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Thirty adult patients with relapsed or refractory malignant lymphoma underwent a Phase I-II trial of salvage chemotherapy combining methyl-gag, high-dose Ara-C, M-Amsa, and ifosfamide (MAMI protocol). All patients had been extensively pretreated. At the time of salvage therapy, 21 patients had visceral involvement and 23 patients were refractory. The overall response rate was 50% (11 patients in complete remission and 3 patients in partial remission). The main toxicity was myelosuppression; 4 treatment-related deaths occurred and 17 patients died of tumor progression with a median of 5 months. The MAMI protocol showed similar antitumoral efficacy to that of other salvage chemotherapy regimens used for poor prognosis malignant lymphoma but was more toxic. However, a response rate of 45% in refractory patients should be taken into account and this drug association deserves further investigation with regard to the selection of patients for bone marrow transplants.

Patients undergoing immunosuppressive therapy have a 21% risk of developing Pneumocystis carinii pneumonia (PCP) if no prophylaxis is used [1]. During the first 6 months after bone marrow transplantation (BMT), the recipients have an estimated 9% risk of developing PCP [2]. Standard prophylaxis with sulfamethoxazole and trimethoprim (SMX/TMP) daily or intermittent doses has been used effectively in transplant and other immunosuppressed patients [2–4]. However, poor compliance and undesirable myelotoxicity are expected with this schedule, especially if other myelotoxic drugs such as ganciclovir have to be administered. Aerosolized pentamidine (AP) has been considered an attractive alternative in AIDS patients who do not tolerate SMX/TMP because only 4% of the patients discontinue AP prophylaxis due to side effects [5].

Dados do Registro Internacional de Transplante de Medula Óssea, International Bone Marrow Transplant Registry (IBMTR) contribuem para o progresso do transplante de medula óssea (TMO) em todo o mundo. Neste artigo relatamos a experiência brasileira em leucemia mielóide aguda e comparamos os resultados do TMO com os dados internacionais. Foi realizado um estudo retrospectivo com dados de tratamento de LMA com o TMO de 16 instituições brasileiras. A análise estatística dos transplantes da modalidade autogênica (TMO auto) e alogênica (TMO alo) foi realizada com o método de Kaplan-Meier e log-rank. Todos os valores de p foram bicaudados. Foram avaliados os dados de 731 pacientes (205 TMO auto e 526 TMO alo). A mediana de sobrevida global dos pacientes submetidos ao TMO auto foi superior à dos submetidos ao TMO alo (1.035 vs 466 dias, p=0,0012). A origem das células-tronco (OCT) no TMO alo em 73% dos pacientes foi de medula óssea (CTMO), em 23% de sangue periférico (CTSP) e em 4% de cordão umbilical. No TMO auto, a OCT foi 63% de CTSP, 22% CTMO e 15% de ambas as fontes. A OCT não teve impacto na sobrevida global (SG). Não houve diferença na SG também entre os pacientes segundo a classificação FAB no TMO alo, mas os pacientes com LMA M3 com o TMO auto tiveram SG longa. Como esperado, a principal causa de óbito entre os pacientes do TMO auto foi relacionada à recidiva de doença (60%), enquanto no TMO alo as principais causas foram a doença enxerto versus hospedeiro e infecções (38%). Em ambos os grupos foi observada SG mais longa nos pacientes tratados em primeira remissão completa (1RC) quando comparados aos de segunda remissão (2RC) e outras fases (p

Nesta revisao, discutem-se os resultados dos transplantes de celulas-tronco hematopoeticas (TCTH) para doencas reumaticas graves e refratarias a terapia convencional realizados no Brasil. Sao analisados os resultados preliminares obtidos no Brasil com o TCTH autologo em casos esporadicos (N=3) e no protocolo cooperativo iniciado em 2001 (N=18). Neste protocolo, dentre os 8 casos de nefrite lupica, houve 3 remissoes sustentadas, 3 obitos, 1 falha de mobilizacao e 1 seguimento ainda muito curto; entre os 7 de esclerose sistemica, houve 3 remissoes apos o TCTH e 2 apos mobilizacao, um obito pos-mobilizacao das CTH e outro apos a primeira dose do condicionamento, este ultimo em uma superposicao com LES; em dois pacientes com vasculite, houve uma remissao em arterite de Takayasu e outra em doenca de Behcet; uma paciente com artrite inflamatoria juvenil foi incluida muito recentemente no protocolo. O seguimento dos pacientes sobreviventes variou de 0 a 48 meses, com uma mediana de 29 meses. Conclui-se com uma discussao do custo-beneficio do TCTH em face das novas formas de imunossupressao disponiveis e das perspectivas futuras em paises desenvolvidos, onde se iniciaram recentemente estudos prospectivos randomizados comparando o transplante com a melhor terapia medicamentosa disponivel, e no Brasil, onde o custo do transplante e muito inferior ao das novas terapias biologicas.

A infusão de células hematopoéticas totipotentes criopreservadas permite a recuperação da hematopoese após quimioterapia mieloablativa. OBJETIVO. A formação de cristais de gelo durante o processo de congelamento é o fator principal que causa ruptura das estruturas celulares. A criopreservação dessas células a uma taxa constante preveniria os danos causados pelo congelamento brusco. MÉTODOS. Vinte e três pacientes com mediana de 25 anos (variação 3-57) tiveram a medula óssea e/ou células-tronco periféricas (CTP) coletadas no período de março de 1993 a outubro de 1994, totalizando 86 congelamentos. Os pacientes apresentavam as seguintes neoplasias: linfoma não-Hodgkin (n=5), leucemia mielóide aguda (n=8), leucemia linfóide aguda (n=6), doença de Hodgkin (n=3) e mieloma múltiplo (n=1). O congelamento foi controlado por um computador, acoplado ao sistema, às seguintes temperaturas: -1°C/min até -45°C e depois a -10°C/min até -80°C. Após o congelamento, as células foram mantidas em freezer a -110°C até o momento da infusão. Para obtenção das CTP, empregou-se o fator de crescimento estimulante de granulócitos (G-CSF). RESULTADOS. Uma mediana de 3,16 x 10(8) céls./kg (variação 0,86-24,22) de CTP e 2,03 x 10(8) céls./kg (variação 0,19-12,21) de medula óssea foi congelada. A mediana para atingir granulócitos maior ou igual a 500/µL e plaquetas maior que 20.000/µL foi de 12 dias (variação 8-40) e 31 dias (variação 8-80), respectivamente. Todos os pacientes tiveram recuperação hematopoética após a infusão das células criopreservadas. CONCLUSÃO. A criopreservação em congelador programável permite o armazenamento de células hematopoéticas e, potencialmente, pode causar menor dano celular. The cryopreservation of hematopoietic stem cells can be used for rescuing the hematopoiesis after high dose chemotherapy. PURPOSE. The ice cristal formation during the freezing procedure is the key point that can be harmful to the cells. The cryopreservation of hematopoietic stem cells in a controlled-rate freezer could decrease the cell damage. METHODS. Twenty-three patients with a median age of 26 years (range 03-57) had bone marrow and/or peripheral blood stem cells harvested from March 1993 through October 1994, ending up to 86 freezing procedures. The patient's diagnoses are as follows: Non-Hodgkin's Lymphoma (n=5); Acute Myelogenous Leukemia (n=8); Acute Lymphocytic Leukemia (n=6); Hodgkin's disease (n=3); Multiple Myeloma (n=1). The cells were frozen away in a controlled-rate freezer chamber at the folowing rate: -1°C/min from room temperature to -45°C and then, at -10°C/min down to -80°C. After freezing, the cells were kept into mechanical freezers until the marrow infusion. To mobilize PBSC (peripheral blood stem cells), G-CSF (granulocyte colony stimulating factor) was given. RESULTS. A median of 3.16x10(8) cells/kg (range 0.86-24.22) of PBSC and 2.03x10(8) cells/kg (0.19-12.21) of bone marrow cells were frozen. The median time to reach granulocytes greater than 500/µL and platelets greater than 20,000/µL was 12 days (range 8-40) and 31 days (range 8-80), respectively. All patients had marrow engraftment after infusion of hematopoietic stem cells. CONCLUSION. The cryopreservation procedure using a controlled-rate freezer can store hematopoietic stem cells and potentially, cause less damage to the cells.

The cryopreservation of hematopoietic stem cells can be used for rescuing the hematopoiesis after high dose chemotherapy.The ice crystal formation during the freezing procedure is the key point that can be harmful to the cells. The cryopreservation of hematopoietic stem cells in a controlled-rate freezer could decrease the cell damage.Twenty-three patients with a median age of 26 years (range 03-57) had bone marrow and/or peripheral blood stem cells harvested from March 1993 through October 1994, ending up to 86 freezing procedures. The patient's diagnoses are as follows: Non-Hodgkin's Lymphoma (n = 5); Acute Myelogenous Leukemia (n = 8); Acute Lymphocytic Leukemia (n = 6); Hodgkin's disease (n = 3); Multiple Myeloma (n = 1). The cells were frozen away in a controlled-rate freezer chamber at the following rate: -1 degree C/min from room temperature to -45 degrees C and then, at -10 degrees C/min down to -80 degrees C. After freezing, the cells were kept into mechanical freezers until the marrow infusion. To mobilize PBSC (peripheral blood stem cells), G-CSF (granulocyte colony stimulating factor) was given.A median of 3.16 x 10(8) cells/kg (range 0.86-24.22) of PBSC and 2.03 x 10(8) cells/kg (0.19-12.21) of bone marrow cells were frozen. The median time to reach granulocytes greater than 500/microL and platelets greater than 20,000/microL was 12 days (range 8-40) and 31 days (range 8-80), respectively. All patients had marrow engraftment after infusion of hematopoietic stem cells.The cryopreservation procedure using a controlled-rate freezer can store hematopoietic stem cells and potentially, cause less damage to the cells.

Nocardiosis has rarely been described after BMT. When the doses of immunosuppressive therapy were tapered, a 46-year-old BMT recipient developed chronic graft-versus-host disease (GVHD) and immunosuppressive drugs were increased. Sixteen days later the patient developed nocardiosis diagnosed by lung biopsy. Trimethoprim/sulfamethoxazole (TMP/SMZ) was initiated but the doses were reduced because of rising creatinine levels. Skin and cerebral dissemination of nocardiosis was observed and TMP/SMZ doses were increased. After 4 months, the brain lesion was unaltered despite resolution of pulmonary lesions. Clinical improvement was observed after drainage of the brain abscess.

The present report concerns a retrospective study of 16 patients with localized intermediate- or high-grade non-Hodgkin's lymphoma of the testis treated in one institution from 1973 to 1990. Ann Arbor stage of disease was IE in 11 and IIE in 5 cases. All except one patient underwent initial inguinal orchidectomy, 11 were disease free after surgery and 12 received inverted Y radiation therapy. All patients achieved a complete remission (CR). Relapse occurred in 8 of 9 patients who did not receive initial chemotherapy, but in only 3 of 7 patients initially treated with chemotherapy including anthracyclins. In 3 cases relapse was confined to the CNS, while diffuse relapse in 8 others included 4 cases of CNS involvement. Eight patients are now alive in CR (5 in first CR, 1 in second CR and 2 in third CR) with a median follow-up of 68.5 months (range 54-101). Chemotherapy thus emerges as the initial treatment of preference for localized testicular lymphoma. Therapy should be preceded by a thorough assessment of the stage of disease and due to the high frequency of CNS relapse, CNS prophylaxis should be considered for all patients.

25 patients with poor-prognosis malignancies were treated with a combination of fixed-dose etoposide (1750 mg/m 2 ), cyclophosphamide (6400 mg/m 2 ) and escalating doses of carboplatin (from 800 to 1600 mg/m 2 ) followed by autologous bone marrow transplantation (ABMT). The median duration of granulocytopenia ( 3 ) and thrombocytopenia ( 3 ) was 23 days and 20.5 days, respectively. The main nonhaematological toxicity was gastro-intestinal, with moderate to severe diarrhoea in 15 patients. No significant renal toxicity was observed. 2 patients died early due to toxicity. The overall response rate was 58% including 42% having complete responses. 4 of the 25 patients are alive with no evidence of disease at 22, 27, 40 and 43 months after ABMT. The encouraging antitumoral activity of this regimen makes it a good candidate for intensified chemotherapy in patients with various malignancies. Toxicity is acceptable and may be reduced in the near future with the widespread use of haematopoietic growth factors.

The prognosis of Burkitt's lymphoma is generally considered to be poor, particularly in the advanced stages of the disease. Although recent chemotherapy protocols have given high rates of cure in children, there are few such reports concerning adults. We therefore conducted a retrospective analysis of the results for treatment of 46 adults in the Institut Gustave Roussy (IGR) between 1978 and 1987, in order to establish an effective treatment strategy for use in a prospective trial. The median age of the patients was 31 years and the majority were Caucasians of European origin. The clinical symptoms and course of the disease were similar to those in the pediatric situation and corresponded to the so-called non endemic forms observed in Europe and the United States. Presentation was generally extra-nodal, usually with abdominal manifestations. As a rule, the disease progressed rapidly and showed a high affinity for the central nervous system in the absence of specific prophylaxis, despite systemic therapy with highly active agents, particularly in the advanced stages. According to Murphy's classification, there were 6 stage I, 11 stage II, 19 stage III and 10 stage IV patients (3 of whom had CNS involvement). Treatment was heterogenous, although all the patients received polychemotherapy including anthracyclins. The best results were obtained from eleven patients treated according to the French Multicenter Protocols for pediatric Burkitt's lymphoma (LMB-84 and LMB-86). Kaplan-Meier 5-year relapse free survival rate among the 46 patients was 42% (stage I: 83%; stage II: 67%; stage III: 30%; stage IV: 30%). In order to standardize our therapeutic approach, we started a prospective study in 1988 using the unmodified pediatric protocol for our adult patients.

Twenty-eight patients with poor prognosis, advanced metastatic non seminomatous germ cell tumors (NSGCT) were treated with early high dose chemotherapy and autologous bone marrow transplantation (ABMT) rescue. The primary tumor was testicular in 19 patients and extragonadal in nine patients. For 19 patients with a testicular primary, the median probability of complete remission (CR) was 0.05 according to our prognostic mathematical model based on pretreatment levels of serum HCG and AFP. The same prognostic model was used for extragonadal primaries. Treatment consisted of two cycles of a modified double dose of cisplatin, vinblastine, bleomycin, VP-16 regimen (mPVeBV) followed by a high dose cisplatin-etoposide-cyclophosphamide regimen (PEC) followed by ABMT. Of the 28 patients, 17 (61%) achieved CR, one of which was surgical CR (sCR), five died of rapidly progressive disease early during the first cycle of mPVeBV, two had treatment-related deaths, three did not respond and one patient refused treatment. Of the 17 patients initially in CR, three relapsed after 4, 4 and 7 months respectively and have subsequently died. Two other patients died while still in CR: one committed suicide and one died of an infectious complication due to transfusion-related AIDS. Twelve patients are alive in CR after a median follow-up of 66 months (range 7-72 months). The non parametric 3-year survival rate is 40%. To demonstrate the effect of intensive chemotherapy with ABMT, a randomized multicenter French study was set up to evaluate the PVeBV regimen with or without high dose treatment and ABMT in poor risk NSGCT patients.

Between April 1984 and May 1985, 17 heavily pretreated patients with relapsing or refractory germ cell tumours were treated with cisplatin 40 mg/m2/day, days 1-5; etoposide 350 mg/m2/day, days 1-5; cyclophosphamide 1600 mg/m2/day, days 2-5 and autologous bone marrow transplantation on day 8 as consolidation of conventional salvage chemotherapy. None of the 11 refractory patients and 4 of the 6 responders to prior salvage treatment are long-term survivors at 68, 72, 74 and 74 months. Mean aplasia duration was 17 days and there were 7 documented episodes of septicaemia in 17 febrile patients. 1 patient died of treatment. Among the 4 survivors, 2 patients have a sustained grade II invalidating neuropathy. We conclude that this regimen is not recommended as salvage therapy in refractory patients but may be a useful consolidation treatment in patients responding to conventional salvage chemotherapy.

Between october 1985 and january 1988, 32 patients with heavily pretreated refractory or relapsing non seminomatous germ cell tumors were included in a phase II trial using etoposide, ifosfamide and high dose cisplatin (VIhP). Eight of 30 evaluable patients (29 per cent) achieved complete response with VIhP treatment alone or followed by surgical excision of residual lesions. Five patients in complete remission relapsed at 3, 4, 5.5 and 7 months, and 3 patients remained continuously free of disease at 17, 21 and 22 months. Severe myelosuppression with a WBC nadir less than 500/mm3 and a platelet nadir less than 20,000/mm3 was observed in 73 per cent of the patients, and renal toxicity (WHO grade 2 or 3) in 29 per cent. The VIhP regimen for salvage therapy gives the same rate of long term survivors than the regimen with conventional cisplatin dosage (VIP) but is much more toxic and cannot be recommended.

In recent years, the prognosis of non-seminomatous germ-cell tumors has been greatly improved by the use of novel chemotherapeutic regimens including platinum derivatives. However, the prognosis remains poor for a certain proportion of these patients. We have therefore developed an intensive chemotherapy protocol (PEC) followed by bone marrow autografting: cisplatin (40 mg/m2/day x 5 d), etoposide (350 mg/m2/day x 5 d), cyclophosphamide (1,600 mg/m2/day x 4 d). Forty-four poor-prognosis patients were thus treated. The results can be stratified into 3 categories, as follows: I: 12 refractory patients: 3 CR, 6 PR, 2 failures, 1 unevaluable. Median survival was short (7 months, range 2-16 months); II: 6 patients with sensitive relapse: 5 CR, 1 unevaluable. Four patients remained in CR at 42, 45, 46 and 48 months; III: 26 patients who received PEC as consolidation therapy in the first CR-PR after courses of conventional chemotherapy and who were selected at the time of diagnosis on the basis of factors of poor prognosis: 16 CR, 3 PR, 7 unevaluable. Two-year disease-free survival (Kaplan-Meier) is 60%. The median duration of neutropenia (less than 0.5 x 10(9)/l) was 15 d (range 6-37) and that of thrombocytopenia (less than 20 x 10(9)/l), 13 d (range 3-32). The most significant non-hematologic toxicity was of the gastrointestinal tract; in particular severe mucositis. Four iatrogenic deaths occurred (2 candidiasis, 1 aspergillosis and 1 hemorrhage). Pharmacokinetic studies were used to determine the optimum time for reinfusing the marrow and provided information on the mechanism of the mucositis. In conclusion, PEC protocol showed a high efficacy with 94% response rate (68.5% CR) among the 35 evaluable pts. Patients refractory to conventional treatment did not appear to benefit from this intensive chemotherapy. However, it appears that it may be useful for patients with relapses sensitive to salvage therapy. Encouraging results were obtained with the PEC protocol administered as early consolidation for patients with identifiable risk factors at diagnosis. A multicenter, randomized trial is currently underway in France to compare this approach with standard conventional chemotherapy.

Chemotherapy has dramatically improved the prognosis of non-seminomatous germ cell tumors (NSGCT). However, some patients relapse and others are refractory to first line chemotherapy. We studied a salvage chemotherapeutic regimen with etoposide 75 gm/m2/day, and cisplatin 40 mg/m2/day, days 1-5 and Ifosfamide 3 g/m2/day, days 1 and 2 (VIhP regimen) in 32 patients. We observed 8 complete remissions with 4 long-term NED patients. Hematological, neurological and renal complications were frequent. In 16 other cases, a protocol using high dose chemotherapy, followed by autologous bone marrow rescue was studied. We observed 8 complete remissions with 4 long-term NED patients. These observations support a dose/effect relationship. A French randomized trial testing high dose chemotherapy, followed in some cases by an autologous marrow graft in poor risk advanced NSGCT, has recently been activated.

SIR-Liposomal formulations of amphotericin B (AmB) have been shown to have fewer toxic effects than do classic preparations (such as AmB deoxycholate), yet they have equivalent antifungal activity [1, 2]. Recently, it has been reported that AmB liposomal emulsion (AmBLE [Intralipid 20%]) reduces renal and infusion-related toxicity. When AmBLE has been used to treat mild fungal infections, reduced toxicity and efficacy similar to that of conventional preparations have been observed [3]. However, no data are available concerning the effectiveness of AmBLE in treating severe fungal infections. We report three cases of fungal septicemia in profoundly granulocytopenic patients who were successfully treated with AmBLE. Case 1. A 9-year-old girl was admitted to the hospital for administration of a second cycle of salvage chemotherapy after a first relapse of non-Hodgkin's lymphoma. Seven days after chemotherapy was started, the patient had fever (temperature of 39?C) and hypotension, and her clinical condition had deteriorated. Findings on chest roentgenograms were normal. Progressive reduction in the total number of blood leukocytes was noted. Samples of blood for culture were taken before empirical antibiotic therapy with ceftazidime plus vancomycin was started.

Twenty-one patients with refractory germ cell tumors were treated with a chemotherapy regimen containing etoposide (VP-16) (V) 75 mg/m2/day (days 1 to 5), ifosfamide (I) 3 g/m2/day (days 1 and 2) with a 3.6 g/m2 continuous infusion of mesna (days 1 and 2), and high-dose cisplatin (hP) 40 mg/m2/day (days 1 to 5). The regimen is referred to as VIhP. Nineteen patients were evaluable for response. Five patients (26%) achieved a complete remission (CR) with chemotherapy alone, and three patients (16%) were in CR after resection of a residual nonactive tumoral mass (e.g., necrosis and/or fibrosis and/or mature teratoma). Thus, a CR rate of 42% was achieved with the entire treatment. One additional patient achieved a CR after resection of active, bulky disease. Among the responders, five patients (26%) are still alive and disease-free at 6, 7, 9, 10, and 18 months after the initiation of the chemotherapy. However, toxicity was heavy in this protocol. Severe myelosuppression was observed with 10 patients developing aplasia and six patients documented sepsis. Reversible Grade 1-2 renal toxicity occurred in 14 patients, and Grade 2-3 peripheral neurotoxicity occurred in six patients. No hemorrhagic cystitis was encountered. We conclude that a VIhP regimen seems to play an active role in refractory germ cell tumors although the presence of high-dose cisplatin in this regimen does not appear to improve the response rate compared to that of a conventional dose. Toxicity, which seems to be enhanced, is currently under detailed study. However, the contribution of VIhP as a first-line treatment in poor prognosis, advanced germ cell tumors warrants further study.

We report a case of hypercalcemia in a 20-year-old woman with an ovarian seminoma. She had neither evidence of bone metastasis nor hyperparathyroidism. Hypercalcemia was well controlled by corticotherapy and chemotherapy, and remained normal after remission was obtained. Different patterns in paraneoplastic hypercalcemia are detailed, with emphasis on PTH-related proteins and vitamin-D metabolites. Eleven cases of neoplasm with hypercalcemia and elevated calcitriol level are reported in the literature. One of them is a seminoma. These elevated levels could be related either to a PTH-like protein, either to 1 alpha-hydroxylase activity in some tumoral cells. Three other cases of seminoma associated with hypercalcemia without dosage of vitamin-D metabolites are reported. Dosage of calcitriol might be performed in paraneoplastic hypercalcemia of seminoma.

Twenty-one patients with refractory germ cell tumors were treated with a chemotherapy regimen containing etoposide (VP-16) (V) 75 mg/m2/day (days 1 to 5), ifosfamide (I) 3 g/m2/day (days 1 and 2) with a 3.6 g/m2 continuous infusion of mesna (days 1 and 2), and high-dose cisplatin (hP) 40 mg/m2/day (days 1 to 5). The regimen is referred to as VIhP. Nineteen patients were evaluable for response. Five patients (26%) achieved a complete remission (CR) with chemotherapy alone, and three patients (16%) were in CR after resection of a residual nonactive tumoral mass (e.g., necrosis and/or fibrosis and/or mature teratoma). Thus, a CR rate of 42% was achieved with the entire treatment. One additional patient achieved a CR after resection of active, bulky disease. Among the responders, five patients (26%) are still alive and disease-free at 6, 7, 9, 10, and 18 months after the initiation of the chemotherapy. However, toxicity was heavy in this protocol. Severe myelosuppression was observed with 10 patients developing aplasia and six patients documented sepsis. Reversible Grade 1-2 renal toxicity occurred in 14 patients, and Grade 2-3 peripheral neurotoxicity occurred in six patients. No hemorrhagic cystitis was encountered. We conclude that a VIhP regimen seems to play an active role in refractory germ cell tumors although the presence of high-dose cisplatin in this regimen does not appear to improve the response rate compared to that of a conventional dose. Toxicity, which seems to be enhanced, is currently under detailed study. However, the contribution of VIhP as a first-line treatment in poor prognosis, advanced germ cell tumors warrants further study.

Nineteen patients were treated with high dose chemotherapy followed by an autologous bone marrow transplantation. The chemotherapy regimen was an association of BCNU, procarbazine, etoposide, melphalan. Six patients had a progressive disease; 4 short-term complete remissions were observed. In 13 responding patients, 6 maintained complete remissions were noted.

Twelve patients were treated with high-dose etoposide give alone or in combination with cisplatin during a clinical trial. We had previously observed, in some subjects who received a combination of high-dose etoposide (350 mg/m2/day X 5 days) and cisplatin (40 mg/m2/day X 5 days), delayed hematological recovery after autologous bone marrow transplantation. Therefore we investigated the pharmacokinetics of etoposide and did not find any drug interaction with cisplatin. In four of these patients we also monitored etoposide salivary excretion and found saliva to plasma ratios in the range 0.003-0.25. The secretion of etoposide into saliva may be of concern if we consider that peroxidases in salivary glands are able to oxidize the drug leading to free radicals. In vitro experiments showed that sulfhydryl compounds are able to inhibit the formation of the etoposide radical. Furthermore, we were able to detect the presence of a new biotransformation product of etoposide in plasma samples of some patients. Fast atom bombardment liquid chromatography-mass spectrometry allowed us to identify this metabolite as the etoposide aglycone. The presence of this derivative in plasma 48 h after the last injection prompted us to delay autologous bone marrow transplantation to 72 h after the end of treatment, since the aglycone is cytotoxic and able to induce DNA strand breaks mediated by topoisomerase II.

In France, more than 80% of children with Burkitt's lymphoma or Burkitt's leukemia (ALL3) are now cured with the LMB (B-cell non- Hodgkin's lymphoma and B-ALL) protocols of the Societe Francaise d'Oncologie Pediatrique, but so far, poor results have been obtained in the few adult studies available. We have analyzed the experience with LMB protocols in adult patients. This retrospective study involved 65 adult patients with small noncleaved cell lymphoma or ALL3 treated with the LMB protocols. They were 17 to 65 years old and not previously treated. Human immunodeficiency virus-infected patients were excluded. The diagnoses were made between September 1984 and August 1991. According to the Murphy classification, 12 patients (18%) had stage I or II disease, 25 (38%), stage III disease; 4 (6%), stage IV disease; and 24 (37%), ALL3 (> or = 25% blasts). According to the Ann Arbor classification, 9 patients had stage I disease; 8 patients, stage II; 5 patients, stage III; 21 patients, stage IV disease; and 22 patients, ALL (> or = 30% blasts). Twelve patients had central nervous system (CNS) involvement before treatment. Thirty-nine patients were treated according to the LMB 84 protocol scheme; 14 according to the LMB 86 protocol, and 12 patients received the LMB 84 induction courses followed by the LMB 86 consolidation courses. Three patients underwent bone marrow transplantation (BMT) while in second complete remission (CR) and 3 others had refractory disease. There were some protocol violations caused by empirical medical decisions: local irradiation was performed in 4 patients, 2 patients received prophylactic radiation to the brain that was not specified in the protocol, 13 patients underwent BMT in first CR, and methotrexate doses were modified in 10 patients. Fifty-eight patients (89%) achieved a CR. There were four (6%) primary induction treatment failures, and three (4%) early treatment-related deaths. Eight patients relapsed between 2 and 30 months after CR (median, 4.7 months). Forty-seven patients are alive in CR (45 first CR, 2 second CR) with a median follow-up of 57 months (24 to 93 months). There were five toxicity-related deaths among patients in CR including four BMT-related deaths and five deaths caused by refractory relapses. One patient died in CR at 62 months of rectal cancer. The 3- year overall survival rate is 74% (SE = 5). According to the stages in the Murphy classification, the 3-year survival rates are stages I and II, 100%; stage III, 80% (SE = 7); and stage IV and ALL, 57% (SE = 8). Seven of 12 patients with initial CNS disease are alive with a median survival of 56 months.(ABSTRACT TRUNCATED AT 400 WORDS)