for maintenance (regimen D) had the longest remission durations and survival. Immunotherapy was not as good as intensive chemotherapy for maintenance.     

Standard induction and low dose ara-C treatment in patients over 60 with AML or MDS

In this retrospective study, 61 induction treatment periods in 57 patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) were evaluated. According to the WHO performance status, 6 patients received no chemotherapy, 20 had low dose cytosine arabinoside (LD ara-C) induction courses, and 35 received standard induction consisting of daunorubicin and cytosine arabinoside. Untreated patients had a poor survival. Of the 20 patients with LD ara-C induction courses, 4 (20%) achieved complete remission (CR). Three patients (15%) died during induction. Of 35 patients with standard induction, 21 patients (60%) achieved CR. Toxicity was considerable - 11 patients (31%) dying during treatment. We conclude that patients over 60 yr of age with RAEB, RAEB-t or AML had a CR rate and survival comparable to those of younger patients if treated with standard induction chemotherapy at the cost of serious therapy-related complications. In patients who were judged not to be able to tolerate standard induction and who were subsequently treated with LD ara-C, complications occurred less frequently, but the CR rate was low and survival short.     

A PHASE Ml STUDY OF CYTOSINE ARABINOSIDE, DAUNORUBICIN, AND VP16–213 IN ADULT PATIENTS WITH ACUTE NON-LYMPHOCYTIC LEUKEMIA

Abstract The combination cytosine arabinoside (ara-C), daunorubicin, and VP16–213 was studied in 28 patients with acute non-lymphocytic leukemia to define the toxicity of the combination and assess its efficacy. Of 21 previously untreated patients, 16 (76%) achieved a complete response (CR) with the median remission duration not reached but exceeding 25 weeks. For CR patients, the median number of days with neutrophils < 500/μI was 19. The median survival for patients with CR is 60 weeks. Two of seven previously treated patients achieved CR for 11 weeks and in excess of 36 weeks, respectively. At the initial VP16–213 dose of 100 mg m^-2 per day for seven days, severe stomatitis was seen in 38% of courses but was less with dose reduction to 75 mg m^-2 per day for seven days. Other toxicity was similar to previous experience with ara-C and daunorubicin alone.     

Sequential standard dose mitoxantrone and cytosine arabinoside for newly diagnosed adult acute myeloblastic leukemia.

Twenty one adult patients with previously untreated acute myeloblastic leukemia (AML) were treated with sequential mitoxantrone and standard dose cytosine arabinoside remission induction therapy. The median age was 33 years (range 17-56 years). Complete remission (CR) was achieved in 80% (17/21 cases) and 76% (16/21 cases) achieved CR after one course of induction therapy. The median duration of disease free survival was 9 months with an actuarial disease free survival of 22% at 43 months. The non-hematological toxicity was acceptable. We conclude that sequential mitoxantrone and cytosine arabinoside combination therapy is an effective antileukemic regimen which produces high CR rates in previously untreated adult patients with AML.     

Cost-effectiveness and quality-of-life assessment of GM-CSF as an adjunct to intensive remission induction chemotherapy in elderly patients with acute myeloid leukaemia

We conducted a prospective, randomized, multicentre clinical trial comparing the effects and costs of GM-CSF as an adjunct to intensive chemotherapy in elderly patients with acute myeloid leukaemia (AML). The patients were randomized to either daunomycin–cytosine arabinoside (control arm: n  = 161) or daunomycin–cytosine arabinoside with GM-CSF (GM-CSF arm: n  = 157). The primary end-point was the effect of GM-CSF on the percentage of complete remissions (CR). Survival duration, disease-free survival, quality of life and costs were evaluated separately.
CR after remission induction treatment was achieved in 55% of the patients in the control group and in 56% of the patients in the GM-CSF group ( P  = NS). The duration of survival and disease-free survival at 2 years after randomization were estimated at 22% and 19% for the control group and 22% and 14% for the GM-CSF group ( P  = NS). Considering the short-term quality of life, the administration of GM-CSF resulted in more problems with regard to depressed mood, diarrhoea and rash/eczema. With regard to the long-term quality of life there were no significant differences between the two groups. The average costs of the primary treatment were higher in GM-CSF-treated patients than in the control group, i.e. US$40782 and US$34465, respectively ( P  < 0.01). The costs during the follow-up period did not differ between the two groups.
The results of this randomized clinical trial indicate that daunomycin–cytosine arabinoside plus GM-CSF is not a cost-effective treatment strategy when compared with daunomycin–cytosine arabinoside alone.     

Sequential mitoxantrone,daunorubicin, and cytosine arabinoside for patients with newly diagnosed acute myelocytic leukemia

Mitoxantrone (M) is a synthetic aminoanthraquinone with anti-leukemic activity in patients with daunorubicin (D) resistant acute leukemia. The Cancer and Leukemia Group B (CALGB) has undertaken a limited access pilot study in which M, 12 mg/m², over 30 min, daily for 3 days, and cytosine arabinoside (Ara-C), 100 mg/m²/day by constant infusion for 7 days were used for the induction of newly diagnosed patients with AML. Responding patients were consolidated with daunorubicin, 45 mg/m²/day for 3 days, and 7 days of Ara-C. After a second consolidation identical to induction, no further therapy was given. Twenty-nine patients with a median age of 50 years (range 18–72) were entered in the study; 18 were males and 11 females. Twenty-four (83%) patients achieved CR, 1 patient achieved a PR, and 4 died in induction from leukemia-related causes. Two patients died in CR from consolidation-related neutropenic sepsis and two additional patients died in CR. Of 24 patients, 7 remain disease-free at a median follow-up interval of 8 years. The regimen is active and well tolerated. The duration of disease-free survival in responding patients is consistent with that seen in similar regimens using intensification chemotherapy without prolonged maintenance. Am. J. Hematol. 56:214–218, 1997. © 1997 Wiley-Liss, Inc.     

A systematic collaborative overview of randomized trials comparing idarubicin with daunorubicin (or other anthracyclines) as induction therapy for acute myeloid leukaemia

A collaborative overview, using individual patient data, has been performed to compare idarubicin versus daunorubicin or other anthracyclines, when used with cytosine arabinoside as induction chemotherapy for newly diagnosed acute myeloid leukaemia. There were 1052 patients in five trials versus daunorubicin, 100 in one trial versus doxorubicin, and 745 in one trial versus zorubicin. In the trials of idarubicin versus daunorubicin, early induction failures were similar with the two treatments (20% idarubicin v 18% daunorubicin; P  = 0.4), but after day 40 the later induction failures were fewer with idarubicin (17% v 29%; P  < 0.0001). Therefore complete remission rates were higher with idarubicin (62% v 53%; P  = 0.002). Among remitters, fewer of the patients allocated to idarubicin relapsed ( P  = 0.008) but slightly more died in remission, leading to a non-significant benefit ( P  = 0.07) in disease-free survival. Overall survival in these five trials was significantly better with idarubicin than with daunorubicin (13% v 9% alive at 5 years; P  = 0.03). There was a trend ( P  = 0.006 for remission rate) for the benefit of idarubicin over daunorubicin to decrease with increasing age. There were no significant differences in outcome in the small trial comparing idarubicin versus doxorubicin, or in the large trial comparing idarubicin versus zorubicin. The induction regimens based on idarubicin achieved, in the particular circumstances of the trials reviewed here, better remission rates and better overall survival than those based on daunorubicin.     

The prognostic significance of leukemic cells clearance kinetics evaluation during the initial course of induction therapy with HAD (homoharringtonine, cytosine arabinoside, daunorubicin) in patients with de novo acute myeloid leukemia

The impact of the percentage of residual leukemic cells (RLCs) at the end of first course of induction chemotherapy (T1) or during aplasia (T2) on complete remission (CR) rate, disease-free survival (DFS), and overall survival (OS) were retrospectively analyzed in 72 cases of de novo acute myeloid leukemia (AML) treated with HAD (homoharringtonine, cytosine arabinoside, and daunorubicin) regimen. The patients were separated into two subgroups by a cutoff of 10% bone marrow leukemic cells at T1 or T2 time point. The CR rate, DFS, and OS were significantly different between the two groups. We further confirmed that the percentage of RLCs at T1 or T2 is an independent prognostic factor of AML.     

Comparative analysis of remission induction therapy for high-risk MDS and AML progressed from MDS in the MDS200 study of Japan Adult Leukemia Study Group

A total of 120 patients with high-risk myelodysplastic syndrome (MDS) and AML progressed from MDS (MDS–AML) were registered in a randomized controlled study of the Japan Adult Leukemia Study Group (JALSG). Untreated adult patients with high-risk MDS and MDS–AML were randomly assigned to receive either idarubicin and cytosine arabinoside (IDR/Ara-C) (Group A) or low-dose cytosine arabinoside and aclarubicin (CA) (Group B). The remission rates were 64.7% for Group A (33 of 51 evaluable cases) and 43.9% for Group B (29 out of 66 evaluable cases). The 2-year overall survival rates and disease-free survival rates were 28.1 and 26.0% for Group A, and 32.1 and 24.8% for Group B, respectively. The duration of CR was 320.6 days for Group A and 378.7 days for Group B. There were 15 patients who lived longer than 1,000 days after diagnosis: 6 and 9 patients in Groups A and B, respectively. However, among patients enrolled in this trial, intensive chemotherapy did not produce better survival than low-dose chemotherapy. In conclusion, it is necessary to introduce the first line therapy excluding the chemotherapy that can prolong survival in patients with high-risk MDS and MDS–AML.     

A comparison between regimens containing chemotherapy alone (busulfan and cyclophosphamide) and chemotherapy (V. RAPID) plus total body irradiation on marrow engraftment following allogeneic bone marrow transplantation

The effect of two conditioning regimens given prior to allogeneic bone marrow transplantation (BMT) on the kinetics of engraftment were compared. 5 patients received busulfan and cyclophosphamide: 7 patients received daunorubicin, vincristine, cytosine arabinoside, methylprednisone and VM-26 plus total body irradiation (TBI). Bone marrow progenitors (BFU-E, CFU-E, CFU-GM, CFU-F) were assayed up to 3 months post-BMT. All progenitors were severely depressed in spite of peripheral blood recovery. There was no stromal recovery in any adult patient post-BMT. There was no significant difference in time to engraftment, or colony forming units, or between patients conditioned with chemotherapy alone or chemotherapy plus TBI. We were unable to detect effects of graft-versus-host disease or cytomegalic viral infection on bone marrow progenitors or peripheral blood recovery in this study.     

Poor response in patients with de novo acute myeloid leukemia and erythroblastic or megakaryocytic dysplasia to treatment with standard doses of cytosine arabinoside and daunorubicin

Erythroid and/or megakaryocytic dysplasia (EMD) was evaluated in diagnostic bone marrow smears of 37 consecutively treated cases with de novo acute myeloid leukemia (AML) M0-M2 and M4-M5 types and three newly diagnosed cases of refractory anaemia with excess of blasts in transformation. This evaluation was possible in 38 of 40 (95%) patients and 17 cases were categorized without EMD and 21 cases with EMD. One or two cycles with 3-4 doses of daunorubicin 45 mg/m2/d and cytosine arabinoside 200 mg/m2/12 h x 14 lead to complete remission in 13 of 16 cases without EMD but only in 4 of 16 cases with EMD (p = 0.004). However, 10 of 13 patients with EMD reached complete remission with 2000 mg/m2/12 h x 10 of cytosine arabinoside plus daunorubicin. After intensive consolidations 20 patients under 65 years with EMD showed significantly worse overall survival (p = 0.017) with a median 11.5 months, while the median survival was estimated 66.8 months in 15 cases under 65 years without EMD. The proposed categorization of de novo AML patients according to the EMD seems to be useful for selection of optimal induction therapy, clinically relevant for survival and might reflect two biologic groups of AML arising in two different stages of differentiation.     

Do de novo acute myeloid leukemias with normal cytogenetics involve two main prognostic categories distinguished by the presence of erythroblastic and/or megakaryocytic dysplasia?

De novo acute myeloid leukemias (AML) patients with normal cytogenetics represent a standard risk cytogenetic group. Erythroblastic and/or megakaryocytic dysplasia (EMD) in diagnostic bone marrow smears of 28 consecutive AML patients with a normal karyotype was studied. Twelve patients 21-85 (median 48) years old were categorized without EMD, 14 patients 34-90 (median 58) years old with EMD, and 2 patients were not evaluable for EMD. One cycle of induction therapy 4 + 7, with 4 doses of daunorubicin 45 mg/m2/d and standard doses of cytosine arabinoside for 7 days induced 10 complete and 2 partial remissions in 12 cases without EMD but lead to only one complete remission, 6 non-responses and 3 induction deaths in 10 cases with EMD (p = 0.002). However, high doses of cytosine arabinoside plus daunorubicin induced complete remission in 6 of 7 patients with EMD. In patients under 66 years treated by intensive consolidations the estimate of median survival was 50.6 months in 10 cases without EMD, significantly higher than 8.0 months in 11 cases with EMD (p = 0.043). De novo AML with normal cytogenetics might be divided into two biological categories, the first favorable-risk category without EMD and the second poor-risk category with EMD.     

An effective age-unrestricted m-AMSA-based second-line regimen for poor prognosis acute myeloid leukaemia

Abstract: The efficacy and toxicity of a regimen consisting of amsacrine (m-AMSA), cytarabine, and thioguanine for remission-induction therapy in poor prognosis categories of acute myeloid leukaemia (AML) were determined in a single arm study of 46 patients. The study group consisted of 17 patients with disease refractory to daunorubicin plus cytarabine-based induction regimens, 22 patients with disease which had relapsed during daunorubicin plus cytarabine maintenance therapy, or following completion of this maintenance programme after receiving > 500 mg daunorubicin/m², and 7 previously untreated patients where cardiac disease contraindicated anthracycline therapy. Complete remission (CR) was attained in 46%, and probability of survival was comparable to published results for first-line treatment with daunorubicin plus cytarabine regimens. There was no statistically significant difference in CR rate or probability of survival between these three categories of poor prognosis AML, and cardiotoxic complications were uncommon despite extensive anthracycline exposure in the majority. In the 43% of patients who were 60–76 years of age, there was no statistically significant difference in CR rate or probability of survival relative to patients <60 years. This observation fails to support the view that less myelotoxic regimens with lesser efficacy should be the basic approach to treatment of AML in patients > 60 years of age.     

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

Summary 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) was 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.Supported by a grant (BU 210/7) of the Deutsche Forschungsgemeinschaft     

Autologous marrow transplantation for patients with chronic myelogenous leukemia (CML) in blast crisis

Eleven patients with chronic myelogenous leukemia (CML) in blast crisis were treated with chemotherapy, followed by infusion of autologous bone marrow that had been collected during the chronic phase of the disease and cryopreserved at ?198°C. The mean age of the nine females and two males in this study was 34 years with an average duration of the chronic phase of the disease of 5.5 years. Seven out of the 11 patients had a splenectomy prior to intensive chemotherapy. The median survival of the first four patients who received 6-thioguanine, cytosine arabinoside, daunorubicin (TAD) chemotherapy was 2.6 weeks and no patient reachieved the chronic phase of CML. The second group of seven patients received more intensive chemotherapy (MAdHAT), which included melphalan 30 mg/m² days 1, 2, and 3; Adriamycin 50 mg/m² intravenously (iv) day 1, hydroxyurea 1500 mg/m² by mouth for 5–7 days, cytosine arabinoside 100 mg/m² continuous infusion for 5–7 days, and VM-26 100 mg/m² iv on day 3. Six out of these seven patients reachieved chronic phase CML after bone marrow reinfusion. The median survival was 29.9 weeks for all patients and 33 weeks for the six patients who reachieved chronic phase CML. All patients subsequently died of recurrent blast crisis. There was no correlation between the time of bone marrow storage and the duration of subsequent chronic phase CML. These studies have shown that autologous bone marrow transplantation after high-dose chemotherapy can result in bone marrow engraftment with reestablishment of chronic phase CML, and prolongation of survival.     

Aggressive chemotherapy combined with G-CSF and maintenance therapy with interleukin-2 for patients with advanced myelodysplastic syndrome,subacute or secondary acute myeloid leukemia — initial results

Summary Aggressive chemotherapy of advanced myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) evolving from MDS, subacute AML and secondary AML has usually been associated with low complete remission (CR) rates, a high incidence of early death, and low disease-free survival. We therefore have initiated a phase-III trial of aggressive chemotherapy consisting of idarubicin, cytosine arabinoside, and VP-16 to improve the CR rate. Each chemotherapy cycle is followed by G-CSF to accelerate neutrophil recovery and to reduce the incidence of infections. Until now, 19 patients with high-risk AML have been entered. The CR rate is 47%, with only one death during induction. Patients achieving CR are randomized to receive either high-dose or low-dose interleukin-2 to eliminate residual leukemic cells and to prolong the duration of remission.Presented at the annual meeting of the German Society for Hematology and Oncology, 4–7 October 1992, Berlin     

Active Immunotherapy for the Treatment of Acute Myelogenous Leukaemia: Report of Two Controlled Trials

S ummary Over 61/2 years, 182 patients with acute myelogenous leukaemia were treated with one of two combinations of chemotherapy containing cytosine arabinoside and an anthracycline (daunorubicin or doxorubicin). Eighty-one patients achieved remission and 79 of them were entered into one of two trials of active immunotherapy. The first trial compared maintenance chemotherapy and i.v. BCG immunotherapy with chemotherapy alone. The results have shown that the group given i.v. BCG survived for a significantly longer time ( P =0·035) than the group treated only with chemotherapy. The i.v. BCG treated group also had a significantly longer survival ( P =0·042) after their first relapse and a higher incidence of subsequent remissions. However, there was no difference in the length of first remissions for the two groups.
The second trial compared two different types of active immunotherapy. The results show no significant difference in remission duration or survival after first relapse for 34 patients randomly allocated to treatment with i.v. BCG or irradiated leukaemic blast cells. Sixteen patients relapsed and subsequently 10 patients entered a second remission after reinduction chemotherapy. These patients were distributed evenly between the two immunotherapy groups and this high rate of second remissions is similar to that for the immunotherapy group in the first Cardiff Trial. In the two trials, 21 (62%) of 34 patients receiving immunotherapy entered a second remission after reinduction chemotherapy and six patients achieved third remissions.     

Autologous peripheral blood stem cell transplantation in first remission adult acute myeloid leukaemia--an intention to treat analysis and comparison of outcome using a predictive model based on the MRC AML10 cohort

The role of autologous peripheral blood stem cell transplantation (APBSCT) in acute myeloid leukaemia (AML) remains controversial. The current study evaluated the application of APBSCT in a large consecutive series of patients with untreated AML, and compared outcome with a predictive model based on MRC AML10 data. Of 148 evaluable patients, 118 patients entered complete remission (CR) after induction therapy comprising three cycles of daunorubicin, cytosine arabinoside and oral 6-thioguanine. Of these patients, 68 (57%) proceeded to consolidation therapy with two courses of intermediate dose cytosine arabinoside, and stem cell mobilisation, and 40 of these patients (34%) underwent the APBSCT procedure after high dose busulphan conditioning. Harvest quality was the main factor precluding APBSCT. Five-year event-free survival (EFS) in patients who achieved CR was 38% and in APBSCT patients was 57%. There were no transplant-related deaths. No significant differences were demonstrated between observed and expected outcomes at 1 and 2 years, based on the predictive model derived from the MRC AML10 study. These data therefore indicate that only a third of eligible adult patients will undergo APBSCT. However, the results demonstrate favourable survival in such patients, with no transplant-related mortality.     

All-trans retinoic acid significantly reduces the incidence of early hemorrhagic death during induction therapy of acute promyelocytic leukemia

Early hemorrhagic death (within the first 10 d of treatment [EHD]) is reported as the main cause of death during induction therapy for acute promyelocytic leukemia (APL). In order to evaluate possible differences in the incidence of EHD during induction regimens based on all-trans retinoic acid (ATRA), we retrospectively analyzed a consecutive series of 86 APL patients, diagnosed and treated at our Institution from 1982. Forty-three patients received combination chemotherapy with anthracyclines and cytosine arabinoside (January 1982 to December 1991), while induction of the remaining 43 was based on ATRA alone or on a combination of ATRA and anthracyclines (January 1992 to October 1996). There were significantly less induction deaths in the ATRA group [9 (chemotherapy group-CT) vs. 2 (ATRA group-RA) overall and 8(CT) vs. 1(RA) of EHD; p = 0.01]. Hemostatic evaluations showed an earlier reduction of D-dimer in the ATRA group. No cases of morphological resistance were observed in the ATRA group after induction. In addition, the number of relapses occurring in the first 24 months from the achievement of complete remission (CR) was significantly lower in the ATRA group (15 vs. 7; p = 0.01), with a disease free survival at 2 yr of 67% vs. 31%. In conclusion, ATRA appears to be able to significantly reduce the incidence of EHD, increasing the number of possible long-term remissions.