Induction chemotherapy in head and neck cancer patients followed by concomitant docetaxel-based radiochemotherapy.

Concurrent chemoradiotherapy has become the standard of care for patients with inoperable squamous cell head and neck carcinoma. More recently, induction chemotherapy has been adopted as an approach in the management of these patients. We report the results of a phase II trial associating induction chemotherapy and concomitant chemoradiotherapy in a series of patients with inoperable squamous cell head and neck cancer. Twenty-nine patients with advanced squamous cell carcinoma ineligible for surgery were enrolled. Induction chemotherapy with docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) every 21 days was administered for two cycles. Radiotherapy followed the induction phase. During radiotherapy, docetaxel was administered weekly at the dose of 33 mg/m(2) . Primary end point of the study was feasibility of treatment. Six (18%) patients failed to conclude the treatment schedule. Although response rates in evaluable patients were very high (disease control rate >90%), toxicities were a matter of concern. The reported treatment schedule proved infeasible. However, some modifications in ancillary therapies aimed at exploiting its efficacy could make it practicable.

Predictors of mortality of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF), a disease with histological features corresponding to usual interstitial pneumonia (UIP), is a disorder of unknown cause. Not only it is the most common subtype of idiopathic interstitial pneumonias but it is also associated with the highest mortality rate. Despite a good number of studies investigating the mortality of patients with UIP the prognostic factors that have been studied have several limitations. To date it is unclear when in the course of the disease and with what modality these patients should be treated. According to the literature we subcategorized predictors of mortality into (a) baseline predictors; (b) dynamic predictors. IPF perspectives in therapy have been also analyzed. Moreover, the principal aims of this review were: (1) to analyze and to clarify the clinical utility of different prognostic factors for IPF; (2) to enable clinicians to better evaluate the eligibility criteria for lung transplantation in the clinical practice.

Chemoimmunotherapy with low dose vinorelbine and interleukin-2 in treatment of patients with metastatic renal cell carcinoma.

Systemic therapies employed in patients with metastatic renal cell carcinoma (MRCC) include chemotherapy to immunomodulatory cytokines (interleukin 2 [IL-2], interferon alpha [INFalpha]), chemoimmunotherapy, adoptive immune therapy and anti-angiogenic therapy. Despite this range of treatment alternatives, the optimal therapy for MRCC patients is far from being established. Thus, attempts with novel therapeutic approaches implementing new drug combinations are justified. We conducted a phase II evaluation of a combination of vinorelbine and IL-2, both at low doses, in 30 patients with MRCC. The rationale of the combination was to damage the tumor tissue to the extent necessary to make it more immunogenic while, at the same time, to obtain an efficient immune response through the concomitant administration of IL-2. The treatment, given in different dose combinations and administration times, resulted feasible, with no renal, neurological or hematological toxicity. The overall survival of the whole group of patients is higher than that usually observed following treatment with immunotherapies (18.2 versus 13.3 months, respectively). While the limited number of treated patients does not allow advancing conclusions on the effective activity of the adopted protocol, the results observed are encouraging.

Hormone-independent in vitro erythroid colony formation by bone marrow cells from Rauscher virus-infected mice.

Bone marrow cells from BALB/c mice infected with Rauscher erythroblastosis virus produced five to twenty-five times more erythroid colonies in vitro in the absence of erythropoietin (EP) as compared to normal cells. A good correlation existed between the state of the disease and the number of hormone-independent erythroid colony-forming cells (CFU-E). A significant number of hormone-independent CFU-E was found as early as 3 days after infection. A linear relationship existed between the number of cells plated and the number of erythroid colonies formed in vitro. Addition of EP did not enhance colony formation, even at low cell concentrations. Feeder layer experiments demonstrated that EP-independent colony formation was not due to the production of endogenous EP. Repeated injections of phenylhydrazine into normal mice did not lead to the loss of EP responsiveness in vitro; this indicated that the hormone independency induced by the virus was not due to continuous erythropoietic stimulation in vivo. Besides hormone independency, the CFU-E from infected mice required less serum in the culture medium. Normal erythroid colonies regressed after 4 days of culture, but EP-independent colonies from infected mice persisted for more than 2 weeks. These three phenomena may be regarded as indicative for a physiologic transformation.

Phytohemagglutinin or pokeweed mitogen induction of in vitro colony formation by T-cells from patients with chronic lymphocytic leukemia.

The colony-forming capacity of peripheral blood T-cells isolated from B-cell chronic lymphocytic leukemia patients was studied and compared with that of peripheral blood T-cells isolated from 2 groups of normal controls (young and aged healthy donors). Upon stimulation with phytohemagglutinin or pokeweed mitogen. T-cells from both the patients and the controls developed into colonies but only in the presence of the appropriate conditioned media. When the responses of the 3 groups were compared, no statistically significant differences were detected. However, the number of patients who failed to respond to phytohemagglutinin was larger than that of normal controls. Studies on a selected group of patients demonstrated that such unresponsiveness was unrelated to the presence of suppressor cells or to inadequate conditions used for stimulation in culture. Rather, this unresponsiveness may be connected with an intrinsic T-cell defect present in certain B-cell chronic lymphocytic leukemia patients.

Hematopoietic precursor cells in mice treated with 4-demethoxydaunorubicin and doxorubicin.

The hematologic toxicity of 4-demethoxydaunorubicin (4-dmDNR), a new anthracycline more potent and less cardiotoxic than doxorubicin (Dx), was studied. Dose-survival curves of bone marrow hematopoietic precursor cells (HPC) in situ were determined with the use of (C57BL X C3H)F1 mice and with assays of colony-forming units--spleen, culture, and erythroid--by in vivo and in vitro methods. Time response of HPC was followed in mice treated at days 0, 2, and 5 with 0.75 mg 4-dmDNR/kg of 4.5 mg Dx/kg and in mice receiving 2.23 mg 4-dmDNR/kg or 3.96 mg Dx/kg twice a week for 4 weeks. The dose-survival curves of HPC for 4-dmDNR were exponential. Slight differences in sensitivity among assayed populations were seen. Although the doses of 4-dmDNR required to reduce the survival of HPC to 37% were similar or lower than those of Dx, following intermittent treatment with doses of 4-dmDNR with the same optimal antitumor activity as with Dx, 4-dmDNR seemed to have a lesser effect on hematopoietic progenitors and a greater effect on peripheral blood cells than did Dx. However, during prolonged administration 4-dmDNR appeared to be toxic at every hematopoietic level.

Effects of high-dose methotrexate and leucovorin on murine hemopoietic stem cells.

This study compares the effects of a high dose of methotrexate (HDMTX) to that of a high dose of methotrexate plus leucovorin protection on the hemopoietic stem cells in a murine model. C57BL X C3H F1 mice were treated with a single large bolus (500 mg/kg body weight) of methotrexate or with the same dose of the drug plus leucovorin administered in fractionated doses during the following 24 hr. At 1 to 2 days after the administration of HDMTX, there was a large bone marrow and spleen depopulation of pluripotent stem cells and of committed and recognizable progenitors. At 2 to 3 days, a severe fall of white blood cells and reticulocytes ensued. The recovery process of hemopoietic precursors followed alternate phases of overshooting and secondary falls. Leucovorin administration appeared to protect all stages of hemopoiesis and prevented the severe drops of bone marrow cellularity and stem cell content which followed the HDMTX bolus. However, the effect of leucovorin on peripheral blood cell reduction was less significant. After treatment with HDMTX, the recovery of bone marrow cells and the burst of splenic hemopoietic activity followed a pattern similar in both leucovorin-protected and unprotected animals, but in the former, the increase in stem cells and hemopoietic progenitors appeared to reach higher values and to last longer. In particular, the overshooting of colony-forming units, culture and erythroid, reached a higher peak in leucovorin-treated mice and was more prolonged. Our results indicate that, in HDMTX-treated mice, leucovorin protection involves the earliest stages of hemopoiesis, assuring the maintenance of a satisfactory endowment of stem and progenitor cells.

Four-step high-dose sequential chemotherapy with double hematopoietic progenitor-cell rescue for metastatic breast cancer.

PURPOSE: High-dose chemotherapy produces high complete remission (CR) rates and some survival advantage in patients with metastatic breast cancer (BC). A current issue is the possibility that these patients may have an even better prognosis with multiple high-dose treatments. In this study, we evaluated the feasibility of a four-step, high-dose sequential chemotherapy (HDSC) with double autologous hematopoietic progenitor-cell rescue. We also tested the hypothesis that peripheral-blood progenitor cells (PBPCs) harvested following a single recruitment with cyclophosphamide (CY) and granulocyte-macrophage colony-stimulating factor (GM-CSF) allow the safe administration of the whole HDSC with closely timed repeated courses of several non-cross-resistant agents. PATIENTS AND METHODS: The treatment plan included CY 7 g/m2, followed by GM-CSF 5 to 7 micrograms/kg/d administered by continuous intravenous (i.v.) infusion on days 2 to 14; PBPCs with or without bone marrow (BM) harvest; mitoxantrone (NOV) 60, 75, or 90 mg/m2 plus melphalan (L-PAM) 140 to 180 mg/m2 with hematopoietic rescue; methotrexate (MTX) 8 g/m2 plus vincristine (VCR) 1.4 mg/m2; and etoposide (VP-16) 1.5 g/m2 plus carboplatin (PP) 1.5 g/m2 with hematopoietic rescue. RESULTS: All 15 patients enrolled completed the entire treatment and there were no toxic deaths. Hematologic reconstitution was good at each step. The median number of days with an absolute neutrophil count (ANC) less than 100/microL and platelet count less than 20,000/microL were 8 and 3, respectively, after NOV plus L-PAM, and 7 and 4, respectively, after VP-16 plus PP. The main non-hematologic toxicity was mucositis, while organ toxicity was mild and reversible. CONCLUSION: This regimen is feasible, with acceptable toxicity. GM-CSF and PBPCs have a pivotal role, as they hasten hematologic reconstitution, abate toxicity, and allow rapid recycling.

MACOP-B treatment in diffuse large-cell lymphoma: identification of prognostic groups in an Italian multicenter study.

PURPOSE: The prognosis of advanced-stage diffuse large-cell lymphoma (DLCL) has improved with the use of the third-generation regimens such as methotrexate with leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B). However, different results have been reported. Therefore, we started a cooperative study to confirm the efficacy of MACOP-B. An analysis of prognostic factors was also performed to identify poor-prognosis patients. PATIENTS AND METHODS: Between June 1986 and March 1989, 180 patients with advanced-stage DLCL were treated with MACOP-B. MACOP-B was given according to the original scheme. Numerous clinical features possibly predictive for complete response (CR), disease-free survival (DFS), and survival were analyzed in univariate and multivariate analyses. RESULTS: One hundred twenty-seven patients (71%) achieved a complete remission, 20 (11%) achieved a partial remission, 24 (13%) had unchanged or progressive disease, and nine (5%) died due to toxicity. With a median follow-up of 28 months, 71% of 127 CRs remain in first remission. Predicted 3-year survival for all 180 patients is 60%, and 3-year DFS for the 127 CRs is 67%. Overall toxicity was acceptable, with mucositis being the most frequent severe side effect. A multivariate regression analysis identified lactate dehydrogenase (LDH) level, bone marrow involvement, and tumor burden as independent risk factors for survival. These factors were also important for achievement of remission and DFS and allowed us to identify three distinct risk groups of patients with good, intermediate, and poor prognosis, with 3-year survival rates of 80%, 59%, and %29, respectively. CONCLUSIONS: These results confirm the effectiveness of MACOP-B in advanced-stage DLCL at low or intermediate risk; however, high-risk patients are in urgent need of new therapeutic approaches. A better definition of prognostic features would allow a more reliable comparison of different treatment regimens, as well as an effective tailoring of therapy by prognostic groups.

Concurrent chemo-radiotherapy with taxotere and cisplatin in head and neck cancer: a feasibility study.

BACKGROUND: For many years surgery was the cornerstone of treatment for head and neck cancers and radiotherapy was the treatment of choice in adjuvant and advanced inoperable settings. Recently, induction sequential chemotherapy followed by radiotherapy has shown good tolerability and has prolonged the median overall survival. This phase II trial explored the feasibility of the concurrent association with radiotherapy of a full-dose chemotherapy based on an original schedule of docetaxel and cisplatin. PATIENTS AND METHODS: Twenty-four patients with head and neck squamous cell carcinoma (HNSCC) were enrolled. Taxotere (docetaxel) was administered on day 1, weekly for 6 weeks. The dose was 33 mg/m2 /w. Cisplatin was administered on day 2 at the dose of 70 mg/m2. Radiotherapy delivered was 60 Gy divided in 30 administrations over 6 weeks. RESULTS AND CONCLUSION: This schedule of treatment for HNSCC proved feasible. Appropriate support treatment, however, appears to be necessary for the feasibility of this concurrent chemo-radiotherapy.

Cytogenetic clonality in chronic myelomonocytic leukemia studied with fluorescence in situ hybridization.

Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome (MDS) subtype, characterized by monocytosis, dysgranulocytosis and a low number of blast cells in the peripheral blood (PB). The clonal nature of MDS has been demonstrated by various techniques: the stem cell involved initially is capable of myeloid and lymphoid differentiation. Fluorescent in situ hybridization (FISH) is a technique which can be utilized without any pretreatment on whole interphase cells. In this study leukocytes of PB Wright-stained smears from four CMML patients with trisomy 8 (three cases) and 9 (one case) have been analyzed by FISH. Utilizing a probe for the centromere of chromosome 8 and for the heterochromatic region of chromosome 9, we observed the cells involved by trisomy. In each of the four cases neutrophils, eosinophils, basophils and monocytes may show trisomy 8 or 9, whereas lymphocytes resulted disomic. The comparison between leukocytes morphology and genotype suggests that the supernumerary chromosome does not influence cellular differentiation and maturation. We conclude that FISH analysis of PB leukocytes of patients with CMML is informative when studying the clonality of the disease. Chromosomal abnormalities seem to involve a hematopoietic cell committed to myeloid but not lymphoid differentiation. Trisomies 8 and 9 seem to confer some proliferative advantage without influencing the morphologic characteristics of leukocytes. Other causes will be investigated to explain dysmorphisms of neutrophils and monocytes typical of this disease.

A human leukemic T cell line (PF-382) inhibits the growth of myeloid and erythroid progenitor cells.

We have recently described a human T cell line, named PF-382, obtained from the pleural effusion of a child with T-acute lymphoblastic leukemia (T-ALL), which expresses phenotypic and functional features of suppression. In this study we report that PF-382 spontaneously releases a factor which inhibits the in vitro growth of myeloid (CFU-GM) and erythroid (BFU-E) progenitor cells. The same effect is obtained when irradiated PF-382 cells are co-cultured with the hemopoietic precursors. In both instances, maximal inhibitory activity is exerted on day 14 CFU-GM and BFU-E obtained from the light density nonadherent fraction of normal human bone marrow and peripheral blood; this finding suggests that the target of the inhibition is represented by the more immature elements within the progenitor cell compartment. Progressive depletion of monocytes, T, B lymphocytes, and NK cells as well as recloning experiments indicate that the inhibitory effect is directly exerted on the target cell and not via an intermediate population of accessory cells. Partial purification by gel filtration and by subsequent high performance liquid chromatography demonstrates that this factor is a protein with a molecular weight of 47 kd. The physicochemical characterization and the specific functional properties suggest that the PF-382 inhibitory factor represents a lymphokine which differs from those so far reported. The PF-382 cell line provides a useful model toward a better understanding of the interrelations between T cell subsets and other hemopoietic compartments.

Staging and therapy monitoring of multiple myeloma by 99mTc-sestamibi scintigraphy: a five year single center experience.

The aim of the present study was the evaluation of the diagnostic value of 99mTc-sestamibi (MIBI) in the detection of bone marrow involvement in patients suffering from multiple myeloma (MM) and its possible role in the follow-up. Between 1998 and 2003, 68 patients with MM and 42 pts with monoclonal gammopathy of undetermined significance (MGUS) were consecutively enrolled in this study. 51/68 MM patients had active disease (AD), 11/62 were in complete remission (CR) and 6/68 in partial remission (PR) after chemotherapy. 18 patients with MM repeated a 99mTc-MIBI scintigraphic study at least 2 months after high-dose chemotherapy. All the scans were scored semi quantitatively according to extension and intensity of tracer uptake. All MGUS pts had a negative 99mTc-MIBI. As far as the MM pts are concerned, 54/68 (49%) pts (48 with AD, 5 with PR and 1 with CR) had a positive 99mTc-MIBI scan, while the 99mTc-MIBI scan was negative in 14/68 pts (10 with CR, 1 with PR and 3 with AD). The overall sensitivity of the 99mTc-MIBI scintigraphy was 92%; specificity was 96%. In the follow up of the pts treated with chemotherapy 99mTc-MIBI closely paralleled the activity of myeloma bone disease. In conclusion, these results indicate that 99mTc-MIBI scintigraphy closely reflects myeloma disease activity in the bone marrow, and that a negative 99mTc-MIBI scan in patients with suspected MM clearly, though not absolutely, indicates absence of disease or clinical remission. The results of this study suggest a clear diagnostic value of 99mTc-MIBI scintigraphy in patients with MM and its potential role during the follow-up for the monitoring of MM bone disease.

Effects of fibroblasts on the growth of erythroid progenitor cells in vitro.

The effect of embryo fibroblasts on the growth of erythroid colony-forming cells in vitro (CFU-e) from mouse bone marrow was investigated. First, the maintenance of CFU-e number in suspension culture was assayed. CFU-e recovered from suspension culture fell rapidly to values below 30% of the initial number. When erythropoietin (EP) was added, the initial decline during the first day was followed by a rise to 80%. In cultures supplemented with irradiated fibroblasts, the number of CFU-e did not show an abortive fall, but there was a slight increase during 3 days of culturing. The influence of fibroblasts on the colony-forming ability of CFU-e was studied in a semisolid culture system composed of an agar underlayer and a methylcellulose overlayer. The number of erythroid colonies scored after 5 days of culture in the presence of different levels of EP was proportional to the number of added fibroblasts and the colony size (depending on the number of fibroblasts) increased to macroscopic dimensions. Fibroblasts alone, without EP, induced colony formation by CFU-e if added in concentrations of 1 X 10(5) or higher. EP was not detectable in medium conditioned by the fibroblasts. These data indicate that fibroblasts may stimulate erythroid colony formation (in the absence of EP) and enhance the colony-forming ability of CFU-e in the presence of EP. From these results, it is suggested that fibroblasts exert proliferation activating effects on CFU-e target cells.

PHA-induced human T cell colony formation: enhancing effect of large granular lymphocytes.

The capacity of phytohemagglutinin (PHA)-stimulated human T cells to develop into colonies in agar has been evaluated in the presence or absence of a variety of peripheral blood mononuclear cell subsets. A subpopulation of non-T, non-B cells with receptors for the Fc portion of IgG (i.e. third population cells or TPC) was found to enhance considerably the T cell colony forming capacity. Since TPC have been previously shown to be highly enriched for large granular lymphocytes (LGL, i.e. cells with cytoplasmic azurophilic granules and acid hydrolases), LGL were purified on Percoll density gradients and tested for their T cell colony enhancing capacity. It was shown that LGL were indeed the cells capable of enhancing the T cell colony formation.

High-dose chemotherapy with tandem autologous transplantation as part of the initial therapy for aggressive non-Hodgkin's lymphoma.

The purpose of the present study was to evaluate the feasibility and the efficacy of employing a high-dose chemotherapy (HDT) regimen with tandem peripheral blood progenitor cells (PBPC) supported transplantation in the initial treatment of aggressive non-Hodgkin's lymphoma (NHL). HDT was preceded by a standard course of conventional dose chemotherapy in 17 out of the 25 patients treated, while in 8 cases it was delivered after only one or two cycles. HDT was a three-step procedure which included high-dose (6-7 g/m2) cyclophosphamide (CY) supported by haematopoietic growth factors, the first myeloablative course with mitoxantrone (NOV) 60, 75 or 90 mg/m2 plus melphalan (L-PAM) 140-180 mg/m2 with haematopoietic rescue, and the second myeloablative course with etoposide (VP) and carboplatin (CARBO) given at 1.5 g/m2 each with haematopoietic rescue. PBPC were collected after CY administration. Twenty-two patients (88%) completed the HDT, haematological reconstitution was rapid and complete at each step and there were no toxic deaths. The activity of the treatment was high with a CR rate over 90% in the entire patient population. The 2-year overall survival (OS) and failure-free survival (FFS) rates of patients in both Age-Adjusted International Prognostic Index (A-AIPI) groups 2 and 3 are 79% and the disease-free survival (DFS) rate for the CRs is 85%. In A-AIPI group 1 the 2-year OS and FFS rates are both 91%.

Complex structural involvement of chromosome 7 in primary myelodysplastic syndromes determined by fluorescence in situ hybridization.

Cytogenetic analysis of 72 consecutive de novo myelodysplastic syndrome patients revealed monosomy 7 in 12 cases. In 4 of these cases, the -7 was the only abnormality, whereas the remaining 8 cases showed additional chromosomal aberrations. Fluorescence in situ hybridization (FISH) utilizing chromosome 7 alpha-satellite and painting probes and other specific probes, when necessary, provided evidence of unusual and unsuspected structural rearrangements involving chromosome 7. FISH analysis showed that the small fragment found in one patient and the ring found in each of two other patients were chromosome 7-derived rings. FISH also revealed the insertion of chromosome 7 sequences into autosomes in three other patients and unusual translocations in the remaining two patients. By comparing the results obtained by using banding techniques to those obtained by using the FISH technique, we deduced the involvement of chromosome 7 with partial deletion of the short arm in all eight examined patients. Our study confirms the ability of FISH to detect chromosomal aberrations that would otherwise not be identified and the tendency of chromosome 7 to be involved in many different rearrangements. From a clinical point of view, we confirm that patients affected by myelodysplastic syndromes with complex karyotypes involving chromosome 7 do not respond to treatment and have a poor prognosis.

First line therapy with fludarabine combinations in 42 patients with either post myelodysplastic syndrome or therapy related acute myeloid leukaemia.

Acute myeloid leukaemias (AML) evolving from a myelodysplastic syndrome (MDS) or secondary to chemoradiotherapy frequently display unfavorable biologic characteristics. This may explain the lower remission rate obtained with conventional chemotherapy. Recently, the association of Fludarabine with intermediate dose Ara-C has produced interesting results particularly in high risk AML patients. Here, we report on 42 secondary AML patients treated with a combination of Fludarabine, intermediate dose Ara-C, G-CSF with or without an antracycline (FLANG, FLAG-IDA or FLAG). Overall, complete remissions (CR) were documented in 14 patients (33%) and partial responses (PR) in 12 (29%), while 10 patients proved resistant (24%). Six patients (14%) died early. The presence of a prognostically unfavorable karyotype had a negative impact on the CR rate (20% compared to 50% for patients with an intermediate prognosis karyotype, p 0.05). Patients treated with FLAG, FLANG and FLAG-IDA had similar CR rates. At the time of this analysis, after a mean follow-up of 12 months, the mean duration of CR is 16 months (range 3-66) and the mean survival is 11 months (range 1-67). The median time to granulocyte recovery (neutrophils > 0.5 x 10(9)/l) was 20 days (range 12-39) and 50 x 10(9)/l platelets were reached at a median of 26 days (range 9-56). Taken together, these Fludarabine containing regimens proved to be an effective and tolerable treatment for patients with secondary AML. Patients above 70 years of age may also benefit from this therapy, however the problem of treating patients with adverse chromosomal abnormalities still remains unresolved.

Mitoxantrone in elderly patients with advanced breast cancer: pharmacokinetics, marrow and peripheral hematopoietic progenitor cells.

The aims of this study were to evaluate the pharmacokinetics, tolerability and hematopoietic toxicity of mitoxantrone in elderly women. Thirteen patients with advanced breast cancer, median age of 73 years, received escalating doses of mitoxantrone 8, 10, 12 and 14 mg/m2 on day 1, q 21. There was a linear relationship between the mitoxantrone dose administered and the mitoxantrone exposure (AUC) in plasma (r = 0.856, pc0.001). After 4 courses of treatment, a significant decrease in bone marrow cellularity (p = 0.0067), and HPC content (BFU-E p = 0.0077) was observed. A remarkable, though not statistically significant decrease in circulating HPCs was observed after 4 courses and was still present 8-12 months after the termination of treatment. Therapy with mitoxantrone in elderly women was well tolerated at the dose of 12 mg/m2 for four courses. The significant hematological toxicity observed in marrow cellularity and HPC content warrant further studies.

Fludarabine, ARA-C, idarubicin and G-CSF (FLAG-Ida), high dose ARA-C and early stem cell transplant. A feasable and effective therapeutic strategy for de novo AML patients.

Forty-three consecutive patients with de novo and untreated non M3 AML aged 60 or less entered the study. The mean age of patients was 50 (range 15-60). The induction regimen (FLAG-Ida) included fludarabine (30 mg/sqm), Ara-C (2 g/sqm) on days 1-5, and idarubicin (10 mg/sqm) on days 1, 3, 5. G-CSF (300 mcg/day) was administered s.c. 12 hours before starting fludarabine and was continued for five days. HDT with stem cell rescue was planned for all patients in first CR after one course of high dose Ara-C (HDAC) consolidation and in good clinical conditions. Forty-two (98%) patients were evaluable for response. One patient died during induction (2%). CR was achieved in 35 patients (82%). Twenty-three patients, 66% of those achieving CR, underwent autologous (N = 17) or allogeneic (N = 6) transplantation. With a median follow up of 24 months, the average median duration of CR is 17 months (range 3-66) and the median survival is 20 months (range 1-83). Overall the 5 year projected disease free survival (DFS) and overall survival (OS) were 37% and 43%, respectively. Among patients who underwent stem cell transplantation DFS and OS were 53% and 69%, respectively. The median time to PMN recovery (> 0.5 x 10(9)/l) was 17 days (range 10-28) and 50 x 10(9)/l platelets were reached at a median of 17 days (12-38). In conclusion FLAG-Ida regimen is effective, low toxic and improves feasibility of stem cell transplant.