The successful use of radiofrequency-induced heat therapy for cutaneous leishmaniasis: a review.

The present gold standard of the treatment of cutaneous leishmaniasis (CL) is pentavalent antimonials either sodium stibogluconate (Pentostam) or meglumine antimoniate (Glucantime), These drugs are quite toxic. They are given by injection and usually administered intramuscularly or intravenously for three weeks or intralesionally for seven or more weeks. That is why the successful introduction of radiofrequency-induced heat therapy using a Thermomed™ 1.8 instrument administered in a single application, with minimal toxic effects, is so important for the treatment of CL.

Deoxycoformycin (pentostatin) in the treatment of splenic marginal zone lymphoma (SMZL) with or without villous lymphocytes.

BACKGROUND: Splenic marginal zone lymphoma (SMZL) is an infrequent B-cell neoplasm that pursues an indolent course. Signs and symptoms, mostly related to hypersplenism, are successfully managed by splenectomy. However, the therapy of patients who are not fit for a surgical procedure or who relapse after splenectomy, is still an unsettled issue. PATIENTS AND METHODS: We report a phase-II study on 16 patients with SMZL, three therapy naïve and 13 pretreated, all showing systemic symptoms or progressive worsening of peripheral cytopenia, who were treated with pentostatin at a dose of 4 mg/m2 every other week for 6-10 wk. In relapsed patients, the median interval between diagnosis and treatment was 26 month (range: 8-49). RESULTS: Overall, 68% of the patients showed a clinical response. Two out three patients, who received pentostatin as first line therapy, attained a complete response (CR). One CR and seven minor or good haematological responses were recorded in relapsed patients. Treatment toxicity, mostly haematological, proved manageable. With a median follow-up of 35 month the median overall survival (OS) is 40 month and the median progression free survival (PFS) is 18 month. CONCLUSION: Our data show that pentostatin administered every other week has a good degree of activity in the treatment of SMZL and suggest that this schedule could be considered a possible therapeutic option for patients who are not fit for splenectomy or have relapsed.

Dose-finding based on efficacy-toxicity trade-offs.

We present an adaptive Bayesian method for dose-finding in phase I/II clinical trials based on trade-offs between the probabilities of treatment efficacy and toxicity. The method accommodates either trinary or bivariate binary outcomes, as well as efficacy probabilities that possibly are nonmonotone in dose. Doses are selected for successive patient cohorts based on a set of efficacy-toxicity trade-off contours that partition the two-dimensional outcome probability domain. Priors are established by solving for hyperparameters that optimize the fit of the model to elicited mean outcome probabilities. For trinary outcomes, the new algorithm is compared to the method of Thall and Russell (1998, Biometrics 54, 251-264) by application to a trial of rapid treatment for ischemic stroke. The bivariate binary outcome case is illustrated by a trial of graft-versus-host disease treatment in allogeneic bone marrow transplantation. Computer simulations show that, under a wide rage of dose-outcome scenarios, the new method has high probabilities of making correct decisions and treats most patients at doses with desirable efficacy-toxicity trade-offs.

Pentostatin and rituximab in the treatment of patients with B-cell malignancies.

Both pentostatin (Nipent) and rituximab (Rituxan) have single-agent activity in B-cell malignancies, including indolent and intermediate-grade non-Hodgkin's lymphoma (NHL). Pentostatin is also active in pretreated patients with chronic lymphocytic leukemia (CLL). In spite of current treatment modalities, few patients with these diseases are cured. The combination of rituximab and pentostatin is an attractive treatment option because both drugs have a limited toxicity profile and can be delivered on an outpatient basis. We describe the design of a phase II multicenter study to evaluate the safety and efficacy of pentostatin in combination with rituximab in patients with previously treated and untreated low-grade NHL and CLL.

Pentostatin treatment of cutaneous T-cell lymphoma.

Mycosis fungoides is an indolent primary cutaneous T-cell lymphoma (CTCL) that usually progresses from localized skin lesions to systemic disease. Sézary syndrome is a distinct variant characterized by generalized erythroderma and circulating cerebriform cells in the peripheral blood. The malignant cell in both diseases is a mature T cell, usually with a CD4-positive, CD8-negative phenotype. Among the treatment modalities used in these diseases are skin-directed therapy, single-agent and combination systemic chemotherapy, and, more recently, bioimmunotherapy. Pentostatin (Nipent), a potent inhibitor of adenosine deaminase, has activity in a wide range of lymphoid malignancies. At The Royal Marsden Hospital, we treated 29 cutaneous T-cell lymphoma patients with pentostatin, including 16 with Sézary syndrome, 5 with mycosis fungoides, and 8 with other cutaneous T-cell lymphomas. The median age of patients was 61 years (range, 26 to 87 years), with a male-female ratio of 2.5:1. The majority (N = 20) had received prior therapy. Pentostatin was administered at a dose of 4 mg/m2/wk for 4 weeks, and injections were continued every 1 to 2 weeks until maximum response. The overall response rate was 35%. However, only patients with Sézary syndrome achieved a good response, demonstrating an overall response rate of 62% (three complete responses plus seven partial responses). The median disease-free interval for responders was 9 months (range, 3 to 84 months). There was no significant treatment-related toxicity. We conclude that pentostatin is an effective single-agent therapy for patients with Sézary syndrome but not for those with other cutaneous T-cell lymphomas.

Adenosine-mediated killing of cultured epithelial cancer cells.

Because micromolar concentrations of adenosine (Ado) have been documented recently in the interstitial fluid of carcinomas growing in animals, we examined the effects of low concentrations of Ado on the growth of cultured human carcinoma cells. Ado alone had little effect upon cell growth. In the presence of one of a number of Ado deaminase (ADA) inhibitors, Ado led to significant growth inhibition of all cell lines tested. Similar effects were found when ATP, ADP, or AMP was substituted for Ado. Surprisingly, the ADA inhibitor coformycin (CF) had a much greater potentiating effect than did 2'-deoxycoformycin (DCF), although DCF is a more potent ADA inhibitor. The growth inhibition of the Ado/CF combination was not abrogated by pyrimidines or caffeine, a nonspecific Ado receptor blocker. Toxicity was prevented by the addition of the Ado transport inhibitor dipyridamole or the Ado kinase inhibitor 5'-amino 5'-deoxyadenosine. S-Adenosylhomocysteine hydrolase is not involved because neither homocysteine thiolactone nor an S-adenosylhomocysteine hydrolase inhibitor (adenosine dialdehyde) potentiated toxicity of the Ado/CF combination. Unexpectedly, substitution of 2'-deoxyadenosine (the toxic moiety in congenital ADA deficiency) for Ado, did not lead to equivalent toxicity. The Ado/CF combination inhibited DNA synthesis and brought about morphological changes consistent with apoptosis. Together, these findings indicate that the Ado-mediated killing proceeds via an intracellular route that requires the action of Ado kinase. The enhanced cofactor activity of CF may be attributable to its being a more potent inhibitor of AMP deaminase than is DCF.

[Therapeutic aspects in the management of hairy cell leukemia]. / Aspects thérapeutiques de la leucémie à tricholeucocytes.

CHRONIC B CELL PROLIFERATION: An estimated 80 to 120 new cases of hairy cell leukemia are diagnosed annually in France. Median survival is 5 years for untreated patients who develop a series of infectious complications. For many years, interferon alpha was the standard therapy but the therapeutic strategy has changed with the arrival of purine analogs, deoxycoformicine and 2-CdA. THERAPEUTIC OPTIONS: We searched Medline, Pascal, and Current Contents for literature on the treatment of hairy cell leukemia over the last 10 years and discuss here available data on response rate, mechanism of action and adverse effects of different therapeutic options. BY TREATMENT: Interferon generally induces partial response and most patients relapse after treatment withdrawal. The purine analogs, desoxycoformycine and 2-chlorodeoxyadenosine, are more active than interferon inducing response in approximately 90% of the cases, even after interferon failure, complete response is achieved in 50% to 70% of patients. Relapse rate at 5 years appears to be limited to 10% n 15%. Besides infections, the main adverse effect is the constant deep and persistent decline in CD4 counts but with no special risk of opportunistic infection. The increased rate of secondary cancers in long-term survivors and its possible relationship with treatments remains a controversial topic.

Toxicity of cordycepin in combination with the adenosine deaminase inhibitor 2'-deoxycoformycin in beagle dogs.

For 3 consecutive days, the nucleoside cordycepin (3'-deoxyadenosine) was administered as 1-hr iv infusions (0, 1, 4, 8, 10, or 20 mg/kg/day) to dogs. These doses were given 1 hr after a bolus iv injection (0.25 mg/kg/day) of 2'-deoxycoformycin (dCF), a potent inhibitor of adenosine deaminase. The hypothesis was that dCF would affect the toxicity of cordycepin. Plasma adenosine deaminase activity was strongly inhibited during the dose period and for 5 days following the final dose of dCF. Dogs given cordycepin alone showed no drug-related toxicities. In dogs given only dCF, drug-related toxicity to lymphoid tissue (lymphopenia and thymus lymphoid depletion), thrombocytopenia, and decreases in food consumption were observed. Cordycepin in combination with dCF produced symptoms associated with severe gastrointestinal toxicity (decreased body weights, emesis, diarrhea, decreased food consumption, and necrosis of the gastrointestinal tract) and bone marrow toxicity (lymphopenia, thrombocytopenia, and depletion of hematopoietic cells). The gastrointestinal tract and bone marrow were sites associated with dose-limiting toxicities. In surviving dogs, most of the effects were reversible by Day 30. The maximum tolerated dose of cordycepin administered in combination with dCF was 8 mg/kg/day (160 mg/m2/day) given daily for 3 days.

Developing allantois is a primary site of 2'-deoxycoformycin toxicity.

In this study, an assessment of normal mouse allantoic development and its sensitivity to 2'-(R)-deoxycoformycin (dCF; Pentostatin) exposure were examined. Both dissecting microscopy and scanning electron microscopy were used to describe the normal growth and morphogenesis of the mouse allantois over gestational days 7-10 as a preliminary step in evaluating potential abnormal allantoic ontogeny and its effect on umbilical cord and placental development. Two abnormal allantoic/umbilical cord phenotypes were observed subsequent to injecting pregnant mice with 5 mg dCF/kg, i.p., on gestational day 7 (GD 7) and evaluating litters on GD 10, 11, and 12. Abnormal phenotypes included: (1) an allantois which extended approximately halfway across the exocoelom but failed to establish a functional contact with the chorion; and (2) a phenotype characterized by reduced expansion of the allantois across the chorionic surface, a very thin umbilical cord, and aberrant vascularization throughout the structure. Both abnormal phenotypes exhibited either an agenesis or hypogenesis of the umbilical cord and chorioallantoic plate, respectively. Neither abnormal phenotype, however, exhibited errors in the directionality of allantoic growth toward the chorion nor in the formation of aberrant contacts between allantois and adjacent yolk sac or amnionic mesenchyme. Statistical interpretation of the experimental data strongly suggested that abnormalities in allantoic/umbilical cord development were directly associated with embryolethality as evidenced by a decline in the frequency of abnormal allantoic/umbilical cord phenotypes over GD 10-12 (73, 36, and 4%; respectively) and a concomitant increase in the frequency of implantation site resorptions over the same time period (7, 47, and 78%). These results strongly suggest that the developing allantois is very sensitive to the effects of dCF exposure, and that interference with its development leads to embryolethality by GD 12.

Subchronic toxicity of pentostatin in Wistar rats.

Pentostatin, an adenosine deaminase inhibitor, has been approved for the treatment of refractory hairy cell leukemia. In a preclinical toxicity study, Wistar rats were administered 0, 1, 10, 25, and 50 mg/kg (0, 6, 60, 150, and 300 mg/m2, respectively) pentostatin intravenously once a week for 26 wk (1.5-75-fold above the therapeutic dose in humans). Lymphoplasmacytic thyroiditis was present in 20% of females given 25 mg/kg and in 20 and 47% of males and females given 50 mg/kg, respectively. Thyroiditis was still present 4 wk following drug withdrawal. Thyroiditis was characterized by glandular enlargement, follicular epithelial hyperplasia and degeneration, colloid depletion, and interstitial infiltrates of lymphocytes and plasma cells. Drug-related changes in other tissues included lymphoid depletion of T-cell regions of thymus, spleen, and lymph nodes; bronchiolization of alveolar ducts with accumulation of mucus and foamy macrophages; testicular atrophy with sperm granulomas; dermoepidermal lymphocytic infiltrates with ulceration and alopecia; and hepatocytomegaly.

Pentostatin increases the acute toxicity of high dose cyclophosphamide.

One dose of pentostatin was added to a standard cyclophosphamide (CY) based transplant regimen in two patients in an attempt to decrease the rate of non-engraftment in haploidentical allogeneic BMT. Despite a normal cardiac history and evaluation prior to transplant, both patients suffered fatal cardiac toxicity within 48 h of receiving the chemotherapy. This phenomenon was further investigated in an animal model. Laboratory rats were treated with progressive doses of CY in a range that produces acute cardiac toxicity. Successive groups of rats were treated with either pentostatin or fludarabine and CY at 400 mg/kg. Neither pentostatin nor fludarabine alone produced early mortality. However, a marked increase in early mortality was noted in those animals treated with pentostatin and high-dose CY. The addition of fludarabine did not increase the early toxicity of CY. Autopsy revealed no gross or microscopic abnormalities in the animals. The implications of adding agents that interfere with adenosine metabolism to CY based transplant regimens is discussed.

Occurrence of embryotoxicity in mouse embryos following in utero exposure to 2'-deoxycoformycin (pentostatin).

Previous investigations had shown that i.p. injection of 2'-deoxycoformycin (dCF; pentostatin; 5 mg/kg) on either E7 or E8 into pregnant mice results in a 61-81% resorption rate at E17. The incidence of visible gross malformations among the surviving conceptuses was exceptionally low (3%) at the time of necropsy on E17 and was unrelated to dCF dose (Knudsen et al., Teratology, 40:5-626, '89; Teratology, 45:91-103, '92). These findings demonstrated the embryotoxicity of dCF but provided no clues as to the site(s) of dCF action. To define the lesion site(s), we have now examined embryos at 72 h (E10), 96 h (E11), and 120 h (E12) following administration of a highly embryotoxic dose of 5 mg dCF/kg to dams on E7. Deoxycoformycin caused multiple abnormalities and growth retardation, and the temporal sequence between maximal abnormal embryo incidence and resorption frequency was established. The quantitative data show that the maximal occurrence of abnormal embryos on E10 (71%) was followed by a maximal resorption rate on E12 (78%). There was a strong correlation (r = -0.82; P < 0.05) between the rapid decline of percent abnormal embryos over E10-E12 and the simultaneous increase in resorption rate, with linear regression analysis showing nearly equal but opposite slopes (-31.2% vs. +35.8% per gestational day, respectively). This suggests that one or more of the abnormalities seen at E10 is associated with the death and resorption of the embryo at E12. The dCF treatment perturbed a wide spectrum of developmental events, including neural tube closure, craniofacial and limb development, turning of the embryo, and growth retardation. None of the individual abnormalities, however, can quantitatively account for the high percentage of dead and resorbed embryos. Therefore, the specific cause of dCF-induced embryolethality is not clear. There is evidence both for direct dCF toxicity at specific embryonic sites as well as for a generalized retardation in the rate of development.

Effects of (R)-deoxycoformycin (pentostatin) on intrauterine nucleoside catabolism and embryo viability in the pregnant mouse.

The viability of early mouse embryos is acutely sensitive to (R)-deoxycoformycin (pentostatin), a tight-binding inhibitor of adenosine deaminase (ADA). Previous studies have shown that a single 5-mg/kg dose on day 7 (plug = day 0) of gestation fully inhibits uteroplacental ADA activity within 0.5 h; causes massive cell death in the neural plate and primary mesenchyme by 6 h, major craniofacial anomalies by day 10, and resorption by day 12 (Knudsen et al., '89; Airhart et al., '91). The present study has examined further the developmental toxicity and early effects of this inhibitor on ADA metabolism. (R)-Deoxycoformycin was administered to pregnant CD-1 (ICR) mice as a single intraperitoneal dose of 0.5-10 mg/kg total body weight on days 6-11 of gestation. The major adverse effect, early resorption, was dose dependent and specific to day 7-8 exposure. Treatment with 5 mg/kg on day 7 resulted in 85% resorptions, 15% malformations, and a 24% reduction in mean fetal weight, whereas the same dose of (S)-deoxycoformycin had no effect. Levels of adenosine and 2'-deoxyadenosine, which are the endogenous substrates of ADA, were monitored in the embryo/decidual unit (E/D) by reversed-phase high-performance liquid chromatography (RP-HPLC). In response to the inhibitor, both nucleosides increased transiently in the antimesometrial compartment (antimesometrial decidua + embryo). Peak levels (Cmax) of adenosine and 2'-deoxyadenosine were dose dependent over the range tested (0.05-10 mg/kg). Exposure to 5 mg/kg on day 7 raised adenosine levels within 0.5 h to 42-fold over the basal level of 0.06 nmol/mg protein. There was an even stronger effect on 2'-deoxyadenosine levels, which were elevated 674-fold over the detection limit of 0.0005 nmol/mg protein. Direct exposure to the inhibitor in serum-free E/D culture produced similar results: 50 microM (R)-deoxycoformycin within 1 h raised adenosine levels 26-fold and 2'-deoxyadenosine levels 410-fold. In vivo studies also showed a general correlation between embryolethality and the length of adenine nucleoside pool expansion, apparent for exposure on day 7, 8, or 9 but not on day 6, suggesting that the embryo becomes sensitive to adenosine or 2'-deoxyadenosine once the neural plate has formed.

Deoxycoformycin in the treatment of mature T-cell leukaemias.

We describe the results of treatment with 2'-deoxycoformycin (DCF) in 68 patients with post-thymic (mature) T-cell malignancies. These included: prolymphocytic leukaemia (T-PLL), 31, HTLV-1 + adult T-cell leukaemia/lymphoma (ATLL), 20, cutaneous T-cell lymphoma (CTCL), comprising mycosis fungoides and Sezary syndrome, 13, and large granular lymphocytic leukaemia, four. Two-thirds of patients were refractory to previous therapy, which included four drug combinations. DCF was given intravenously at 4 mg m-2 weekly for the first 4 weeks and then every 2 weeks until maximal response. Toxicity was very low with only one death resulting from prolonged neutropenia. Overall response rates, partial (PR) and complete. (CR), were 38%, with variations according to diagnosis. Best responses, 54%, were seen in CTCL but limited to Sezary patients, one CR, six PR, whilst none of the mycosis fungoides responded. Responses in T-PLL were recorded in 48% including three CR (of 8-12 months' duration unmaintained) and 12 PR. Fifteen per cent of responses were seen in ATLL. The only ATLL responders - two CR, one PR - were those patients who received combination chemotherapy prior to DCF, with reduction of tumour bulk but short of PR. When results were analysed according to membrane phenotypes it was apparent that responses were seen mainly in cases with CD4+, CD8- T cells -22 of 47 (47%) - contrasting with only three of 19 (16%) with other T-cell phenotypes. We conclude that DCF is a useful therapy for the treatment of T-cell leukaemias, in particular Sezary syndrome and T-PLL, and should play a part in strategies to improve the natural history of this group of lymphoid malignancies.

Developmental toxicity of pentostatin (2'-deoxycoformycin) in rats and rabbits.

The developmental toxicity of the potent adenosine deaminase (ADA) inhibitor, pentostatin (2'-deoxycoformycin), was investigated in pregnant rats and rabbits administered daily iv doses during organogenesis. Rats received 0, 0.01, 0.10, or 0.75 mg/kg on gestation days 6-15 and rabbits received 0, 0.005, 0.01, or 0.02 mg/kg on gestation days 6-18 and maternal and fetal parameters were evaluated on gestation day 21 (rats) or 30 (rabbits). Live fetuses were examined for external, visceral, and skeletal malformations and variations. In rats, maternal body weight gain and food consumption were significantly suppressed at doses of 0.10 and 0.75 mg/kg during the treatment period but returned to control levels during posttreatment. Increased postimplantation loss and decreased numbers of live fetuses, litter size, and fetal body weight were observed at 0.75 mg/kg. A statistically significant increase in the incidence of vertebral malformations occurred at 0.75 mg/kg. The incidence of certain skeletal variations (extra presacral vertebrae, extra ribs, hypoplastic vertebrae) was also increased at 0.75 mg/kg. Ossification of cervical centra was reduced at 0.75 mg/kg compared with controls. In rabbits, marked maternal toxicity (death, body weight loss, and decreased food consumption) and reproductive toxicity (abortion and premature delivery) occurred in all pentostatin-treated groups. However, there were no significant effects on number of live fetuses, pre- or postimplantation loss, litter size, or fetal body weights in the animals with live litters. There was also no apparent increase in the incidence of malformations or variations in the live fetuses of pentostatin-treated rabbits. Thus, these studies demonstrate developmental toxicity of pentostatin in rats and rabbits, and teratogenicity in rats, at maternally toxic doses.

Proliferative bone lesions in rats given anticancer compounds.

Proliferative endosteal lesions were observed in metaphysis and diaphysis of femur and sternebra of Wistar (CRL:[WI]BR) rats administered 3 chemically-distinct anticancer compounds with dissimilar mechanisms of action: trimetrexate glucuronate, an antifolate; pentostatin, an adenosine deaminase inhibitor; and CI-980, a mitotic inhibitor. Islands of woven bone, often circumscribed by conspicuous myelostromal proliferation, were seen on Days 8-28 in rats given trimetrexate glucuronate daily by gavage, and on Day 4 but not Day 29 in rats given a single intravenous dose of pentostatin. Intravenous administration of CI-980 for 1 or 5 days resulted in marrow necrosis, marked centripetal new bone formation, and myelostromal proliferation on Days 4 and 8, respectively. These lesions were not present at the termination of these latter studies (Days 29 and 35, respectively). In conclusion, anticancer compounds induced local bone marrow injury and the release of local inflammatory mediators which may have provided the stimulus for bone formation and myelostromal proliferation.

Successful treatment of hair cell leukemia with 2'-deoxycoformycin after failure of interferons alpha or beta.

Two patients with hairy cell leukemia (HCL) who failed alpha-2a-interferon and one who failed beta-ser-interferon were treated with 2'-deoxycoformycin (DCF), 4 mg/m2, by intravenous bolus infusion every 2 weeks. All three patients achieved a complete response, continuing for 9+, 14+, and 15+ months. Treatment was discontinued when complete remission was diagnosed. DCF-induced remission has not been previously reported after beta-ser-interferon failure. These patients, as well as 12 others in the literature reviewed herein, demonstrate the efficacy of DCF in HCL patients unresponsive to alpha, beta, and gamma interferon.

Early postimplantation embryolethality in mice following in utero inhibition of adenosine deaminase with 2'-deoxycoformycin.

Adenosine deaminase (ADA) catalyzes the hydrolytic deamination of adenosine (or 2'-deoxyadenosine) to inosine (or 2'-deoxyinosine). Previously, we have shown that ADA activity is subject to strong cell-specific developmental regulation in placental tissues of mice between days 6 and 11 of gestation (Knudsen et al.:Biology of Reproduction 39:937-951, 1988). In the present study, we examined the effects of intrauterine exposure to 2'-deoxycoformycin (dCF; pentostatin), a potent irreversible inhibitor of ADA, on early postimplantation development. Deoxycoformycin was administered to pregnant ICR mice as a single intraperitoneal injection at a dose of 5 mg/kg on one of days 6 through 11 of gestation (plug day 0). A marked increase in the incidence of implantation site resorptions was observed following treatment specifically on days 7 (61% resorbed) or 8 (78% resorbed). No effect was observed following treatment on days 6, 9, 10, or 11. ADA-immunoreactive protein was shown, by ABC-immunoperoxidase staining on days 7 or 8 of gestation, to be present at high levels in decidual cells of the antimesometrial region but at below-detectable levels in the embryo. Treatment of pregnant dams with dCF on day 7 produced a complete (greater than 99%) inhibition of ADA activity in the antimesometrial decidua by 30 min, induced excessive cell death in the prospective neural plate and primary mesenchyme of the trilaminar disc by 6 h, and arrested embryonic development at an early somite stage. These results suggest that the antimesometrial decidua plays a protective role in preventing an inappropriate accumulation of endogenous ADA substrates in the implantation site.