Autologous peripheral blood stem cell transplantation with induction of autologous graft-versus-host disease in acute myeloid leukemia

We studied whether the induction of autologous graft-versus-host disease (GVHD) has an antileukemic effect and consequently increases the survival of patients undergoing autologous peripheral blood stem cell transplantation (PBSCT). In all, 22 acute myeloid leukemia patients with favorable and intermediate cytogenetic risk, in their first complete remission, were administered cyclosporine c.i.v. from day 0 to day +28 at a dose of 3.0 mg/kg per day and interferon-gamma (IFN-gamma) at 0.025 mg/m(2) s.c. every other day from day +14 to day +42 following autologous PBSCT. Natural-killer (NK)-cell activity assays and skin biopsies were performed. Successful engraftment was achieved in all patients at a median of 13 days without significant additional toxicity. Histologically confirmed cutaneous GVHD developed in 12 patients, and NK-cell activity was significantly augmented after autologous PBSCT in those patients (P=0.03). After a median follow-up duration of 37.7 months (range, 7.3-72.8), the 3-year disease-free survival (DFS) and overall survival (OS) rates were 64.4 and 73.1%, respectively, without significant correlation with GVHD status or augmentation of NK-cell activity. These data suggest that the administration of cyclosporine and IFN-gamma following autologous PBSCT improves OS and DFS, which may be attributable to the antileukemic effect, although no difference in survival could be demonstrated between cutaneous GVHD-positive and -negative groups.     

A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study

Interest in high-dose cytarabine (HDAC) for both induction and postremission therapy for acute myeloid leukemia (AML) prompted the Southwest Oncology Group (SWOG) to initiate a randomized trial comparing HDAC with standard-dose cytarabine (SDAC) for remission induction of previously untreated AML and to compare high-dose treatment versus conventional doses for consolidation therapy. Patients less than 65 years of age with de novo or secondary AML were randomized for induction between SDAC 200 mg/ m2/d for 7 days by continuous infusion or HDAC at 2 g/ m2 intravenously every 12 hours for 12 doses; both groups received daunorubicin (DNR) at 45 mg/m2/d intravenously for 3 days. Complete responders to SDAC were randomized to receive either two additional courses of SDAC plus DNR or one course of HDAC plus DNR. Complete responders to HDAC were nonrandomly assigned to receive one additional course of HDAC plus DNR. Of patients randomized between SDAC (n = 493) and HDAC (n = 172) induction, 361 achieved complete remission (CR). The CR rate was slightly poorer with HDAC: 55% versus 58% with SDAC for patients aged less than 50, and 45% (HDAC) versus 53% (SDAC) for patients aged 50 to 64 (age-adjusted one-tailed P = .96). With a median follow-up time of 51 months, survival was not significantly better with HDAC (P = .41); the estimated survival rate at 4 years was 32% (HDAC) versus 22% (SDAC) for those aged less than 50, and 13% (HDAC) versus 11% (SDAC) for those aged 50 to 64. However, relapse-free survival was somewhat better following HDAC Induction (P = .049): 33% (HDAC) versus 21% (SDAC) at 4 years for those aged less than 50, and 21% (HDAC) versus 9% (SDAC) for those aged 50 to 64. Induction with HDAC was associated with a significantly increased risk of fatal (P = .0033) and neurologic (P < .0001) toxicity. Among patients who achieved CR with SDAC, survival and disease-free survival (DFS) following consolidation randomization were not significantly better with HDAC compared with SDAC (P = .77 and .46, respectively). Patients who received both HDAC induction and consolidation had the best postremission outcomes; however, the proportion of CR patients who did not go on to protocol consolidation therapy was more than twice as high after HDAC induction compared with SDAC. Induction therapy with HDAC plus DNR was associated with greater toxicity than SDAC plus DNR, but with no improvement in CR rate or survival. Following CR induction with SDAC, consolidation with HDAC increased toxicity but not survival or DFS. In a nonrandomized comparison, patients who received both HDAC induction and consolidation had superior survival and DFS compared with those who received SDAC induction with either SDAC or HDAC consolidation.     

Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study

The associations of cytogenetics with complete remission (CR) rates, overall survival (OS), and outcomes after CR were studied in 609 previously untreated AML patients younger than 56 years old in a clinical trial comparing 3 intensive postremission therapies: intensive chemotherapy, autologous transplantation (ABMT), or allogeneic bone marrow transplantation (alloBMT) from matched related donors. Patients were categorized into favorable, intermediate, unfavorable, and unknown cytogenetic risk groups based on pretreatment karyotypes. CR rates varied significantly (P <.0001) among the 4 groups: favorable, 84% (95% confidence interval [CI], 77%-90%); intermediate, 76% (CI, 71%-81%); unfavorable, 55% (CI, 48%-63%); and unknown, 54% (CI, 33%-74%). There was similar significant heterogeneity of OS (P <.0001), with the estimated relative risk of death from any cause being 1.50 (CI, 1.10-2.05), 3. 33 (CI, 2.43-4.55), and 2.66 (CI, 1.59-4.45) for the intermediate, unfavorable, and unknown risk groups, respectively, compared with the favorable group. In multivariate analyses, the effects of cytogenetic risk status on CR rate and OS could not be explained by other patient or disease characteristics. Among postremission patients, survival from CR varied significantly among favorable, intermediate, and unfavorable groups (P =.0003), with significant evidence of interaction (P =.017) between the effects of treatment and cytogenetic risk status on survival. Patients with favorable cytogenetics did significantly better following ABMT and alloBMT than with chemotherapy alone, whereas patients with unfavorable cytogenetics did better with alloBMT. Cytogenetic risk status is a significant factor in predicting response of AML patients to therapy; however, to tighten treatment correlates within genetically defined AML subsets, a significantly larger leukemia cytogenetic database is warranted.     

Liposomal daunorubicin versus standard daunorubicin: long term follow-up of the GIMEMA GSI 103 AMLE randomized trial in patients older than 60 years with acute myelogenous leukaemia

This randomized phase III clinical trial explored the efficacy of DaunoXome (DNX) versus Daunorubicin (DNR) in acute myeloid leukaemia (AML) patients aged >60 years. Three hundred and one AML patients were randomized to receive DNR (45 mg/m(2) days 1-3) or DNX (80 mg/m(2) days 1-3) plus cytarabine (AraC; 100 mg/m(2) days 1-7). Patients in complete remission (CR) received a course of the same drugs as consolidation and then were randomized for maintenance with AraC+ all trans retinoic acid or no further treatment. Among 153 patients in the DNR arm, 78 (51.0%) achieved CR, 55 (35.9%) were resistant and 20 (13.1%) died during induction. Among 148 patients in the DNX arm, 73 (49.3%) achieved CR, 47 (31.8%) were resistant and 28 (18.9%) died during induction. Univariate analysis showed no difference as to induction results. After CR, DNX showed a higher incidence of early deaths (12.5% vs. 2.6% at 6 months, P = 0.053) but a lower incidence of relapse beyond 6 months (59% vs. 78% at 24 months, P = 0.064), with a cross in overall survival (OS) and disease-free survival (DFS) curves and a later advantage for DNX arm after 12 months from diagnosis. DNX seems to improve OS and DFS in the long-term follow-up, because of a reduction in late relapses.     

Timed sequential induction chemotherapy and risk-adapted postremission therapy for acute myelogenous leukemia

Cytogenetic analysis at the time of diagnosis predicts outcome in patients with acute myelogenous leukemia (AML). For those patients with favorable risk cytogenetics, stem cell transplant can be delayed until the time of relapse. For those patients with nonfavorable cytogenetic risk profiles, stem cell transplant may be required for optimal survival benefit. We treated patients with de novo AML and age less than 60 years first with etoposide, mitoxantrone, cytarabine, and G-CSF (EMA-G) to induce remission. Patients in complete remission were assigned to treatment with chemotherapy alone if they had favorable risk cytogenetics defined as the identification of a core-binding factor translocation. Patients with any other cytogenetic profile were assigned to treatment with either autologous or allogeneic stem cell transplant depending on the availability of an HLA-matched donor. Following EMA-G, 33 of 40 patients (83%) achieved CR. Of the 25 patients who actually were treated with postremission chemotherapy, 21 were treated with their assigned risk-adapted therapy. Of the 33 patients in remission, 5 year relapse-free survival (RFS) and overall survival (OS) was 46 and 38%, respectively. Our intensive and risk-adapted, stem cell transplant approach to the treatment of patients with AML requires a better definition of risk and does not appear to substantially improve results compared with more standard approaches.     

Phase II evaluation of an intensified induction therapy with standard daunomycin and cytarabine followed by high dose cytarabine for adults with previously untreated acute myeloid leukemia: a Southwest Oncology Group study (SWOG-9500)

Induction therapy for acute myeloid leukemia (AML) usually consists of 7 days of cytarabine at 100-200 mg/m(2)/day and an anthracycline. Such combinations produce complete response (CR) rates of 60-80% in patients with de novo AML. On the basis of a previous report, suggesting a higher CR rate using a regimen of standard daunomycin and cytarabine followed by 3 days of high-dose cytarabine (HDAC), 101 eligible patients received this regimen in a phase II trial. Sixty patients [59%, 95% confidence interval (CI) 49-69%] achieved a CR, and 10 patients died of infection during induction. Although cytogenetic risk group affected overall survival (P = 0.0016) and relapse-free survival (P = 0.0043), it had no impact on CR rate (P = 0.63). Patients received postremission therapy with repetitive courses of alternate day high-dose cytarabine; this was associated with considerable toxicity and the majority of patients could not receive all of the scheduled postremission therapy. The estimated median survival was 23 months (95% CI 15-34 months), and the estimated probability of surviving 5 years was 34% (95% CI 24-43%). The results of this intensive induction regimen were similar to that seen in previous trials and were not as promising as reported in the previous pilot study.     

Overall and event-free survival are not improved by the use of myeloablative therapy following intensified chemotherapy in previously untreated patients with multiple myeloma: a prospective randomized phase 3 study

We compared the efficacy of intensified chemotherapy followed by myeloablative therapy and autologous stem cell rescue with intensified chemotherapy alone in patients newly diagnosed with multiple myeloma. There were 261 eligible patients younger than 66 years with stage II/III multiple myeloma who were randomized after remission induction therapy with vincristine, adriamycin, dexamethasone (VAD) to receive intensified chemotherapy, that is, melphalan 140 mg/m(2) administered intravenously in 2 doses of 70 mg/m(2) (intermediate-dose melphalan [IDM]) without stem cell rescue (n = 129) or the same regimen followed by myeloablative therapy consisting of cyclophosphamide, total body irradiation, and autologous stem cell reinfusion (n = 132). Interferon-alpha-2a was given as maintenance. Of the eligible patients, 79% received both cycles of IDM and 79% of allocated patients actually received myeloablative treatment. The response rate (complete remission [CR] plus partial remission [PR]) was 88% in the intensified chemotherapy group versus 95% in the myeloablative treatment group. CR was significantly higher after myeloablative therapy (13% versus 29%; P =.002). With a median follow-up of 33 months (range, 8-65 months), the event-free survival (EFS) was not different between the treatments (median 21 months versus 22 months; P =.28). Time to progression (TTP) was significantly longer after myeloablative treatment (25 months versus 31 months; P =.04). The overall survival (OS) was not different (50 months versus 47 months; P =.41). Intensified chemotherapy followed by myeloablative therapy as first-line treatment for multiple myeloma resulted in a higher CR and a longer TTP when compared with intensified chemotherapy alone. However, it did not result in a better EFS and OS.     

A multicenter,open, non-comparative,phase II study of the combination of cladribine (2-chlorodeoxyadenosine), cytarabine,and G-CSF as induction therapy in refractory acute myeloid leukemia - a report of the Polish Adult Leukemia Group (PALG)

OBJECTIVES: To evaluate the efficacy and toxicity of cladribine (2-chlorodeoxyadenosine, 2-CdA), cytarabine (Ara-C), and granulocyte-colony stimulating factor (G-CSF) (CLAG) regimen in refractory acute myeloid leukemia (AML) in the multicenter phase II study. METHODS: The induction chemotherapy consisted of 2-CdA 5 mg/m2, Ara-C2 g/m2, and G-CSF. In the case of partial remission (PR), a second CLAG was administered. Patients in complete remission (CR) received two consolidation courses based on HD Ara-C, mitoxantrone or idarubicine, with or without 2-CdA. RESULTS: Fifty-eight patients from 11 centers were registered; 50 primary resistant and eight early relapsed (CR1 < 6 months). CR was achieved in 29 (50%) patients, 19 (33%) were refractory, and 10 (17%) died early. Forty of 50 primary resistant patients received daunorubicin (DNR) and Ara-C as the first-line induction therapy (DA-7), 10 received additional 2-CdA (DAC-7). The CR rates after CLAG were 58% and 10%, respectively in each group (P = 0.015). Five of six patients with myelodysplastic syndrome (MDS)/AML achieved CR. Hematologic toxicity was the most prominent toxicity of this regimen. The overall survival (OS, 1 yr) for the 58 patients as a whole, and the 29 patients in CR were 42% and 65%, respectively. Disease-free survival (DFS, 1 yr) was 29%. Only first-line induction treatment with DA-7 significantly influenced the probability of CR after CLAG. None of the analyzed factors significantly influenced DFS and OS. CONCLUSION: CLAG regimen has significant anti-leukemic activity and an acceptable toxicity in refractory AML. The addition of 2-CdA to the first-line induction treatment may worsen the results of salvage with CLAG. The high CR rate in patients with MDS preceding AML deserves further observation.     

Intensive induction chemotherapy with regimen containing intermediate dose cytarabine in the treatment of de novo acute myeloid leukemia

To improve long‐term outcome of de novo acute myeloid leukemia (AML) patients by intermediate dose of cytarabine integrated in induction therapy and to explore the impact of cytogenetic abnormalities on the prognosis. Eighty‐seven AML patients were treated with HAD regimen containing intermediate dose cytarabine (IDAra‐C) as induction therapy, 83 from which with karyotype results were divided into three cytogenetic groups according to SWOG criteria. Complete remission (CR) rate, disease‐free survival (DFS), and overall survival (OS) among different groups were evaluated. The CR rate of the 87 cases was 80/87 (92%). Median DFS and OS have not reached (NR). DFS rates at 1 and 3 years were 76.3% and 63.4%, respectively. OS rates at 1 and 3 years were 86.0% and 58.7%, respectively. According to SWOG criteria, CR rate, median DFS, and OS were 100%, NR and NR for the favorable group; 88.9%, NR, and 16 months for the intermediate group; 83.3%, 4.5 months, and 7.5 months for the adverse group. The differences among the three groups were statistically significant excepting for CR rate between adverse and intermediate groups. HAD regimen containing IDAra‐C as induction chemotherapy regimen is effective in de novo AML of adult patients and can achieve higher CR rate and longer survival than standard dose of cytarabine (SDAra‐C) regimen. Most of the patients were able to endure the therapy. Cytogenetics is still an important prognostic factor despite of the incorporation of IDAra‐C in induction chemotherapy. The differences among the three groups were statistically significant. Am. J. Hematol., 2009. © 2009 Wiley‐Liss, Inc.     

All-trans retinoic acid for the treatment of newly diagnosed acute promyelocytic leukemia. Japan Adult Leukemia Study Group [see comments]

We conducted a multicenter trial of treatment with all-trans retinoic acid (ATRA) for newly diagnosed acute promyelocytic leukemia (APL) in the AML-92 study and compared it with our previous study with standard intensive chemotherapy, the AML-89 study, in the view of complete remission (CR) rate, incidence of early death, and event-free survival (EFS). Patients were scheduled to receive oral ATRA 45 mg/m2 daily until CR. If patients had leukocyte counts above 3 x 10(9)/L at the start of therapy, they received daunorubicine (DNR) 40 mg/m2 for 3 days and behenoyl cytosine arabinoside (BHAC) 200 mg/m2 for 5 days in addition to ATRA. During the ATRA therapy, if patients showed myeloblast plus promyelocyte counts higher than 1 x 10(9)/L in the peripheral blood, they received additional DNR and BHAC in the same schedule, as well. A total of 110 patients were entered into the study. Median age was 43 years (range, 16 to 74). Twenty-eight (26%) of 109 patients (one died before the start of therapy) received ATRA alone. Ninety-seven patients (89%) achieved CR; 48 of 49 (98%) aged less than 40 years, 44 of 52 (84%) aged between 40 and 69, and 5 of 8 (63%) aged above 70 achieved CR, respectively; 25 of 28 (89%) with ATRA alone, 46 of 51 (90%) with ATRA plus initial chemotherapy and 26 of 30 (87%) with ATRA plus later chemotherapy attained CR, respectively. Nine (8%) patients died within 28 days after the start of therapy. In contrast, 44 of 62 patients (71%) attained CR, and 13 (21%) died within 28 days in the AML-89 study with the combination of DNR, BHAC, 6-mercaptopurine and prednisolone. Seven developed retinoic acid syndrome and one died of it in the present study. Other toxicities associated with this drug included cheilitis, desquamation, muscle pain, and hypertriglyceridemia. Predicted 23 months EFS for all ATRA-treated patients and disease-free survival (DFS) in the CR cases were 75% and 81%, respectively, in a median follow-up period of 21 months. Compared to the AML-89 study, there was a highly significant difference in remission rate (P = .004), EFS (P = .0007), and also early mortality rate (P = .02). Present results demonstrated that ATRA with or without chemotherapy gives a statistical improvement in CR rate and early mortality rate, as well as superior survival in newly diagnosed APL.     

标准剂量去甲氧柔红霉素联合阿糖胞苷治疗急性髓细胞白血病

目的:探讨标准剂量的去甲氧柔红霉素(IDA)联合阿糖胞苷(Ara-C)治疗急性髓细胞白血病(AML)的疗效和不良反应。方法:14例AML患者,年龄13～70岁(中位年龄36岁),男8例,女6例。初治AML10例,难治、复发AML4例。所有患者均在治疗前进行染色体核型分析,4例染色体异常。诱导方案为IDA 12 mg·m-2·d-1,第1～3天,Ara-C 100 mg·m-2·d-1,持续静脉点滴,第1～7天。结果:1个疗程结束后总有效率92．9％(13／14),完全缓解率85．7％(12／14),其中初治AML的CR率为90．0％(9／10),复发、难治AML的CR率为75．0％(3／4),3例染色体异常患者达细胞遗传学缓解,未发生早期死亡。化疗的不良反应主要为骨髓抑制和粒细胞缺乏所致感染,未见严重的非造血系统不良反应。结论:标准剂量的IDA联合Ara-C 24 h持续静脉点滴,为初治、复发难治AML的高效、安全的方案。     

Alternating v repeated postremission treatment in adult acute myelogenous leukemia: a randomized phase III study (AML6) of the EORTC Leukemia Cooperative Group

The value of a postremission treatment in acute myelogenous leukemia (AML), with alternating combinations of non-cross-resistant drugs, has been prospectively assessed. Of 515 evaluable patients, 347 (67.4%) entered into complete remission (CR), following induction treatment with daunorubicin (DNR), vincristine (VCR), and cytosine arabinoside (ara-C). After one consolidation course, 248 patients were randomized for six courses of intensive maintenance: either repeated treatment with DNR-VCR-ara-C, or alternating treatment where amsacrine (AMSA) was combined with high dose ara-C on cycle 1,3, and 5 and with 5-azacytidine on cycle 2, 4, and 6. Ninety-nine patients were not randomized: 57 were introduced in a bone marrow transplantation (BMT) program, and 42 went off study, mainly for treatment toxicity or refusal. The main prognostic factors for achievement of CR were performance status, cytogenetics, and age, and for the disease-free survival (DFS): age and number of courses to CR. The rate of second remission was fairly high (64%) for patients relapsing off therapy. The DFS appeared identical (median, 53 weeks), in the two randomized arms, the alternating treatment not showing superiority to the repeated one, in spite of an increased toxicity. The median overall survival for patients achieving a CR was 90 weeks. The reason for the failure of alternating maintenance treatment to improve the DFS is probably related to an insufficient dose intensity: five patients who relapsed during maintenance arm B achieved a second CR with a more intensive combination of high-dose ara-C and AMSA. In addition, 60 patients underwent a BMT (43 allogeneic and 17 autologous). The DFS of patients treated with allogeneic BMT tended to be superior to the one obtained with the chemotherapy program. However the overall survival, as well as the event-free survival, seemed equivalent, including patients who relapsed before the planned BMT. Comparisons between allogeneic BMT, autologous BMT, and intensive consolidation during first CR deserve further prospective studies in AML.     

Cytosine arabinoside with daunorubicin or adriamycin for therapy of acute myelocytic leukemia: a CALGB study

A randomized comparison of the relative efficacy and toxicity of daunorubicin (DNR) at 30 or 45 mg/sq m or adriamycin (ADM) at 30 mg/sq m, given on the first 3 days of a 7-day continuous infusion of cytosine arabinoside (ara-C) at 100 mg/sq m/day, shows the outcome to be dependent on anthracycline, dose, and patient age. DNR 45 is significantly better than DNR 30 or ADM 30 for inducing complete remissions (CR) in patients younger than 60 yr, (72%, 59%, 58% CRs, respectively). DNR 30 is better than DNR 45 or ADM 30 for inducing CR in patients older than 60 yr (47%, 31%, 35%, respectively). There was a corresponding shift in the induction mortality for the age, dose, and anthracycline groups. Adriamycin was significantly more toxic to the gastrointestinal tract than daunorubicin. The duration of complete remission, with cyclic courses of maintenance therapy, was independent of the patient's age, the dose, or choice of anthracycline used in induction, and of whether the maintenance courses were given every 4 wk or every 8 wk.     

Clinical studies of acute myeloid leukemia in the Japan Adult Leukemia Study Group

Acute myeloid leukemia (AML) is the most common adult leukemia in Japan. The treatment for AML consists of induction, consolidation, and maintenance therapies. To improve outcomes in the treatment of AML, the Japan Adult Leukemia Study Group has conducted six studies in AML patients aged 15-64?years since 1987. In AML201 study, IDR (12?mg/m(2)/day for 3?days) or DNR (50?mg/m(2)/day for 5?days) in combination with Ara-C (100?mg/m(2)/day continuous infusion for 7?days) was established as the standard induction therapy, and four courses of combination chemotherapy using non-cross-resistant agents for non-core binding factor (CBF) AML or three courses of high-dose Ara-C for CBF AML was established as the standard consolidation therapy. The AML97 study showed that allo-HSCT from an HLA-identical sibling donor reduced relapse incidence and improved disease-free survival (DFS), but did not significantly impact overall survival (OS) in poor or intermediate risk patients. Despite these studies by JALSG, only about one-third of AML patients remain free of disease for more than 7?years. The JALSG is now conducting the AML209 study to adapt individual therapies according to genetic alterations.     

Induction therapy with vincristine, adriamycin, dexamethasone (VAD) and intermediate-dose melphalan (IDM) followed by autologous or allogeneic stem cell transplantation in newly diagnosed multiple myeloma

We performed a phase II study to test the efficacy and feasibility of induction therapy with vincristine, adriamycin and dexamethasone (VAD) and intermediate-dose melphalan, 70 mg/m2 (IDM), to autologous or allogeneic stem cell transplantation in newly diagnosed multiple myeloma (MM). A total of 77 patients received two cycles of VAD (n = 62) and/or two cycles of i.v. IDM 70 mg/m2 (n = 15) combined with G-CSF. PBSC were harvested after the first IDM, successfully in 87% of patients. Patients with a response to induction received myeloablative therapy with PBSCT (n = 50) followed by IFN maintenance or allo-BMT (n = 11). Seventy-two per cent of patients achieved a response after VAD which increased to 85% after IDM. Of patients who received PBSCT and allo-BMT, 24% and 45% achieved CR, respectively. Toxicity of induction consisted mainly of bone marrow suppression after IDM (median 8 days) with prolonged aplasia in 11% of patients after the second IDM. Only six infections WHO grade 3 occurred during induction. Treatment-related mortality of PBSCT and allo-BMT was 6% and 18%, respectively. Median time of follow-up is 44 months, and 50% of patients after PBSCT and 60% of patients after allo-BMT are still in remission. Survival rates of all patients were 82%, 75% and 63%, and for transplanted patients 86%, 79% and 68% after 12, 24 and 36 months. Well known prognostic factors, including alpha-IFN maintenance after PBSCT, were not significant for response or survival although patients in CR after allo-BMT had a strong tendency for better outcome. VAD/IDM is an effective and safe induction therapy for autologous and allogeneic stem cell transplantation. Based on these observations a phase III trial was started in October 1995 comparing IFN maintenance with PBSCT and allo-BMT after response to induction with VAD and IDM.     

Randomized comparison of fixed-schedule versus response-oriented individualized induction therapy and use of ubenimex during and after consolidation therapy for elderly patients with acute myeloid leukemia: the JALSG GML200 Study

We conducted a multicenter prospective randomized study to compare a fixed-scheduled induction therapy with a response-oriented individualized induction therapy for elderly patients with acute myeloid leukemia (AML). Newly diagnosed AML patients, aged between 65 and 80, were randomly assigned to receive fixed or individualized induction. Both groups received daunorubicin (DNR) 40?mg/m(2) for 3?days and behenoyl cytarabine (BHAC) 200?mg/m(2) for 8?days. In the individualized group, bone marrow biopsy was done on days 8 and 10, and according to the cellularity and blast ratio, the patients received additional DNR and BHAC for two to four more days. All patients achieving complete remission (CR) were randomized a second time to determine whether they would receive ubenimex. CR was obtained in 60.1?% of the fixed group and 63.6?% of the individualized group. Predicted 4-year relapse-free survival (RFS) was 9?% for the fixed group and 18?% for the individualized group. There were no statistically significant differences in CR and RFS between the fixed and individualized groups. In the ubenimex group, prolonged RFS was observed. Notably, gender was a prognostic factor in this study, as 102 female patients had a significantly higher CR rate (72.5 vs. 54.3?%, p?=?0.0048) and better OS (24 vs. 14?% at 4?years, p?=?0.018), compared with 140 male patients.     

Total body irradiation, etoposide, cyclophosphamide, and autologous peripheral blood stem-cell transplantation followed by randomization to therapy with interleukin-2 versus observation for patients with non-Hodgkin lymphoma: results of a phase 3 randomized trial by the Southwest Oncology Group (SWOG 9438)

To determine the effect of posttransplantation immunotherapy with IL-2 on the progression-free survival (PFS) and overall survival (OS) of patients with non-Hodgkin lymphoma (NHL) after autologous stem-cell transplantation (PBSCT), patients with previously treated NHL were treated with cyclophosphamide, etoposide, total body irradiation (TBI), and PBSCT. Twenty-eight to 80 days after PBSCT, patients were randomized to IL-2 versus observation. Three hundred seventy-six eligible patients were registered (with 4-year PFS of 34% and 4-year OS of 52%), and 194 eligible patients were randomized to continuous infusion intravenous IL-2 (9 million units/m(2)/day for 4 days followed 5 days later by 1.6 million units/m(2)/day for 10 days) versus observation. In randomized patients, there was no significant difference in PFS (hazard ratio of IL-2 to observation = 0.90; P =.56) or in OS (hazard ratio of IL-2 to observation = 0.88; P =.55). There were no deaths related to IL-2 treatment. Grade 4 IL-2-related toxicities (n = 14) were reversible. These results confirm earlier SWOG findings that cyclophosphamide, etoposide, TBI, and PBSCT can be administered to patients with relapsed/refractory NHL with encouraging PFS and OS. Posttransplantation IL-2 given at this dose and schedule of administration had no significant effect on PFS or OS. This study is registered at www.clinicaltrials.gov as NCT00002649.     

大剂量阿糖胞苷巩固治疗急性髓细胞白血病后无病生存分析

目的：探讨大剂量阿糖胞苷（HDAra—C）对急性髓细胞白血病（AML）缓解后巩固治疗的无病生存（DFS）影响。方法：以阿糖胞苷3g，静滴2～3h，q12h，连续应用6个剂量为1疗程，共用5疗程。结果：中位完全缓解期为13．5（3～167）个月，中位DFS为17．5（3～167）个月，中位总生存为22．5（7～169）个月。3年和5年的DFS率分别为54％和42％。3年和5年OS率分别为68％和49％。结论：HDAra—C用于AML的缓解后巩固治疗，可望缩短化疗时间，提高无病生存率，改善牛活质量，且患者能耐受治疗中所出现的不良反应。     

Intensified consolidation therapy with dose-escalated doxorubicin did not improve the prognosis of adults with acute lymphoblastic leukemia: the JALSG-ALL97 study

We designed a treatment protocol for newly diagnosed adult acute lymphoblastic leukemia (ALL) in the pre-imatinib era, employing intensified consolidation therapy with a total of 330 mg/m² doxorubicin and adopting slightly modified induction and maintenance regimen of the CALGB 8811 study. Of 404 eligible patients (median age 38 years, range 15–64 years), 298 (74%) achieved complete remission (CR). The 5-year overall survival (OS) rate was 32%, and the 5-year disease-free survival (DFS) rate was 33%. Of 256 Philadelphia chromosome (Ph)-negative patients, 208 (81%) achieved CR and the 5-year OS rate was 39%, and 60 of them underwent allogeneic-hematopoietic stem cell transplantation (allo-HSCT) from related or unrelated donors during the first CR, resulting in 63% 5-year OS. Of 116 Ph-positive patients, 65 (56%) achieved CR and the 5-year OS rate was 15%, and 22 of them underwent allo-HSCT from related or unrelated donors during the first CR, resulting in 47% 5-year OS. In Ph-negative patients, multivariate analysis showed that older age, advanced performance status and unfavorable karyotypes were significant poor prognostic factors for OS and higher WBC counts for DFS. The present treatment regimen could not show a better outcome than that of our previous JALSG-ALL93 study for adult ALL.     

Parameters for predicting allogeneic PBSCT outcome of acute myeloid leukemia: cytogenetics at presentation versus disease status at transplantation

In addition to the clinical disease status at transplantation, the cytogenetic risk at presentation also provides critical information for predicting the prognosis or deciding the future therapeutic strategy. As such, the current study examined various parameters, including the cytogenetics at presentation and clinical disease status at transplantation, regarding their effect on the transplant outcomes of acute myeloid leukemia (AML) patients in an allogeneic peripheral blood stem cell transplantation (PBSCT) setting. A total of 36 patients receiving an allogeneic PBSCT from matched sibling donors were included in a state of first complete remission (CR) (n=22, 61%) or beyond the first CR (n=14, 39%). The cytogenetic risk was classified according to Medical Research Council (MRC) 10 criteria: favorable, 7 patients (20%); intermediate, 21 patients (58%); unfavorable eight patients (22%). The 3-year overall survival rates were 80% for the favorable, 63% for the intermediate, and 0% for the unfavorable cytogenetic risk groups (p=0.0002), and 62% for the patients in a state of first CR and 35% for those beyond the first CR (p=0.0524). Multivariate analysis revealed that higher CD34+ cell doses, favorable cytogenetics at presentation, and a lower marrow blast percentage at transplantation were all strongly associated with favorable transplant outcomes, including overall survival (OS), progression-free survival (PFS), and the probability of progression. The cytogenetic risk at presentation was found to be a useful parameter in predicting the transplant outcomes for patients with AML, regardless of the clinical disease status. However, an additive innovative therapeutic strategy is still needed to overcome an unfavorable cytogenetic risk with refractory AML after allogeneic PBSCT.