Current management strategies and long-term clinical outcomes of upper extremity venous thrombosis.

UNLABELLED: Essentials Few data exist on outcome of upper extremity deep and superficial vein thrombosis (UEDVT and UESVT). We followed 102 and 55 patients with UEDVT or UESVT, respectively, for a median of 3.5 years. Risk of recurrent venous thromboembolism was low in both diseases, and the mortality high. Postthrombotic symptoms were infrequent and cancer patients had a higher risk of recurrent VTE. SUMMARY: Background There is scant information on the optimal management and clinical outcome of deep and superficial vein thrombosis of the upper extremity (UEDVT and UESVT). Objectives To explore treatment strategies and the incidence of recurrent venous thromboembolism (VTE), mortality, postthrombotic symptoms, and bleeding in patients with UEDVT and UESVT and to assess the prognosis of cancer patients with UEDVT. Patients/methods Follow-up of patients with UEDVT or UESVT, who were enrolled previously in a diagnostic management study. Results We followed 102 and 55 patients with UEDVT and UESVT, respectively, both for a median of 3.5 years. Anticoagulant treatment was started in 100 patients with UEDVT (98%) and in 40 (73%) with UESVT. Nine patients with UEDVT (9%) developed recurrent VTE, 26 (26%) died, 6 (8%) of 72 patients had moderate postthrombotic symptoms, and 5 (5%) experienced major bleeding. One patient with UESVT had a recurrent VTE, 18 (33%) died, none had moderate postthrombotic symptoms, and none had major bleeding. Of the cancer patients with UEDVT, 18% had recurrent VTE vs. 7.5% in non-cancer patients (adjusted hazard ratio 2.2, 95%CI 0.6-8.2). The survival rate was 50% in cancer patients with UEDVT vs. 60% in those without (adjusted HR 0.8, 95%CI 0.4-1.4). Conclusions The risk of recurrent VTE was low in patients with UEDVT, and negligible for UESVT. Mortality was high for both diseases. Postthrombotic symptoms were infrequent and mild. Anticoagulant therapy of UEDVT carried a substantial risk of major bleeding. Cancer patients had a significant risk of recurrent VTE.

The role of anthracyclines in adult acute lymphoblastic leukaemia.

The role of anthracyclines (ANT) in the treatment of adult acute lymphoblastic leukaemia (ALL) is poorly defined as regards drug dosage, schedule, preferable compound, and indications for use in specific treatment phases or disease subset. We therefore reviewed ANT treatment results in adult ALL. Altogether, an early and intensive use of ANT would improve both initial response rate and long-term disease-free survival; idarubicin (IDR) exhibits a considerable antileukaemic activity deserving further evaluation as possible reference drug; and the prognosis of CD10+ t(9;22)/BCR-ABL- ALL can be particularly good following an early dose-intensive ANT consolidation program.

Safety of vitamin K antagonist treatment for splanchnic vein thrombosis: a multicenter cohort study.

BACKGROUND: The treatment of splanchnic vein thrombosis (SVT) is challenging, due to the increased risk of bleeding and potentially life-threatening complications. Current recommendations are based on evidence from the treatment of venous thrombosis in usual sites, but small observational studies in SVT population suggest that the bleeding risk may offset the benefit of anticoagulant treatment in this setting. The aim of this study was to evaluate the safety of vitamin K antagonists (VKAs) in SVT patients. METHODS: We retrospectively included SVT patients treated with VKAs followed by 37 Italian anticoagulation clinics, until June 2013. The primary outcome was the incidence of major bleeding (MB), according to the ISTH definition, during VKA treatment. Vascular events, including both arterial and venous thrombosis, and mortality were also documented. RESULTS: Three hundred and seventy-five patients were included (median age 53 years; 54.7% males). During a median VKA treatment duration of 1.98 years, 15 MB events occurred, corresponding to an incidence rate of 1.24 (95% confidence interval [CI], 0.75-2.06) per 100 patient-years. Gastrointestinal bleeding represented 40% of all MB events. At multivariate analysis, the presence of esophageal varices emerged as independent predictor of MB (hazard ratio 5.4; 95% CI, 1.4-21.1). The incidence rate of vascular events on treatment was 1.37 (95% CI, 0.84-2.23) per 100 patient-years and the mortality rate was 0.83 (95% CI, 0.44-1.54) per 100 patient-years. CONCLUSIONS: Selected SVT patients followed by anticoagulation clinics for the management of VKA treatment show a low rate of major bleeding and vascular events.

Role of early anthracycline dose-intensity according to expression of Philadelphia chromosome/BCR-ABL rearrangements in B-precursor adult acute lymphoblastic leukemia.

INTRODUCTION: The use of anthracycline antibiotics in adult acute lymphoblastic leukemia (ALL) has resulted in an improved outcome to remission induction therapy. However,the exact role of these drugs in consolidation therapy is less clear, especially in specific ALL subsets. MATERIALS AND METHODS: A retrospective analysis was conducted on the outcome of 308 patients (median age 35 years, range 13-75) with the most frequent subtype, early-B ALL, treated between 1974 and 1998 on eight consecutive protocols. Anthracycline-related effects were assessed by evaluating the impact of planned anthracycline dose-intensity (A-DI) on long-term outcome. A-DI (in mg/m(2)/week) during the first twelve weeks of consolidation therapy was classified as either "high" (doxorubicin>20, idarubicin>7) or "low". RESULTS: Complete remission was achieved in 78% of cases. With a median follow-up of 6.5 years, on multivariate analysis, disease-free survival (DFS) correlated only with expression of the Philadelphia (Ph) chromosome and/or associated BCR-ABL rearrangements (Ph/BCR(+)) (P=0.0001) and planned A-DI (P<0.0001). On this basis, four major prognostic groups with significantly different DFS could be identified: (1) Ph/BCR(-), "high" A-DI (n=102), median 3.5 years and 41% at five years, respectively; (2) Ph/BCR(-), "low" A-DI (n=64), 1.3 years and 16%; (3) Ph/BCR(+), "high" A-DI (n=35), 1.7 years and 20%; (4) Ph/BCR(+), "low" A-DI (n=39), 0.75 years and 0%. When analyzed separately for Ph/BCR(-) (n=166) and Ph/BCR(+) (n=74) patients, the A-DI effect on DFS was preserved in the former (P=0.018) whereas, in Ph/BCR(+) patients, only age <50 years (P=0.004) and blast count <25 x 10(9)/l (P=0.02) correlated with better DFS. However, Ph/BCR(+) patients with the best prognostic profile (age <50 years and blast count <25 x 10(9)/l; n=21) who were treated on "high" A-DI regimens experienced a median DFS of 2.2 years with DFS 21% at five years, compared to 0.67-1 years and 0-10% in other cases (n=53, P<0.01). CONCLUSION: A "high" A-DI may act as a positive treatment-related prognostic factor in early B-lineage ALL. Although mainly restricted to patients with Ph/BCR(-) ALL, A-DI could also influence the outcome in Ph/BCR(+) patients with other favorable prognostic factors.

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.

The role of idarubicin in adult acute lymphoblastic leukaemia: from drug resistance studies to clinical application.

Idarubicin (4-demethoxydaunorubicin) is more potent and less cardiotoxic than daunorubicin or doxorubicin. These properties suggested a role in acute myelogenous leukaemia, that was confirmed by prospective randomized trials. In acute lymphoblastic leukaemia of adults, on the contrary, there is very little information regarding idarubicin. We have used idarubicin since 1991 and found, in a retrospective comparison with a doxorubicin regimen, a decreased incidence of primarily refractory disease. The role of idarubicin in the postremission phase could not be assessed in detail but an early intensive use of anthracyclines, either idarubicin or doxorubicin, was associated with an improved outcome in early-B CD10+ and t(9;22)/BCR-leukaemias. Concurrent in vitro studies demonstrated that idarubicin, at pharmacologically relevant concentrations, was less sensitive to P-glycoprotein-mediated drug efflux than daunorubicin and was a more effective agent to use with cyclosporin-A to circumvent this drug resistance mechanism. Idarubicin is a very effective drug for the early management of adult acute lymphoblastic leukaemia and may be presently considered (along with cyclosporin-A or other modulator) as the reference anthracycline for cases overexpressing the P-glycoprotein drug resistance mechanism.

Age-adapted moderate-dose induction and flexible outpatient postremission therapy for elderly patients with acute lymphoblastic leukemia.

We report the results of a recent trial in elderly acute lymphoblastic leukemia (ALL) patients (> or = 60 years). Initial chemotherapy consisted of one 14-day course with single-dose idarubicin plus vincristine-prednisone-L-asparaginase. Idarubicin was preferred to other anthracyclines because of its shorter time to response. Sequential outpatient postremission therapy included single-dose idarubicin plus vincristine-cyclophosphamide-L-asparaginase pulses, cranial irradiation with intrathecal methotrexate-cytarabine, flexible weekly vincristine-cyclophosphamide alternating with cytarabine-teniposide, and two-year standard maintenance with mercaptopurine-methotrexate. Granulocyte colony-stimulating factor (G-CSF) was added to induction and early consolidation courses. Twenty-two patients mainly with high-risk features entered the study: median age was 64 years (60-73), 40% of cases were CD10- B-lineage and T-lineage ALL, 38% of CD10+ B-lineage ALL carried a BCR-ABL rearrangement, while 23% coexpressed myeloid antigen, 86% had L2 morphology, 50% had a blast count greater than 10 x 10(9)/1, 54% had hepato-splenomegaly and lymphadenopathy. The complete remission (CR) rate after induction therapy was 59%. A partial remission was obtained in two cases. There were four early deaths (18%) and three refractory ALL (14%). Median time to response was 21 days. With G-CSF, the median duration of absolute neutropenia was 10.5 days. Flexible postremission therapy was very well tolerated, causing no major toxicity. With a median follow-up of 2.6 years, 3 patients remain alive in first CR (23%), 2 of whom at 21.3 months and 39.6 months, respectively. Median survival of responders was 12 months compared to only 1.2 months for nonresponders (p < 0.001). This moderate-dose idarubicin-containing and G-CSF-supported regimen was associated with a high early remission rate in elderly ALL. Postremission therapy results were modest, though not appreciably different from the general experience in this patient population. Because further escalation of drug intensity appears unjustified, attempts to document and reverse drug resistance patterns and restore a dysregulated apoptosis must be considered.

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.

Clinical sensitivity to anthracyclines in PH/BCR+ acute lymphoblastic leukemia.

Translocation t(9;22) or Philadelphia chromosome (Ph)/BCR-ABL rearrangement positive acute lymphoblastic leukemia (Ph/BCR+ ALL) is associated with a very short survival of about one year in most patients. We analyzed long-term outcome of 76 adults with Ph/BCR+ ALL, in order to detect which factors were associated with longer survival. Modifiable prognostic factors included type of treatment, allogeneic marrow transplant (allo-BMT), and early anthracycline dose intensity (high = H/A, low = L/A); unmodifiable factors were age, gender, FAB morphology, phenotype, blast count, P190/210 transcript, hepatospleno-lymphadenopathy, LDH level. Median patient age was 43 years (range 15-71). Four favorable prognostic factors (FPF) were found associated with greater likelihood of complete remission (blast count < 50 x 10(9)/l, p = 0.08), longer remission duration (age < 50 years, p < 0.001; H/A, p < 0.05), and lower relapse rate (allo-BMT, p = 0.017). Age and anthracycline dose intensity exerted a synergistic prognostic effect. According to the cumulative incidence of FPF in each patient (FPF 0-1 = 29, 2-3 = 42, 4 = 5), the probability of survival increased from nil to 0.22 to 0.60 at 5 years (p < 0.005). Adult Ph/BCR+ ALL is relatively sensitive to anthracyclines, which therefore should be prescribed at full dosage to patients not eligible to allo-BMT or in the waiting list for unrelated donor transplantation.

Strategies for the treatment of recurrent acute lymphoblastic leukemia in adults.

Bone marrow recurrence of adult acute lymphoblastic leukemia is typically an aggressive and most often rapidly fatal condition, an ideal setting for testing the latest research developments and experimental therapeutic options. Here we review recurrence mechanisms and treatment possibilities in order to identify the most appropriate clinical conduct. Choice of retreatment drugs and their dosages, related or unrelated donor bone marrow transplants, autologous peripheral blood stem cell transplants, immune manipulations, reversal of drug resistance, and restoration of apoptosis are all part of an integrated short-term therapeutic and decisional network to be developed for specific patient and disease prognostic subgroups.

Role of anthracyclines in the treatment of adult acute lymphoblastic leukemia.

In acute myelogenous leukemia, early treatment is usually attempted with the so-called 3+7 regimen, employing daunorubicin (DNR) or idarubicin (IDR) for 3 consecutive days. In acute lymphoblastic leukemia (ALL), the role of agreement regarding ANT dosage and schedule, preferable compound, and indications for remission induction and consolidation treatment phases. Here we review the role of these drugs in adult ALL. The results indicate that ANTs may offer the best survival chance when used at full dosage during induction and early consolidation treatment. IDR may be a better choice that DNR or doxorubicin, and CD10+ t(9;22)/bcr- ALL may have an excellent prognosis following an early dose-intensive ANT consolidation program.

The use of anthracyclines in adult acute lymphoblastic leukemia.

A critical review of the role of anthracyclines in the management of adult patients with acute lymphoblastic leukemia was performed to define current indications for their use. Major pertinent clinical series were reviewed with reference to anthracycline type, cumulative dosage and dose intensity, and administration schedule during both induction therapy and postremission consolidation, comparing results, whenever possible, with non-anthracycline treatment groups. A subgroup analysis was performed to evidentiate disease subtypes likely associated with a favorable outcome to anthracycline treatment. The results indicated that anthracyclines may still play a primary role in this setting. In particular, anthracyclines should be used at full therapeutic doses, especially during induction and early consolidation; idarubicin could be a better choice than daunorubicin or adriamycin; finally, an early brief intensive treatment with anthracyclines may provide an excellent probability of long-term disease-free survival in CD10+ t(9;22)-negative B-precursor adult ALL, obviating the need for prolonged maintenance or late reinduction therapy.

A new combination of carboplatin, high-dose cytarabine and cross-over mitoxantrone or idarubicin for refractory and relapsed acute myeloid leukemia.

BACKGROUND AND OBJECTIVE: High-dose cytarabine (HIDAC) and new anthracycline-type drugs (mitoxantrone, idarubicin) are the mainstay of several active regimens against relapsed and refractory acute myeloid leukemia (AML). The present study was undertaken to assess the feasibility, toxicity, and antileukemic activity of carboplatin (CBDCA) added to a combination of the two former agents. DESIGN AND METHODS: Two regimens (R) of CBDCA plus HIDAC and either mitoxantrone or idarubicin (crossover) were sequentially evaluated. R-1 consisted of CBDCA 300 mg/m2/d (24-hour infusion) on days 1-4, HIDAC 1 g/m2/bd on days 1-5, and mitoxantrone/idarubicin 12/6 mg/m2/d on days 1-3, followed by granulocyte colony-stimulating factor (G-CSF). R-2, an attenuated-toxicity regimen, consisted of CBDCA and G-CSF as above, HIDAC on alternate days (1, 3, 5), and mitoxantrone/idarubicin 8/5 mg/m2/dose. Intended post-remission therapy included a similar, lower intensity course and a myeloablative phase supported by an allogeneic or autologous blood cell transplant. RESULTS: Twenty-nine patients (median age 53 years, one child) formed the study group: 10 (34%) had a primary refractory disease (8 to idarubicin-cytarabine-etoposide, ICE), 6 (21%) were at second or subsequent relapse, and 5 (17%) had a first remission lasting < 12 months. In addition, 4 patients (14%) had received prior HIDAC and 10 (34%) were relapsing after a bone marrow/blood cell transplant. Twelve patients were treated with R-1 and 17 with R-2. The complete response rate was 25% with R-1 and 53% with R-2, due to a significantly lower death rate by pancytopenic complications (p = 0.023). The probability of response by risk class was: primary refractory 30% (43% with R-2), > 2nd relapse 33% (50% with R-2), 1st relapse < 12 months 40% (50% with R-2), 1st relapse > 12 months 50% (75% with R-2), prior HIDAC 75%, and prior transplant 30% (33% with R-2). Seven patients could undergo an autologous (n = 5) or allogeneic (n = 2) bone marrow/peripheral blood cell transplant after one consolidation cycle. Overall survival was 4.2 months, significantly longer in responders (complete and partial: median 11 months) than non-responders (p < 0.001). Median duration of complete remission was 10 months and 2-year probability 0.31, but no patient remained disease-free at 3 years. INTERPRETATION AND CONCLUSIONS: R-2 was well tolerated, exerted a significant activity in high-risk AML, and is amenable to further improvements. However, the lack of long-term disease-free survivors indicates the need for innovative post-remission strategies.

Short course infusional idarubicin plus intermittent cytarabine and etoposide for refractory hematologic malignancies: clinical and preliminary pharmacological results.

BACKGROUND AND OBJECTIVE: Idarubicin (IDA) is relatively immune to the multidrug resistance P-gp mechanism that is frequently expressed in recurrent and refractory hematologic malignancies. Owing to rapid metabolism in vivo, a continuous infusion (CI) of IDA might prolong exposure time to the parent drug rather than its more P-gp susceptible alcohol metabolite. For this reason we developed a brief retreatment schedule incorporating CI IDA in order to obtain clinical as well as preliminary pharmacological data in patients with refractory leukemias and lymphomas. DESIGN AND METHODS: Eligible patients had either advanced-stage acute myeloid or lymphoid leukemias (AML, ALL) or high-grade non-Hodgkin's lymphomas (NHL) which failed curative-intent frontline or salvage regimens in use at our institution during the study period (July-October 1992). CI IDA 5 mg/m2/d was employed together with intermittent (every 8 hours) intermediate-dose cytarabine (500 mg/m2) and etoposide (200 mg/m2); all drugs were given for 2-4 days. A preliminary pharmacokinetic evaluation of CI IDA was carried out in three patients, including a comparison with bolus delivery in one. The in vitro effects of CI-type vs bolus-type IDA delivery in terms of intracellular IDA accumulation and related pro-apoptotic activity were assessed in P-gp- and P-gp+ human leukemic CEM cells by means of cytofluorimetry (IDA fluorescence intensity = FI, annexin V expression), with and without the addition of P-gp inhibitor cyclosporin A (CsA). RESULTS: Complete (2) or partial (4) responses were achieved in a total of 12 patients (17% and 33%, respectively), despite prior treatments with anthracyclines (100% of cases) and cytarabine-etoposide (33% of cases). Hematological toxicity caused the duration of treatment to be reduced from 4 days to 2 days after the first 4 patients. The procedural death rate was 42% (5/12), which was probably related in part to the sum of adverse prognostic characteristics: median patient age 55 years, two-thirds of cases having previously failed second/third-line regimens. The pharmacokinetic study showed an increased plasma AUC value with CI IDA in one patient (2.9-fold increase vs bolus delivery) due to the prolonged presence of low IDA plasma levels (10-20 ng/mL vs 50 ng/mL), as seen in two other cases as well. On the other hand, the in vitro study did not prove to be in favor of CI IDA because the FI threshold (> 1500 units) associated with increased apoptosis of P-gp+ cells (> 10%) was achieved only with bolus-type IDA exposure (50 ng/mL for 30') plus CsA. INTERPRETATION AND CONCLUSIONS: This short regimen demonstrated activity against end-stage leukemias and lymphomas and might prove to be more effective and less toxic in younger patients and in those with less advanced disease. In view of the results from plasma pharmacokinetics and in vitro intracellular IDA accumulation and apoptosis assays in lymphoblastic CEM cells, CI IDA 5 mg/m2/day may not represent a better therapeutic option than a rapid bolus injection, particularly in P-gp+ neoplasms. If obtaining an adequate intracellular drug concentration is the primary treatment goal, a higher CI IDA dosage, the addition of a P-gp down-regulator such as CsA and others, and in vivo study focusing on tumor samples from patients could all be helpful.

Outcome assessment of age group-specific (+/- 50 years) post-remission consolidation with high-dose cytarabine or bone marrow autograft for adult acute myelogenous leukemia.

BACKGROUND AND OBJECTIVE: To assess outcome of an age-adapted post-remission strategy for adult patients with acute myelogenous leukemia (AML, FAB-M3 excluded), including autologous bone marrow transplantation (ABMT) or high-dose cytarabine (HIDAC) consolidation. DESIGN AND METHODS: AML patients in first complete remission (CR) after doxorubicin-cytarabine-thioguanine (DoxAT) chemotherapy were scheduled to receive two identical early consolidation courses followed by HIDAC (1 g/m2/bd for 6 days), if aged > 50 years, or HiDAC plus total body irradiation (TBI) plus ABMT if aged < 50 years, the bone marrow being harvested prior to the HiDAC/TBI regimen and unpurged. Results were examined by treatment intention and in actual treatment groups, by selected pretreatment and therapy-related variables, and compared with age and disease matched historical patients treated with DoxAT consolidation without additional HIDAC or ABMT. RESULTS: One-hundred and eight (70%) of 153 patients achieved a response and were evaluable after a follow-up of 3.3-8.8 years. According to treatment intention, long-term relapse-free survival (RFS) was significantly improved in both age groups compared with controls (< 50 years: 41% vs 15%, p < 0.05; > 50 years: 33% vs 22%, p < 0.005). Actually, 41 patients proceeded to ABMT and 24 to the HIDAC cycle (including 5 aged < 50 years), 23 had early consolidation only (1: refusal; 1: inadequate marrow harvest; 21: complications), 10 relapsed and 2 died very early into remission, 7 were submitted to an allogeneic BMT, and one denied any post-remission therapy. The long-term RFS rates for ABMT and HIDAC groups were 53% and 54% (47% for 19 patients aged > 50), respectively, significantly better than for historical patients or those unable to go beyond early consolidation (p < 0.005, adjusted for early adverse events). Overall 5-year survival rate was 40% (p < 0.0001), 54% for CR patients, 60% after ABMT, and 65% after HIDAC. Relative to the ABMT and HIDAC intensive treatment groups, only the presence of hepatosplenomegaly at diagnosis was associated with a significantly worse outcome like that of the control study. INTERPRETATION AND CONCLUSIONS: This age-adapted double post-remission consolidation strategy with ABMT (allo-BMT) or HIDAC was applicable to only about two thirds of responders and was effective in about half these cases, regardless of patient age or specific treatment modality. While the loss of CR patients from treatment realization was unrelated to the study design and depended mainly on recurrence of AML and toxic complication, the exact place of ABMT vs HIDAC consolidation remains unsettled, calling for a new study in comparable patient and risk groups.

Therapeutic impact of adult-type acute lymphoblastic leukemia regimens in B-cell/L3 acute leukemia and advanced-stage Burkitt's lymphoma.

BACKGROUND: Adult B/L3-ALL is a rare disease subset characterized by an aggressive clinical course and a poor response to conventional adult ALL-type chemotherapy. Recent data from the GMALL Group showed that prognosis can be improved with an innovative treatment regimen. In the current retrospective survey we focus on therapeutic results obtained at our Institutions during a 15-year period with ALL-type regimens in 34 adults with either B/L3-ALL or advanced-stage Burkitt's lymphoma. METHODS: Five successive ALL treatment programs were developed. They included a homogeneous induction phase with early intrathecal chemoprophylaxis, multidrug postremission consolidation followed by cranial irradiation (4 trials), high-dose chemotherapy plus autografting (2 trials), late consolidation (2 trials), and variable-length maintenance (4 trials). Early response and prolonged disease-free survival rates were analyzed according to selected clinical and therapeutic variables. RESULTS: Overall, a complete remission was achieved in 62%, with a median duration of 1.6 years and a 10-year remission rate of 49%. A diagnosis of B/L3-ALL (p = 0.007), the use of idarubicin instead of adriamycin during induction (p = 0.018), a serum creatinine < 1.6 mg/dL, and an uninvolved central nervous system were associated with higher response rates. As regards long-term disease-free survival, results were significantly better in patients with < 1 x 10(9)/L L3/blast cells in the peripheral blood (p = 0.0029) and/or aged < 50 years (p = 0.04), and in those consolidated with the most recent rotational high-dose plus peripheral blood stem cell autotransplant regimen. CONCLUSIONS: According to the results presented, ALL-like regimens may still represent a worthwhile therapeutic choice. The use of idarubicin during induction, the prognostic subclassification of patients, a careful control of dysmetabolic complications, the selection of the proper chemo-radioprevention for meningeal disease and perhaps the introduction of high-dose chemotherapy supported by autologous stem cell rescue appear to be the mainstay of further improvements.

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.

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.