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Purpose: Quantitative relationships between 9-β-D-arabinofuranosyl-2-fluoroadenine (F-ara-A) concentrations and lymphosuppression have not been reported, but would be useful for regimen design. A population pharmacokinetic/pharmacodynamic model was constructed in this study using data from 41 hematopoietic cell transplant (HCT) recipients conditioned with busulfan in combination with fludarabine (total dose 120 mg/m², Protocol 1519) or with fludarabine (total dose 250 mg/m²) with rabbit antithymocyte globulin (rATG, Protocol 2041)., Methods: Individual pharmacokinetic parameters were fixed to post hoc Bayesian estimates, and circulating absolute lymphocyte counts (ALC) were obtained during the 3 weeks prior to graft infusion. A semi-physiological cell-kill model with three lymphocyte transit compartments was applied and aptly characterized the time course of suppression of circulating ALC by fludarabine administration. Drug- and system-specific parameters were estimated using a maximum likelihood expectation maximization algorithm, and the final model was qualified using an internal visual predictive check., Results: The final model successfully characterized the time course and variability in ALC. Pharmacodynamic parameters exhibited considerable between subject variability (38.9-211 %). The HCT protocol was the only covariate associated with the pharmacodynamic parameters, specifically the lymphocyte kill rate, the transit rate between lymphocyte compartments, and the baseline ALC., Conclusions: This model can be used to simulate the degree of lymphosuppression for design of future fludarabine-based conditioning regimens.

This is a phase I study of 7-hydroxystaurosporine (UCN-01) and fludararbine monophosphate (FAMP) in relapsed lymphoma. UCN-01 alone was administered in cycle 1 and with FAMP in cycles 2-6. FAMP was escalated in cohorts from 1 to 5 days. UCN-01 and FAMP pharmacokinetics and apoptosis of malignant lymphocytes was evaluated. Eighteen patients were enrolled. Standard FAMP with UCN-01 was tolerated without dose-limiting toxicity (DLT) and those seen were common to either agent alone. One patient died due to Stevens-Johnson syndrome. Seven of 18 patients responded. No pharmacological effect of UCN-01 by FAMP was noted. Lymphocytosis occurred in 15 of 18 patients following UCN-01 to paradoxically increase circulating tumor cells. UCN-01 induced apoptosis in six of eight patients with chronic lymphocytic leukemia (CLL). UCN-01 does not increase FAMP toxicity. Transient lymphocytosis followed by apoptosis occurs with UCN-01. Mobilization from tissue reservoirs may play a role in the induction of cell death in malignant lymphocytes.

Despite its common use in nonmyeloablative preparative regimens, the pharmacokinetics of fludarabine are poorly characterized in hematopoietic cell transplantation (HCT) recipients and exposure-response relationships remain undefined. The objective of this study was to evaluate the association between plasma F-ara-A exposure, the systemically circulating moiety of fludarabine, and engraftment, acute GVHD, TRM and OS after HCT. The preparative regimen consisted of CY 50 mg/kg/day i.v. day -6; plus fludarabine 30-40 mg/m²/day i.v. on days -6 to -2 and TBI 200 cGy on day -1. F-ara-A pharmacokinetics were carried out with the first dose of fludarabine in 87 adult patients. Median (range) F-ara-A area-under-the-curve (AUC((0-∞))) was 5.0 μg h/mL (2.0-11.0), clearance 15.3 L/h (6.2-36.6), C(min) 55 ng/mL (17-166) and concentration on day(zero) 16.0 ng/mL (0.1-144.1). Despite dose reductions, patients with renal insufficiency had higher F-ara-A exposures. There was strong association between high plasma concentrations of F-ara-A and increased risk of TRM and reduced OS. Patients with an AUC((0-∞)) greater than 6.5 μg h/mL had 4.56 greater risk of TRM and significantly lower OS. These data suggest that clinical strategies are needed to optimize dosing of fludarabine to prevent overexposure and toxicity in HCT.

A multicentre single-arm study testing the efficacy and toxicity of the oral combination of fludarabine and cyclophosphamide (FC) over 5 d in 75 patients with untreated B cell-chronic lymphocytic leukaemia. Oral FC demonstrated high efficacy with overall (OR) and complete response (CR) rates of 80% and 53%, respectively. Out of the 30 CR patients studied for Minimal Residual Disease (MRD) using 4-colour flow-cytometry and the 22 using Clonospecific polymerase chain reaction, 22 (66%) and 16 (68%), respectively, were MRD negative. Median survival and median treatment-free interval had not been reached at 7 years of follow-up. Median progression-free survival (PFS) was 5 years. Toxicity was acceptable, with 52% and 16% of National Cancer Institute grade 3/4 neutropenia and infections, respectively. Gastrointestinal toxicity was mild. Oral FC demonstrated a high efficacy and an acceptable safety profile and may be considered as the standard first line treatment in chronic lymphocytic leukaemia.

We report a high incidence of myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) in patients entered into the preceding Medical Research Council Chronic Lymphocytic Leukaemia Pilot study of autografting [corrected] Of 115 newly diagnosed patients treated with fludarabine, 65 patients proceeded to autologous transplant. Conditioning was cyclophosphamide and total body irradiation in 49 (75%) patients and chemotherapy in 12 (18%). Ten patients have developed MDS/AML; eight had undergone an autograft. Five-year actuarial risk of developing MDS/AML postautograft was 12.4% (95% confidence interval, 2.5-24%). No analysed potential risk factor was predictive for MDS/AML development. We hypothesise that potential causative factors are fludarabine, low cell dose and transplant conditioning.

Purpose: Although intravenous (IV) fludarabine phosphate is effective against indolent B-cell non-Hodgkin's lymphoma (B-NHL), IV administration for 3 to 5 consecutive days is inconvenient in an outpatient setting. To assess the efficacy and toxicity of oral fludarabine phosphate in patients with indolent B-NHL, we conducted a multicenter phase II study., Patients and Methods: Patients with relapsed indolent B-NHL received fludarabine phosphate tablets orally once daily on days 1 through 5 every 28 days for three to six cycles. The efficacy was separately analyzed in a mantle-cell lymphoma (MCL) cohort and indolent B-NHL except for MCL (IL) cohort. The primary end point was the overall response rate (ORR)., Results: Fifty-two patients, including 46 in the IL cohort (41 with follicular lymphoma) and six in the MCL cohort, were registered, and all patients were eligible. Forty-one patients (79%) had received rituximab as prior therapy. In the IL cohort, the ORR and complete response rate were 65% (30 of 46 patients; 95% CI, 50% to 79%) and 30% (14 of 46 patients; 95% CI, 18% to 46%), respectively. One of six patients with MCL achieved a partial response. The median times to treatment failure for the 46 patients in the IL cohort and for the six patients in the MCL cohort were 8.6 and 6.1 months, respectively. Hematologic toxicities, including grade 4 neutropenia (37%), were the most frequent toxicities, and nonhematologic toxicities were mild., Conclusion: Oral fludarabine phosphate is highly effective in patients with relapsed indolent B-NHL who have mostly been pretreated with rituximab and is more convenient than the IV formulation.

The increasing number of allogeneic stem cell transplantations has made the management of graft-versus-host disease (GVHD) a continuing problem for transplantation professionals. GVHD is a complicated disease the treatment of which requires an equally multifaceted approach. Despite therapeutic efforts to decrease its distressing and potentially lethal clinical manifestations, treatment is still not optimal. Fludarabine phosphate is a purine analogue, which is known to cause immunosuppression and long-lasting T-cell lymphopenia it is commonly employed in the therapy of hematological malignancies and non-myeloablative stem cell transplantation conditioning regimens. Myelosuppression, especially leuko- and lymphopenia is the major dose-limiting toxicity of fludarabine. However, a prolonged reduction in CD4+ T-cell count may be a desired effect for the treatment of GVHD. Clinical observations, preclinical data on the management of GVHD and well-known immunosuppressive properties suggest that fludarabine should be tested in clinical grounds for GVHD prophylaxis and treatment.

Fludarabine monophosphate is a purine nucleoside antimetabolite with efficacy in the treatment of lymphoproliferative disorders and chronic lymphocytic leukemia. It is the 2-fluoro, 5' phosphate derivative of 9-beta-D-arabinofuranosyl adenine (ara-A, vidarabine) and the mechanism of action is through inhibition of DNA synthesis and the cytolytic effects through the induction of endonuclease-independent apoptosis.

To comparatively assess first-line treatment with fludarabine and 2 anthracycline-containing regimens, namely CAP (cyclophosphamide, doxorubicin plus prednisone) and ChOP (cyclophosphamide, vincristine, prednisone plus doxorubicin), in advanced stages of chronic lymphocytic leukemia (CLL), previously untreated patients with stage B or C CLL were randomly allocated to receive 6 monthly courses of either ChOP, CAP, or fludarabine (FAMP), stratified based on the Binet stages. End points were overall survival, treatment response, and tolerance. From June 1, 1990 to April 15, 1998, 938 patients (651 stage B and 287 stage C) were randomized in 73 centers. Compared to ChOP and FAMP, CAP induced lower overall remission rates (58.2%; ChOP, 71.5%; FAMP; 71.1%; P <.0001 for each), including lower clinical remission rates (CAP, 15.2%; ChOP, 29.6%; FAMP, 40.1%; P =.003). By contrast, median survival time did not differ significantly according to randomization (67, 70, and 69 months in the ChOP, CAP, and FAMP groups, respectively). Incidences of infections (< 5%) and autoimmune hemolytic anemia (< 2%) during the 6 courses were similar in the randomized groups, whereas fludarabine induced, compared to ChOP and CAP, more frequent protracted thrombocytopenia (P =.003) and less frequent nausea-vomiting (P =.003) and hair loss (P <.0001). For patients with stage B and C CLL first-line fludarabine and ChOP regimens both provided similar overall survival and close response rates, and better results than CAP. However, there was an increase in clinical remission rate and a trend toward a better tolerance of fludarabine over ChOP that may influence the choice between these regimens as front-line treatments in patients with CLL.

Patients with lymphoid malignancies such as chronic lymphocytic leukemia, particularly those who receive the newer purine analogs, are at increased risk for infectious morbidity and mortality. Defects in cell-mediated immunity appear to be a major predisposing factor in these patients. An expanding spectrum of pathogens associated with lymphocytopenia and depletion of CD4 has been described in the setting of therapy with purine analogs. During the past 2 years new knowledge about the immunosuppression related to that treatment has continued to accumulate.

The aim of this study was to investigate the combination of fludarabine phosphate, dexamethasone, cytosine arabinoside and cis-platinum (FLUDAP) in the treatment of patients with relapsed/refractory aggressive non-Hodgkin's lymphoma (NHL). This regimen comprises: dexamethasone 100 mg/d continuous infusion (cont. inf.) d1-3; cytosine arabinoside (ara-C) 1 g/m2/d cont. inf. d 2,3; fludarabine phosphate 30 mg/m2 short inf. 4hr prior to each 24hr ara-C inf.; cis-platinum 50 mg/m2 4hr inf. at the start of each 24hr ara-C inf. G-CSF (lenograstim, Granocyte) is given at 263 microg s.c. daily from day 7 until the neutrophil count reaches 1.0x10(9)/l. The regimen repeats at 21 day intervals. A total of 33 patients were registered (median age 47 years; 24 males, 9 females); the majority (73%) were refractory to their previous treatment and most had advanced disease by Ann Arbor stage. Thirteen (39%) of the 33 enrolled patients (52% of the 25 fully evaluable patients who received at least 2 courses of FLUDAP) responded to treatment. A maximum response of complete remission was achieved in 5 patients, good partial remission in 3, and partial remission in 5. Twelve patients went on to successful stem cell supported intensification therapy. Median survival times were higher in the responding patients, and in those patients transplanted post-FLUDAP. The toxicity associated with the FLUDAP regimen was generally predictable; frequently reported severe events included haematological toxicity and infection. In conclusion, the FLUDAP regimen shows promise as a salvage regimen and increases the available therapeutic options in the treatment of recurrent/refractory aggressive NHL.

We conducted a multicenter phase II clinical study of fludarabine phosphate, a new purine nucleotide analogue, in patients with chronic lymphocytic leukemia (CLL). Fludarabine phosphate was administered at a dose of 20 mg/m2/day intravenously for 5 days every 4 weeks as one course. Six courses as a maximum were repeated. The response rate was 38.5% (95% confidence intervals: 20.2% to 59.4%), with 1 complete remission and 9 partial remissions out of 26 treated patients. Major drug-related adverse reactions were fever, nausea, weakness, and paresthesia of the fingers; as a grade-3 reaction, varicella was also reported. Neutropenia and thrombocytopenia were observed as manifestations of hematologic toxicity. Clinical laboratory test results revealed abnormalities in hepatic function, including increased GPT, but none of these was rated grade 3 or 4.

Purpose: Fludarabine phosphate (F-AMP), a purine analog, requires daily intravenous administration. A pharmacokinetic study of an oral formulation (10 mg immediate-release tablet) was undertaken in patients with "low-grade" non-Hodgkin's lymphoma and B-cell chronic lymphocytic leukemia., Patients and Methods: Oral F-AMP was incorporated into the "conventional" treatment schedule. Single oral trial doses of 50, 70, and 90 mg of F-AMP were given on the first day of three cycles of treatment; a comparative 50-mg intravenous trial dose was given on the first day of the fourth cycle. Intravenous F-AMP (25 mg/m2) was given on days 2 to 5 at 4-week intervals. Pharmacokinetic samples taken after each trial dose were analyzed for plasma 2-fluoro-arabinofuranosyladenine (2F-ara-A) concentration (its main metabolite); area under the curve 0 to 24 hours (AUC(0-24h)) and maximum concentration (Cmax) were calculated. Eighteen patients received all three oral trial doses, and bioavailability was determined in 15 patients who completed four courses of therapy., Results: Oral administration of F-AMP resulted in a dose-dependent increase in Cmax and AUC(0-24h) of 2F-ara-A and achieved an AUC(0-24h) similar to intravenous administration, although at a lower Cm. The linear increase in mean AUC(0-24h) by factors of 1.36 +/- 0.22 (mean +/- SD) and 1.72 +/- 0.31 corresponded well with the increase in oral dose from 50 to 70 mg (factor of 1.4) and 90 mg (factor of 1.8), respectively. Bioavailability (approximately 55%, with low intraindividual variation) and time to Cmax were dose independent., Conclusion: Oral doses of F-AMP can achieve an AUC(0-24h) of 2F-ara-A similar to intravenous administration, with dose-independent bioavailability. The tablet will greatly enhance the use of F-AMP in a palliative setting.

We have conducted a phase I clinical study of fludarabine phosphate, a new purine nucleoside derivative, in patients with chronic lymphocytic leukemia and adult T-cell leukemia/lymphoma. The patients were given intravenous administration at a dose of 15 mg/m2/day followed by 20 mg/m2/day and 25 mg/m2/day, each dose given consecutively for 5 days. The dose limiting factors were thrombocytopenia and neutropenia. The thrombocyte count and neutrocyte count dropped to their lowest value in week 1 to 2 after administration, but the changes were reversible, and these counts recovered in most patients. The maximum tolerated dose of the study drug was 25 mg/m2/day, and it was decided to administer 20 mg/m2/day as the recommended dose for the subsequent phase II clinical study.

Purpose: Fludarabine phosphate (F-AMP) has significant activity in follicular lymphoma and in B-cell chronic lymphatic leukemia, where it has demonstrated high complete response (CR) rates. Lymphoplasmacytoid (LPC) lymphoma, Waldenstrom's macroglobulinemia (WM), and mantle-cell lymphoma (MCL) also present with advanced-stage disease and are incurable with standard alkylator-based chemotherapy. A phase II trial was undertaken to determine the activity of F-AMP in patients newly diagnosed with these diseases., Patients and Methods: Between 1992 and 1996, 78 patients (aged 18 to 75 years) received intravenous F-AMP (25 mg/m2/d for 5 days, every 4 weeks) until maximum response, plus two further cycles as consolidation. The primary end point was response rate; secondary end points included time to progression (TTP), duration of response, and overall survival (OS)., Results: Forty-four (62%) of 71 assessable patients had a response to F-AMP (LPC lymphoma, 63%; WM, 79%; MCL, 41%); the CR rate was 15%. At a median follow-up of 1.5 years, 19 of 44 responding patients have had progression of lymphoma; the median duration of response was 2.5 years. The median survival has not yet been reached. There was no significant difference in the duration of response or OS between patients with different histologies; TTP was shorter in patients with MCL (P = .015). Myelosuppression was relatively common, and the treatment-related mortality (TRM) was 5%, mostly associated with pancytopenia and infection., Conclusion: Single-agent fludarabine phosphate is active in previously untreated LPC lymphoma and WM, with only moderate activity in MCL. However, the CR rate is low, and the TRM is relatively high. Its role in combination chemotherapy remains to be demonstrated.

Purpose: The aim of this phase II trial was to assess the efficacy of fludarabine monophosphate in untreated and pretreated mantle-cell lymphomas (MCL)., Patients and Methods: Fifteen patients with MCL were included in the study. In two cases, fludarabine was the first-line therapy, the second in four cases, the third in five cases, and the fourth in four cases. The diagnosis of MCL was based on the criteria of the European Lymphoma Task Force (ELTF), with morphologic, immunologic, and cytogenetic data. Patients were treated with intravenous fludarabine 25 mg/m2/d for 5 days every 4 weeks., Results: Toxicity of fludarabine was mild: World Health Organization (WHO) grade 3 and 4 granulocytopenia occurred in 15 of 56 assessable cycles (cy) (27%), there was no grade 3 or 4 thrombocytopenia, one grade 3 bacterial lung infection, and no treatment-related death. There were five partial responses (33%) but no complete response. The duration of these responses was short and ranged from 4 to 8 months., Conclusion: These results suggest that fludarabine can be moderately effective in the treatment of MCL. Fludarabine appears to be far less effective than in chronic lymphocytic leukemia (CLL) and follicular non-Hodgkin's lymphoma (NHL). Therefore, fludarabine should be evaluated in association with other chemotherapeutic agents in MCL.

Fludarabine phosphate (FDR) has demonstrated a remarkable clinical activity in chronic lymphocytic leukemia (CLL). Myelosuppression is the main toxicity although autoimmune hemolytic anemia (AIHA) is frequently reported. The pathogenesis of AIHA is still unknown however the role of T-cell immunosuppression is suspected. One case of thrombopenia after FDR has been described in a patient with a previous history of an autoimmune thrombocytopenia. We here report a 73-year-old man with a B-CLL and no previous autoimmune disorder who received six courses of fludarabine phosphate and developed afterwards an autoimmune thrombocytopenia.

Purpose: To provide fludarabine to physicians for the management of patients with advanced refractory chronic lymphocytic leukemia (CLL) and to determine the response rate and duration, toxicity, and survival with this agent., Patients and Methods: This phase II protocol was open to all eligible patients whose local physicians obtained written permission from the National Cancer Institute (NCI) to register patients onto this protocol. Of 791 national and international enrolled patients, 724 with a median age of 65 years received fludarabine, of which 703 were assessable for response., Results: Thirty-two percent of assessable patients responded (95% confidence interval [CI], 29% to 36%), with 21 patients (3%) obtaining a complete response and 205 (29%) a partial response. The median duration of response was 13.1 months and the median survival time from registration was 12.6 months. Age, performance status (PS), and Rai stage correlated with survival (P < .01). Grade 4 hematologic toxicity was reported in 43% and was associated with infection in 22%. Neurotoxicity (primarily grade 1 motor dysfunction) was reported in 14% patients and correlated with age., Conclusion: This study describes the toxicity and activity of fludarabine in refractory CLL in a setting that more closely resembles clinical practice than most published trials. The low response rate may be related to advanced stage (89% Rai high-risk), disease-related symptoms (63% had B symptoms), and/or degree of prior treatment. Other contributing factors inherent in a group C treatment protocol included lack of central pathology review, variable supportive care, and a tendency to use this mechanism at a later stage in the disease.

The authors evaluated retrospectively a group of 12 patients with B-chronic lymphatic leukaemia to whom fludarabine was administered. All patients had been treated in the past by combined chemotherapy (1-4 regimes, median 3). Fludarabine was administered in amounts of 30 mg/m2/day for 5 days to 4 patients and for 3 days to patients. The median of the number of administered cycles was 3. Only two patients achieved partial remission of the disease, the reminder did not respond to therapy. All patients had complications which very probably were associated with the administered treatment. A total of 21 episodes were recorded in the course of 36 cycles, 1 complication per 1.7 cycles. The most frequent complications were infections, a total of 14 episodes, incl. 3 invasive aspergilloses. Infections were more frequent in patients with a 5-day cycle, the majority was recorded after the first two cycles. Eight patients (67%) died from complications which developed in the course of treatment or after its termination. The author's experience with the administration of fludarabine in intensively pretreated patients with advanced forms of B-chronic lymphatic leukaemia indicates that this treatment is associated with a large number of serious complications, which are not compensated by a corresponding therapeutic effect.

Anti-HBe-positive patients with precore mutants may have severe, progressive liver disease. Therapy with interferon has been effective, but relapses are frequent. To evaluate and compare two antiviral treatments, lymphoblastoid interferon (ly-IFN) and adenine arabinoside 5'-monophosphate (ARA-AMP), 20 patients with anti-HBe-positive chronic hepatitis (5 cirrhosis and 15 CAH) and viral replication (HBcAg in the liver and HBV DNA in serum) were treated. Patients were randomized into two groups: 11 patients received ARA-AMP, 5 mg/kg/day during 7 weeks, and 9 received human ly-IFN, 5,000,000 units, three times per week, during 4 months. Baseline clinical, biochemical and histological features were not significantly different between the two groups. At the end of therapy, 8 (89%) patients in the interferon group and 5 (45%) in the ARA-AMP group showed normal ALT levels and no HBV DNA in serum by a liquid hybridization assay (P < 0.05). At 1 year of follow-up, a persistent response was observed in 33% of ly-IFN patients and in 27% of ARA-AMP patients, a transient response in 56% and 18%, and nonresponse in 11% and 55%, respectively. HBV DNA remained detectable by polymerase chain reaction (PCR) in 19 of the 20 patients. Among the responders, an improvement in histological lesion and the disappearance of intrahepatic HBcAg were observed; in the nonresponders, histological lesion remained stable or worsened. In conclusion, the efficacy of interferon and ARA-AMP was similar in treating anti-HBe-positive chronic hepatitis. Although interferon treatment led to initial improvement in a larger number of patients, there was a much higher rate of relapses with this drug.

Objective: To assess the efficacy of the purine analogue fludarabine monophosphate (FAMP) as salvage therapy in patients at Groote Schuur Hospital with chronic lymphocytic leukaemia (CLL) refractory to standard therapy., Design: Non-randomised trial., Setting: Tertiary care, referral academic hospital., Patients: Seven patients with B-lineage CLL, 4 in Rai stage IV and 1 each in stages A(I), A(II) and A(III), refractory to treatment with chlorambucil or cyclophosphamide, with or without whole-body irradiation., Intervention: Intravenous FAMP at a dose of 25 mg/m2 daily for 5 days every 28 days., Main Outcome Measures: Partial remission, complete remission, stable disease or progressive disease., Results: Two patients entered CR and 4 PR after a median of 8 courses of treatment (range 2 - 12). One patient died of Pneumocystis carinii pneumonia after 3 courses of therapy. The most common adverse effect of the treatment was myelosuppression, with the nadir of neutrophil counts being less than 0.5 x 10(9)/1 in 5 patients. Three developed infections and required hospitalisation while on therapy., Conclusion: FAMP is effective as a cytoreductive agent in patients with CLL refractory to alkylating agents, with or without whole-body irradiation.

In the present study we report our results on the efficacy of Fludarabine monophosphate in 20 B-chronic lymphocytic leukemia (CLL) patients, refractory to conventional chemotherapy. Of the 20 patients 14 were males and 6 females with a median age of 58 years (44-70). Eight had Binet stage B and 12 stage C. They were previously treated with chlorambucil, prednisone, mini-CHOP or irradiation. Their disease duration prior to fludarabine administration was 49 months (7-180). Fludarabine was given at a dose of 25 mg/m2 daily, for five consecutive days, monthly for six months and if responding for six additional months. Treatment was administered on an outpatient basis. Complete response (CR) was observed in 7 patients (33%) and partial remission (PR) in 5 (25%). Of the complete responders 5 were males and 2 females with a median age of 60 years (range 55-68); three of them had stage B and 4 stage C disease; the median number of fludarabine courses for achieving CR was 3 (range 2-5). In all CR patients a residual monoclonal CD5/CD19 positive lymphocyte population was found in the peripheral blood. All CRs relapsed shortly after discontinuation of therapy within 12 months. The main toxicity observed was upper respiratory tract and/or pulmonary infections in 8 patients, requiring hospitalization. Among the CRs one patient died during the administration of the third course of therapy, due to a severe hypersensitivity reaction with Stevens-Johnson syndrome. The importance of maintenance therapy is also stressed as PR was sustained in some patients using 3 day cycles every 2-4 months. One patient was maintained in this fashion for 60 + months. This study showed that fludarabine is effective in CLL patients refractory to conventional chemotherapy thus it may be given as the treatment of choice if such patients still require treatment.

A conjugate of adenine arabinoside monophosphate (ara-AMP) with the liver-targeting molecule lactosaminated human serum albumin (L-HSA) was administered by intravenous infusion for 28 days to eight patients with chronic type B hepatitis. The daily dose varied among the patients, ranging from 34 mg/kg to 53 mg/kg (equal to 1.5 and 2.3 mg/kg ara-AMP, respectively). Pharmacokinetic analysis indicated that, at every dose tested, the conjugate was disposed of without accumulation. Viral DNA serum levels fell markedly during treatment; values rose again when treatment was ceased. The L-HSA-ara-AMP conjugate did not cause either the neurotoxic side effects of free ara-AMP or other adverse clinical reactions. It produced a significant increase both in serum alkaline phosphatase activity and platelet number, and a small but significant decrease in erythrocyte number. These laboratory parameters returned to normal levels within 2 months after treatment. The conjugate induced the production of small amounts of antibodies (approximately 20 pmol of conjugate bound by 1 mL of serum) in one patient only. In conclusion, the present results indicate that the L-HSA-ara-AMP conjugate can exert the antiviral activity of ara-AMP in chronic type B hepatitis patients without producing the neurotoxic side effects which hamper a 4-week period of treatment with the free drug.

Purpose: Fludarabine monophosphate (FAMP) is a major drug in the treatment of chronic lymphocytic leukemia and showed efficacy in selected groups of patients with low-grade lymphomas, most of them pretreated. The aim of this trial was to assess the efficacy and the toxicity of FAMP in untreated patients with follicular lymphoma., Patients and Methods: Fifty-four untreated patients with advanced follicular lymphoma were treated with intravenous (i.v.) fludarabine at a dose of 25 mg/m2/d during 5 days every 4 weeks, to a maximum of nine cycles., Results: The toxicity of the drug was mild, mainly granulocytic. Granulocytopenia > or = 3 (World Health Organization [WHO]) was observed during 48 of 328 cycles (14.6%) and in 22 of 53 (41%) patients assessable for toxicity. Fludarabine had to be stopped prematurely because of toxicity in nine patients: marrow toxicity in five, peripheral neuropathy in two, and interstitial pneumonitis and hepatitis in one patient each. Among 49 patients assessable for response, the overall response rate was 65% and the complete response (CR) rate 37%. The median progression-free survival interval for all patients was 13.6 months., Conclusion: These results confirm that fludarabine is active when used as first-line treatment in patients with follicular lymphoma and has a low toxicity rate. It may be used as single treatment in elderly patients. Associations of fludarabine with other drugs active against follicular lymphoma need to be determined.

We report the first known case of fulminant bone marrow necrosis (BMN) occurring after infusion of fludarabine monophosphate in a patient with recurrent low-grade non-Hodgkin's lymphoma (NHL). Extensive BMN is characterized by the development of fever, bony pain, a leukoerythroblastic peripheral blood film, variable degrees of pancytopenia and elevations in lactate dehydrogenase and alkaline phosphatase. The diagnosis of BMN is rarely entertained ante-mortem. Although the precise role chemotherapy may have played in triggering fatal BMN remains speculative, we alert clinicians to be aware of this entity as more patients with indolent lymphomas and leukemias are treated with this and other potent nucleoside analogs.

This study compared the response to adenine arabinoside 5'-monophosphate (ARA AMP) in 60 patients with chronic hepatitis B according to the pretreatment serum hepatitis B virus DNA concentration. The level of hepatitis B virus replication was defined as low (30 patients) or high (30 patients) when serum hepatitis B virus DNA concentration was below or above 100 pg/ml, respectively. Patients received a 28 day course of ARA AMP and a second course of ARA AMP was given six months later to patients with persistent hepatitis B virus replication. At the end of the first course of ARA AMP, 11 of the patients (37%) with low replication and one of the patients (3%) with high replication became negative for hepatitis B virus DNA (p = 0.0012); five of the patients (17%) with low replication and none of the patients with high replication had HBe seroconversion (p = 0.06). Two of these five patients lost HBsAg. Kinetics of serum hepatitis B virus DNA during treatment showed a considerable but transient antiviral effect of ARA AMP. Three of 32 retreated patients became negative for hepatitis B virus DNA and one patient had HBe seroconversion. In conclusion, ARA AMP exerts a considerable but transient antiviral effect on hepatitis B virus. Complete and sustained inhibition of hepatitis B virus replication was only obtained in the patients with low hepatitis B virus replication.

In an Illinois Cancer Center phase II trial, fludarabine phosphate was administered to a total of 14 patients (9 men, 5 women) with advanced, measurable, gastric adenocarcinoma. Fludarabine phosphate was given as a rapid intravenous (IV) bolus at a starting dose of 20 mg/m2/d for the first 5 days of a 28-day cycle. For subsequent cycles, the dose was escalated in increments of 2 mg/m2/d, provided that no toxicities greater than grade 1 were noted. In cases of grade 3 toxicity, dose reductions of 2 mg/m2/d were required, and patients who experienced grade 4 toxicities were removed from study. Receiving one complete 5-day course of fludarabine phosphate and surviving for 4 weeks on study were required for a patient to be evaluable for response. None of the patients responded to treatment. Although fludarabine phosphate was ineffective against gastric adenocarcinoma in this study, toxicity was acceptable at the 20 mg/m2/d times 5 every 28 days dose and schedule.

Fludarabine monophosphate (FAMP) has been shown to be highly effective against low-grade malignant B-cell lymphoproliferative diseases. Because some opportunistic infections were observed in patients treated with FAMP, we investigated the influence of this drug on several parameters of immunocompetence. For 17 consecutive patients treated with FAMP for CLL or low-grade malignant lymphoma we studied T-cell subpopulations during and after therapy by flow cytometry and our findings were correlated with the clinical course of their disease. A pronounced decrease in the various T-cell subpopulations was seen in all cases, that for CD4+ cells was still present 11-13 months after the end of the therapy. In 7 patients a severe opportunistic infection developed; the outcome was fatal in 2 cases. Only 5 patients did not experience any serious infection. These results show that FAMP therapy in a dose of 25 mg/m2/day for 5 d every 4 weeks might be too toxic for patients with very advanced disease. However, in view of the efficacy of FAMP, the possibility of less intensive schedules for these advanced cases should be explored.

We have conducted a phase II trial of fludarabine phosphate for advanced measurable adenocarcinoma of the pancreas. The drug was administered every 4 weeks by a daily-times-5 bolus schedule beginning at 20 mg/m2/day. No responses were observed in 20 evaluable patients, 18 of whom were previously untreated. Dose-limiting toxicity was leukopenia, and gastroenterologic side effects were frequent. Life-threatening or fatal renal dysfunction occurred in 3 patients. In this schedule fludarabine phosphate is ineffective against adenocarcinoma of the pancreas and appears to have unpredictable severe renal toxicity.

Purpose: In a phase II trial we investigated fludarabine phosphate (FAMP) as therapy for patients with relapsed lymphoma to determine its effectiveness and toxicity in this disease., Patients and Methods: The 67 assessable patients had a median age of 56 years and had received a median of three chemotherapy regimens before treatment with FAMP. The starting dose was 25 mg/m2 administered intravenously over 30 minutes daily for 5 days every 3 to 4 weeks., Results: High response rates were observed for follicular small cleaved-cell lymphoma (FSCCL) (62%), follicular mixed small- and large-cell lymphoma (80%), and follicular large-cell lymphoma (FLCL) (100%). Responses also occurred in small lymphocytic lymphoma (SLL) (33%), transformed lymphoma (33%), mycosis fungoides (40%), and Hodgkin's disease (25%). No responses were observed in other intermediate- or high-grade lymphomas (N = 20). Overall, there were five patients with a complete response, 23 patients with a partial response, and an overall response rate of 37%. Toxicity was primarily hematologic and infectious. No significant gastrointestinal, hepatic, renal, or neurologic toxicity occurred., Conclusions: We conclude that FAMP has major activity in follicular lymphoma. Fundamental research is needed to understand this differential efficacy in low-grade lymphoma yet lack of efficacy in intermediate- and high-grade lymphoma. Clinical investigations should be done using FAMP in varying dose schedules and in combination regimens.

Using a loading dose/continuous infusion schedule, fludarabine phosphate was administered to 51 patients with previously treated chronic lymphocytic leukemia (CLL). All patients had evidence of active disease, and the majority had advanced Rai stages. Of the 42 patients assessable for response, 22 (52%) achieved a partial response, five (12%) had stable disease, and 15 (36%) progressed. Thirteen of the 22 responders improved their Rai stages with fludarabine therapy, including six patients who achieved stage 0. Response rates for pretreatment stages III and IV were 60% and 53%, respectively. Patients with final Rai stages 0 to II had better survival than those with stages III and IV. Patients who had undergone splenectomy before starting therapy were more likely to respond. Myelosuppression was the primary toxicity and did not appear to be cumulative. Severe leukopenia and thrombocytopenia, although infrequent, were associated with several deaths in the early cycles of treatment. Nonhematologic toxicity was mild with no serious neurotoxicity noted. Infections were common with 22 minor, 18 major, and 10 fatal episodes. Fludarabine phosphate by this alternative dosing schedule is effective in refractory advanced CLL and is well tolerated by the majority of patients.

In a clinical phase-II study fludarabine phosphate was given to 20 patients with advanced chronic lymphocytic leukemia who had failed on prior conventional therapy. Fludarabine was administered at a dose of 25 mg/m2/d for 5 days. Treatment cycles were repeated every 4 weeks until maximal response, followed by two cycles for consolidation. Four of the 20 patients achieved complete remission and seven patients partial remission, resulting in an overall response rate of 55% (11/20). Fludarabine therapy was well tolerated, with mild myelosuppression and secondary infections comprising the predominant side effects. These data warrant further confirmation and a randomized comparison of fludarabine with established regimens, which is currently underway.

Nineteen evaluable patients with advanced endometrial cancer refractory to one prior chemotherapeutic regimen were treated with a 5-day schedule of fludarabine phosphate. No responses were noted. The major toxicity was grade 2 or greater leukopenia in 45% of patients. Fludarabine phosphate at this dose and schedule does not appear to be an active agent for patients with refractory endometrial cancer.

Twenty-seven evaluable patients with advanced malignant melanoma received fludarabine phosphate in a daily x 5 injection. Initial dosing was based on the presence of previous radiation therapy. There was no response seen in these patients despite appropriate dose escalation. Myelosuppression occurred without significant sequelae.

Thirty-three patients with chronic lymphocytic leukemia (CLL) with advanced Rai stage (III-IV) or progressive Rai stage (0-II) disease were treated with fludarabine as a single agent. Eleven patients (33%) obtained a complete remission (CR), 13 (39%) a clinical CR with residual nodules as the only evidence of disease (nodular partial remission [PR]), and two patients (6%) achieved a PR for a total response rate of 79%. Response was rapid, usually occurring after three to six courses of treatment. The major morbidity was infection. Febrile episodes occurred in 13% of the courses (pneumonia 6%, minor infection 4%, and transient fever of undocumented cause 3%). Fludarabine appears to be the most cytoreductive single agent so far studied in CLL.

Fludarabine phosphate is the 2-fluoro, 5'-monophosphate derivative of vidarabine (ara-A) with the advantages of resistance to deamination by adenosine deaminase (ADA) and improved solubility. The mechanism of cytotoxic action of the compound appears to involve metabolic conversion to the active triphosphate. Fludarabine phosphate has substantial activity against lymphoid malignancies, particularly chronic lymphocytic leukemia (CLL) and low-grade non-Hodgkin's lymphoma (NHL). Its single-agent activity in CLL appears at least comparable to those of other conventional combination regimens. Its activity in Hodgkin's disease, mycosis fungoides, and macroglobulinemia, although suggestive, needs to be further defined and clinical trials are warranted in hairy cell leukemia, prolymphocytic leukemia, and previously untreated myeloma. The compound does not appear active against most common solid tumors. Early clinical trials indicated significant myelosuppression and the potential for severe neurotoxicity. Toxicity on the currently used low-dose schedules includes transient and reversible myelosuppression, nausea and vomiting, diarrhea, somnolence/fatigue, and elevations of liver enzymes and/or serum creatinine. Possible pulmonary toxicity has been suggested in several patients. The currently used low-doses of fludarabine phosphate, even with repeated administration, are well tolerated and appear safe with a negligible risk for severe neurotoxicity. Based on its single-agent activity and tolerability, the Food and Drug Administration recently granted group C designation of the drug for the treatment of patients with refractory CLL outside the clinical trials setting. The use of fludarabine phosphate in combination regimens and its impact on the natural history of the lymphoid malignancies is yet to be determined. Fludarabine phosphate may well occupy a pivotal role in the management of CLL and low-grade NHL.

Fludarabine phosphate is a nucleotide analogue of adenine arabinoside with antitumor activity in murine and human lymphoid malignancies; it has occasional, unpredictable neurotoxicity after high dose bolus injections in adults. To avoid this toxicity, we studied a loading dose plus 5-day continuous infusion in 47 evaluable pediatric patients. Dose limiting myelosuppression was seen in children with solid tumors after a loading dose of 8 mg/m2 followed by 23.5 mg/m2/day for 5 days. In children with leukemia, no dose limiting toxicity was seen at dose level 6, consisting of a loading dose of 10 mg/m2 and an infusion of 30.5 mg/m2/day for 5 days. One complete and 3 partial remissions were seen in 26 evaluable children with acute lymphoblastic leukemia. 9-beta-D-arabinofuranosyl-2-fluoroadenine plasma concentrations and the area under the moment curve increased linearly with dose. The terminal half-life was similar, while the total body clearance was shorter than that reported for adults receiving bolus or continuous doses. Lymphoblasts isolated from 2 patients during fludarabine phosphate (9-beta-D-arabinofuranosyl-2-fluoroadenine) treatment increased their ability to convert 1-beta-D-arabinofuranosylcytosine to 1-beta-D-arabinofuranosylcytosine 5'-triphosphate by more than 10-fold. The antileukemic activity of 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-phosphate and its ability to alter the metabolism of 1-beta-D-arabinofuranosylcytosine indicate that timed combinations of these 2 agents should be tested.

There have been six different phase I trials of Fludara I.V. (fludarabine phosphate) in patients with solid tumors and three different phase I trials of Fludara I.V. in patients with acute leukemia. In addition, one trial of the agent given intraperitoneally has also been published. In patients with solid tumors, the two most often used schedules are a daily bolus schedule of 18 to 25 mg/m2/d for 5 days repeated every 28 days, and a 20 mg/m2 loading dose followed by a 48-hour continuous infusion of the agent at a dose of 25 to 30 mg/m2/d. The dose-limiting toxicity in these studies has been myelosuppression. No dosage or schedule could be recommended for patients with acute leukemia because of the severe neurotoxicity (progressive dementia with blindness leading to coma) noted with doses greater than or equal to 96 mg/m2/d for 5 to 7 days. Other toxicities noted in phase I trials have included somnolence, mild to moderate nausea and vomiting, and a rare and reversible interstitial pneumonitis. Of greatest interest is that a profound lymphopenia has been noted as a side effect of Fludara I.V. That toxicity has proven to be of benefit for patients with chronic lymphocytic leukemia, low-grade lymphoma, and mycosis fungoides, all of which are responsive to Fludara I.V. therapy.

Fludara I.V. (fludarabine phosphate) is a purine analogue that has been synthesized and found to have activity in lymphoid neoplasms in phase I and II studies. Fludara I.V. has been used extensively in the management of chronic lymphocytic leukemia in the last 5 years. In studies of Fludara I.V. as a single agent, the response rate was 59% in 78 patients. The true complete remission (CR) rate (no evidence of disease) was 13% with 16% having a CR with persistent lymphoid nodules. These patients are considered to be in CR using the National Cancer Institute Working Group Guidelines. The other patients (31%) achieved a partial remission (PR). Fludara I.V. has also been used as a single agent in previously untreated patients. Thirty (83%) of the 36 patients obtained a complete or partial response. Thirty-six percent of the patients achieved a true CR and 39% a CR with persistent lymphoid nodules in the bone marrow. Thus, the complete remission rate was 75%. Fludara I.V. has now been combined with prednisone in the management of 101 previously treated patients with chronic lymphocytic leukemia. Fourteen percent of patients have achieved a true CR, 24% a nodular CR, and 19% a PR. The results were very similar to those obtained with Fludara I.V. as a single agent. Other investigators have explored Fludara I.V. by continuous infusion. Twenty-two of 42 evaluable patients, in that study, achieved a PR. Fludara I.V. had minimal evidence of toxicity except for episodes of fever. The episodes of fever were more common in patients who had received previous treatment and had stage III or IV disease according to the Rai staging system. Some of these episodes of fever were associated with pneumonia. It appears that the spectrum of organisms causing the febrile episodes is that usually associated with immune deficiency (monocyte or T-cell deficiency). Future studies with Fludara I.V. will explore different schedules and combination approaches.

Twenty evaluable patients with advanced cervical cancer refractory to one prior chemotherapy regimen were treated with a 5-day schedule of fludarabine phosphate. No responses were noted. The major toxicities were anemia and leukopenia. Based on this study, fludarabine phosphate does not appear to be an active agent for patients with chemotherapy refractory cervical cancer.

This article presents data from the phase I and II clinical investigations of Fludara I.V. (fludarabine phosphate) (NSC 312887), which is the 5'-phosphorylated derivative of the novel antimetabolite, 9-beta-D-arabinofuranosyl-2-fluoroadenine. The comprehensive phase I evaluation of this new antitumor agent was conducted in 51 patients with advanced malignancy and 15 additional patients with aggressive forms of leukemia. Three separate phase I schedules of drug administration were examined. Myelosuppression was the dose-limiting toxicity on each schedule administered to patients with solid tumors. The drug was also examined at higher doses in patients with leukemia, and the dose-limiting toxicity on the high-dose protocol was unacceptable: serious neurologic toxicity. The observation of antitumor responses in patients with advanced non-Hodgkin's lymphoma prompted additional phase II investigation in patients with lymphoproliferative malignancy. The encouraging phase II data demonstrate that Fludara I.V. has promise for patients with low-grade histologic subtypes of non-Hodgkin's lymphoma and chronic lymphocytic leukemia. While interesting additional basic and clinical research projects regarding Fludara I.V. remain, it is important to expeditiously pursue approval for this drug. Adequate data exists to demonstrate that the low-dose administration of Fludara I.V. is both safe and effective. While the development of this drug has stimulated renewed interest in the clinical investigation of the chronic lymphoproliferative malignancies, the time for making it readily available to these patients has arrived.

Fludara I.V. (fludarabine phosphate) was tested by the Eastern Cooperative Oncology Group in non-Hodgkin's lymphoma patients who failed or relapsed after prior chemotherapy and radiation. Fifty-seven patients with low- or intermediate-grade (working formulation) lymphoma were treated with 18 mg/m2 daily for 5 days every 28 days. Preliminary data analysis shows an overall response (complete response [CR] plus partial response [PR]) rate of 28%, consisting of 18% CR and 27% PR in patients with low-grade histologies and 11% CR and 6% PR in patients with intermediate-grade histologies. Toxicity was mild and mainly included moderate myelosuppression. A 9% incidence of reversible neurologic side effects was seen. Based on this activity in previously treated patients, combination studies with Fludara I.V. in untreated patients are planned.