Retrospective Analysis of Adult Patients With Relapsed/Refractory Acute Myeloid Leukemia Treated with FLAG at a Comprehensive Cancer Center.

BACKGROUND: FLAG ± Ida (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin), is a salvage chemotherapy regimen for relapsed or refractory (R/R) acute myeloid leukemia (AML), with complete remission (CR) rates historically ranging from 52% to 63%. We review the outcomes for patients with R/R AML treated with FLAG ± Ida at the University of California Davis Comprehensive Cancer Center. PATIENTS AND METHODS: Adult patients (≥ 18 years) with R/R AML who received FLAG or FLAG + Ida from January 1, 2012 to October 31, 2016 were identified via chart review. Outcomes evaluated were CR, CR with incomplete hematologic recovery (CRi), overall response rate, overall survival (OS), relapse-free survival, and adverse events. RESULTS: Forty-two patients were included. The median age was 52 years (range, 23-73 years), and 57% were male. Sixteen (38.1%) patients had relapsed disease, and 26 (61.9%) had refractory disease. Most (n = 35; 83.3%) patients had European LeukemiaNet intermediate-risk AML. Responses were CR in 20 (47.6%) and CRi in 6 (14.3%). The median OS was 10 months (range, 0.8-51 months), and the median relapse-free survival was 12 months (range, 1-51 months) for responders. The median OS for patients who achieved CR was not reached, and the estimated 48-month survival rate was 56%. The median OS after CRi or no response was 3.47 and 2.17 months, respectively. The median OS was not significantly different when censored for stem cell transplant following chemotherapy, nor with use/deferral of idarubicin. The most common adverse effects were pancytopenia and infection. CONCLUSION: Patient outcomes after treatment with FLAG ± Ida for R/R AML remain similar to prior reports, confirming its role as a salvage regimen for these patients.

Two successful deliveries of healthy children by a young woman diagnosed and treated during induction and relapsed therapy for acute promyelocytic leukemia.

INTRODUCTION: Acute promyelocytic leukemia is an oncologic emergency. The limited cases reported in the literature have led to poor understanding of the safety of management of acute promyelocytic leukemia during pregnancy. CASE REPORT: Herein is an acute promyelocytic leukemia case of a 22-year-old young pregnant woman who had various social problems. The patient was diagnosed with acute promyelocytic leukemia in her the second trimester of her first pregnancy.Management and outcome: She was treated with all-trans-retinoic acid with idarubicin and successfully delivered a healthy baby. She completed induction with idarubicin but defaulted her all-trans-retinoic acid, 6-mercaptopurine and methotrexate maintenance. She relapsed after one year and was salvaged with all-trans-retinoic acid high dose cytarabine and arsenic trioxide. She went into remission and had autologous stem cells collected and was planned for an autologous stem cell transplant but she defaulted. She relapsed when she was pregnant with her second baby during her third trimester (29+weeks) 10 months later. Salvage chemotherapy with arsenic trioxide, all-trans-retinoic acid and idarubicin was given. Patient underwent an emergency lower segment caesarian section at 31 weeks of pregnancy due to abnormal fetal cardiotocography. A healthy baby was delivered. DISCUSSION: This drug regimen is controversial during pregnancy owing to the teratogenic effects and fatal retinoic acid syndrome especially in early gestation. In this case, patient was started the induction therapy of all-trans-retinoic acid treatment at her second trimester during her first pregnancy. CONCLUSION: Our lady demonstrated the possibility of using all-trans-retinoic acid and arsenic trioxide and chemotherapy during second and third trimester with successful pregnancy outcomes.

Intra-arterial idarubicin_lipiodol without embolization can provide prolonged complete response in hepatocellular carcinoma: A case report.

Hepatocellular carcinoma is the fourth leading cause of cancer death. For unresectable intermediate-stage hepatocellular carcinoma, the standard treatment is transarterial chemoembolization. To date, the overall survival at three years remains low, and there is currently no consensus about the best anticancer agent and optimal treatment regimen. We report the case of a hepatocellular carcinoma patient with a vascular contraindication to embolization who achieved a complete response after four intra-arterial infusions of idarubicin emulsified with lipiodol. The patient maintained his response over a three-year period without any hepatocellular carcinoma treatment, demonstrating the major role of the anticancer agent in the efficacy of transarterial therapies for intermediate-stage hepatocellular carcinoma.

Intra-arterial idarubicin_lipiodol without embolisation in hepatocellular carcinoma: The LIDA-B phase I trial.

BACKGROUND & AIMS: Idarubicin shows high cytotoxicity against hepatocellular carcinoma (HCC) cells, a high hepatic extraction ratio, and high lipophilicity leading to stable emulsions with lipiodol. A dose-escalation phase I trial of idarubicin_lipiodol (without embolisation) was conducted in patients with cirrhotic HCC to estimate the maximum-tolerated dose (MTD) and to assess the safety, efficacy, and pharmacokinetics of the drug, and the health-related quality of life achieved by patients. METHODS: Patients underwent two sessions of treatment with a transarterial idarubicin_lipiodol emulsion without embolisation. The idarubicin dose was escalated according to a modified continuous reassessment method. The MTD was defined as the dose closest to that causing dose-limiting toxicity (DLT) in 20% of patients. RESULTS: A group of 15 patients were enrolled, including one patient at 10 mg, four patients at 15 mg, seven patients at 20 mg, and three patients at 25 mg. Only two patients experienced DLT: oedematous ascitic decompensation and abdominal pain at 20 and 25 mg, respectively. The calculated MTD of idarubicin was 20 mg. The most frequent grade ≥3 adverse events were biological. One month after the second session, the objective response rate was 29% (complete response, 0%; partial response, 29%) based on modified Response Evaluation Criteria In Solid Tumours. The median time to progression was 5.4 months [95% confidence limit (CI) 3.0-14.6 months] and median overall survival was 20.6 months (95% CI 5.7-28.7 months). Pharmacokinetic analysis of idarubicin showed that the mean Cmax of idarubicin after intra-arterial injection of the idarubicin-lipiodol emulsion is approximately half the Cmax after intravenous administration. Health-related quality of life results confirmed the good safety results associated with use of the drug. CONCLUSIONS: The MTD of idarubicin was 20 mg after two chemolipiodolisation sessions. Encouraging safety results, and patient responses and survival were observed. A phase II trial has been scheduled. LAY SUMMARY: There is a need for transarterial regimens that improve the responses and survival of patients with unresectable HCC. In this phase I trial, we showed that two sessions of treatment with a transarterial idarubicin_lipiodol emulsion without embolisation was well tolerated and gave promising efficacy in terms of tumour control and patient survival.

Improved stability of lipiodol-drug emulsion for transarterial chemoembolisation of hepatocellular carcinoma results in improved pharmacokinetic profile: Proof of concept using idarubicin.

OBJECTIVES: To investigate the relationship between the improved stability of an anticancer drug-lipiodol emulsion and pharmacokinetic (PK) profile for transarterial chemoembolisation (TACE) of hepatocellular carcinoma (HCC). METHODS: The stability of four doxorubicin- or idarubicin-lipiodol emulsions was evaluated over 7 days. PK and clinical data were recorded after TACE with the most stable emulsion in eight unresectable HCC patients, after institutional review board approval. RESULTS: The most stable emulsion was the one that combined idarubicin and lipiodol (1:2 v:v). At 7 days, the percentages of aqueous, persisting emulsion and oily phases were 50-0-50, 33-0-67, 31-39-30, and 10-90-0 for the doxorubicin-lipiodol (1:1 v:v), doxorubicin-lipiodol (1:2 v:v), idarubicin-lipiodol (1:1 v:v), and the idarubicin-lipiodol (1:2 v:v) emulsion, respectively. After TACE, mean idarubicin Cmax and AUC0-24h were 12.5 ± 9.4 ng/mL and 52 ± 16 ng/mL*h. Within 24 h after injection, 40% of the idarubicin was in the liver, either in vessels, tumours, or hepatocytes. During the 2 months after TACE, no clinical grade >3 adverse events occurred. One complete response, five partial responses, one stabilisation, and one progression were observed at 2 months. CONCLUSION: This study showed a promising and favourable PK and safety profile for the idarubicin-lipiodol (1:2 v:v) emulsion for TACE. KEY POINTS: • Transarterial chemoembolisation (TACE) regimens that improve survival in hepatocellular carcinoma are needed. • Improved emulsion stability for TACE resulted in a favourable pharmacokinetic profile. • Preliminary safety and efficacy data for the idarubicin-lipiodol emulsion for TACE were encouraging.

Formulation and optimization of idarubicin thermosensitive liposomes provides ultrafast triggered release at mild hyperthermia and improves tumor response.

Drug delivery through thermosensitive liposomes (TSL) in combination with hyperthermia (HT) has shown great potential. HT can be applied locally forcing TSL to release their content in the heated tumor resulting in high peak concentrations. To perform optimally the drug is ideally released fast (seconds) and taken up rapidly by tumor cells. The aim of this study was to develop a novel thermosensitive liposome formulation of the anthracycline idarubicin (IDA-TSL). The hydrophobicity of idarubicin may improve its release from liposomes and subsequently rapid cellular uptake when combined mild hyperthermia. Here, we investigated a series of parameters to optimize IDA-TSL formulation. The results show that the optimal formulation for IDA-TSL is DPPC/DSPC/DSPE-PEG (6/3.5/0.5 mol%), with ammonium EDTA of 6.5 pH as loading buffer and a size of ~85 nm. In vitro studies demonstrated minimal leakage of ~20% in FCS at 37 °C for 1h, while an ultrafast and complete triggered release of IDA was observed at 42 °C. On tumor cells IDA-TSL showed comparable cytotoxicity to free IDA at 42 °C, but low cytotoxicity at 37 °C. Intravital microscopy imaging demonstrated an efficient in vivo intravascular triggered drug release of IDA-TSL under mild hyperthermia, and a subsequent massive IDA uptake by tumor cells. In animal efficacy studies, IDA-TSL plus mild HT demonstrated prominent tumor growth inhibition and superior survival rate over free IDA with HT or a clinically used Doxil treatment. These results suggest beneficial potential of IDA-TSL combined with local mild HT.

Clinical and economic impact of drug eluting beads in transarterial chemoembolization for hepatocellular carcinoma.

WHAT IS KNOWN AND OBJECTIVE: Drug eluting beads (DEBs) theoretically improve the efficacy and safety of transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC). Nonetheless, their economic profile has not been assessed. Our retrospective before/after study aimed to compare efficacy, safety and economic profile of two strategies of TACE without (Period 1) or with the possibility of using DEBs (Period 2). METHODS: All HCC patients treated by TACE in our hospital between March 2006 and May 2013 were included. Economic analyses were performed from the French Public Health Insurance point of view according to the French Diagnosis-Related Group prospective payment system and from the analytic accountability. RESULTS AND DISCUSSION: One hundred and sixty-one patients were included. Median time to treatment failure and overall survival were 13.1 and 23.8 months in Period 1 vs. 14.1 and 30.2 months in Period 2 (P = 0.45 and P = 0.40). Mean hospital durations and tariffs were 14.9 ± 7.7 days and € 11 472 ± 5901 in Period 1 vs. 12.4 ± 8.4 days and € 7654 ± 4625 in Period 2 (P = 0.03 and P < 10(-4) ). WHAT IS NEW AND CONCLUSION: The possibility of using DEBs did not improve the prognosis in HCC patients treated by TACE. Nonetheless, it had a better medico-economic profile.

Have all-trans retinoic acid and arsenic trioxide replaced all-trans retinoic acid and anthracyclines in APL as standard of care.

Until recently, the standard of care in the treatment of APL has involved the combination of all-trans retinoic acid with anthracycline-based chemotherapy during both induction and consolidation. Additionally, the intensity of consolidation chemotherapy has evolved according to a universally accepted relapse-risk stratification algorithm based on the white cell and platelet counts at presentation. That standard of care is being challenged by the increasing incorporation of arsenic trioxide into front-line treatment protocols, based on two complementary observations. The first is the undoubted anti-leukaemic activity of arsenic trioxide as shown in the relapsed and refractory setting, and in the initial management of low- and intermediate-risk patients. The second is an improved understanding of the action of both all-trans retinoic acid and arsenic trioxide in mediating APL cell eradication, with increasing recognition that PML-RARA fusion protein degradation rather than direct induction of terminal differentiation is the primary mechanism for their ability to eliminate leukaemia initiating cells. As a result, we believe the standard of care for initial therapy in APL is shifting towards an all-trans retinoic acid plus arsenic trioxide-based approach, with additional chemotherapy reserved for patients with high-risk disease.

Lipiodol trans-arterial chemoembolization of hepatocellular carcinoma with idarubicin: first experience.

BACKGROUND: There is still no consensus about the best chemotherapeutic agent for transarterial chemoembolization (TACE). A recent in vitro study demonstrated that idarubicin, an anthracycline, was by far the most cytotoxic drug on human hepatocellular carcinoma (HCC) cell lines. Idarubicin is much more lipophilic than doxorubicin, leading to higher cell penetration through lipidic membranes and greater accumulation of the drug in the lipiodol. Furthermore, idarubicin has the ability to overcome multidrug resistance. Therefore, we designed this pilot human study to evaluate the safety and efficacy of lipiodol TACE using idarubicin. METHODS: In 21 consecutive patients treated by lipiodol TACE with idarubicin (10 mg) for HCC, safety data, tumor response (Response Evaluation Criteria in Solid Tumors, mRECIST), time to treatment failure (TTTF), and overall survival were evaluated. RESULTS: Postembolization syndrome was observed after 30.9% (17 of 55) of sessions. No patient died from a TACE-related complication. No hematological grade 3-5 adverse event was observed. At least one grade 3 or higher adverse event occurred in 19% (4 of 21) of patients. On imaging, no progression was encountered; four patients (24%) exhibited stable disease, 12 (57%) exhibited a partial response, and five (19%) exhibited a complete response. Median TTTF was 16.7 months (Kaplan-Meier analysis). At 6 months, 94.7% (95% confidence interval [CI] 68.1-99.2) of patients did not reach treatment failure, whereas treatment failure was not reached in 50.6% (95% CI 21.6-73.9) of patients at 1 year. Overall survival was 83.5% (95% CI 57-94.4) at 1 year. CONCLUSION: Idarubicin seems safe and effective in lipiodol TACE of HCC. This warrants further study to determine the potential of this drug to replace doxorubicin for TACE.

[Current treatment of acute myeloid leukaemia in adults]. / A felnottkori heveny myeloid leukaemia korszeru kezelése.

Recent cytogenetical findings and novel molecular biology results of acute myeloid leukaemia have shed new lights of our understanding in the diagnosis and treatment of the disease. Acute myeloid leukaemia is not only represented by the wide variety of morphological and immunophenotypic diversity but also demonstrates cytogenetical and molecular biological heterogeneity of its own. It has an unfavorable prognosis, especially in the elderly. Overall survival of younger patients (<50-60 years) has increased in the past years due to high dose chemotherapy (daunorubicine, cytarabine). But in case of unfavorable prognostic factors (not only cytogenetical but also molecular biological characters of the disease), allogeneic stem cell transplantation is needed for successful overall outcome. Better understanding the biology of acute myeloid leukaemia could establish novel targeted therapies and help us eventually to cure the disease.

Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia.

PURPOSE To determine the efficacy and toxicity of the combination of sorafenib, cytarabine, and idarubicin in patients with acute myeloid leukemia (AML) younger than age 65 years. PATIENTS AND METHODS In the phase I part of the study, 10 patients with relapsed AML were treated with escalating doses of sorafenib with chemotherapy to establish the feasibility of the combination. We then treated 51 patients (median age, 53 years; range, 18 to 65 years) who had previously untreated AML with cytarabine at 1.5 g/m(2) by continuous intravenous (IV) infusion daily for 4 days (3 days if > 60 years of age), idarubicin at 12 mg/m(2) IV daily for 3 days, and sorafenib at 400 mg orally twice daily for 7 days. RESULTS Overall, 38 (75%) patients have achieved a complete remission (CR), including 14 (93%) of 15 patients with mutated FMS-like tyrosine kinase-3 (FLT3; the 15th patient had complete remission with incomplete platelet recovery [CRp]) and 24 (66%) of 36 patients with FLT3 wild-type (WT) disease (three additional FLT3-WT patients had CRp). FLT3-mutated patients were more likely to achieve a CR than FLT3-WT patients (P = .033). With a median follow-up of 54 weeks (range, 8 to 87 weeks), the probability of survival at 1 year is 74%. Among the FLT3-mutated patients, 10 have relapsed and five remain in CR with a median follow-up of 62 weeks (range, 10 to 76 weeks). Plasma inhibitory assay demonstrated an on-target effect on FLT3 kinase activity. CONCLUSION Sorafenib can be safely combined with chemotherapy, produces a high CR rate in FLT3-mutated patients, and inhibits FLT3 signaling.

[A short duration treatment with intensive consolidation therapy for patients with acute myelogenous leukemia--13 year experience in a single institute].

Fifty-seven patients with acute myelogenous leukemia (AML) received the following treatment in our hospital between May 1992 and April 2005. Group A: combination of enocitabine, daunorubicin, 6-mercaptopurine riboside and prednisolone (BHAC-DMP) for remission induction, BHAC-DMP or idarubicin (IDR)+cytarabine (Ara-C) for first consolidation, combination of prednisolone, Ara-C, mitoxantrone and etoposide (PAME) for second consolidation, and PAME for late intensification; Group B: IDR+Ara-C for remission induction, PAME for first consolidation, and high-dose Ara-C+mitoxantrone for second consolidation; Group C (acute promyelocytic leukemia, APL) : all-trans retinoic acid (ATRA) for remission induction, BHAC-DMP or IDR+Ara-C for first consolidation, and PAME for second consolidation. The complete remission (CR) rate was 77% in Group A, 76% in Group B, and 71% in Group C. Five-year relapse-free survival rate of the CR patients was 35% in Group A, 49% in Group B, and 70% in Group C. All of the patients had severe neutropenia, but the number of infectious death was small. A short duration treatment with intensive consolidation therapy was effective for patients with AML and improved their quality of life (QOL).

Using quantification of the PML-RARalpha transcript to stratify the risk of relapse in patients with acute promyelocytic leukemia.

BACKGROUND AND OBJECTIVES: The detection of PML-RARalpha by real-time polymerase chain reaction (RQ-PCR) is becoming an important tool for monitoring minimal residual disease (MRD) in patients with acute promyelocytic leukemia (APL). However, its clinical value remains to be determined. Our aim was to analyze any associations between the risk of relapse and RQ-PCR results in different phases of treatment, comparing these data with those yielded by conventional qualitative reverse transcriptase-PCR. DESIGN AND METHODS: Follow-up samples from 145 APL patients treated with the PETHEMA protocols were evaluated by the RQ-PCR protocol (Europe Against Cancer program) and by the RT-PCR method (BIOMED-1 Concerted Action). Hematologic and molecular relapses and relapse-free survival were recorded. We then looked for associations between relapse risk and RQ-PCR results. RESULTS: After induction therapy, no association was found between positive RQ-PCR results and relapse. The PCR result here did not imply any change in the scheduled therapy. After the third consolidation course, two out of three cases with positive RQ-PCR relapsed in contrast to 16 out of 119 (13%) patients with negative RQ-PCR. During maintenance therapy and out-of treatment, all patients with >10 PML-RARalpha normalized copy number (NCN) (n=19) relapsed while all patients with <1 NCN at the end of the study remained in hematologic remission (p<0.0001). In the intermediate group (NCN 1-10) (n=18), the relapse-free survival at 5 years was 60%. Hematologic relapses were predicted if a positive RQ-PCR result had been obtained in a follow-up sample within the previous 4 months. INTERPRETATION AND CONCLUSIONS: Based on the information provided by RQ-PCR in samples obtained after the end of consolidation and subsequently, a relapse risk stratification could be established for APL patients. This stratification divides patients into three groups: those at high risk of relapse, those with an intermediate risk and those with a low risk of relapse.

Outcome of patients with acute promyelocytic leukemia failing to front-line treatment with all-trans retinoic acid and anthracycline-based chemotherapy (PETHEMA protocols LPA96 and LPA99): benefit of an early intervention.

To determine prognosis of acute promyelocytic leukemia (APL) failing to front-line therapy with all-trans retinoic acid (ATRA) and anthracyclines, outcome of 52 patients (32 M/20 F; age: 37, 3-72) included in PETHEMA trials LPA96 and LPA99 who presented with either molecular failure (MOLrel, n=16) or hematological relapse (HEMrel, n=36) was analyzed. Salvage therapy consisted of ATRA and high-dose ara-C-based chemotherapy (HDAC) in most cases (83%), followed by stem-cell transplantation (autologous, 18; allogeneic, 10; syngeneic, 1). Fourteen patients with MOLrel (88%) achieved second molecular complete response (molCR), whereas 81% HEMrel patients responded to second-line treatment, with 58% molCR. After median follow-up of 45 months, four MOLrel and 18 HEMrel patients, respectively, experienced a second relapse. Outcome after MOLrel compared favorably to HEMrel, with longer survival (5-year survival: 64+/-14 vs 24+/-8%, P=0.01) and lower relapse risk (5-year relapse risk: 30+/-13 vs 64+/-9%; P=0.044). Additionally, age

t(8;16) AML developed subsequent to breast cancer therapy.

We report a breast cancer patient who developed acute myeloid leukemia (AML) one year following her adjuvant chemotherapy consisting of cyclophosphamide, adriamycin and 5-fluorouracil. Cytogenetic examination of bone marrow samples resulted in t(8;16)(p11.2;p13.3), which is a chromosome rearrangement observed in de novo and treatment related AML M4/M5 with a poor prognosis.

High-dose cytarabine and mitoxantrone in consolidation therapy for acute promyelocytic leukemia.

The objective of our study was to evaluate high-dose cytarabine in consolidation therapy in patients with newly diagnosed acute promyelocytic leukemia (APL). Patients (age 16-60 years) received induction therapy according to the AIDA protocol (all-trans retinoic acid, idarubicin) followed by one cycle of ICE (idarubicin, cytarabine, etoposide) and two cycles of HAM (cytarabine 3 g/m(2) q12h, days 1-3; mitoxantrone 10 mg/m(2), days 2 and 3). From 1995 to 2003, 82 patients were enrolled. In total, 72 patients (88%) achieved a complete remission, and 10 patients (12%) died from early/hypoplastic death (ED/HD). A total of 71 patients received at least one cycle of HAM. Relapse-free survival (RFS) and overall survival (OS) after 46 months were 83 and 82%, respectively. White blood cell count above 10.0 x 10(9)/l at diagnosis and additional chromosomal aberrations were unfavorable prognostic markers for OS, whereas no prognostic markers for RFS were identified including FLT3 mutations. In conclusion, high-dose cytarabine in consolidation therapy for patients with newly diagnosed APL is an effective treatment approach.

A single, high dose of idarubicin combined with cytarabine as induction therapy for adult patients with recurrent or refractory acute lymphoblastic leukemia.

BACKGROUND: The majority of adult patients who are treated for lymphoblastic disease will either develop recurrent disease or will be refractory to their initial therapy. One option for patients with recurrent/refractory disease is to administer a reinduction regimen that employs a dose-intense combination of anthracycline and cytarabine. These salvage regimens are relatively distinct from the traditional vincristine/prednisone-based programs that are used typically as primary induction therapy. The authors studied a regimen that contained high-dose cytarabine and a single high dose of idarubicin as salvage induction therapy for patients with recurrent or refractory lymphoblastic disease. METHODS: Twenty-nine previously treated adult patients with recurrent or refractory acute lymphoblastic leukemia were treated with a new intensive regimen. Eight patients had primary refractory disease. Twenty-one patients had recurrent disease, and 16 of these patients developed recurrent disease while they were still receiving their primary therapy. The treatment regimen consisted of cytarabine 3.0 g/m(2) by 3-hour infusion daily for 5 days and idarubicin 40 mg/m(2) given as a single dose on Day 3. Filgrastim (granulocyte-colony stimulating factor) 5 microg/kg administered subcutaneously every 12 hours was started on Day 7 and was continued until the absolute neutrophil count was > 5000/microL. Response was assessed using standard criteria. RESULTS: There were 11 complete responses (38%; 95% confidence interval, 20-56%). Four patients subsequently underwent allogeneic bone marrow transplantation. Moderate but acceptable toxicity was observed given the severely myelosuppressive nature of the regimen. There was only one treatment-related death (3%). Two patients, both with significant prior exposure to anthracyclines, suffered reductions in left ventricular function to the 20-30% range during episodes of severe systemic infection. After recovery from infection, the ejection fraction in one patient improved to 50%. CONCLUSIONS: The authors conclude that this regimen has moderate activity and a relatively low incidence of mortality for this high-risk group of patients. This regimen may be most suitable for patients who can undergo potentially curative allogeneic bone marrow transplantation if they achieve a complete response.

Prolonged administration of all-trans retinoic acid in combination with intensive chemotherapy and G-CSF for adult acute myelogenous leukemia: single-centre pilot study in different risk groups.

INTRODUCTION: An exploratory trial was conducted to evaluate toxicity and potential therapeutic role of all trans-retinoic acid (ATRA) given long-term together with chemotherapy and G-CSF to adult patients with acute myelogenous leukemia (AML). MATERIALS AND METHODS: ATRA was administered orally at 45 mg/m(2)/day on days 1-14 and 25 mg/m(2)/day on days 15-28 of two standard cycles (idarubicin, etoposide, cytarabine, G-CSF) and of up to three high-dose courses (cytarabine, G-CSF). The results obtained in 19 patients enrolled in the ATRA trial were compared with those from 29 comparable cases treated with the same schedule without ATRA, according to patient risk class and an in vitro study. RESULTS: ATRA was administered for a median of 52 days to the patients selected for study who achieved a remission. ATRA-related toxicity was mostly non-severe apart from high incidence of headache in conjunction with high-dose cytarabine. Complete remission (CR) rate after cycle 1 (54%), kinetics of hematological recovery, postremission treatment realization, disease-free survival (DFS 37.5% at three years) and overall survival (30% at three years) were not different between ATRA-treated and untreated patients. The only significant prognostic factor was the patient risk class, as defined by cytogenetics and other clinical criteria: DFS rate was 57% at three years in standard-risk cases compared to only 19% in the high-risk group, with no influx by ATRA in either category. The in vitro study, in patients with a definite clinical response, failed to document any inhibitory or pro-apoptotic effect of ATRA on AML blast cells. CONCLUSION: As a consequence to these results, the pilot ATRA phase was closed. This study does not suggest a significant role for the present ATRA schedule as an adjunct to standard antileukemic therapy in adult AML.