RESUMO
A soluble form of CD8 antigen (sCD8) has been shown to be released by activated CD8 + lymphocytes. Measurements of sCD8 may serve as an index of suppressor/cytotoxic cell activity. To assess the clinical significance of this observation in response to malignancy, we have investigated the sCD8 concentrations in 38 patients with hairy cell leukemia (HCL) not yet treated with any systemic therapy. The median plasma sCD8 level of the 20 nonsplenectomized patients was 1,025 U/ml and was significantly higher than that in the 18 patients who had previous splenectomy (median = 200 U/ml, p less than 0.0001), or in 14 normal controls (median = 350 U/ml, p less than 0.0001). Compared to controls, splenectomized patients had also significantly lower levels of sCD8 (p less than 0.01). The median concentration of soluble interleukin-2 receptor (sIL2R) in nonsplenectomized patients was 14,500 U/ml and was in the same range as in splenectomized patients (15,000 U/ml). There was no overlap in sIL2-R levels between controls (median = 300 U/ml) and patients. Investigation of serial plasma samples in 7 patients who received deoxycoformycin (DCF) and 11 patients treated with interferon alpha (IFN-alpha) showed a normalization of sCD8 levels and a decrease of sIL2R concentrations in those patients who showed hematological improvement. Normalization of sIL2R was, however, only observed in patients with complete remission. Our observation indicates that splenectomy might cause a reduction of the activation of suppressor/cytotoxic cells in patients with HCL. Treatment with either DCF or IFN-alpha also modulates the sCD8 levels to normal range. Measurements of sCD8 and sIL2-R might give more insight into the pathogenesis of HCL and serve as parameters for monitoring different phases of the disease and response to therapy.
Assuntos
Antígenos de Diferenciação de Linfócitos T/análise , Leucemia de Células Pilosas/imunologia , Receptores de Interleucina-2/análise , Esplenectomia , Antígenos/análise , Antígenos CD8 , Coformicina/análogos & derivados , Coformicina/uso terapêutico , Humanos , Interferon Tipo I/uso terapêutico , Leucemia de Células Pilosas/terapia , PentostatinaRESUMO
Interferon-alpha (IFN-a) or 2'-deoxycoformycin (pentostatin; DCF) have each been shown to be highly active in hairy-cell leukemia (HCL). In this phase II study of the Leukemia Cooperative Group of the European Organization for Research and Treatment of Cancer (EORTC), the efficacy and toxicity of DCF were investigated in patients who were resistant to IFN-a treatment. Resistance was defined as: (1) progressive disease (PD) under IFN-a therapy for more than 2 months; (2) stable disease (SD) after more than 6 months of IFN-a treatment; (3) relapse within 3 months of discontinuing IFN-a; and (4) intolerance to IFN-a because of World Health Organization (WHO) grade 3 or 4 toxicity. DCF was applied at a dosage of 4 mg/m2 weekly x 3, then 4 mg/m2 every other week x 3. Responders were given a maintenance therapy once per month for a maximum of 6 months. At the time of report, 33 patients with resistant disease were evaluable for response and toxicity. Median duration of IFN-a therapy before DCF administration was 14.7 months (range, 1 to 41 months). Complete remissions (CRs) were achieved in 11 patients and partial remissions (PRs) in 15, resulting in a total response rate of 78.8%. Median interval between beginning of DCF therapy to best response was 3.9 months with a range from 2.0 to 7.0 months. Two patients who achieved PR have relapsed 7 and 14 months after cessation of DCF therapy. The median duration of response was over 11.5 months (range, over 3.0 to over 24.0 months). Three patients died within the first 6 weeks of DCF treatment: one of drug-unrelated cardiomyopathy and two of fungal pneumonia. The patients with early death (n = 3) and nonresponsive disease (n = 4) received IFN-a treatment for a longer period (median, 18.0 months) than did the 26 responsive patients (median, 10.0 months). Major side effects included nausea, skin rash, and infections and were otherwise mild. Thus, DCF is highly active in patients with HCL resistant to IFN-a.
Assuntos
Antineoplásicos/uso terapêutico , Coformicina/uso terapêutico , Interferon Tipo I/uso terapêutico , Leucemia de Células Pilosas/tratamento farmacológico , Ribonucleosídeos/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Contagem de Células Sanguíneas , Coformicina/efeitos adversos , Coformicina/análogos & derivados , Resistência a Medicamentos , Feminino , Humanos , Leucemia de Células Pilosas/sangue , Masculino , Pessoa de Meia-Idade , Pentostatina , Indução de RemissãoAssuntos
Leucemia de Células Pilosas/terapia , Antineoplásicos/uso terapêutico , Coformicina/análogos & derivados , Coformicina/uso terapêutico , Eritropoese , Feminino , Humanos , Interferon Tipo I/uso terapêutico , Radioisótopos de Ferro , Leucemia de Células Pilosas/diagnóstico , Leucemia de Células Pilosas/fisiopatologia , Pessoa de Meia-Idade , Pentostatina , Proteínas Recombinantes , EsplenectomiaRESUMO
Adult T-cell leukemia (ATL) was first discovered and reported in Japan, where it has a high incidence in the southwest region. The retrovirus HTLV-I (human T-cell lymphotropic virus type I) is considered to be related to its etiology. In ATL endemic areas, HTLV-I carriers are found at a fairly high percentage even among healthy individuals. ATL shows diverse clinical features. It can be divided into 5 types (acute type, chronic type, smoldering type, crisis type, and lymphoma type). ATL cells originate from the CD4-positive subset of peripheral T cells; they show a characteristic notch in the nucleus and a lobulation tendency. ATL resists chemotherapy, and patients with acute and lymphoma types have quite a poor prognosis. A definite diagnosis of ATL is made by documenting the presence of HTLV-I proviral DNA in the DNA of tumor cells. HTLV-I infection is caused by transmission of live lymphocytes via three routes (from mother to children, from males to females, and by transfusion). Familial occurrence of ATL is frequently seen. HTLV-I infection is also seen in other countries, but its incidence is highest in Japan. It is thus an urgent task for Japanese physicians to eliminate HTLV-I infection.
Assuntos
Leucemia de Células T , Antígenos de Diferenciação de Linfócitos T/imunologia , Antineoplásicos/uso terapêutico , Coformicina/análogos & derivados , Coformicina/uso terapêutico , Feminino , Infecções por HTLV-I/epidemiologia , Humanos , Japão , Leucemia de Células T/tratamento farmacológico , Leucemia de Células T/epidemiologia , Leucemia de Células T/imunologia , Leucemia-Linfoma de Células T do Adulto/epidemiologia , Masculino , Pentostatina , FotoquimioterapiaRESUMO
We conducted a phase II trial of deoxycoformycin (pentostatin [DCF]) in chronic lymphocytic leukemia (CLL). Eligibility criteria included age greater than 18 years, Cancer and Leukemia Group B (CALGB) performance status 0 to 2, lymphocyte count greater than or equal to 15,000 cells/microL, international stage B or C disease (multiple lymph nodes involved and/or hemoglobin [Hgb] less than 11 g and/or platelets less than 100,000/microL) and no more than one prior treatment regimen. DCF dose was 4 mg/m2 intravenously (IV) weekly for 3 weeks and then every 2 weeks. There were 39 eligible patients (35 men and four women; median age, 63 years; median time from diagnosis to study entry, 3 years). Of these 39 patients, 31% were stage B and 33% had no prior treatment. Median laboratory values at entry were Hgb 10.5 g, WBC 96,100/microL, and platelets 93,500/microL. Nodal involvement was present in 90%, splenomegaly in 81%, and hepatomegaly in 47%. Patients received a median of nine DCF injections, with a range of four to 26. Three patients were not evaluable for response. Overall, 3% achieved a complete response (CR), 23% a partial response (PR), 28% showed clinical improvement (CI), and 38% had stable disease (SD). Associated toxicities (grade 2 or worse) observed were infections (52%), worsening of thrombocytopenia (26%) or anemia (33%), nausea and vomiting (31%), rash or pruritus (20%), and stomatitis (8%). We conclude that DCF is an active agent in CLL with acceptable toxicity.
Assuntos
Inibidores de Adenosina Desaminase , Antineoplásicos/uso terapêutico , Coformicina/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Nucleosídeo Desaminases/antagonistas & inibidores , Ribonucleosídeos/uso terapêutico , Idoso , Antineoplásicos/efeitos adversos , Coformicina/efeitos adversos , Coformicina/análogos & derivados , Avaliação de Medicamentos , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Linfocitose/patologia , Masculino , Pessoa de Meia-Idade , Pentostatina , Indução de Remissão , Trombocitopenia/patologiaRESUMO
This is a review of current treatment for hairy cell leukemia (HCL). Data for this analysis were obtained from the Italian HCL Registry, as well as from other published series. We have given space to the impact of interferon and pentostatin on the management of this disease. Other issues are also discussed, such as the relevance of achieving a complete remission with respect to overall and relapse-free survival. We include a final section on recommendations which may prove useful in designing an appropriate therapeutic strategy.
Assuntos
Leucemia de Células Pilosas/terapia , Corticosteroides/uso terapêutico , Antineoplásicos/uso terapêutico , Coformicina/análogos & derivados , Coformicina/uso terapêutico , Terapia Combinada , Humanos , Interferon Tipo I/uso terapêutico , Leucemia de Células Pilosas/tratamento farmacológico , Leucemia de Células Pilosas/radioterapia , Leucemia de Células Pilosas/cirurgia , Oximetolona/uso terapêutico , Cuidados Paliativos , Pentostatina , Esplenectomia , Esplenomegalia/radioterapia , Esplenomegalia/cirurgiaRESUMO
Deoxycoformycin, a potent and specific adenosine deaminase antagonist, reduced ischemic hippocampal damage and the associated hypermotility in Mongolian gerbils. Cerebral ischemia was induced by a bilateral 5 min occlusion of the carotid arteries. Deoxycoformycin (500 micrograms/kg IP), administered 15 min prior to ischemia, prevented the increase in locomotor activity normally observed with this model and significantly reduced the ischemia-induced damage to CA1 hippocampal neurons. The results suggest that deoxycoformycin may be useful in the prevention of brain damage due to cerebral ischemia.
Assuntos
Adenosina Desaminase/metabolismo , Coformicina/uso terapêutico , Hipocampo/patologia , Ataque Isquêmico Transitório/tratamento farmacológico , Nucleosídeo Desaminases/metabolismo , Ribonucleosídeos/uso terapêutico , Animais , Coformicina/análogos & derivados , Gerbillinae , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Ataque Isquêmico Transitório/enzimologia , Ataque Isquêmico Transitório/patologia , Masculino , Pentostatina , Fatores de TempoRESUMO
An analysis of the clinical outcomes in 66 patients with hairy cell leukemia treated with pentostatin under the Special Exception mechanism of the Division of Cancer Treatment, National Cancer Institute, between 1983 and 1987 has revealed a favorable balance of risk and benefit. Hematologic parameters and performance status were improved in most patients treated outside the clinical trials mechanism. The treating physicians considered 37 patients (56%) to be complete responders and 15 patients (23%) to be partial responders. Four patients (6%) died while receiving pentostatin. Life-threatening leukopenia (wbc count, less than 1,000/mm3) was reported in 24% of patients, and severe or life-threatening infection occurred in 11%. The experience gained with these patients supplements the information presently being collected from the controlled clinical trials and supports the development of a group C treatment protocol.
Assuntos
Antineoplásicos/uso terapêutico , Coformicina/uso terapêutico , Leucemia de Células Pilosas/tratamento farmacológico , Ribonucleosídeos/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Coformicina/efeitos adversos , Coformicina/análogos & derivados , Feminino , Humanos , Leucemia de Células Pilosas/patologia , Masculino , Pessoa de Meia-Idade , PentostatinaAssuntos
Antineoplásicos/uso terapêutico , Coformicina/uso terapêutico , Leucemia de Células Pilosas/terapia , Ribonucleosídeos/uso terapêutico , Antineoplásicos/efeitos adversos , Coformicina/efeitos adversos , Coformicina/análogos & derivados , Terapia Combinada , Humanos , Interferon Tipo I/uso terapêutico , Pentostatina , Proteínas Recombinantes , Indução de RemissãoRESUMO
2'-Deoxycoformycin (pentostatin [dCF]), a potent inhibitor of adenosine deaminase (ADA), was administered in a biweekly low-dose (2 to 4 mg/m2) intravenous (IV) schedule to patients with advanced hairy cell leukemia. Twenty-three patients were treated, including 12 patients previously treated by splenectomy and five patients treated with interferon. Twenty-one of 23 patients had objective responses, including 20 who achieved a complete remission (CR). Responses occurred rapidly, with an average time to CR of 5.4 months. Treatment was not continued once CR was achieved, and 15 of 20 patients remain in remission with an average duration of 12.6 months. CRs were achieved in both patients previously treated with interferon (three of five) and patients with marked splenomegaly (three of three). Relapses, when seen, have occurred in the bone marrow alone and the one patient who required retreatment was reinduced into CR. Toxicity has been mild and reversible, with nausea and vomiting, conjunctivitis, and skin rash as the main complications of treatment. dCF is the most effective single agent in the treatment of hairy cell leukemia, inducing a high percentage of CRs in all subgroups. Two multiinstitutional trials are now underway to compare its effectiveness v alpha interferon.
Assuntos
Antineoplásicos/uso terapêutico , Coformicina/uso terapêutico , Leucemia de Células Pilosas/tratamento farmacológico , Ribonucleosídeos/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Medula Óssea/patologia , Coformicina/efeitos adversos , Coformicina/análogos & derivados , Feminino , Humanos , Leucemia de Células Pilosas/patologia , Masculino , Pessoa de Meia-Idade , Pentostatina , Recidiva , Indução de RemissãoRESUMO
This work considers the new advances in hairy cell leukemia therapy. During the last decades the only useful treatments were splenectomy, or, in case of failure or relapse, various chemotherapeutic approaches. Sometimes leukapheresis, radiotherapy, androgens, allogenic bone marrow transplantation, corticosteroids and lithium salts were used with few good results. Interferon and 2-deoxicoformycin recently introduced for the treatment of HCL have determined a dramatic change in the outlook of this disease, producing a high percentage of complete and partial remission.
Assuntos
Antineoplásicos/uso terapêutico , Coformicina/uso terapêutico , Interferons/uso terapêutico , Leucemia de Células Pilosas/terapia , Ribonucleosídeos/uso terapêutico , Coformicina/análogos & derivados , Humanos , Leucemia de Células Pilosas/tratamento farmacológico , Leucemia de Células Pilosas/cirurgia , Pentostatina , EsplenectomiaAssuntos
Antineoplásicos/uso terapêutico , Coformicina/uso terapêutico , Leucemia de Células Pilosas/tratamento farmacológico , Ribonucleosídeos/uso terapêutico , Inibidores de Adenosina Desaminase , Coformicina/análogos & derivados , Terapia Combinada , Avaliação de Medicamentos , Humanos , Interferon Tipo I/uso terapêutico , Estudos Multicêntricos como Assunto , Pentostatina , Indução de RemissãoRESUMO
Knowledge of the vital role of adenosine deaminase in lymphatic tissues has led to the development of enzyme inhibitors for treatment of lymphoid neoplasms. Deoxycoformycin is a potent ADA inhibitor and has been shown to be active in acute lymphoblastic leukemia at high doses but associated with unpredictable toxicity. In indolent lymphocytic leukemia or lymphoma with low ADA concentrations, this drug is effective at low doses with mild toxicity. The on-going EORTC trial shows that pentostatin is highly effective in hairy cell leukemia and can achieve durable complete remissions even if interferon alpha has failed. It will probably play an important role in the treatment of prolymphocytic leukemia, T- and B-cell chronic lymphocytic leukemia and Sézary syndrome.
Assuntos
Antineoplásicos/uso terapêutico , Coformicina/uso terapêutico , Leucemia de Células Pilosas/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Prolinfocítica/tratamento farmacológico , Ribonucleosídeos/uso terapêutico , Síndrome de Sézary/tratamento farmacológico , Adenosina/metabolismo , Inibidores de Adenosina Desaminase , Coformicina/análogos & derivados , Coformicina/farmacologia , DNA de Neoplasias/metabolismo , Avaliação de Medicamentos , Humanos , Estudos Multicêntricos como Assunto , Proteínas de Neoplasias/antagonistas & inibidores , PentostatinaRESUMO
Forty-six bone marrow biopsies from twelve hairy cell leukemia (HCL) patients, treated with either interferon(IFN)-alpha-2 (n = 8) or 2'deoxycoformycin(DCF) (n = 4), were examined using cryostat sections and an immunoperoxidase technique. Using this sensitive method we were able to demonstrate residual hairy cell (HC) infiltration in five cases, in which evaluation with conventional staining techniques on plastic embedded biopsies revealed complete remission. The amount of HCs in these five samples ranged from 1 to 7% (mean: 3%) of bone marrow cells. Consecutive biopsies in individual HCL patients revealed no changes of the immunological phenotype (CD19, CD22, CD25, CD10, CD11c, FMC7, HLA-DR, surface immunoglobulins) during IFN and DCF treatment. Within the infiltrated bone marrow a considerable number of "reactive" T lymphocytes was identified with prevalence of the T-helper (CD4+) subtype in untreated cases, whereas T-suppressor/cytotoxic (CD8+) cells were within the normal range. IFN treatment resulted in a reduction of CD4+ T lymphocytes (p less than 0.02). Minor alterations of CD8+ T lymphocytes and NK cells (HNK-1 + lymphoid cells) were found in bone marrow during IFN treatment. In DCF-treated patients bone marrow T lymphocytes were markedly reduced below the values of normal bone marrow. This DCF-induced T-cell depression might be related to the clinical observation of persistent cellular immune dysfunctions in HCL patients despite a DCF-induced remission.
Assuntos
Antineoplásicos/uso terapêutico , Medula Óssea/efeitos dos fármacos , Coformicina/uso terapêutico , Interferon Tipo I/uso terapêutico , Leucemia de Células Pilosas/terapia , Ribonucleosídeos/uso terapêutico , Adulto , Idoso , Antígenos de Superfície/análise , Biópsia , Medula Óssea/imunologia , Medula Óssea/patologia , Coformicina/análogos & derivados , Feminino , Humanos , Leucemia de Células Pilosas/imunologia , Leucemia de Células Pilosas/patologia , Masculino , Pessoa de Meia-Idade , Pentostatina , Fenótipo , Linfócitos T/classificação , Linfócitos T/efeitos dos fármacosRESUMO
Immune function in patients with hairy cell leukemia (HCL) was examined serially during treatment with alternating monthly cycles of recombinant interferon alpha-2a and 2'-deoxycoformycin (dCF). At presentation, most patients had normal numbers of T lymphocytes and their cells had normal proliferative responses to mitogens [phytohemagglutinin (PHA) and concanavalin A (Con A)] and alloantigens. Patients had severe monocytopenia, decreased delayed-type hypersensitivity (DTH) reactions, and decreased peripheral blood natural killer (NK) activity. Treatment caused a profound decrease in all lymphocyte subpopulations. T cells were more affected than B cells or NK cells. Numbers of CD4+ and CD8+ lymphocytes decreased to levels less than 200 cells/microliters in all patients during treatment. This decrease in T cell number was associated with a marked decrease in proliferative responsiveness to PHA, Con A, and alloantigens. These abnormalities persisted throughout the 14 months of treatment and have continued for up to 6 months beyond discontinuation of treatment. NK cell activity increased during treatment, but cycled depending on the phase of treatment; highest activities were observed after interferon (IFN)-alpha and lower levels of activity were observed after dCF. DTH responses generally did not improve during therapy. Levels of IgM, IgG, IgA, and IgD did not change during treatment, but IgE levels rose in most patients. All immunosuppressive effects were attributable to dCF since patients receiving IFN-alpha 2a alone did not exhibit these same immunosuppressive effects, and patients receiving dCF alone after IFN failure exhibited similar abnormalities. Despite this severe immunosuppression from dCF, life-threatening opportunistic infections have not been observed in our patient population. Six patients developed localized Herpes zoster infection among 21 patients who had received dCF. Pending the results of long-term follow-up, we recommend that dCF be reserved for patients who have failed splenectomy and IFN therapy.
Assuntos
Coformicina/uso terapêutico , Imunossupressores/uso terapêutico , Leucemia de Células Pilosas/imunologia , Ribonucleosídeos/uso terapêutico , Coformicina/análogos & derivados , Quimioterapia Combinada , Feminino , Herpes Zoster/induzido quimicamente , Humanos , Interferon Tipo I/uso terapêutico , Leucemia de Células Pilosas/complicações , Leucemia de Células Pilosas/tratamento farmacológico , Contagem de Leucócitos/efeitos dos fármacos , Ativação Linfocitária , Masculino , Pentostatina , Proteínas Recombinantes , Linfócitos T/efeitos dos fármacosRESUMO
Peripheral blood (PB) and bone marrow (BM) changes during 200 weeks' follow-up of 15 patients with hairy cell leukemia (HCL) undergoing low-dose 2'-deoxycoformycin (dCF) therapy are reported. Thirteen patients rapidly achieved complete remissions (CR) (median, 16 weeks). Previous splenectomy (two patients), or chemotherapy (two patients) had no effect on dCF response. Twelve patients have remained in CR. Patients with marked BM infiltration (hairy cell index [HCI] greater than 0.5; n = 5) had more pronounced pancytopenia and showed a slower hematologic recovery than those with a lesser degrees of infiltration. Additionally, patients with cytologic type II HCL (n = 5) had more pronounced pancytopenia with a greater tumor load in the BM, and exhibited slower hematologic recovery than those with type I (n = 5) HCL. There was a gradual decline in BM cellularity from 65% to 25% during year 1, a level which remained stable thereafter. Reticulin in the BM regressed in all nine patients in whom it was increased before dCF therapy. The authors have not seen any dysplastic changes in the hematopoietic cells during the period of follow-up.
Assuntos
Antineoplásicos/farmacologia , Medula Óssea/efeitos dos fármacos , Coformicina/uso terapêutico , Leucemia de Células Pilosas/tratamento farmacológico , Ribonucleosídeos/uso terapêutico , Adulto , Idoso , Medula Óssea/análise , Medula Óssea/patologia , Coformicina/análogos & derivados , Coformicina/farmacologia , Feminino , Seguimentos , Hemoglobinas/análise , Humanos , Leucemia de Células Pilosas/sangue , Leucemia de Células Pilosas/patologia , Contagem de Leucócitos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Pentostatina , Indução de Remissão , Reticulina/análise , Esplenomegalia/tratamento farmacológicoRESUMO
Deoxycoformycin (DCF), an adenosine deaminase (ADA) inhibitor, has been shown to be active in lymphoid neoplasms. The mechanism of cytotoxicity might involve accumulation of deoxyadenosine triphosphate (dATP), depletion of the nicotinamide adenine dinucleotide (NAD) and ATP pool, induction of double-stranded DNA strand breaks, or inhibition of S-adenosyl homocysteine hydrolase (SAH-hydrolase). We have investigated the biochemical changes in the circulating malignant cells of patients with chronic leukemia/lymphoma who were treated with DCF (4 mg/m2 weekly). Blood samples were taken from 17 patients with 60% or more circulating leukemic cells before, 4, 24, and 48 hours and five days after the first administration of DCF. Leukemic cells were separated and studied for changes in ADA, dATP, ATP, NAD, and SAH-hydrolase levels and DNA strand breaks and the data analyzed according to clinical response. Inhibition of ADA activity was found in all except one patient at 4 to 24 hours after the first administration of DCF. dATP started to accumulate at four hours, reached a maximum level between 24 and 48 hours, and returned to base values on the fifth day. Intracellular ATP and NAD levels were transiently reduced in some of the patients. However, no correlation between these changes and a clinical response could be found. DNA strand breaks could be studied in 13 patients. A significant increase in DNA breaks at 24 to 48 hours was found in six of the seven responders but only in one of the six nonresponders. At 24 hours, SAH-hydrolase levels were reduced in all seven responders studied, but only in two of the seven nonresponders. The difference in inhibition of SAH-hydrolase was statistically significant (P = .0023). These results suggest that DNA strand breaks and inhibition of SAH-hydrolase correlate with clinical response.
Assuntos
Coformicina/uso terapêutico , Leucemia de Células Pilosas/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Células Neoplásicas Circulantes , Ribonucleosídeos/uso terapêutico , Síndrome de Sézary/tratamento farmacológico , Inibidores de Adenosina Desaminase , Adenosil-Homocisteinase , Coformicina/análogos & derivados , DNA de Neoplasias/análise , Avaliação de Medicamentos , Humanos , Hidrolases/sangue , Contagem de Leucócitos , Proteínas de Neoplasias/sangue , Nucleotídeos/sangue , PentostatinaRESUMO
Clinical, pharmacologic, and immunologic effects of 2'-deoxycoformycin (dCF) were evaluated in 15 patients with advanced malignancies. Toxicity was less severe with a low dose (4 mg/m2) of dCF, but this dose still resulted in suppression of cellular adenosine deaminase activity, skin test reactivity, and lymphocyte responses to mitogens. Improvement in cutaneous T cell lymphoma plaques was seen after dCF. Further investigations of antitumor efficacy with the use of this low dosage schedule should continue in patients with hematologic neoplasms, and additional preliminary studies of the combination of an adenosine deaminase inhibitor with an adenosine analog should also be considered.
Assuntos
Inibidores de Adenosina Desaminase , Antineoplásicos/efeitos adversos , Coformicina/efeitos adversos , Imunossupressores/efeitos adversos , Neoplasias/tratamento farmacológico , Nucleosídeo Desaminases/antagonistas & inibidores , Ribonucleosídeos/efeitos adversos , Adenosina Desaminase/metabolismo , Adulto , Idoso , Coformicina/administração & dosagem , Coformicina/análogos & derivados , Coformicina/uso terapêutico , Feminino , Humanos , Imunidade/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Neoplasias/enzimologia , Neoplasias/imunologia , PentostatinaRESUMO
2'-Deoxycoformycin, a potent inhibitor of adenosine deaminase, was administered to three patients with cutaneous T cell lymphoma refractory to multiple treatment modalities. Patient 1, who received 5 mg/m2/day for 3 days at 35- to 71-day intervals, has achieved a complete remission greater than 16 months in duration. Patient 2 had progressive disease despite two courses of 2'-deoxycoformycin at a dose of 5 mg/m2/day for 3 days at 28-day intervals. The third patient, who was treated with 4 mg/m2 2'-deoxycoformycin weekly to biweekly, had an initial response, but the disease progressed after eight treatments. Only one patient had any side effects: Patient 1 developed reversible episcleritis, mild elevation of liver enzymes, and persistent nausea and vomiting. In red blood cells of all patients, there was near complete inhibition of adenosine deaminase (91% to 96%) and S-adenosylhomocysteine hydrolase (89% to 95%) activities with treatment. In peripheral blood lymphocytes, adenosine deaminase was inhibited by 85% to 98% and S-adenosylhomocysteine hydrolase by 51% to 88%. The deoxyadenosine triphosphate level, reflected by the total cellular adenine deoxyribonucleotide measurement in erythrocytes, was noted to be modestly elevated during treatment, with the highest level in the patient who demonstrated the only complete response and the only toxic effects. Low-dose 2'-deoxycoformycin appears to be safe but may be an insufficiently intensive regimen to treat refractory cutaneous T cell lymphoma. With proper biochemical monitoring, higher doses may be both safe and more effective.
Assuntos
Antineoplásicos/uso terapêutico , Coformicina/uso terapêutico , Linfoma/tratamento farmacológico , Ribonucleosídeos/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Adenosina Desaminase/sangue , Inibidores de Adenosina Desaminase , Adenosil-Homocisteinase , Idoso , Antineoplásicos/efeitos adversos , Coformicina/efeitos adversos , Coformicina/análogos & derivados , Eritrócitos/enzimologia , Humanos , Hidrolases/sangue , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Pentostatina , Linfócitos T/enzimologiaRESUMO
Thirty-one patients with hairy-cell leukemia were treated with 2'-deoxycoformycin (DCF) in a National Cancer Institute of Canada multicenter trial. The DCF was administered in a cycle (4 mg/m2 iv weekly X 3), which was repeated every 8 weeks. Following a complete remission, consolidation was done with two further cycles of DCF. Of 28 patients evaluable for response, 25 obtained a complete remission; 3 had a partial response. To date there has been only one relapse; the median time with no therapy was 429.5 days (range 99-743 days). Toxicity was moderate and included nausea and vomiting, lethargy, and skin rash; with the first cycle of treatment, neutropenia and an increased incidence of fever or infection were also observed. We conclude that low-dose DCF is highly effective in treating hairy-cell leukemia.