Search

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.

Purpose: Systemically administered fludarabine phosphate (F-araAMP) slows growth of human tumor xenografts that express Escherichia coli purine nucleoside phosphorylase (PNP). However, this treatment has been limited by the amount of F-araAMP that can be administered in vivo. The current study was designed to (1) determine whether efficacy of this overall strategy could be improved by intratumoral administration of F-araAMP, (2) test enhancement of the approach with external beam radiation, and (3) optimize recombinant adenovirus as a means to augment PNP delivery and bystander killing in vivo., Methods: The effects of systemic or intratumoral F-araAMP in mice were investigated with human tumor xenografts (300 mg), in which 10 % of the cells expressed E. coli PNP from a lentiviral promoter. Tumors injected with an adenoviral vector expressing E. coli PNP (Ad/PNP; 2 × 10(11) viral particles, 2 times per day × 3 days) and the impact of radiotherapy on tumors treated by this approach were also studied. Radiolabeled F-araAMP was used to monitor prodrug activation in vivo., Results: Intratumoral administration of F-araAMP in human tumor xenografts expressing E. coli PNP resulted in complete regressions and/or prolonged tumor inhibition. External beam radiation significantly augmented this effect. Injection of large human tumor xenografts (human glioma, nonsmall cell lung cancer, or malignant prostate tumors) with Ad/PNP followed by intratumoral F-araAMP resulted in excellent antitumor activity superior to that observed following systemic administration of prodrug., Conclusion: Activation of F-araAMP by E. coli PNP results in destruction of large tumor xenografts in vivo, augments radiotherapy, and promotes robust bystander killing. Our results indicate that intratumoral injection of F-araAMP leads to ablation of tumors in vivo with minimal toxicity.

Background: Previous studies have shown that Herpes Simplex Virus thymidine kinase (HSV-tk)/ganciclovir (GCV) comprised the most commonly used suicide gene therapy for prostate cancer, with modest results being obtained. However, novel suicide genes, such as Escherichia coli purine nucleoside phosphorylase (PNP), have been utilized to demonstrate more potent tumor killing and an enhanced bystander effect on local, non-expressing cells compared to HSV-tk., Methods: PNP/fludarabine (Fludara®; fludarabine phosphate; Berlex Labs, Richmond, CA, USA) was deliveried by prostate-specific, rat probasin-based promoter, ARR2PB. After infection of various cell lines with ADV.ARR(2) PB-PNP and administration of androgen analog, R1881, expression of PNP mRNA was detected; in vivo, the antitumor effect of the ARR(2) PB-PNP/Fludara system was monitored and analyzed, as well as animal survival., Results: After in vitro infection with ADV.ARR(2) PB-PNP (multiplicity of infection  =  10), LNCaP cells were more sensitive to a lower concentration Fludara (LD(50) , approximately 0.1 µg/ml) in the presence of R1881. Furthermore, robust bystander effects after R1881/Fludara treatment were observed in LNCaP cells after infection with bicistronic vector ADV.ARR2PB/PNP-IRES-EGFP in contrast to a much weaker effect in cells treated with ADV.CMV-HSV-tk/GCV. In vivo, tumor size in the ADV.ARR2PB-PNP/Fludara treatment group was dramatically smaller than in the control groups, and the mice treated with our system had a significantly prolonged survival, with three of eight mice surviving up to the 160-day termination point, as well as no systemic toxicity., Conclusions: The ARR(2) PB-PNP/Fludara system induced massive tumor cell death and a prolonged life span without systemic cytotoxicity; therefore, it might be a more attractive strategy for suicide gene therapy of prostate cancer., (Copyright © 2011 John Wiley & Sons, Ltd.)

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.

The purpose of this study was to determine the effect of alemtuzumab on treatment-related mortality (TRM), relapse, overall survival (OS), and disease-free survival (DSF) in patients with acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS) undergoing reduced intensity conditioning (RIC). We compared the outcome of 95 patients treated at the University of Chicago with fludarabine melphalan (Flu + Mel) + alemtuzumab conditioning and 59 patients treated at the M.D. Anderson Cancer Center with Flu + Mel conditioning. Both groups had similar patient and donor characteristics. There were no significant differences in TRM, relapse, survival, and DFS between the 2 groups. The incidence of acute graft-versus-host disease (aGVHD) grade II-IV (relative risk [RR] 5.5, P < .01) and chronic GVHD (cGVHD) (RR 6.6, P < .01) were significantly lower in patients receiving alemtuzumab. The addition of alemtuzumab to an RIC regimen dramatically reduces the incidence of aGVHD and cGVHD in patients with AML and MDS undergoing allogeneic transplantation. TRM, relapse risk, OS and DFS are not affected.

Nucleoside analogs are rationally designed anticancer agents that disrupt DNA and RNA synthesis. Fludarabine and cladribine have important roles in the treatment of hematologic malignancies. Clofarabine is a next generation nucleoside analog which is under clinical investigation. The bone marrow toxicity, tumor cell cytotoxicity and human tumor xenograft activity of fludarabine, cladribine and clofarabine were compared. Mouse and human bone marrow were subjected to colony forming (CFU-GM) assays over a 5-log concentration range in culture. NCI-60 cell line screening data were compared. In vivo, a range of clofarabine doses was compared with fludarabine for efficacy in several human tumor xenografts. The IC90 concentrations for fludarabine and cladribine for mouse CFU-GM were >30 and 0.93 microM, and for human CFU-GM were 8 and 0.11 microM, giving mouse to human differentials of >3.8- and 8.5-fold. Clofarabine produced IC90s of 1.7 microM in mouse and 0.51 microM in human CFU-GM, thus a 3.3-fold differential between species. In the NCI-60 cell line screen, fludarabine and cladribine showed selective cytotoxicity toward leukemia cell lines while for clofarabine there was no apparent selectivity based upon origin of the tumor cells. In vivo, clofarabine produced a dose-dependent increase in tumor growth delay in the RL lymphoma, the RPMI-8226 multiple myeloma, and HT-29 colon carcinoma models. The PC3 prostate carcinoma was equally responsive to clofarabine and fludarabine. Bringing together bone marrow toxicity data, tumor cell line cytotoxicity data, and human tumor xenograft efficacy provides valuable information for the translation of preclinical findings to the clinic.

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.

Purpose: To compare the efficacy and safety of fludarabine phosphate with cyclophosphamide, vincristine, and prednisone (CVP) in 381 previously untreated, advanced-stage, low-grade (lg) non-Hodgkin's lymphoma (NHL) patients in a phase III, multicenter study., Patients and Methods: Between 1993 and 1997, patients were randomly assigned to treatment with either fludarabine (25 mg/m2 intravenously [IV] daily for 5 days every 4 weeks) or CVP (cyclophosphamide 750 mg/m2 IV on day 1; vincristine, 1.4 mg/m2 IV on day 1; and prednisone, 40 mg/m2 orally on days 1 through 5 every 4 weeks). Results Overall response (OR) rates were significantly improved in the fludarabine arm versus the CVP arm, both for the intent-to-treat (ITT) population and assessable patients (P < .001). Complete response (CR) rates in the ITT population were also higher after fludarabine treatment. The CR rate was 38.6% for fludarabine compared with 15.0% for CVP. There were no statistically significant differences in time to progression (TTP), time to treatment failure (TTF), and overall survival (OS) between treatment groups. WHO grades 3 and 4 hematologic adverse events were more common in the fludarabine arm. However, concerning the higher incidence of granulocytopenia, this did not translate to more infections in fludarabine-treated patients., Conclusion: Newly diagnosed lgNHL patients who received fludarabine achieved higher OR and CR rates compared with CVP-treated patients. No differences in TTP, TTF, and OS were noted. Fludarabine is a highly active single agent in lgNHL. Combination therapies incorporating fludarabine are now being further evaluated as first-line therapy in follicular NHL.

Background: The primary objective of this study was to investigate the tolerability, efficacy and pharmacokinetic profile of oral fludarabine phosphate in relapsed patients with indolent B-cell non-Hodgkin's lymphoma (B-NHL)., Patients and Methods: Patients received fludarabine phosphate orally for 5 days, for a total of one to three cycles. Tolerability was assessed using the National Cancer Institute Common Toxicity Criteria. Efficacy was assessed using the International Workshop Criteria for NHL. Pharmacokinetic samples were taken on day 1 and day 5 of the first treatment cycle., Results: Twelve patients were enrolled. One patient at 40 mg/m2/day developed grade 4 hyperuricemia. At 50 mg/m2/day, one patient developed grade 3 febrile neutropenia and grade 4 leukopenia, and another patient showed lasting grade 4 neutropenia. Most common toxicities included grade 3 or 4 lymphopenia (83%), leukopenia (50%) and neutropenia (50%). All the toxicities were reversible. The overall response rate was 67%. The AUC0-24h values on day 5 indicated a dose-dependent increase in systemically available 2-fluoro-arabinofuranosyl-adenine (2F-ara-A)., Conclusions: Oral fludarabine phosphate is safe and effective for relapsed patients with indolent B-NHL. The dose of 40 mg/m2/day is recommended for a following pivotal phase II study.

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.

Cancer is a complex group of diseases. Many of the current treatment modalities available provide limited effectiveness and significant side effects. This circumstance creates a challenge for health care providers. There is great need for the development of innovative therapies that increase efficacy and decrease morbidity. In general, chemotherapeutic agents are unable to distinguish cancer cells from normal cells. As a result of therapy, patients may develop significant myelosuppression. Patients who are undergoing chemotherapy need to be observed for signs of hematologic and nonhematologic toxicities. Patients should be advised that periodic blood tests are indicated to monitor for anemia, neutropenia, and thrombocytopenia. If myelosuppression develops, measures to prevent complications such as bleeding and infection are indicated. Strategies to combat fatigue should also be discussed. Understanding of the biology of cancer has increased significantly in recent years. As knowledge of the science grows, new therapies are developed and clinical trials are initiated to investigate feasibility and efficacy of agents. Many of these trials involve agents that target specific biologic processes of cancer. While the complexities of cancer treatment are prolonging the life expectancy of patients who have the disease, patients are presenting with increasing numbers and types of morbidities. Nurses need to be aware of the rationale for treatment, mechanism of action of the agents administered, and expected toxicities of therapies. With this knowledge, symptoms can be identified earlier, life-threatening sequela can possibly be averted, and patients and families can be educated about what to expect and how to make knowledgeable decisions about treatment options. Enhancing patients' knowledge base may also increase their adherence to challenging therapies.

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.

Gene-directed enzyme prodrug therapy (GDEPT) based on the Escherichia coli enzyme, purine nucleoside phosphorylase (PNP), provides a novel strategy for treating slowly growing tumors like prostate cancer (CaP). PNP converts systemically administered prodrug, fludarabine phosphate, to a toxic metabolite, 2-fluoroadenine, that kills PNP-expressing and nearby cells by inhibiting DNA, RNA and protein synthesis. Reporter gene expression directed by a hybrid prostate-directed promoter and enhancer, PSMEPb, was assayed after plasmid transfection or viral transduction of prostate and non-CaP cell lines. Androgen-sensitive (AS) LNCaP-LN3 and androgen-independent (AI) PC3 human CaP xenografts in nude mice were injected intratumorally with an ovine atadenovirus vector, OAdV623, that carries the PNP gene under PSMEPb, formulated with cationic lipid for enhanced infectivity. Fludarabine phosphate was then given intraperitoneally for 5 days at 75 mg/m2/day. PNP expression was evaluated by enzymic conversion of its substrate using reverse phase HPLC. OAdV623 showed excellent in vitro transcriptional specificity for CaP cells. In vivo, expression of PNP persisted for > 6 days after OAdV623 injection and a single treatment provided 100% increase in tumor doubling time and > 50% inhibition of tumor growth for both LNCaP-LN3 and PC3 lines, with increased tumor necrosis and apoptosis and decreased tumor cell proliferation. OAdV623 significantly suppressed the growth of AS and AI human CaP xenografts in mice.

Purpose: A prospective, multicenter, open-label, phase II clinical trial to assess oral fludarabine phosphate treatment in terms of safety, efficacy, and quality of life. Reference to a historical group of patients treated with the intravenous (IV) formulation allowed the two formulations to be compared., Patients and Methods: Patients with previously untreated B-cell chronic lymphocytic leukemia received 10-mg tablets of fludarabine phosphate to a dose of 40 mg/m(2)/d for 5 days, repeated every 4 weeks, for a total of six to eight cycles. Efficacy was assessed using International Workshop on Chronic Lymphocytic Leukemia and National Cancer Institute criteria for response. Safety monitoring included WHO toxicity grading for adverse events. Quality of life was also assessed., Results: Eighty-one patients received treatment. According to International Workshop on Chronic Lymphocytic Leukemia criteria, the overall response rate was 71.6% (complete remission, 37.0%; partial remission, 34.6%). The response rate using National Cancer Institute criteria was 80.2% (complete remission, 12.3%; partial remission, 67.9%). Median time to progression was 841 days (range, 28 to 1,146 days). The most frequently reported grade 3/4 toxicity was myelosuppression. WHO grade 3/4 hematological toxicities included granulocytopenia (32.1%), anemia (9.9%), and thrombocytopenia (4.9%). Gastrointestinal toxicity was more common with the oral formulation than with IV fludarabine phosphate, but was generally mild to moderate and did not require treatment. Statistically significant improvements in mean emotional and insomnia quality-of-life scores were seen after treatment., Conclusion: This study demonstrates that oral fludarabine phosphate is clinically effective and generally well tolerated by patients with previously untreated B-cell chronic lymphocytic leukemia. Oral fludarabine phosphate has a similar clinical efficacy and safety profile to the IV formulation. Oral fludarabine phosphate does not adversely affect quality of life and may improve emotional and insomnia scores.

Background: Purine analogues [fludarabine monophosphate (FAMP); deoxycoformycin and 2-chlorodeoxyadenosine) and extracorporeal photochemotherapy (ECP) have been suggested to be active agents in advanced cutaneous T-cell lymphoma (CTCL) patients., Objectives: To explore further the clinical efficacy and safety of FAMP monochemotherapy in advanced CTCL and to evaluate if the sequential association of ECP to FAMP in selected patients may improve the response rate (RR) and/or lengthen the remission duration., Patients and Methods: Forty-four CTCL patients [17 Sézary syndrome (SS); 26 mycosis fungoides (MF), stage IIB-IV or with peripheral blood involvement; one MF associated with lymphomatoid papulosis (LyP)] were enrolled in this pilot cohort study. All the patients received FAMP 25 mg m(-2) 5 days monthly; 19 patients (43.2%) underwent ECP after FAMP was discontinued. The majority of patients with erythrodermic CTCL or peripheral blood involvement underwent the combined FAMP-ECP schedule., Results: After a median follow-up of 4.2 years, the overall FAMP RR was 29.5% (13/44); a higher RR was obtained in SS (35.3%) than in MF patients (25.9%). According to the treatment group, the RR of the FAMP-ECP group (63.2%) was significantly higher than that of the FAMP monotherapy group (24%; P=0.021). No statistically significant difference was found in time-to-progression (TTP) or survival by therapy group, even if the TTP of the patients treated with the FAMP-ECP combination therapy was higher (median 13 vs. 7 months). A decrease or a normalization in the CD4+CD26- circulating subset was observed in responding patients, paralleling the reduction in the circulating Sézary cells., Conclusions: FAMP confirms its clinical activity as a single agent in SS; conversely, FAMP results do not compare favourably with other therapeutic approaches for advanced stage MF patients. The sequential association of ECP after FAMP seems to increase the RR, even if future randomized studies are needed to confirm these results.

Background: We have recently established a new method for bone marrow transplantation (BMT) in mice: bone marrow cells are directly injected into the intra-bone marrow (IBM) cavity. IBM-BMT induces persistent donor-specific tolerance and enhances the rapid recovery or reconstitution of the hematolymphoid system of donor origin without any signs of graft-versus-host disease (GVHD) or graft failure. Furthermore, the prior injection of fludarabine can reduce the irradiation dose to the sublethal level (4.5 Gy x 2). Therefore, we hypothesize that IBM-BMT plus fludarabine is applicable to allogeneic leg transplantation in rats., Methods: Brown Norway (BN; RT1An) rats were injected intravenously with 50 mg/kg of fludarabine phosphate, followed by sublethal fractionated irradiation (4.5 Gy x 2) 1 day before IBM-BMT. The hind limbs from Fischer 344 (F344; RT1Al) rats were transplanted on day 0, and bone marrow cells (3 x 10(7) cells/50 microL) obtained from the donor F344 rats were injected into the bone marrow cavity of the left tibias of the recipient BN rats., Results: The hematolymphoid cells in the recipient BN rats were completely reconstituted by the cells of the donor F344 rats. The limbs transplanted from the donor F344 rats were accepted for >1 year without any clinical signs of rejection (10 of 10). The lymphocytes of the BN rats showed tolerance to both donor-type and recipient-type major histocompatibility complex determinants in mixed lymphocyte reaction, but showed a significant response to the third-party major histocompatibility complex determinants., Conclusions: Using a combination of the injection of fludarabine, low-dose irradiation, and IBM-BMT, we have succeeded in allogeneic limb transplantation without using any immunosuppressants after the operation. This strategy would be applicable to the transplantation of other vascularized organs in humans.

Background: Mixed chimerism can induce tolerance to alloantigens and restore self-tolerance to autoantigens, thereby permitting islet transplantation. However, the minimal level of donor chimerism that is required to prevent islet allograft rejection and recurrence of autoimmune diabetes has not been established., Methods: We investigated whether allogeneic Balb/c donor chimerism can be induced in C57BL/6 mice, in prediabetic NOD mice, and in diabetic NOD mice after transplantation of a modest dose of bone marrow by using purine nucleoside analogue, fludarabine phosphate and cyclophosphamide conditioning therapy, followed by short-term anti-CD40 ligand monoclonal antibody and rapamycin posttransplant treatment. We also investigated whether the induced donor chimerism is sufficient to prevent the onset of diabetes in prediabetic NOD mice and protect donor islet grafts in diabetic NOD mice., Results: Allogeneic donor chimerism could be induced under the authors' approach that is nonmyeloablative and radiation-free. Diabetes onset was prevented in chimeric prediabetic NOD mice. The induction of mixed chimerism protected donor-specific islet grafts in diabetic NOD mice. At 60 days after islet transplantation, all donor Balb/c islet grafts survived in diabetic NOD mice whose level of donor-derived lymphocytes was higher than 30% at the time of islet transplantation (n=8). In contrast, Balb/c islet grafts were rejected in five of seven diabetic NOD mice whose level was lower than 30%., Conclusions: Our data demonstrate that a donor lymphocyte chimerism (>30%) at the time of islet transplantation is required to protect donor-specific islet grafts, and indicate that a strictly non-irradiation-based protocol can be used to achieve this goal.

Current treatment of non-Hodgkin's lymphoma (NHL) is based, to a large extent, on stratification of patients into groups based on disease subtype (indolent or aggressive) and stage, and still relies heavily on traditional approaches based on external beam irradiation and alkylating agent-based chemotherapy. Here, we describe risk-based patient management, and the benefits made possible by different treatments. Early-stage localized disease is effectively managed with irradiation and/or chemotherapy; chlorambucil in the case of indolent disease and CHOP-based therapy in the case of aggressive disease. Progress is underway in two crucial areas of the treatment of advanced-stage low-grade NHL: development of first-line therapies to improve the number and quality of complete responses (CRs), and investigation of novel radioimmunotherapy or monoclonal antibody/chemotherapy combination regimens to combat relapsed and refractory disease. New chemotherapy approaches, such as fludarabine phosphate-based combination chemotherapy for low-grade advanced-stage NHL have improved the number and quality of remissions in chemotherapy-naïve and relapsed patients, but it remains to be seen what the long-term impact on survival may be. Monoclonal antibody based therapies including radioimmunotherapy, is emerging as a highly effective tool for the treatment of NHL, and shows synergy with fludarabine phosphate-based chemotherapy, though its optimal role has yet to be determined. At present, for patients with untreated disseminated disease; recurrent disease; or high-grade disease in the presence of poor risk factors; alternative treatment strategies are needed.

Purpose: A prospective, multicenter, open-label phase II clinical trial was conducted to assess the efficacy and safety of oral fludarabine phosphate. Reference to an historical group of patients treated with the intravenous (IV) formulation allowed the investigators to compare the two formulations., Patients and Methods: Efficacy was assessed using the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) and National Cancer Institute (NCI) criteria for complete remission (CR), partial remission (PR), stable disease, or disease progression. Safety monitoring included World Health Organization (WHO) toxicity grading for all adverse events., Results: Seventy-eight (96.3%) of 81 recruited patients with previously treated B-cell chronic lymphocytic leukemia (CLL) received 10-mg tablets of fludarabine phosphate to a dose of 40 mg/m(2)/d for 5 days, repeated every 4 weeks, for a total of six to eight cycles. According to IWCLL criteria, the overall remission rate was 46.2% (CR, 20.5%; PR, 25.6%). The comparative figures using NCI criteria were 51.3% (CR, 17.9%; PR, 33.3%). Overall, 30 incidents of severe adverse events were reported for 22 patients. WHO grade 3 or grade 4 hematologic toxicities included granulocytopenia (53.8%), leukocytopenia (28.2%), thrombocytopenia (25.6%), and anemia (24.4%). Gastrointestinal adverse events were more common with the oral formulation than previously reported with IV fludarabine phosphate. However, these events were generally mild to moderate., Conclusion: This study demonstrates that oral fludarabine phosphate has similar clinical efficacy to the IV formulation and a safety profile that is both predictable and essentially similar to that of the IV formulation.

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.

This article details both the contribution of the purine nucleoside analogs to the current management of relapsed indolent non-Hodgkin's lymphoma (NHL) and the role of pentostatin (Nipent) in that management. Of the three purine nucleoside analogs, pentostatin has received the least attention with regard to the management of indolent NHL. Although data in the literature appear to indicate that fludarabine (Fludara) and 2-chlorodeoxyadenosine (cladribine [Leustatin]) are more active in NHL, this conclusion could be flawed because many of the studies investigating pentostatin in indolent NHL have contained a large number of patients previously treated with the other purine analogs. As these agents are most likely cross-resistant, it is unfair to conclude that pentostatin is less active. Recently, there has been interest in using a new, more protracted schedule of 2 mg/m2/d of pentostatin for 5 days. Although the schedule used in the trials conducted in indolent NHL might not be optimal, pentostatin has nevertheless shown significant activity in these disorders.

Anti-HIV-1 combination therapies, including protease and reverse transcriptase inhibitors, can reduce plasma viremia to undetectable levels within the first 2 weeks of treatment. This reduction is followed by a slower decline that primarily results from the presence of viral reservoirs such as CD4+ memory cells, dendritic cells, and macrophages. For this reason, we evaluated a new drug combination therapy that includes a lympholytic drug: (2-fluoro-ara-AMP, fludarabine) to eliminate cells already infected and an antiviral drug (azidothymidine [AZT]) to protect cells not yet infected. We used C57BL/6 mice infected with the retroviral complex LP-BM5, which developed severe immunodeficiency (i.e., murine AIDS), to select the most effective fludarabine regimen to inhibit disease progression, and then to evaluate the efficacy and toxicity of the fludarabine and AZT combinations. The results obtained show that intraperitoneal administration of fludarabine at 3 mg/mouse twice a day for 4 weeks is the most effective regimen in reducing splenomegaly, lymphadenopathy, hypergammaglobulinemia, and proviral DNA content in spleen and lymph nodes and in restoring the architecture of lymph nodes. Subsequently, we evaluated the combined or sequential administration of fludarabine and AZT. The data reported in this paper show that the sequential administration of the two drugs provides additive antiviral effects that reduce spleen and lymph node weights to normal values and proviral DNA content by approximately 95% in all infected organs; the phenotypes of blood T and B cells moved toward control values, although the number of B cells was significantly reduced by fludarabine treatment. Finally, we evaluated the outcome of the disease after suspension or continuation of different treatment regimens. In all treatment groups, the disease progressed and increased proviral DNA content was found in infected organs, but animals receiving the sequential administration of fludarabine and AZT were less affected than those receiving only fludarabine or the simultaneous administration of both. The results obtained suggest that fludarabine could be part of a new therapeutic approach aiming at eradicating HIV from those cells that have been already infected and that are not protected by highly active antiretroviral therapy (HAART).

Conjugates of antiviral and antiblastic nucleoside analogs (NAs) with galactosyl-terminating peptides selectively enter hepatocytes after binding of the carrier galactose residues to the asialoglycoprotein receptor. Since NAs, when set free from the carrier within hepatocytes, partly exit from these cells into the bloodstream, we considered the possibility that administration of galactosyl-terminating conjugates of NAs could result in plasma concentrations of these drugs that would be higher in liver sinusoids than in capillaries of other organs. In the present study we demonstrated the validity of this hypothesis. We injected rats with a conjugate of adenine arabinoside (ara-A) with lactosaminated poly-L-lysine and found that the plasma concentrations of ara-A were >2-fold higher in blood of liver than in systemic circulation. Liver blood was collected from the inferior vena cava after closing below and above the outflows of the hepatic veins. The present result suggests that conjugation with galactosyl-terminating peptides might be a way to selectively increase the concentrations of NAs not only in hepatocytes, which have the asialoglycoprotein receptor, but also in cells infiltrating the liver, such as neoplastic cells of micrometastases nourished by hepatic sinusoids.

We report on a case of severe astrovirus gastroenteritis in a chronic lymphocytic leukemia (CLL) patient treated with fludarabine monophosphate (FAMP). Astrovirus was detected in stools using both an immunoenzymatic assay and an electronic microscopy analysis. Treatment consisted in symptomatic care and the outcome was favorable. Astrovirus infection might constitute a common etiology of gastroenteritis in patients with hematologic malignancies that have been severely immunocompromised with FAMP or other purine analogues, and therefore should be more systematically investigated.

The present study was carried out to establish a human chronic lymphocytic leukemia (CLL) mouse model by transplantation of a JOK-1 human CLL cell line into SCID (severe combined immunodeficient) mice and to examine anti-leukemic effects of fludarabine phosphate, a prodrug of 9-beta-D-arabinofuranosyl-2-fluoroadenine (2F-ara-A). In vitro cytotoxic screening pattern of 2F-ara-A differed from those of other anticancer agents. Intraperitoneal inoculation with JOK-1 cells in SCID mice allowed the cells to infiltrate into a variety of organs including the liver and thymus, and resulted in the death of the mice with a median survival time of 29.5 days, associated with hepatomegaly, splenomegaly and enlarged lymph nodes. The ascitic cells expressing the human B-lymphocytic cell surface antigen CD19 actually grew after a latent period of 15 days. In this model, twice daily administration of fludarabine phosphate at a dose of 135 mg/kg for 5 days prolonged the survival time of the mice for considerably longer period than once-a-day treatment. Fludarabine phosphate in the doubled course of twice daily increased life span of 32.9%, which was in a similar range to that of doxorubicin. Thus, intraperitoneal inoculation of the human JOK-1 CLL cells into SCID mice seems to serve as an animal model potentially for human leukemia, suggesting that transplantation and subsequent infiltration processes of human CLL cells is useful measures to explore mechanistic aspects for drug-induced modulation of the tumor progression.

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.

To preliminarily observe the antiviral effect of receptor-targeted drug, the Lactosaminated Human Serum Albumin Arabinoside Adenine Monophosphate (L-HSA-Ara-AMP), 10 patients with chronic type B hepatitis (HBsAg, HbeAg/HBV DNA positive) were treated with this drug for 5 days. The daily dose of L-HSA-Ara-AMP was 35 mg/Kg (containing 1.5 mg Ara-AMP), whereas the usual daily dose of free Ara-AMP is 10 mg/Kg. In 10 patients treated, three patients' HBeAg became negative and six patients' HBeAg titer fell. Anti-HBc IgM all became negative in 4 anti-HBc IgM positive patients. In 8 HBV DNA positive patients, four patients' HBV DNA became negative and the other four patients' HBV DNA decreased. HBsAg remained positive in all of the ten patients. No adverse effects were observed. The results showed that L-HSA-Ara-AMP inhibits HBV as effective as free Ara-AMP, but at a daily dose 6.7 times lower than free Ara-AMP.

Background and Aims: In patients with terminal Hepatitis B Virus-related liver diseases, liver transplantation carries a consistent risk of Hepatitis B Virus recrudescence in the graft. In the attempt to reduce the reinfection rate with antiviral therapy, we studied a total of 16 viraemic patients., Patients and Methods: Twelve patients received Ganciclovir, starting 4-67 days (mean 25 days) before transplantation and prolonged for 10 days after transplantation; four patients were treated with Lactosaminated Arabinoside-Monophosphate 6 hours before surgery and prolonged for 28 days after surgery. All received hepatitis B immunoglobulins., Results: At transplantation, HBV-DNA had decreased to about 10(4) virus/ml (as assessed by the polymerase chain reaction assay) in 10 of the 12 patients treated with Ganciclovir. Of these patients, 4 died perioperatively from causes unrelated to Hepatitis B Virus reinfection. Of the eight survivors, only the patient who maintained a titre of 10(6) virus/ml at the time of transplantation developed viral recurrence 4 months after surgery. Before transplantation, 2 of the patients treated with Lactosaminated Arabinoside-Monophosphate had a viraemic load of 10(6) and 2 of 10(4) virus/ml. In all cases, viraemia became undetectable at the end of therapy. None died and Hepatitis B Virus recurred 2 months after transplantation in one. The overall rate of Hepatitis B Virus recurrence was 16.6%. The recurrence rate decreased to 9% in patients in whom the viraemic load decreased to around 10(4) virus/ml following treatment, compared to an overall recurrence rate of 50% in our historical series of patients transplanted for Hepatitis B Virus-related cirrhosis., Conclusion: Antiviral therapy was effective in decreasing the risk of Hepatitis B Virus reinfection of the liver graft by decreasing the viral load before surgery.

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.

Following monochemotherapy with fludarabin phosphate (fludara), complete (18%), and partial remission (27%) with stabilization (45%) was recorded in patients with B-cell chronic lymphocytic leukemia, most of whom were resistant to alkylating cytostatic drugs and their combinations containing anthracyclines. Long-term remission was registered in patients with low and moderate grade non-Hodgkin's lymphoma, resistant to standard cytostatic treatment, due to the therapeutic synergism of fludara and cytosinarabinoside (FAVAMP).

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.

Fludarabine phosphate selectively eliminates normal and malignant mononuclear cells in large animals and man through the inhibition of DNA synthesis. The drug depletes mononuclear cells from culture within 24 hours of initial exposure, CD4 and CD8 T cells being more sensitive than either CD20 B cells or CD34 bone marrow precursors. Mitogenic activation of lymphocytes enhances cellular elimination from culture. Fludarabine inhibits PHA-induced T-cell proliferation by >90 per cent and mixed lymphocyte reactions (allogeneic and xenogeneic) by >95 per cent. Fludarabine exerts its cytolytic effects through the induction of endonuclease-independent apoptosis. A 5-day course of fludarabine (50 mg/m2 intravenously once daily) induces both T- and B-cell lymphopenia in Cynomolgus monkeys and Papio baboons. Transient neutropenia was the only side-effect seen in experimental animals. Pretreatment of Cynomolgus monkeys with this regimen of fludarabine causes a prolongation of ABO-compatible skin allograft survival from 8 days (control) to 16 days (drug treated group). Secondary allotransplantation into presensitized recipients showed a similar prolongation of graft survival with fludarabine pretreatment (8 days vs 5 days control). Fludarabine promises to be a potent immunosuppressive agent with low clinical toxicity.

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.

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.

Various anti-viral agents, e.g., interferon, have recently been used for the treatment of viral hepatitis. In the present study, duck hepatitis B virus (DHBV) was cultured in vitro and the anti-DHBV effects of acyclovir (ACV) and vidarabin 5'-monophosphate (VMP) were studied. The portal perfusion method was applied to the livers of 7-day-old white ducks weighing 100 g, bred in Japan, and hepatocytes were infected with DHBV in vitro. Duck hepatocytes infected with DHBV were cultured in medium containing ACV or VMP, and the anti-DHBV effects of these drugs were assessed by determining DHBV-DNA and duck hepatitis B surface antigen in the medium. Both ACV and VMP had anti-DHBV effects when used immediately after infection; however, both drugs were ineffective in hepatocytes obtained from a DHBV carrier duck. In conclusion, the anti-DHBV effects of these drugs were very limited. However, this culture system appears to be useful for studies of hepatitis virus and anti-viral drugs.

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.