High-dose idarubicin and busulphan as conditioning to autologous stem cell transplantation in adult patients with acute myeloid leukaemia

Between 30 and 50% of patients with acute myeloid leukaemia (AML) relapse after autologous stem cell transplantation (ASCT). One possibility of reducing the relapse rate could be the adoption of conditioning regimens specifically designed for AML. We report treatment results achieved with a new conditioning for ASCT, based on high-dose idarubicin (IDA) plus oral busulphan. Patients (n = 40) were conditioned with a regimen consisting of 3 d continuous intravenous infusion IDA at 20 mg/m2, followed by 4 d conventional dose oral busulphan. Unpurged peripheral blood stem cells were used in all cases. All patients had non-M3-AML and were in first complete remission (CR). The median number of CD34+ cells infused was 6.9 x 10(6)/l (2.6-24). No case of transplant-related mortality occurred. In all cases, left ventricular ejection fraction remained unmodified after ASCT. Thirty-three of 40 patients (82%) had grade 3-4 mucositis requiring total parenteral nutrition in all cases. After a median follow up for surviving patients of 32 months from ASCT, 30 patients (75%) are alive and 26 (65%) are in continuous CR. Our data show that a conditioning regimen based on high-dose IDA plus busulphan results in an encouraging reduction of the relapse rate after ASCT in AML.     

Busulfan,cyclophosphamide, and etoposide as conditioning for autologous stem cell transplantation in multiple myeloma

Autologous stem cell transplantation (ASCT) has enabled the use of high-dose alkylating agents either as a single agent or in combination with other cytotoxic agents and/or total body irradiation (TBI) for the treatment of multiple myeloma. Despite improved complete remission rates, relapse and regimen-related toxicities remain challenging. In an effort to increase event-free survival and decrease the high incidence of regimen-related toxicity, we have studied the use of etoposide in combination with reduced-dose busulfan and cyclophosphamide as a conditioning regimen for ASCT in a group of 26 patients with advanced multiple myeloma. Median follow-up for the group was 30 months. There was no early treatment-related mortality. The main toxicity was mucositis. Otherwise, there was 1 case of reversible, clinically diagnosed hepatic veno-occlusive disease. Post-engraftment, 10 patients (38%) achieved CR, 15 (58%) patients achieved PR or SD, and 1 patient developed progressive disease (4%). Five patients in PR and 1 with progressive disease before transplant attained a CR post-transplant. The median times for event-free survival and overall survival after transplantation were 24 and 43 months, respectively. In conclusion, conditioning with busulfan, cyclophosphamide, and etoposide followed by ASCT is a safe regimen with comparable effectiveness to other previously used preparative regimens, thus providing another approach of non-TBI containing high-dose chemotherapy for patients with multiple myeloma.     

Autologous stem-cell transplantation for patients with acute myeloid leukemia aged over 60 yr

OBJECTIVES: Preliminary reports have suggested that autologous stem-cell transplantation (ASCT) is feasible in elderly patients with acute myeloid leukemia (AML). The objective of this study was to describe the disease characteristics and treatment results from a series of 22 elderly AML patients undergoing ASCT. METHODS: The median age was 64 yr (range 61-71). Twenty patients were in first complete remission (CR1), two in CR2, and all were in performance status 0-1. The median interval between CR achievement and ACST was 3 months (range 2-5). In 20 cases peripheral blood stem cells were infused, in two bone marrow. RESULTS: All patients had a successful engrafment. One patient (5%) died from transplant-related complications. The median number of days to granulocytes > 500 mm-3 and platelets > 20 000 mm-3 was 11(range 9-15) and 13 (range 9-20), respectively. Non-hematologic toxicity included WHO grade III-IV stomatitis in 32% patients and grade IV nausea and vomiting in one (4.5%). Seven patients had fever of unknown origin, while in 14 a documented infection was diagnosed. Median duration of hospitalization was 31 d (range 16-60). CONCLUSIONS: After a median follow-up of 12 months from ASCT, nine patients are alive in continuous CR and 13 died from AML relapse. Median survival from diagnosis and disease-free survival (DFS) was 19 and 14 months, respectively. Our data show that ASCT with a standard conditioning regimen is feasible in AML patients aged more than 60 yr. Toxicity and hemopoietic recovery do not substantially differ from those observed in young adults. DFS and overall survival (OS) duration are encouraging, but a longer follow up is needed on a larger series of patients.     

Non-myeloablative hematopoietic stem cell transplantation is of limited value in advanced or refractory acute myeloblastic leukemia. The Mexican experience

Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective strategy for preventing relapse of acute myelogenous leukemia (AML). We analyzed the outcome of 31 primary AML patients who received a reduced-intensity conditioning regimen for allogeneic HSCT in first or second remission. Thirty-one AML patients, 20 in first complete remission (FCR), 8 in second complete remission (SCR) and 3 in a partial remission (SPR) were included. All received busulfan 4 mg/kg/d/2 days, fludarabine 30 mg/m(2)/d/3 days and cyclophosphamide 350 mg/m(2)/d/3 days as conditioning regimen. The median number of CD34+ cells infused was 5.6 x 10(6)/kg and 5.2 x 10(6) in FCR and SCR group, respectively. All patients received cyclosporine-A (CsA) and methotrexate as graft vs. host disease (GvHD) prophylaxis. All patients showed myeloid engraftment (neutrophils >0.5 x 10(9)/l) after a median of 13 days in FCR group and 15 days in SCR group. Platelet recovery >20 x 10(9)/l was achieved after a median of 13 days in both groups. Relapse for 20 patients in FCR was 35% compared to 91% for 11 in SCR/SPR (p < 0.05). Conclusions. Reduced-intensity conditioning followed by allogeneic HSCT can induce stable remission in primary AML patients transplanted in FCR. A high relapse rate was documented in patients with refractory or relapsed AML.     

A new intensive induction schedule, including high-dose Idarubicin, high-dose Aracytin and Amifostine, in older AML patients: feasibility and long-term results in 42 patients

OBJECTIVE: We evaluated the feasibility of a new regimen in elderly patients with acute myeloid leukemia (AML). The main end points were overall response rate (ORR) and toxicity; secondary end points were feasibility of peripheral blood stem cells (PBSC) collection, leukemia-free survival, and overall survival (OS). PATIENTS AND METHODS: We treated 42 fit elderly patients with high-dose (HD) idarubicin plus HD-cytarabine (Ara-C), with amifostine. RESULTS: We observed one treatment-related death (2%). The main extrahematological toxicity was represented by grade III to IV infections in 64% of patients. Hematological toxicity was acceptable with 15 days (range, 9-29 days) to reach >500 x 10(6)/L absolute neutrophil count and 16 days (range, 3-39 days) to achieve an unsupported platelet count >20,000 x 10(6)/L. Median duration of severe neutropenia was 12 days (range, 1-36) and median number of febrile days and intravenous antibiotics therapy was 6 (range, 0-17) and 17 days (range, 0-34), respectively, Median duration of hospitalization was 31 days (range, 20-61). ORR was 83% (34 of 41); 32 patients received intensive consolidation therapy; 15 patients were able to mobilize a sufficient number of CD34+ cells; and 14 were transplanted. CONCLUSION: According to the intention to treat criteria all patients were analyzed for outcomes. Five-year OS was 19%, with median follow-up of 38 months. Patients with unfavorable cytogenetic and those with secondary AML had poorer OS; about 40% of patients could mobilize a sufficient amount of PBSC for autologous stem cell transplantation.     

Fludarabine, cytarabine, and G-CSF (FLAG) for the treatment of acute myeloid leukemia relapsing after autologous stem cell transplantation

 Twenty-six patients affected by acute myeloid leukemia (AML) who relapsed after autologous stem cell transplantation (ASCT) were treated with the FLAG regimen (fludarabine, cytarabine, and G-CSF). Their median age was 39 years (range 14–59). The median interval from achievement of CR to ASCT was 4 months (2–8). The conditioning regimen was BAVC (BCNU, amsacrine, VP-16, cytarabine) in eight patients, BuCy (busulfan, cyclophosphamide) in 13, and TBI-Cy (total body irradiation, cyclophosphamide) in five. Relapse occurred after a median of 7 months (2–18). ASCT had been performed in CR1 for 23 patients and in CR2 for three. Nineteen patients had been given bone marrow, seven peripheral blood stem cells collected following consolidation plus G-CSF. Overall, CR was obtained by 13 patients (50%), all remitters requiring a single course. The median time for hematological recovery of neutrophils >500/μl and platelets >20,000/μl was 24 and 30 days, respectively. The median duration of G-CSF administration was 25 days, while the median hospitalization was 31 days. There were four deaths in induction (15%), while nine patients (35%) were resistant. After achieving CR, two patients received allogeneic BMT, five a second ASCT, and four were consolidated with HD-ARA-C. Only two patients were judged unable to receive any further therapy. There were 14 documented infections, while nine patients experienced fever of unknown origin. WHO >2 nonhematological toxicity consisted of stomatitis (50%), hepatic dysfunction (11%), diarrhea (11%), and lethargy (4%). Median overall survival and disease-free survival were 6 and 13 months, respectively. Six patients are in CCR at present. We conclude that FLAG is effective in patients with AML who are relapsing after ASCT. The toxicity is acceptable, enabling most patients to receive further treatment, including second transplantation procedures. Received: October 19, 1998 / Accepted: March 30, 1999     

Idarubicin, cytarabine, and topotecan in patients with refractory or relapsed acute myelogenous leukemia and high-risk myelodysplastic syndrome.

In an effort to develop more effective therapy for patients with refractory or relapsed acute myelogenous leukemia (AML) and high-risk myelodysplastic syndrome (MDS), we investigated the efficacy of a combination chemotherapy consisting of idarubicin, cytarabine, and topotecan. Twenty-seven patients were treated: four with primary refractory AML, nine with AML in first relapse, four with AML in second relapse, and 10 with MDS-RAEB/RAEBT. Patients received as salvage therapy a single course of idarubicin 12 mg/m(2) IV bolus on days 1-3, cytarabine 1 g/m(2) over two hours q 12 hr on days 1-5, and topotecan 1.25 mg/m(2) over 24 hr on days 1-5. Median age was 42 years (range 17-65 years). All patients were evaluable for response: 14 (51.9%) achieved complete remission, 10 with AML (59%) and four with MDS (40%), respectively. Thirteen AML patients (excluding four relapsed after autologous stem cell transplantation) were grouped into four categories to stratify the probability of achieving complete remission (CR): group 1, first CR duration > or = 2 years and receiving first salvage treatment (S1); group 2, first CR duration 1-2 years and receiving S1; group 3, first CR duration 0-1 years and receiving S1; and group 4, first CR duration 0-1 years and receiving S2, S3, or S4 after failing S1. The response rate of each group was as follows: group 1, one of two (50%); group 2, one of one (100%); group 3, four of four (100%); group 4, two of six (33.3%). The median remission duration and survival of patients with AML were six and 12 months, respectively. Median duration of survival in 10 MDS patients was 15 months, and all four MDS patients achieving a CR maintained continuous CR with a median follow-up of 11 months. Severe myelosuppression was observed in all patients, resulting in fever or documented infections in 89% of patients. Median time to recovery of neutrophils > or =0.5 x 10(9)/l was 22 days (11-34) and for platelets > 20 x 10(9)/l 35 days (11-58). Reversible grade 3-4 toxicities included diarrhea (two patients) and mucositis (seven patients). We conclude that combination chemotherapy with intermediate dose cytarabine, idarubicin, and topotecan has significant antileukemic activity and acceptable toxicity in salvage AML and high-risk MDS.     

Treatment of patients with high-grade non-Hodgkin's lymphoma aged over 70 years with an all-oral regimen combining idarubicin, etoposide and alkylators

In elderly patients age-specific comorbidity often reduces the possibility of administering intensive chemotherapy and of obtaining response to treatment. Therefore, chemotherapy must differ from that for non-elderly patients, while maintaining the primary goal of a complete clinical response. We treated 19 patients over the age of 70 years (median age 75 years, range 70-86) with stage II-IV high-grade non-Hodgkin's lymphoma (NHL) with a combination regimen including idarubicin plus etoposide and prednimustine (or chlorambucil+prednisone), all administered orally on an outpatient basis. The therapeutic schedule included six 5-day courses of idarubicin 20 mg/sqm on day 1 (or 10 mg/sqm on days 1 and 3 in the nine patients last treated), etoposide 60 mg/sqm/12 h days 2-5, prednimustine 60 mg/sqm days 2-5, G-CSF 300 microg/day from day+7 until PMN>1000/microl. In ten patients prednimustine was replaced by chlorambucil 10 mg/sqm, days 2-5, and prednisone 50 mg days 2-5, because of non-availability of the drug. Of the 19 patients submitted to this regimen 15 (79%) obtained a clinical response: eight reached a complete response (CR), and seven a partial response (PR). Hematologic toxicity was generally mild. Only three patients had to be hospitalised for infection. Except alopecia, non-hematologic toxicities were negligible. At a median follow-up of 16 months, five of eight patients who obtained CR relapsed (median CR duration 7 months). The actuarial median survival is 34 months (range 6-46). This study demonstrates the feasibility and efficacy of an all-oral regimen including idarubicin, plus etoposide and prednimustine (or chlorambucil+prednisone) in NHL patients aged over 70 years.     

Dose-dependent effect of etoposide in combination with busulfan plus cyclophosphamide as conditioning for stem cell transplantation in patients with acute myeloid leukemia

To evaluate the efficacy and toxicity of two different etoposide (VP-16) dosages (30 or 45 mg/kg) in combination with busulfan/cyclophosphamide as conditioning therapy followed by stem cell transplantation in acute myeloid leukemia (AML), 90 patients with AML received either 30 mg/kg (n = 60) or 45 mg/kg (n = 30) etoposide in combination with busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg). The stem cell source was allogeneic related bone marrow (BM) (n = 53), allogeneic unrelated BM (n = 5), allogeneic unrelated peripheral blood (PBSC) (n = 2), syngeneic BM (n = 2), autologous BM purged (n = 9) or unpurged (n = 9), autologous PBSC (n = 10). Fifty-six patients (62%) were in first CR, 26 (29%) were > first CR, and eight (9%) were transplanted in relapse. Principal toxicities in both groups were mucositis and hepatotoxicity. Forty-five mg/kg etoposide resulted in greater hepatic toxicity (P = 0.03), and a higher incidence of VOD (23 vs 12%, P = 0.04) and acute GVHD grade III/IV (13 vs 5%, NS). The treatment-related mortality was 17% in the 30 mg/kg group and 33% in the 45 mg/kg group, mainly due to infections, intestinal pneumonia and GVHD. Hematological recovery of leukocytes 1/nl was comparable in both groups (17 vs 16 days). After a median follow-up of 16 months 19% in the 30 mg/kg group and 23% in the 45 mg/kg group relapsed. In patients who had undergone allogeneic related bone marrow transplantation in first CR no relapses occurred after a median follow-up of 3 years. For all patients the 3-year estimated disease-free survival was 62% in the 30 mg/kg group and 40% in the 45 mg/kg group (P = 0.03). For patients in first CR who underwent allogeneic related stem cell transplantation the 3 year disease-free survivals were 80% and 66%, respectively (P = 0.4). We conclude that etoposide 30 mg/kg or 45 mg/kg in combination with busulfan/cyclophosphamide is a highly active regimen for bone marrow transplantation of patients with AML with a low relapse rate. However, conditioning with 30 mg/kg rather than 45 mg/kg etoposide resulted in less toxicity and a better overall survival due to a lower transplant-related mortality. Bone Marrow Transplantation (2000) 26, 711-716.     

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。     

Tandem transplant of peripheral blood stem cells for patients with poor-prognosis Hodgkins's disease or non-Hodgkin's lymphoma.

To improve the results of high-dose therapy with autologous stem cell transplantation, new conditioning regimens with acceptable toxicity must be developed. The aim of this study was to evaluate the feasibility and toxicity of two myeloablative regimens performed at a 2-month interval. After salvage chemotherapy and collection of peripheral stem cell progenitors (median CD34+ cells/kg: 11 x 106/kg), (n = 15) patients with aggressive non-Hodgkin's lymphoma with poor prognostic factors or refractory Hodgkin's disease (n= 9) received intensified regimens. The first conditioning regimen, consisting of BCNU-cyclophosphamide-VP16-mitoxantrone was followed by transplantation of a median number of 4 x 10(6) CD34+ cells/kg; then, after a median interval of 56 days, a second preparative regimen, combining busulfan-aracytine-melphalan or TBI + aracytine-melphalan, was followed by transplantation of a median of 4 x 10(6) CD34+ cells/kg. After regimens 1 and 2, respectively: median time to neutrophil recovery >500/microl was 11 days (both times); median time to platelet counts >50,000/microl was 14 and 36 days, but values > 20,000/microl were reached by days 13 and 16 (P = 0.9); mucositis grade III-IV was observed in 11 and 15 cases. The median number of days with fever >38 degrees C was significantly higher (7.8 days) after the second transplant (P <0.05). Three cases of veno-occlusive disease (VOD) were observed after the second transplant. At a median follow-up of 18 months, 14/24 (58%) patients remained in CR, seven patients had died (two of VOD and five after relapse) and two were alive in relapse. These results indicate that tandem transplants performed at a 2-month interval in poor risk lymphoma can be used with acceptable hematotoxicity. VOD remains the major drawback and hepatotoxic drugs, such as busulfan, should be used with caution. Longer term follow-up of a larger cohort of patients is needed to ascertain the overall efficacy.     

IDA-FLAG (idarubicin, fludarabine, cytarabine, G-CSF), an effective remission-induction therapy for poor-prognosis AML of childhood prior to allogeneic or autologous bone marrow transplantation: experiences of a phase II trial

A phase II trial was designed to explore the potential feasibility and efficacy of a reinduction therapy consisting of fludarabine, cytarabine, idarubicin and granulocyte colony stimulating factor (G-CSF) for acute myelogenous leukaemia (AML) patients with poor prognosis.
Twenty-three patients aged 1.2–17.5 years with refractory ( n  = 3), relapsed ( n  = 19) or secondary ( n  = 1) AML were treated with the IDA-FLAG regimen, a combination therapy of idarubicin (days 2–4, 12 mg/m²/d), fludarabine (days 1–4, 30 mg/m²/d), cytarabine (days 1–4, 2000 mg/m²/d) and G-CSF (day 0 up to ANC > 1 × 10⁹/l, 400 μg/m²/d). They received a total of 37 courses of IDA-FLAG and/or FLAG (IDA-FLAG without idarubicin). 17/23 patients achieved a complete remission (CR) with a median duration of 13.5 months (1–39 months), one patient showed a partial remission, and five were nonresponders while in CR, 11 patients underwent bone marrow or PBSC (peripheral blood stem cells) transplantation. Overall, nine patients remain in continuous complete remission with a median duration of 17.5 months (9.5–39 months). The toxicity of the IDA-FLAG courses was more severe than for the FLAG courses with marked neutropenia and thrombocytopenia (for IDA-FLAG: median 22.5 and 25 d respectively; for FLAG: median 10.5 and 14 d respectively). Pulmonary infections were the main nonhaematological toxicity. One patient died in CR from invasive aspergillosis.
The IDA-FLAG regimen produced a CR of >12 months in more than half of the patients and can be recommended as a therapeutic option prior to allogeneic or autologous bone marrow transplantation.     

Hematopoietic stem cell transplantation for childhood myeloid malignancies after high-dose thiotepa, busulfan and cyclophosphamide

Seventeen children with advanced myeloid malignancies (induction failure, relapse, myelodysplasia, secondary AML, or CR >1) received thiotepa 750 mg/m2 i.v., busulfan 12 mg/kg or 640 mg/m2 p.o., and cyclophosphamide 120 mg/kg i.v. as a preparative regimen for allogeneic or autologous hematopoietic stem cell (HSC) transplantation. Of the 15 allogeneic transplants, eight were from matched siblings, one was from a mismatched sibling, and six were from unrelated donors. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine or tacrolimus and methotrexate. Regimen-related toxicity was common but tolerable, affecting mainly the skin and gastrointestinal tract. Three patients died early and were not evaluable for engraftment; engraftment occurred in the remaining patients. Nine patients with active disease at the time of transplant were evaluable for response; all achieved remission. With a median follow-up of 40 months (range, 10-71 months), nine patients are alive and disease-free. The 3-year actuarial event-free survival was 51% (95% confidence interval (CI) 27-76%). Seven patients died of transplant-related complications: infection (n = 4), chronic GVHD (n = 1), veno-occlusive disease, VOD, (n= 1) and pulmonary alveolar hemorrhage (n = 1). Only one patient had leukemia relapse and died. We conclude that the use of high-dose thiotepa, busulfan and cyclophosphamide is an effective conditioning regimen for childhood myeloid malignancies and may be tested in patients with less advanced disease (eg CR1).     

FLAG-IDA in the treatment of refractory/relapsed acute myeloid leukemia: single-center experience

We evaluated the efficacy and toxicity profiles of the combination of fludarabine, high-dose cytosine arabinoside (AraC), idarubicin, and granulocyte colony-stimulating factor (G-CSF) in refractory/relapsed acute myeloblastic leukemia (AML) patients. Between October 1998 and February 2002, 46 AML patients were treated with FLAG-IDA (fludarabine 30 mg/m(2), AraC 2 g/m(2) for 5 days, idarubicin 10 mg/m(2) for 3 days, and G-CSF 5 micro g/kg from day +6 until neutrophil recovery). Thirty patients were in relapse after conventional chemotherapy including cytarabine, etoposide, and daunorubicin or mitoxantrone according to the GIMEMA protocols. Four were in relapse after autologous peripheral stem cell transplantation and two after allogeneic bone marrow transplantation. Ten patients had refractory disease (after 10 days of standard doses of cytarabine, 3 days of mitoxantrone or daunorubicin, and 5 days of etoposide). Recovery of neutrophils and platelets required a median of 19 and 22 days from the start of therapy. Complete remission (CR) was obtained in 24 of 46 patients (52.1%) and 3 of 46 (6.6%) died during reinduction therapy: 2 due to cerebral hemorrhage and 1 due to fungemia ( Candida tropicalis). Fever >38.5 degrees C was observed in 40 of 46 patients (86.9%), 27 had fever of unknown origin (FUO) and 13 documented infections; 31 of 46 (67.3%) developed mucositis and 14 of 46 (30.4%) had grade 2 WHO transient liver toxicity. After achieving CR, 11 patients received allogeneic stem cell transplantation, 4 patients received autologous stem cell transplantation, 4 were judged unable to receive any further therapy, and 5 refused other therapy. Ten patients are at present in continuous CR after a median follow-up of 13 months (range: 4-24). In our experience, FLAG-IDA is a well-tolerated and effective regimen in relapsed/refractory AML. The toxicity is acceptable, enabling most patients to receive further treatment, including transplantation procedures.     

Multicentre phase III trial on fludarabine, cytarabine (Ara-C), and idarubicin versus idarubicin, Ara-C and etoposide for induction treatment of younger, newly diagnosed acute myeloid leukaemia patients

Fludarabine plus cytarabine (Ara-C) and idarubicin (FLAI) is an effective and well-tolerated induction regimen for the treatment of acute myeloid leukaemia (AML). This phase III trial compared the efficacy and toxicity of FLAI versus idarubicin plus Ara-C and etoposide (ICE) in 112 newly diagnosed AML patients <60 years. Fifty-seven patients received FLAI, as the first induction-remission course, and 55 patients received ICE. Post-induction treatment consisted of high-dose Ara-C (HDAC). After HDAC, patients in complete remission (CR) received a second consolidation course (mitoxantrone, etoposide, Ara-C) and autologous stem cell transplantation (auto-SCT) or allogeneic (allo)-SCT, according to the age, disease risk and donor availability. After a single induction course, CR rate was 74% in the FLAI arm and 51% in the ICE arm (P = 0.01), while death during induction was 2% and 9% respectively. Both haematological (P = 0.002) and non-haematological (P = 0.0001) toxicities, especially gastrointestinal (i.e. nausea, vomiting, mucositis and diarrhoea), were significantly lower in FLAI arm. In both arms, relapses were more frequent in patients who were not submitted to allo-SCT. After a median follow-up of 17 months, 30% and 38% of the patients are in continuous CR in FLAI and ICE arm respectively. Our prospective randomised study confirmed the anti-leukaemic effect and the low toxic profile of FLAI as induction treatment for newly diagnosed AML patients.     

Phase I trial with escalating doses of idarubicin and multidrug resistance reversal by short-course cyclosporin A, sequential high-dose cytosine arabinoside, and granulocyte colony-stimulating factor for adult patients with refractory acute leukemia

BACKGROUND AND OBJECTIVES. Patients with refractory acute myeloid or lymphoid leukemia (AML, ALL) were treated with a high-dose regimen comprising idarubicin (IDR) plus short-course cyclosporin A (CsA) as multidrug resistance type-1 (MDR1) blocking agent. The principal aim was to define the maximum tolerated dose (MTD) of IDR, which is reported to be a less MDR1-sensitive anthracycline. The short CsA infusion was patterned after the results of a previous in vitro study. DESIGN AND METHODS. This was a phase I trial, in which eligible patients received high-dose cytarabine (HDAC) 3 g/m(2)/bd on days 1, 2 and 8, 9, and IDR 12.5-20 mg/m(2)/d on days 3 and 10, with increments of 2.5 mg/m(2)/d from the baseline per treatment group. Intravenous CsA infusion started 4 hours before IDR and lasted 12 hours. Recombinant granulocyte colony-stimulating factor (G-CSF) was added from day 11. IDR MTD was evaluated through analysis of regimen-related toxicity (RRT). RESULTS. Eighteen patients were treated (16 AML, 2 ALL; MDR1+: 8/8 studied). Overall response rate was 61%. Toxicity was severe but manageable up to an IDR dose of 17.5 mg/m(2)/d, while grade 4 RRT developed with IDR 20 mg/m(2)/d. High-grade toxicity, not strictly regimen-related, was sometimes observed at lower IDR concentrations in patients with unresolved complications from prior extensive treatments. In keeping, the complete response (CR) rate was 92% (11/12) for patients with an ECOG performance score <2 compared to 0% (0/6) in the others (p=0.000). Apart from that, induction of markedly hypocellular, leukemia-free bone marrow on day 11 was associated with achievement of CR (13 evaluable: CR 8/10 vs 0/3, p=0.035). INTERPRETATION AND CONCLUSIONS. IDR at 17.5 mg/m(2)/d (x2) can be associated with short-course CsA and HDAC for the management of refractory acute leukemias. While this regimen could deserve testing in a larger phase II trial, to document activity in MDR1+ disease, it remains important to select the most suitable patients in order to avoid the occurrence of life-threatening cumulative toxicity.     

Autologous stem cell transplantation with busulfan, cyclophosphamide, and etoposide as an intensifying frontline treatment in patients with peripheral T cell lymphomas: a multicenter retrospective trial

The effectiveness of high-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) as a frontline treatment in peripheral T cell lymphomas (PTCLs) is still unclear. We retrospectively investigated the clinical outcomes of HDT/ASCT as an intensifying frontline treatment in 31 patients with newly diagnosed PTCLs. The conditioning regimen of HDT/ASCT consisted of busulfan, cyclophosphamide, and etoposide (BuCyE). At diagnosis, five (16.1 %) patients were classified as high risk according to the prognostic index for PTCL (PIT). The disease status of the patients before HDT/ASCT consisted of 23 patients (74.2 %) with complete response (CR) and eight patients (25.8 %) with partial response (PR). Six (75 %) out of eight patients with PR at pretransplantation were improved in terms of the response to CR after HDT/ASCT. At a median follow-up of 32.4 months, the 3-year probability of overall survival (OS) and progression-free survival (PFS) was 64.5?±?8.6 %. Transplant-related mortality occurred in three patients (9.7 %), due to septic shock, hemorrhage, and delayed pneumonia, respectively. Bone marrow involvement of PTCL at diagnosis was a poor prognostic factor for OS. In conclusion, frontline HDT/ASCT with a conditioning regimen of BuCyE may be an effective and tolerable intensifying therapeutic option to improve outcomes in patients with PTCLs.     

Autologous stem cell transplantation for acute myeloid leukemia patients in first complete remission: a 10-year follow-up study of 118 patients

We assessed the impact of unpurged autologous stem cell transplantation (ASCT) on long-term outcome of 118 patients with acute myeloid leukemia (AML) in first complete remission (CR1). With a median follow-up of 95 months, the 10-year overall survival, disease-free survival and relapse risk are, respectively, 54%, 50% and 46%. De novo AML, the presence of a favorable karyotype and intensification of treatment prior to ASCT are independently associated with clinical outcome by multivariate analysis. Thus, a remarkable proportion of AML patients in CR1 can be cured with high-dose therapy and ASCT.     

Nonmyeloablative stem cell transplantation in patients with ALL and AML results in low nonrelapse mortality despite high rate of infections and GVHD

28 patients with high-risk acute lymphoblastic (ALL) or acute myelogenous leukemia (AML) underwent nonmyeloablative stem cell transplantation (NST) from HLA-identical donors because of one or several contraindications against myeloablative conditioning. Out of 28 patients, nine (32%) had pulmonary or hepatosplenic infiltrates due to invasive fungal infections (IFI) before NST. Out of a total of 28 patients, 17 (61%) had uncontrolled leukemia before NST. Conditioning was performed with fludarabine 180 mg/m(2), busulfan 8 mg/kg and antithymocyte globulin 40 mg/kg. After NST, fever of unknown origin, sepsis or pneumonia developed in 18/28 patients (64%) overall. IFI reactivated in 3/9 patients after NST. Out of, 28 patients, 13 (46%) had late onset of acute graft-versus-host disease (GvHD), which developed at a median of 83 days after NST. GvHD frequently developed after donor lymphocyte infusions. After a median follow-up of 8 months (2-46 months), 14/28 patients (50%) have died from relapse and 1/28 patients (4%) has died from sepsis. Among 28 patients, 13 (46%) are alive in complete remission (CR). Six of 17 patients (35%) with uncontrolled disease and 7/11 patients (63%) with CR before NST are alive in CR. Probability of overall survival at 2 years is 38%. In summary, NST offers a therapeutic alternative to patients with high-risk ALL or AML, who have contraindications against conventional high-dose conditioning. Low NRM was encountered despite high morbidity, but relapse rate was high. Therefore, controlled studies are necessary to elucidate the place of NST in the therapy of high-risk acute leukemias.     

Umbilical cord blood transplant from unrelated HLA-mismatched donors in children with high risk leukemia

In the last 3 years, 14 children with high-risk leukemia (11 ALL, 2 AML and 1 CML) underwent cord blood transplantation from unrelated HLA-mismatched donors at a median of 99 days from the start of search. Eight patients were transplanted in second CR, one in accelerated phase, three at relapse and two patients in first CR. Conditioning regimen (fractionated TBI, etoposide, CY and anti-lymphocyte serum) and prophylaxis of GVHD (CsA and 6-methylprednisolone) were identical for all patients. Neutrophils >0.5x10(9)/l were reached at a median of 33 days from transplant, but in four cases we observed an autologous hematopoietic reconstitution (three spontaneous, one after autologous BM rescue). Acute and chronic GVHD were observed in 10/14 and 3/8 evaluable cases, respectively. Three patients died of transplant-related toxicity and three patients relapsed. The probabilities of event-free, disease-free and overall survival were 50, 53 and 64%, respectively. Cord blood transplant from HLA-mismatched unrelated donor is a valid option for the treatment of children with high-risk leukemia. With our eligibility criteria, conditioning regimen and prophylaxis of graft-versus-host disease, the main obstacles to successful transplant were represented by graft failure and fatal acute GVHD.