Although much needs to be learned about the serious clinical problem of herpes infection of the cornea, we have come a long way. We now have effective topical antiviral drugs. We have animal models which, with a high degree of reliability, clearly predict the effect to be expected clinically in man, as well as the toxicity. We have systemically active drugs and the potential of getting highly active, potent, completely selective drugs, with the possibility that perhaps the source of viral reinfection can be eradicated. The biology of recurrent herpes and stromal disease is gradually being understood, and this understanding may result in new and better therapy of this devastating clinical disease. (+info)
Fludarabine, cyclophosphamide, and dexamethasone (FluCyD) combination is effective in pretreated low-grade non-Hodgkin's lymphoma.
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PURPOSE: Fludarabine phosphate is effective as a single agent in low-grade non-Hodgkin's lymphoma (NHL). Combined with other antineoplastic agents it enhances the antitumor effect. Our aim was to define the therapeutic efficacy and toxicity of a combination of fludarabine, cyclophosphamide and dexamethasone (FluCyD) in patients with advanced low-grade lymphoma. PATIENTS AND METHODS: Twenty-five adults with pretreated advanced-stage low-grade NHL were treated with three-day courses of fludarabine 25 mg/m2/day, cyclophosphamide 350 mg/m2/day, and dexamethasone 20 mg/day, every four weeks for a maximum of six courses. RESULTS: Of the 25 patients, 18 (72%) responded, 8 (32%) achieving CR and 10 (40%) PR. Seven were failures. The median follow-up was 21 months (5-26). Eight CR patients remain in CR after 5-21 months. Of 10 PR patients, 3 are in continuous PR without further treatment after 12, 17 and 18 months. Myelosuppression was the most prevalent toxic effect. Although severe granulocytopenia (granulocyte count nadir < 500/microliter) and thrombocytopenia (platelet count nadir < 50,000/microliter) occurred in only 10% and 16% of courses, respectively, slow granulocyte or platelet count recovery caused delay of 40% of the courses. Nine patients (36%) required discontinuation of therapy because of persistent granulocytopenia and/or thrombocytopenia: three after one course, three after 2-4 courses, and three after five courses. Thirteen infectious episodes in 11 patients complicated 11% of courses. Two of 10 patients monitored for the circulating EBV load showed increased viral load. One of these developed aggressive lymphoma. CD4+ lymphocytes declined from a pre-therapy median value of 425/microliter to 141/microliter post-treatment (P = 0.001). Non-hematologic toxicities were rare and mild. CONCLUSIONS: The combination of fludarabine with cyclophosphamide and dexamethasone is effective in pretreated advanced-stage low-grade NHL. It may broaden the range of therapeutic options in the salvage treatment of these patients. The main toxicity of this combination is prolonged myelosuppression that may cause treatment delay or withdrawal. The benefit of adding granulocyte colony-stimulating factor, particularly in patients with poor marrow reserve, needs to be investigated. (+info)
Autologous transplantation of chemotherapy-purged PBSC collections from high-risk leukemia patients: a pilot study.
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We have recently demonstrated that the combination of the alkylating agent nitrogen mustard (NM) and etoposide (VP-16) is capable of eliminating, ex vivo, leukemic cells contaminating PBSC collections and this is associated with a significant recovery of primitive and committed hematopoietic progenitor cells. Based on these data a pilot study on autologous transplantation of NM/VP-16 purged PBSC for high-risk leukemic patients was recently initiated. Twelve patients (seven females and five males) with a median age of 46 years (range 18-57) have been treated. Two patients had acute myeloblastic leukemia (AML) resistant to conventional induction treatment, four patients had secondary AML in I complete remission (CR), one patient was in II CR after failing a previous autologous BM transplantation, while two additional AML individuals were in I CR achieved after three or more cycles of induction treatment. Two patients with high-risk acute lymphoblastic leukemia (ALL) in I CR and one patient with mantle cell lymphoma and leukemic dissemination were also included. Eight patients showed karyotypic abnormalities associated with a poor clinical outcome. The mobilizing regimens included cytosine arabinoside and mitoxantrone with (n = 6) or without fludarabine (n = 3) followed by subcutaneous administration of G-CSF (5 microg/kg/day until the completion of PBSC collection) and G-CSF alone (n = 3) (15 microg/kg/day). A median of two aphereses (range 1-3) allowed the collection of 7.2 x 10(8) TNC/kg (range 3.4-11.5), 5 x 10(6) CD34+ cells/kg (range 2.1-15.3) and 9.2 x 10(4) CFU-GM/kg (0.3-236). PBSC were treated with a constant dose of 20 microg of VP-16/ml and a median individual-adjusted dose (survival < or = 5% of steady-state BM CFU-GM) of NM of 0.7 microg/ml (range 0.25-1.25). Eleven patients were reinfused after busulfan (16 mg/kg) and Cy (120 mg/kg) conditioning with a median residual dose of 0.3 x 10(4) CFU-GM/kg (0-11.5). The median time to neutrophil engraftment (>0.5 x 10(9)/l) for evaluable patients was 25 days (range 12-59); the median time to platelet transfusion independence (>20 and >50 x 10(9)/l) was 40 days (18-95) and 69 days (29-235), respectively. Hospital discharge occurred at a median of 25 days (18-58) after stem cell reinfusion. Four individuals are alive in CR (n = 3) or with residual nodal disease (n = 1 lymphoma patient) with a follow-up of 32, 26, 3 and 14 months, respectively. Seven patients died due to disease progression or relapse (n = 5) or extrahematological transplant toxicity (n = 2). Our data suggest that pharmacological purging of leukapheresis collections of leukemic patients at high-risk of relapse is feasible and ex vivo treated cells reconstitute autologous hematopoiesis. (+info)
Effect of 9-beta-D-arabinofuranosyladenine 5'-monophosphate and 9-beta-D-arabinofuranosylhypoxanthine 5'-monophosphate on experimental herpes simplex keratitis.
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Treatment of established experimental keratitis caused by herpes simplex virus with 9-beta-d-arabinofuranosyladenine 5'-monophosphate (Ara-AMP) or 9-beta-d-arabinofuranosylhypoxanthine 5'-monophosphate (Ara-HxMP) showed that the Ara-AMP, in a concentration of 2 or 20%, had a significant effect on the keratitis but that 0.4% Ara-HxMP showed only minimal activity. Ara-AMP was also effective in the treatment of idoxuridine-resistant keratitis. No local toxicity with a high concentration (20%) of Ara-AMP was seen, but the duration of therapy was brief. (+info)
Fludarabine and epirubicin in the treatment of chronic lymphocytic leukaemia: a German multicenter phase II study.
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PURPOSE: Fludarabine has been reported to be the most effective single-agent in previously treated chronic lymphocytic leukaemia (CLL). Based on the in vitro synergism of fludarabine with anthracyclines and on results showing a higher efficacy of CHOP against COP we attempted to improve treatment results with a combination of fludarabine and an anthracycline. PATIENTS AND METHODS: The aim of the multicenter study was to evaluate the rate and duration of remissions and investigate the toxic and immunosuppressive effects of fludarabine and epirubicin in the treatment of CLL in Binet stages B and C as first-line therapy or in first relapse. Thirty-eight patients were treated with fludarabine 25 mg/m2 on days 1-5 and epirubicin 25 mg/m2 on days 4 and 5. RESULTS: The overall response rate (OR) was 82% (95% confidence interval (95% CI): 66%-92%) with a CR rate of 32% (95% CI: 18%-49%). For the 25 previously untreated patients the OR was 92% (95% CI: 74%-99%) including 40% CRs (95% CI: 21%-61%). Granulocytopenia grade 3 occurred in 23% of all evaluable cycles, and grade 4 in 17%. The median remission duration was 19 months (range 6-37 months). CONCLUSION: The results show that the combination of fludarabine and epirubicin is tolerable and highly effective in the treatment of CLL. With the addition of epirubicin to fludarabine, it appears possible to achieve a higher response rate and a more rapid response, especially of nodal manifestations. This regimen can be administered in an outpatient facility except for the first cycle because of the risk of a tumour lysis. The possible benefit of the combination presented here in the treatment of CLL in comparison to single-agent fludarabine treatment is presently under study in a prospective randomized multicenter study. (+info)
Fludarabine treatment in B-cell chronic lymphocytic leukemia: response, toxicity and survival analysis in 47 cases.
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BACKGROUND AND OBJECTIVE: Fludarabine monophosphate (FAMP) is a purine analog with specific therapeutic activity in B-cell chronic lymphocytic leukemia (CLL). Its current use as front-line therapy of CLL is still a matter of debate both because of the controversial results of the clinical trials so far reported and because of the toxicity profile of the drug. In order to contribute to clarifying the possible role of FAMP, we report a retrospective analysis of the results obtained with the purine analog in CLL patients in different phases of the disease. DESIGN AND METHODS: Forty-seven patients affected by advanced CLL, 36% untreated, 31.9% relapsed and 31.9% resistant, were treated with FAMP 25 mg/m2/day, either for 4 days every 3 weeks in 29 cases, or for 5 days every 4 weeks in 18. The median number of FAMP cycles was 6 (range 2-11). Response was defined according to total tumor mass (TTM) score reduction and toxicity was expressed according to WHO grading criteria. The median follow-up of the series was 13 months from the beginning of FAMP therapy. RESULTS: Out of 47 evaluable patients the response rate was 74.4%, with 34% complete response (CR). The overall response rate was 94%, 80% and 46.6% in untreated, relapsed and resistant cases, respectively; a significantly higher number of responses was associated with no previous treatment and number of FAMP cycles. Fifty-three percent of all cases and 58.8% of untreated ones did not experience any toxicity. Treatment-related side effects were mainly autoimmune phenomena in untreated patients and infectious complications in treated ones. One heavily pre-treated patient died because of neurologic complications. Median time to re-treatment was18 months (range 1-30) and was influenced by age and previous treatment. The overall median survival was 35.7 months with a significantly higher proportion of surviving cases among RAI 0-II stages, responders and patients receiving more than 5 FAMP cycles. INTERPRETATION AND CONCLUSIONS: The present report confirms the high efficacy of FAMP in previously pre-treated cases with acceptable toxicity and encourages its use as front-line treatment provided that the results of randomized trials demonstrate its superiority over conventional chemotherapy. The possible development of autoimmune phenomena should, however, be considered seriously. (+info)
Randomized phase II study of fludarabine + cytosine arabinoside + idarubicin +/- all-trans retinoic acid +/- granulocyte colony-stimulating factor in poor prognosis newly diagnosed acute myeloid leukemia and myelodysplastic syndrome.
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Preclinical data suggest that retinoids, eg, all-trans retinoic acid (ATRA), lower concentrations of antiapoptotic proteins such as bcl-2, possibly thereby improving the outcome of anti-acute myeloid leukemia (AML) chemotherapy. Granulocyte colony-stimulating factor (G-CSF) has been considered to be potentially synergistic with ATRA in this regard. Accordingly, we randomized 215 patients with newly diagnosed AML (153 patients) or high-risk myelodysplastic syndrome (MDS) (refractory anemia with excess blasts [RAEB] or RAEB-t, 62 patients) to receive fludarabine + ara-C + idarubicin (FAI) alone, FAI + ATRA, FAI + G-CSF, or FAI + ATRA + G-CSF. Eligibility required one of the following: age over 71 years, a history of abnormal blood counts before M.D. Anderson (MDA) presentation, secondary AML/MDS, failure to respond to one prior course of chemotherapy given outside MDA, or abnormal renal or hepatic function. For the two treatment arms containing ATRA, ATRA was given 2 days (day-2) before beginning and continued for 3 days after completion of FAI. For the two treatment arms including G-CSF, G-CSF began on day-1 and continued until neutrophil recovery. Patients with white blood cell (WBC) counts >50,000/microL began ATRA on day 1 and G-CSF on day 2. Events (death, failure to achieve complete remission [CR], or relapse from CR) have occurred in 77% of the 215 patients. Reflecting the poor prognosis of the patients entered, the CR rate was only 51%, median event-free survival (EFS) time once in CR was 36 weeks, and median survival time was 28 weeks. A Cox regression analysis indicated that, after accounting for patient prognostic variables, none of the three adjuvant treatment combinations (FAI + ATRA, FAI + G, FAI + ATRA + G) affected survival, EFS, or EFS once in CR compared with FAI. Similarly, there were no significant effects of either ATRA ignoring G-CSF, or of G-CSF ignoring ATRA. As previously found, a diagnosis of RAEB or RAEB-t rather than AML was insignificant. There were no indications that the effect of ATRA differed according to cytogenetic group, diagnosis (AML or MDS), or treatment schedule. Logistic regression analysis indicated that, after accounting for prognosis, addition of G-CSF +/- ATRA to FAI improved CR rate versus either FAI or FAI + ATRA, but G-CSF had no effect on the other outcomes. We conclude that addition of ATRA +/- G-CSF to FAI had no effect on CR rate, survival, EFS, or EFS in CR in poor prognosis, newly diagnosed AML or high-risk MDS. (+info)
Fludarabine-based non-myeloablative chemotherapy followed by infusion of HLA-identical stem cells for relapsed leukaemia and lymphoma.
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Many patients have not been offered potentially curative allogeneic marrow transplants because of the toxicity of myeloablative regimens in the setting of advanced age or organ dysfunction. We treated five patients, ineligible for myeloablative chemotherapy due to one of these criteria, with fludarabine-based non-myeloablative chemotherapy followed by reinfusion of G-CSF-mobilised allogeneic peripheral blood progenitor cells (PBPC). Two patients died early of multi-organ failure. Another patient with massive splenomegaly was infused with a suboptimal number of PBPC; no engraftment was documented. The remaining two patients demonstrated mixed chimerism early post-transplant, but by 3 and 6 months respectively, engraftment was almost entirely of donor origin. One of these patients, transplanted with relapsed AML, remains in remission with extensive chronic GVHD at 17 months. The other patient, transplanted with chemorefractory mantle cell lymphoma, progressed early post-transplant but entered remission coincident with the onset of severe GVHD following cessation of cyclosporin A, suggesting a powerful graft-versus-mantle cell lymphoma effect. These preliminary observations suggest this approach results in engraftment and GVHD/graft-versus-tumour effects similar to myeloablative regimens and may provide an alternative in patients ineligible for conventional conditioning regimens. (+info)