Chromosome 7 monosomy and deletions in myeloproliferative diseases.

We studied deletion and monosomy of chromosome 7 in 150 patients with myeloproliferative diseases. We found 8/150 patients with monosomy 7 by cytogenetics and 4/150 with deletions of the long arm of chromosome 7 by restriction fragment length polymorphism (RFLP) analysis performed with Southern and polymerase chain reaction. To overcome limitation of RFLP analysis, we restricted loss of heterozygosity study with microsatellites to 45 patients, observing deletion 7q31.1 in 7/45 patients. In all patients with molecular alterations the deletion was observed only in myeloid cells, while the monosomy was detected in both myeloid precursor and lymphocytes. This finding suggests a CD34-totipotent stem cell origin for the monosomy and a colony forming unit - granulocyte, erythrocyte, monocyte, megakaryocytes (CFU-GEMM) stem cell origin for the deletions.

Risk-oriented postremission strategies in adult acute lymphoblastic leukemia: prospective confirmation of anthracycline activity in standard-risk class and role of hematopoietic stem cell transplants in high-risk groups.

INTRODUCTION: Although definite risk classes are well known, risk-adapted modulation of first-line therapy is seldom attempted in adult ALL. So, a prospective validation of the therapeutic efficacy of a protocol (or a component thereof) in specific risk groups is uncommon. MATERIALS AND METHODS: From 1996-1999 a risk-oriented program (08/96) was evaluated in 102/121 unselected patients (median age 35 years, blast count 0-450 x 10(9)/l, 100 B(lin) (lineage), 21 T(lin)) responsive to induction therapy. The standard risk (SR) class was B(lin) CD10+ Ph- with blasts < 10 x 10(9)/l (prior studies: disease-free survival (DFS) rate 52% at five years with dose-intensive anthracycline-containing programs). The SR protocol was therefore anthracycline-rich (early consolidation cycles with total idarubicin 96 mg/m2), and comprised long-term maintenance. High-risk (HR) patients were eligible to the following three options: allogeneic hematopoietic stem cell transplantation (HSCT) from related family donor; short sequence with high-dose cyclophosphamide-cytarabine-methotrexate followed by melphalan/total body irradiation with autologous HSCT; or T(lin) ALL chemotherapy regimen inclusive of high-dose cytarabine and methotrexate. RESULTS: Treatment realization and three-year DFS rates according to risk class, HR subset and postremission treatment intensity were the following. SR group (n = 28): realization rate 93%, DFS 68.5%. HR group (n = 74): realization rate 80%, DFS 39% (P = 0.052 vs SR category). In HR group, three-year DFS rates by disease subtype were the following. B(lin) Ph- (n = 35) 43%; Ph+ (n = 19) 13% at 2.7 years (P = 0.006 vs other HR subtypes); T(lin) (n = 18) 59.5%. And DFS rates by treatment intensity were: allograft (n = 21) 40%; autograft (n = 28) 27%; shift to SR protocol (n = 13) 52% (P = ns vs allograft/autograft); T(lin) program (n = 10) 57%. Matched analyses of treatment protocols and disease subtypes suggested a possible therapeutic role of the autograft regimen in B(lin) Ph- ALL with a blast count < 25 x 10(9)/l, and of T(lin) protocol for T(lin) ALL. Comparisons with retrospective control cohorts were confirmatory of anthracycline activity in SR subclass. CONCLUSION: The intended strategy was applicable to the majority of study patients, confirming the value of anthracyclines in SR class and, preliminarily, the usefulness a T(lin)-specific treatment. Apart from the case of Ph+ ALL, the indications for high-dose procedures with HSCT remains largely undetermined in this study.

P-Glycoprotein Expression in Acute Myeloid Leukaemia Cells at Diagnosis: Its relationship to Daunorubicin or Idarubicin Induction Therapy and Survival; Malignancy.

We investigated the expression of P-glycoprotein (P-gp) in 50 adults with de novo diagnosed acute myeloid leukaemia (AML) and the relationship between presence of P-gp in leukaemic cells and efficacy, as remission induction and survival rate, of two different anthracyclines, daunorubicin (DNR) and idarubicin (IDR). We found that 30 out of 50 patients (60%) were negative (Group 1) and 20 (40%) were positive (Group 2) for P-gp expression evaluated by mean of MRK16 MoAb using a cut-off of 10% positive cells. Thirty-five out of 50 patients (70%) obtained complete remission (CR); depending on P-gp expression, the CR rate was 80% for group 1 and 45% for group 2 (p < 0.005). The median duration of overall survival was 20 months for patients in Group 1 as compared with 10 months for patients of Group 2 (p < 0.005). Regarding the anthracycline used, no significant difference in CR was observed in patients of Group 1 (75% of CR with DNR vs. 90% with IDR); Group 2 obtained 40% of CR with DNR vs. 70% with IDR (p < 0.005). The median duration of overall survival (OS) with the two regimens was comparable in Group 1, while it was significantly longer in patients of Group 2 treated with IDR compared with DNR regimen (p < 0.005). These results confirm the prognostic value of P-gp expression in AML at first appearance and we suggest that idarubicin could be a valid anthracycline drug in the treatment of AML to be evaluated as potential drug of choice in patients with primary or drug-induced multidrug resistance.

Sensitivity to the abl inhibitor STI571 in fresh leukaemic cells obtained from chronic myelogenous leukaemia patients in different stages of disease.

STI571 (CGP57148B) is an inhibitor of BCR/ABL, the cause of chronic myeloid leukaemia (CML). A difference exists between CML patients in chronic phase, in which responses to STI571are durable, and patients in blast crisis, who generally experience only transient responses. Leukaemic cells from six CML patients from whom samples could be obtained during chronic phase and at the time of blast crisis (BC) were compared for sensitivity to STI571, using an in vitro assay. BC samples showed a sensitivity similar to that obtained during chronic phase, suggesting that no substantial intrinsic resistance to STI571 was present in BC.

Incidence and outcome of pneumonia in patients with acute leukemia receiving first induction therapy with anthracycline-containing regimens.

BACKGROUND AND OBJECTIVES: Even though the risk of pneumonia is higher in patients with advanced disease, the potential risk of death is particularly relevant during induction therapy, when patients can be potentially cured of their hematologic disease: our study was aimed at evaluating the risk and outcome of pneumonia in these patients. DESIGN AND METHODS: We retrospectively studied all 458 patients affected by acute leukemia receiving an anthracycline-containing induction regimen in the years 1984-1989. RESULTS: Of the 458 patients, 109 (23.8%) developed pneumonia: 91 had acute myelogenous leukemia (AML) and 18 had acute lymphoblastic leukemia (ALL). At univariate analysis, advanced age, AML and total blast count significantly correlated with the risk of pneumonia. At multivariate analysis, only age (p< 0.0001) and total blast count (p=0.002) retained their prognostic significance. Pneumonia responded to treatment in 67 (61.5%) patients, while 42 (38.5%) patients died. Among patients with pneumonia, 51 (46.8%) patients achieved a complete remission: 9/18 ALL and 42/91 AML. At univariate analysis, the most significant determinant of a positive outcome was the achievement of complete remission; a higher absolute neutrophil count at the onset of pneumonia, the absence of rales, a single infiltrate and the absence of microbiological demonstration of infection were also related to a positive outcome. At multivariate analysis, the achievement of complete remission and, with borderline significance, a single infiltrate maintained their prognostic value. INTERPRETATION AND CONCLUSIONS: Pneumonia remains one of the most relevant risks of morbidity and mortality during induction therapy for acute leukemia. A fatal outcome is associated, in most cases, with a failure to achieve remission of leukemia.

Role of alpha1 acid glycoprotein in the in vivo resistance of human BCR-ABL(+) leukemic cells to the abl inhibitor STI571.

BACKGROUND: Chronic myeloid leukemia is caused by a chromosomal translocation that results in an oncogenic fusion protein, Bcr-Abl. Bcr-Abl is a tyrosine kinase whose activity is inhibited by the antineoplastic drug STI571. This drug can cure mice given an injection of human leukemic cells, but treatment ultimately fails in animals that have large tumors when treatment is initiated. We created a mouse model to explore the mechanism of resistance in vivo. METHODS Nude mice were injected with KU812 Bcr-Abl(+) human leukemic cells. After 1 day (no evident tumors), 8 days, or 15 days (tumors >1 g), mice were treated with STI571 (160 mg/kg every 8 hours). Cells recovered from relapsing animals were used for in vitro experiments. Statistical tests were two-sided. RESULTS: Tumors regressed initially in all STI571-treated mice, but all mice treated 15 days after injection of tumor cells eventually relapsed. Relapsed animals did not respond to further STI571 treatment, and their Bcr-Abl kinase activity in vivo was not inhibited by STI571, despite high plasma concentrations of the drug. However, tumor cells from resistant animals were sensitive to STI571 in vitro, suggesting that a molecule in the plasma of relapsed animals may inactivate the drug. The plasma protein alpha1 acid glycoprotein (AGP) bound STI571 at physiologic concentrations in vitro and blocked the ability of STI571 to inhibit Bcr-Abl kinase activity in a dose-dependent manner. Plasma AGP concentrations were strongly associated with tumor load. Erythromycin competed with STI571 for AGP binding. When animals bearing large tumors were treated with STI571 alone or with a combination of STI571 and erythromycin, greater tumor reductions and better long-term tumor-free survival (10 of 12 versus one of 13 at day 180; P:<.001) were observed after the combination treatment. CONCLUSION: AGP in the plasma of relapsed animals binds to STI571, preventing this compound from inhibiting the Bcr/Abl tyrosine kinase. Molecules such as erythromycin that compete with STI571 for binding to AGP may enhance the therapeutic potential of this drug.

Differential recognition of a BCR/ABL peptide by lymphocytes from normal donors and chronic myeloid leukemia patients.

The BCR/ABL oncogenic fusion protein transforms normal bone marrow stem cells into neoplastic cells. It has been shown that peptides derived from the junctional region of this oncogenic fusion protein can be recognized by human T-lymphocytes obtained from normal donors. In this study, we investigated the immunogenicity in patients with chronic myeloid leukemia (CML) of a 17 mer b3/a2 Bcr/abl peptide (B/A1), which was shown to induce proliferative responses in lymphocytes from normal donors. A total of 56 CML patients in chronic phase were studied. Twenty-two patients were studied at diagnosis without any treatment (group I). Fourteen patients were receiving IFN (group II), 14 patients were being treated with hydroxyurea (group III), and 6 patients were on different regimens (group IV). Patients were initially assessed for general immunological competence using both in vivo and in vitro assays. Patients were also selected for the expression of HLA-DR0401, the HLA specificity known to present peptide B/A1 to CD4 lymphocytes. With the exception of the six patients in group IV, the results of all these assays (in vitro phytohemagglutinin/tetanus toxoid responses, in vivo skin reaction to ubiquitous antigens) in CML patients did not significantly differ from those obtained in normal donors, thus excluding the presence of generalized immunosuppression. Eight patients with HLA-DR0401 and a b3/a2 type of fusion were identified and further studied. In these eight patients dendritic cells were obtained from adherent peripheral blood mononuclear cells and used to stimulate CD4 lymphocytes. No patient developed a specific response to the bcr/abl peptide, although patients' lymphocytes proliferated in response to a promiscuous tetanus toxoid peptide in all but one case. In contrast, response to the bcr/abl peptide was observed in seven of eight HLA-DR0401 healthy donors tested. These data suggest that immunocompetent, HLA-DR0401+ CML patients are unable to respond to peptide B/A1, at difference from healthy donors. The implication of these results for the immunotherapy of CML is discussed.

Defibrotide in recurrent thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is a common illness characterized by platelet thrombi within the microvascularization. In its natural course, this disease has had a mortality rate of 90%. Plasma infusion or exchange achieved a survival rate of 70% to 90%. However, 10% to 30% of patients surviving the initial TTP episode relapse at regular intervals. The treatment of recurrent forms of the disease remains a challenge; several approaches have been shown to induce medium to long term remissions. We describe a patient with recurrent TTP whose disease remitted after administration of defibrotide.

P-Glycoprotein Expression in Acute Myeloid Leukaemia Cells at Diagnosis: Its relationship to Daunorubicin or Idarubicin Induction Therapy and Survival.

We investigated the expression of P-glycoprotein (P-gp) in 50 adults with de novo diagnosed acute myeloid leukaemia (AML) and the relationship between presence of P-gp in leukaemic cells and efficacy, as remission induction and survival rate, of two different anthracyclines, daunorubicin (DNR) and idarubicin (IDR). We found that 30 out of 50 patients (60%) were negative (Group 1) and 20 (40%) were positive (Group 2) for P-gp expression evaluated by mean of MRK16 MoAb using a cut-off of 10% positive cells. Thirty-five out of 50 patients (70%) obtained complete remission (CR); depending on P-gp expression, the CR rate was 80% for group 1 and 45% for group 2 (p lt; 0.005). The median duration of overall survival was 20 months for patients in Group 1 as compared with 10 months for patients of Group 2 (p < 0.005). Regarding the anthracycline used, no significant difference in CR was observed in patients of Group 1 (75% of CR with DNR vs. 90% with IDR); Group 2 obtained 40% of CR with DNR vs. 70% with IDR (p < 0.005). The median duration of overall survival (OS) with the two regimens was comparable in Group 1, while it was significantly longer in patients of Group 2 treated with IDR compared with DNR regimen (p < 0.005). These results confirm the prognostic value of P-gp expression in AML at first appearance and we suggest that idarubicin could be a valid anthracycline drug in the treatment of AML to be evaluated as potential drug of choice in patients with primary or drug-induced multidrug resistance.

Fractionated cyclophosphamide added to the IVAP regimen (idarubicin-vincristine-L-asparaginase-prednisone) could lower the risk of primary refractory disease in T-lineage but not B-lineage acute lymphoblastic leukemia: first results from a phase II clinical study.

BACKGROUND AND OBJECTIVE: In a prior study, primary resistant acute lymphoblastic leukemia (RES-ALL) was observed in 11 of 176 (6%) adult patients treated with a four drug regimen (IVAP), its incidence being higher in T-cell or Philadelphia (Ph) chromosome/BCR-ABL rearrangement positive ALL cases with a blast cell count >25x10(9)/L (RES-ALL rate 19%, p=0.04). Aiming to minimize this percentage of resistant disease, fractionated cyclophosphamide (f-CY) was then added to the IVAP regimen. DESIGN AND METHODS: Study 08-96 was a prospective, collaborative phase II trial carried out at eight general hospital centers specialized in the care of hematologic malignancies. Historical IVAP-treated patients served as a retrospective control group. All consecutive, untreated patients (>15 years) with a diagnosis of ALL or advanced-stage lymphoblastic lymphoma (LBL) were eligible. RES-ALL was defined as the persistence of >5% ALL cells in the bone marrow 28-40 days after the start of the IVAP regimen (idarubicin 10 mg/m(2)/d on days 1 and 2; vincristine 2 mg on days 1, 8 and 15; L-asparaginase 6,000 U/m(2) on alternate days 3 6 from day 8; prednisone 60 mg/m(2)/d on days 1-21). In the new study, two f-CY schedules were sequentially adopted: CY 150 or 75 mg/m(2)/bd, given for 4 consecutive days before IVAP (f-CY 1200 or 600, expressing total CY dose in mg/m(2)). RESULTS: Eighty-eight patients were evaluable (age range 15-74 years, blast count 0-240x10(9)/L, 14 T-lineage, 74 B-lineage, 13 Ph/BCR-ABL+). The first 39 patients received the f-CY 1200 schedule, 22 patients received f-CY 600, and the last 27 patients were not given any f-CY. These changes were dictated by the results of interim analyses of the f-CY groups (RES-ALL rate not reduced, myelotoxicity increased). Altogether, compared with the historical IVAP and no f-CY groups, the incidence of RES-ALL was not decreased by the addition of f-CY 1200/600 in B-lineage ALL, regardless of Ph/BCR-ABL expression and blast count. However, none of 14 T-ALL cases in the new study had RES-ALL (8 in f-CY groups, 5 of whom with >25x10(9)/L blast cells), compared to 5/39 (13%, overall) or 4/21 (19%, with >25x10(9)/L blast cells) among the control cases. Owing to small sample size, this difference was not statistically significant. INTERPRETATION AND CONCLUSIONS: This preliminary experience suggests that T-ALL may be more sensitive than B-lineage ALL to an early therapy including f-CY. The hypothesis could be tested in a larger clinical trial.

Induction-consolidation with an idarubicin-containing regimen, unpurged marrow autograft, and post-graft chemotherapy in adult acute lymphoblastic leukaemia.

Between 1991 and 1993 we conducted a collaborative trial in adult acute lymphoblastic leukaemia, introducing an idarubicin (IDA)-containing regimen for induction and early consolidation, and increasing consolidation intensity with an autologous bone marrow transplantation phase (ABMT, patients aged <51 years) followed by further chemotherapy for 12 weeks and low-dose maintenance for 6 months (ABMT patients) or 18 months. 96 patients were evaluable for antileukaemic response after induction with vincristine-prednisone-L-asparaginase plus cumulative IDA 36 or 20 mg/m2 (IVAP-1 and IVAP-2), and for disease-free survival (DFS) after a minimum follow-up >3.5 years with an off-therapy interval >1.5 years. The response rate was 44% (7/16) with IVAP-1 and 90% (72/80) with IVAP-2 (P=0.0001), due to regimen-related toxicities. Post-remission therapy was administered as planned to most cases but protocol violation was registered in some patients eligible to ABMT and post-graft chemotherapy. The 5-year disease-free survival (DFS) rate was 31%. Multivariate analysis indicated that DFS was improved in patients receiving a transplant (11 allogeneic, DFS 70%; 32 ABMT, 36%; 37 neither, 17%; P < 0.001) and was negatively affected by high-risk features such as blast cell count >25x10(9)/l, T-cell or mature B-cell immunophenotype, and t(9;22)/t(4;11) (all P values <0.05). The 5-year DFS rate was 54% for 26 patients with no high-risk factor, 26% for 35 patients with any one, and 6% for 18 patients with any two (P<0.005). IVAP-2 brought about a high complete response rate and post-remission treatment including ABMT was feasible and modestly toxic. In spite of the short post-graft chemotherapy phase, the long-term DFS rate was good in cases with no high-risk feature. However, because autografting may be redundant in the standard-risk category, its role requires further investigation for high-risk cases.

Granulocyte colony-stimulating factor (G-CSF, filgrastim) after or during an intensive remission induction therapy for adult acute lymphoblastic leukaemia: effects, role of patient pretreatment characteristics, and costs.

An early intensive anthracycline therapy can improve therapeutic outcome in adult acute lymphoblastic leukaemia (ALL) but is usually associated with marked myelosuppressive effects and significant morbidity by infections. To reduce this risk, we employed granulocyte colony-stimulating factor (G-CSF, filgrastim 5 microg/kg/d) as an adjunct to a myelotoxic, 14-day long induction regimen with idarubicin-vincristine-L-asparaginase-prednisone (IVAP). Owing to changes in study design, patients received 'late' (n = 28) or 'early' (n = 37) G-CSF from days 15 or 4 of IVAP, respectively, until resolution of severe neutropenia. Study endpoints included time to recovery from neutropenic nadir, duration of neutropenia <0.5 x 10(9)/l, incidence of infectious complications, assessment of variables affecting G-CSF response, clinical outcome and costs. Sixty-five consecutive cases were evaluable. Patients in early G-CSF group recovered significantly faster from the neutropenic nadir (p < 0.002), contracted less infectious complications (p = 0.007), and required less intravenous antibiotic (p = 0.008) and antifungal (p = 0.002) medications. Although these reductions did not compensate for the increased G-CSF treatment cost, the overall supportive care cost was not significantly increased by early G-CSF. Interestingly, T-ALL phenotype (p = 0.02) and higher neutrophil presentation count (p = 0.03) were associated with a shorter neutropenic course even with late G-CSF. Early G-CSF may be a valid approach to mitigate chemotherapy-induced neutropenia of IVAP and other similarly myelosuppressive adult ALL regimens.

Thrombotic complications in acute promyelocytic leukemia during all-trans-retinoic acid therapy.

A case of acute renal failure, due to occlusion of renal vessels in a patient with acute promyelocytic leukemia (APL) treated with all-trans-retinoic acid (ATRA) and tranexamic acid has been described recently. We report a case of acute renal failure in an APL patient treated with ATRA alone. This case further supports the concern about thromboembolic complications associated with ATRA therapy in APL patients. The patients, a 43-year-old man, presented all the signs and symptoms of APL and was included in a treatment protocol with ATRA. After 10 days of treatment, he developed acute renal failure that was completely reversible after complete remission of APL was achieved and therapy discontinued. We conclude that ATRA is a valid therapeutic choice for patients with APL, although the procoagulant tendency is not completely corrected. Thrombotic events, however, could be avoided by using low-dose heparin.

Inhibition of the ABL kinase activity blocks the proliferation of BCR/ABL+ leukemic cells and induces apoptosis.

The BCR/ABL fusion protein transforms myeloid stem cells. Both chronic myelogenous leukemias (CML) and a subset of acute lymphoblastic leukemias (ALL) are associated with the expression of BCR/ABL proteins. This knowledge has not yet been translated into any specific tool to control ABL driven neoplastic cells growth. CGP57148B is an ATP-competitive inhibitor of the ABL protein kinase; it has been shown to inhibit the kinase activity of ABL both in vitro and in vivo and to inhibit the growth of v-abl and bcr/abl transfectants, as well as the in vitro formation of bone marrow (BM)-derived colonies in the presence of growth factors in some CML patients. These studies were performed to investigate the activity of CGP57148B on the spontaneous proliferation of both fresh and cultured, leukemic and normal, BCR/ABL positive and negative cells, and to study its mechanism of action. Six cell lines derived from BCR/ABL+ leukemias (K562, BV173, KCL22, KU812, MC3, LAMA84), thirteen BCR/ABL negative lines, both neoplastic (KG1, SU-DHL-1, U937, Daudi, NB4, NB4.306) and derived from normal cells (PHA blasts, LAK, fibroblasts, LCL, renal epithelial cells, endothelial cells, CD34(+) cells), and 14 fresh leukemic samples were tested using a tritiated thymidine uptake assay. The in vivo phosphorylation of the BCR/ABL protein was evaluated by western blot, while apoptosis was detected by the annexin V/propidium binding test. The induction of differentiation was assayed by immunofluorescence using multiple antibodies. All six BCR/ABL+ lines showed a dose dependent inhibition of their spontaneous proliferative rate, which was not accompanied by differentiation. The treatment caused, within minutes, dephosphorylation of the BCR/ABL protein, followed in 16-24 hours by a decrease in cycling cells and induction of apoptosis. No significant inhibition of DNA synthesis was observed in any BCR/ABL negative normal or neoplastic line at concentrations

Lack of T-cell-mediated recognition of the fusion region of the pml/RAR-alpha hybrid protein by lymphocytes of acute promyelocytic leukemia patients.

In previous studies, it was shown that the fusion region of the pml/RAR-alpha protein, expressed by acute promyelocytic leukemia (APL) cells, can be specifically recognized in vitro by donor (D. E. ) CD4 T cells in a HLA class II DR11-restricted fashion. We present here the results on the recognition of several pml/RAR-alpha peptides by APL patients expressing HLA DR11. The in vitro immunization of peripheral blood lymphocytes from four patients in remission (S. R., F. R., M. M., P. G.) with BCR1/25, a 25-mer pml/RAR-alpha, did not elicit either a polyclonal or a clonal immune response specific to the peptide. We then generated new donor anti-pml/RAR-alpha CD4(+) T-cell clones. These clones were tested for their recognition of BCR1/25. One clone (C3/5, CD3(+), CD4(+), CD8(-)) was selected for further analysis. Clone C3/5 showed specific proliferation, cytotoxicity, and cytokine (tumor necrosis factor alpha, granulocyte-macrophage colony-stimulating factor) production when challenged with autologous lymphoblastic cell lines pulsed with peptide BCR1/25. C3/5 cells developed specific proliferation and cytotoxicity when challenged with peptide-pulsed lymphoblastic cell lines and peripheral blood lymphocytes from the four DR11(+) APL patients. APL blasts, available only from patients F. R. and P. G., were not lysed by C3/5 and were unable to present peptide BCR1/25. Incubation of APL cells with IFN-gamma failed to induce HLA class II molecules and recognition by the C3/5 clone. Since APL cells do not express HLA class II molecules, we tested in two donors (D. E. and C. H. R.) and in patients S. R. and P. G. whether the use of 9-mer peptides (BCR1/9) would generate a CD8/HLA class I-restricted response. No peptide-specific T-cell line or clone could be generated from both donors and patients. These findings are discussed in relation to possible therapeutic approaches to the immunotherapy of APL.

Anthracycline drugs and MDR expression in human leukemia.

We investigated the expression of P-glycoprotein (P-gp) in 50 adults with de novo acute myeloid leukemia (AML) at the initial diagnosis in order to further define the relationship between the presence of P-gp on leukemic cells and the efficacy of two different anthracycline drugs, Daunorubicin (DNR) and Idarubicin (IRR), in terms of remission, induction and survival. We found that 30 (60%) of the 50 patients were negative for P-gp expression (group 1) and 20 patients (40%) were positive (group 2) for P-gp expression by MRK16MoAb using a cut of 10% positive cells. Among the 50 patients, 35 (70%) obtained complete remission (CR); depending on P-gp expression the CR rate was 80% for group 1 and 45% for group 2 (p < 0.005). The median duration of overall survival (OS) was 20 months for patients in group 1, compared to 10 months for patients in group 2 (p < 0.005). Regarding the anthracycline used, no difference in CR has been observed in patients of group 1 (75% CTR with DNR versus 90% CR with IDR); on the contrary in group 2 we observed 40% CR with DNR versus 70% CR with IDR (p < 0.005). No significant difference has been achieved in group 1 terms of median duration of overall survival between DNR and IDR regimen; on the contrary the median duration of OS in patients of group 2 treated with IDR regimen was significantly longer than DNR regimen (p < 0.005). These results confirm the prognostic value of P-gp expression in AML at diagnosis and we suggest that Idarubicin could be a valid anthracycline drug for reversing multidrug resistance.

Idarubicin in combination with cytarabine and VP-16 in the treatment of post myelodysplastic syndrome acute myeloblastic leukemia (MDS-AML).

Fifteen patients with a primary myelodysplastic syndrome (MDS) transformed into acute myeloblastic leukemia (AML) were treated with an intensive chemotherapy regimen containing idarubicin. A complete response (CR) was obtained in 10 patients (66.6%). In five of them this was achieved after a single course of chemotherapy. The median time to achieve a CR was 32 days (range 16-42). A partial remission (PR) was obtained in 2 patients after two induction courses of chemotherapy. One patient died during the first induction course following acute respiratory distress syndrome (ARDS) complication, whereas the chemotherapy regimen failed in 2 patients. A short interval between MDS and transformation into AML was associated with a better chance of achieving a CR. Age, karyotype, type of MDS, peripheral blood or bone marrow findings appeared to have no influence on the response to treatment. The median event free survival for patients who achieved CR was 15 months and the median actuarial survival 18 months. These preliminary results need to be confirmed in a multicentre prospective study comparing idarubicin with other anthracyclines.

Alpha interferon as initial treatment of essential thrombocythemia. Analysis after two years of follow-up.

AIMS AND BACKGROUND: Recombinant alpha-interferon has been shown to be effective in essential thrombocythemia and in thrombocytosis associated with other myeloproliferative disorders. PATIENTS AND METHODS: Twenty-five untreated patients were enrolled in our study from May 1989 to April 1992. Recombinant alpha interferon-2b was administered at an initial dose of 2 megaunits (MU)/m2 three times a week at escalating doses to 5 MU/m2 or the maximum tolerated dose. The mean follow-up for patients still in treatment at the time of this report was 35.9 months (range, 24-63). RESULTS: Fourteen patients (56%) had achieved a complete remission by a mean time of 152 days; 6 patients (24%) had achieved a good partial remission by a mean of 180 days. In addition to the favorable effect on platelet count, a marked improvement in clinical symptoms was observed. Treatment had to be discontinued in 9 patients (36%), 5 for toxicity (3 neurologic, 1 anemia and 1 severe hypertriglyceridemia) at a median of 155 days from the beginning of therapy (range, 30-400). Four patients refused to continue therapy because of low tolerance (flu-like syndrome) at mean of 160 days from the beginning of therapy (range, 34-301). CONCLUSIONS: In our study, lower doses were administered compared with previous short-time trials. The present data show that interferon is an effective alternative to cytostatic agents in long-term treatment of patients with essential thrombocythemia, even when used at lower dosages.