RESUMO
We report the results of a French multicentric pilot study of remission induction therapy in metastatic neuroblastoma. Thirty-five successive unselected patients entered the study over 1 year and were treated by alternating sequences of cisplatin/VM-26 (PE) and vincristine/cyclophosphamide/doxorubicin (CADO). Three courses of each sequence were delivered. Disease reevaluation was extensive, with special focus on bone marrow status. Using strict criteria, 24 patients (68%) achieved a good partial response (GPR), which comprised normalization of bone marrow, and ten (28%) achieved a partial response (PR), and one progressed. The overall response rate was 96%. Thirty-two patients underwent surgery, and complete macroscopic removal of the primary was achieved in 21 (65%). After completion of induction and surgery, six patients (17%) were in complete remission (CRm), without evidence of any residual disease; nine (26%) were in very good partial remission (VGPRm; same as CRm except persistence of nonpathologically evaluable improved bone scan), and 19 (51%) were in partial remission (PRm). Toxicity was acceptable, and no treatment-related deaths occurred. These results show no substantial improvement compared with those previously reported with similar but nonalternating regimens. We advocate a two-category concept (response, remission) to describe initial therapy results in metastatic neuroblastoma and emphasize the need to assess bone marrow by an extensive evaluation.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neuroblastoma/secundário , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Pré-Escolar , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Resistência a Medicamentos , Feminino , Humanos , Lactente , Masculino , Neuroblastoma/tratamento farmacológico , Podofilotoxina/administração & dosagem , Podofilotoxina/efeitos adversos , Indução de Remissão , Vincristina/administração & dosagem , Vincristina/efeitos adversosRESUMO
Twenty-one patients with advanced Wilms' tumor entered a phase II study with high-dose ifosfamide (3 g/m2 over two days every 15 days). Mesna and hyperhydration were associated with minimal bladder toxicity. After two courses, five partial responses and six complete responses were observed. Ten patients did not respond. The median duration of response was 2 months (range, 1 to 7). Therapy was delayed because of leukopenia for 1 or 2 weeks in only three cases. Fever and infection were not observed. Seven patients presented with hematuria, three of whom were among the 17 patients coadministered mesna, which did not interfere with subsequent therapy.
Assuntos
Ifosfamida/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Tumor de Wilms/tratamento farmacológico , Adolescente , Adulto , Criança , Pré-Escolar , Avaliação de Medicamentos , Feminino , Humanos , Ifosfamida/efeitos adversos , Lactente , MasculinoRESUMO
PURPOSE: We analyzed the clinical features and outcome of patients with radiation-associated osteosarcoma treated during the era of contemporary chemotherapy. PATIENTS AND METHODS: The characteristics and outcome of 23 patients (17 males and six females) treated during childhood or adolescence for a solid tumor who later developed osteosarcomas within the radiation field between 1981 and 1996 were reviewed. RESULTS: The median dose of radiation delivered to the first cancer was 47 Gy. Nineteen patients also received chemotherapy. The median time between radiotherapy and the diagnosis of secondary osteosarcoma was 8 years. Histologic slide review showed conventional central osteosarcoma with various differentiation patterns in 21 cases, together with one case of high-grade surface osteosarcoma and one of periosteal osteosarcoma. The sites of involvement were the craniofacial bones in six cases, the first cervical vertebra in one, the girdle bones in seven, and the extremities of long bones in nine. Three patients had metastatic disease at the diagnosis of osteosarcoma. Palliative therapy was administered to seven patients. The aim of treatment was curative for 16 patients, two of whom underwent amputation without further therapy. Intensive chemotherapy regimens were administered to 14 patients before and/or after surgery. Fifteen patients achieved complete surgical remission. Twelve patients were alive and disease-free at a median follow-up duration of 7.5 years. Overall and event-free survivals at 8 years were 50% and 41%, respectively. CONCLUSION: Patients with radiation-related osteosarcoma and resectable lesions can be cured with surgery and intensive preoperative and postoperative chemotherapy.
Assuntos
Neoplasias Ósseas/terapia , Neoplasias Induzidas por Radiação/terapia , Segunda Neoplasia Primária/terapia , Osteossarcoma/terapia , Adolescente , Adulto , Antimetabólitos Antineoplásicos/uso terapêutico , Neoplasias Ósseas/mortalidade , Criança , Pré-Escolar , Terapia Combinada , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Lactente , Masculino , Metotrexato/uso terapêutico , Recidiva Local de Neoplasia , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Neoplasias Induzidas por Radiação/mortalidade , Segunda Neoplasia Primária/mortalidade , Osteossarcoma/mortalidade , Dosagem Radioterapêutica , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/radioterapia , Sarcoma de Ewing/tratamento farmacológico , Sarcoma de Ewing/radioterapiaRESUMO
PURPOSE: The usual therapy of osteosarcoma is neoadjuvant chemotherapy, followed by surgery, then by postoperative chemotherapy. There is no prognostic factor to predict, at diagnosis, the histologic response and final outcome. Inactivation of the retinoblastoma-susceptibility gene RB is associated with the pathogenesis of several human cancers. In primary osteosarcomas, loss of heterozygosity (LOH) at the RB locus has been found in greater than 60% of cases. The aim of this study was to determine the potential early prognostic value of LOH of RB gene on the biopsy material at diagnosis. PATIENTS AND METHODS: Forty-seven patients with primary osteosarcoma, treated in four French institutions, were studied. LOH was studied by polymerase chain reaction (PCR) of an informative RB DNA polymorphism. RESULTS: Assessment of LOH at the RB gene could be completed on 34 heterozygous patients only. LOH was found in 24 cases (70%). The event-free survival (EFS) rate at 60 months is 100% for patients without LOH, 43% for all patients with RB LOH, and 65% for nonmetastatic patients with RB LOH. The difference in EFS is highly significant at P = .008 and P = .024, respectively. Histologic response after preoperative chemotherapy did not show significant correlation with LOH status. CONCLUSION: RB gene LOH appears to be an early predictive feature for osteosarcomas that indicates a potential unfavorable outcome. RB LOH study might shortly help to identify high-risk patients earlier. If this is verified, therapy could then be adapted earlier to the individual's real risk of relapse.
Assuntos
Neoplasias Ósseas/genética , Neoplasias Ósseas/mortalidade , Genes do Retinoblastoma , Osteossarcoma/genética , Osteossarcoma/mortalidade , Adolescente , Adulto , Sequência de Bases , Criança , Heterozigoto , Humanos , Dados de Sequência Molecular , PrognósticoRESUMO
PURPOSE: To clarify treatment strategy for lymphocyte-predominant Hodgkin's lymphoma (LPHL), the French Society of Pediatric Oncology initiated a prospective, nonrandomized study in 1988. Patients received either standard treatment for Hodgkin's lymphoma or were not treated beyond initial adenectomy. PATIENTS AND METHODS: From 1988 to 1998, 27 patients were available for study. Twenty-four patients were male, and median age was 10 years (range, 4 to 16 years). Twenty-two, two, and three patients had stage I, II, and III disease, respectively. Thirteen patients (stage I, n = 11; stage III, n = 2) received no further treatment after initial surgical adenectomy (SA). Fourteen patients received combined treatment (CT; n = 10), involved-field radiotherapy alone (n = 1), or chemotherapy alone (n = 3). The two groups were comparable for clinical status, treatment, and follow-up. RESULTS: Twenty-three of 27 patients achieved complete remission (CR). With a median follow-up time of 70 months (range, 32 to 214 months), overall survival to date is 100%, and overall event-free survival (EFS) is 69% +/- 10% (SA, 42% +/- 16%; CT, 90% +/- 8.6%; P <.04). If we considered only the patients in CR after initial surgery (n = 12), EFS was no longer significantly different between the two groups. Patients with residual mass after initial surgery (n = 15) had worse EFS if they did not receive complementary treatment (P <.05). CONCLUSION: Although based on a small number of patients, our study showed that (1). no further therapy is a valid therapeutic approach in LPHL patient in CR after initial lymph node resection, and (2). complementary treatment diminishes relapse frequency but has no impact on survival.
Assuntos
Doença de Hodgkin/terapia , Excisão de Linfonodo , Adolescente , Criança , Pré-Escolar , Terapia Combinada , Feminino , Doença de Hodgkin/patologia , Humanos , Masculino , Recidiva Local de Neoplasia , Estudos Prospectivos , Indução de Remissão , Análise de Sobrevida , Resultado do TratamentoRESUMO
We saw bone marrow necrosis in a case of acute myelomonocytic leukemia. The diagnosis was made during the patinet's life, and the bone marrow microcirculation was studied immediately postmortem. Histology and injection of the bone marrow arteries showed an acute microcirculation failure. The pathogenesis and possible relationship with soluble immune complexes was studied.
Assuntos
Doenças da Medula Óssea/etiologia , Medula Óssea/irrigação sanguínea , Leucemia Mieloide/complicações , Microcirculação , Adulto , Doenças da Medula Óssea/patologia , Humanos , Leucemia Mieloide/patologia , Masculino , Microcirculação/patologia , NecroseRESUMO
The EORTC Children Leukemia Group (CLG) is part of the offspring of the EORTC Hemopathies Working Party which in 1978 split into a paediatric and to an 'adult' branch. At that time, the Berlin-Frankfurt-Munster (BFM) designed by H. Riehm for acute lymphoblastic leukaemia (ALL) appeared much more efficacious than all others and the CLG decided to adapt that treatment strategy for its own clinical trials. The main results of these may be summarised as follows:for standard risk patients, the deletion of cyclophosphamide from consolidation and reconsolidation courses does not jeopardise the patient's outcomefor medium- and high-risk patients receiving high-dose methotrexate (MTX), cranial radiotherapy is superfluouswith the dose scheduling of the BFM regimen, E-Coli L-Asparaginase is more efficacious than Erwinia L-Asparaginasethe addition of monthly intravenous (i.v.) 6-mercaptopurine to conventional maintenance chemotherapy is detrimentalthe assessment by quantitative polymerase chain reaction (PCR) of minimal residual disease at completion of induction is feasible in a cooperative setting and can be used as a powerful and independent prognostic factor. The CLG also conducted clinical studies of acute myeloblastic leukaemia. Since 1989, lymphoblastic non-Hodgkin's lymphomas have been treated within the ALL trials. The CLG collaborates with other Groups within the I-BFM Study Group and participants in the meta-analytic studies conducted by the Oxford team by the Oxford Children ALL Collaborative Group.
Assuntos
Agências Internacionais/história , Leucemia/história , Oncologia/história , Pesquisa/história , Criança , História do Século XX , Humanos , Cooperação Internacional , Leucemia/terapia , Leucemia Mieloide Aguda/história , Leucemia Mieloide Aguda/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/história , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Ensaios Clínicos Controlados Aleatórios como Assunto/históriaRESUMO
Phase II studies using ifosfamide both alone and combined with vindesine and cisplatin have shown the effectiveness of this drug in patients with Ewing's sarcoma (ES) who had relapsed during VAC (vincristine, actinomycin, cyclosphosphamide)/VAd (vincristine, Adriamycin) therapy. In November 1984, these results led the SFOP to adopt a protocol consisting of (1) initial chemotherapy with three cycles of IVA (ifosfamide, 3 g/m2 on days 1 and 2; actinomycin D, 750 mg/m2 on days 1-3; vincristine, 1.5 mg/m2 on day 1) alternating every 3 weeks with IVAd (vincristine on day 22; ifosfamide on days 21-23; Adriamycin, 60 mg/m2 on day 22); (2) radical surgery if possible; (3) local radiotherapy (RT); and (4) maintenance chemotherapy with alternating IVA and VAd (vincristine, Adriamycin) for up to 9 months. In May 1987, 87 patients with previously untreated ES entered the study; 61 had localized ES. To date, 54 patients with localized disease and 22 with metastatic disease have finished initial chemotherapy; 40 patients with localized disease have been evaluated. In all, 28 patients (70%) were in complete remission (17 patients) or had a tumor regression of greater than 50% 11 patients) and were considered to be good responders; 12 patients were considered to be poor responders. After local radiotherapy in all but 7 patients and surgical resection in 29, 52 of 54 were considered to be in clinical remission. A total of 13 patients with metastatic disease were good responders at the completion of the initial chemotherapy. These results confirm the efficacy of primary chemotherapy using ifosfamide for the treatment of ES.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Sarcoma de Ewing/tratamento farmacológico , Adolescente , Neoplasias Ósseas/mortalidade , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Terapia Combinada , Dactinomicina/administração & dosagem , Doxorrubicina/administração & dosagem , França , Humanos , Ifosfamida/administração & dosagem , Oncologia , Pediatria , Indução de Remissão , Sarcoma de Ewing/mortalidade , Sociedades Médicas , Vincristina/administração & dosagemRESUMO
One hundred and six patients with stage Ic to IV ovarian carcinoma were treated by a protocol consisting of optimal debulking surgery followed by 9 cycles of CHAP chemotherapy. Clinical response was confirmed by a second-look procedure. Sixty-nine patients (65%) responded with 54 histological complete remissions (50.8%). Nineteen patients did not receive any complementary treatment due to a negative reaction, or prolonged neutropenia. Seven patients received maintenance chemotherapy, 10 an abdominal radiotherapy, 22 intraperitoneal chemotherapy and 11 autologous bone marrow transplantation. The 5-year survival rate was 32.5% and disease-free survival rate was 39.7%. Prognostic-factor analysis showed that age, initial staging, residual disease and cytological grading were significant. The authors propose a classification based on the risk of relapse, and different therapeutic indications for improving response rate and patient survival.
Assuntos
Cisplatino/administração & dosagem , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/efeitos adversos , Cisplatino/uso terapêutico , Terapia Combinada , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgia , PrognósticoRESUMO
Primary undifferentiated sarcomas (also called embryonal sarcomas or malignant mesenchymomas) are an exceptional form of cancer of the liver, occurring preferentially in children or adolescents. They can exhibit poor differentiation, embryonal rhabdomyosarcoma being the most frequent. To date, therapeutic success has been reported only rarely. The authors describe the case of a 16 year old boy with primary hepatic sarcoma showing a rhabdomyoblastic differentiation, who is in complete remission two years after total surgical resection and polychemotherapy.
Assuntos
Neoplasias Hepáticas/patologia , Mesenquimoma/patologia , Rabdomiossarcoma/patologia , Adolescente , Terapia Combinada , Humanos , Neoplasias Hepáticas/terapia , Masculino , Rabdomiossarcoma/terapiaRESUMO
The authors reported one documented observation of a deep-frozen, non irradiated, intercalary allograft; it was perforated by drilling and then fixed by a blade plate. This allograft was removed 27 months after its implantation. Histological examination of the removed bone graft showed newly formed mature bone which developed near preexisting devitalized bone. The external cortex was also revitalized and reossified close to the periosteum, as it was previously reported. But osteogenesis filled all the paths of the perforations and extended to the haversian canals located in the vicinity of the perforations. The authors conclude that cortical perforations induce both cortical and medullary osteogenesis of the graft. If osteogenesis is observed in the whole medullary canal, it is more focal and located in the vicinity of the holes in the cortex.
Assuntos
Neoplasias Ósseas/cirurgia , Transplante Ósseo/patologia , Criopreservação , Osteossarcoma/cirurgia , Neoplasias Ósseas/patologia , Criança , Feminino , Humanos , Recidiva Local de Neoplasia/patologia , Osteossarcoma/patologia , Reoperação , Transplante Homólogo/métodos , Transplante Homólogo/patologiaRESUMO
UNLABELLED: Over 11 years we treated 30 osteosarcomas: 20 of them were high grade non metastatic osteosarcomas of the lower limb, which were treated by neoadjuvant chemotherapy (Rosen T10, or OS 87 protocol of the French Society for Pediatric Oncology). MATERIAL AND METHODS: There were 12 males and 8 females; the mean age was 19 years (range 12-51). The site of the tumor was the femoral neck (1 case), femoral diaphysis (2 cases), distal femur (12 cases), proximal tibia (4 cases), distal tibia (1 case), 3 were IIA and 17 IIB according to Enneking system. Conservative treatment was performed in 17 cases: there were 12 knee prostheses, 4 allografts and 1 knee arthrodesis with allograft. RESULTS: a) Surgical complications: Mechanical complications occurred in 10 patients. The function was preserved 8 times. In 2 patients the knee became stiff. An infection occurred in 3 patients: a conservative treatment was possible in 2 of them with a fair result. In the third case, an above-the-knee amputation had to be done. b) Functional results were studied according to Enneking rating. 14 arthroplasties (12 done as first surgical treatment and 2 after mechanical complication) had a 68, 19 score. c) Oncologic results: 8 patients were good respondents and 12 patients were bad respondents to chemotherapy according to Huvos grading. One local relapse was observed which could be treated by mean of a second chemotherapy and a prosthetic reconstruction. The patient is still alive and disease-free at 7 years (9 years after the diagnosis of the osteosarcoma). 5 patients had distant metastasis (lung, bones, and brain). One out of 5 was good respondent and 4 out of 5 are presently dead. Using Kaplan Meier statistical analysis, the overall survival wzs 76.8 per cent and the event-free survival was 67.4 per cent at 80 months. CONCLUSION: We preferred a simple prosthetic reconstruction without osseous sleeve or an intercalary allograft if possible: these procedures allow the patient very rapid autonomy to have despite a prolonged chemotherapy.
Assuntos
Neoplasias Ósseas/terapia , Prótese do Joelho/efeitos adversos , Osteossarcoma/terapia , Transplante Homólogo/efeitos adversos , Análise Atuarial , Adolescente , Adulto , Neoplasias Ósseas/patologia , Criança , Terapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Osteossarcoma/patologia , Prognóstico , Reoperação , Taxa de SobrevidaRESUMO
The authors report a case of rhabdomyosarcoma in a 17 year old boy which recurred after combination chemotherapy and radical prostatectomy, followed by death of the patient due to haematological complications of second-line chemotherapy. The diagnosis of these rhabdomyosarcomas is facilitated by the various immunohistochemical stains now available. Chemotherapy is undeniably effective and, combined with surgery and radiotherapy, ensures a 5-year survival of 47% to 93% depending on the stage. The first-line chemotherapy avoids the need for radiotherapy in the early stages and allows less mutilating surgical procedures, while maintaining the survival rate.
Assuntos
Neoplasias da Próstata , Rabdomiossarcoma , Adolescente , Humanos , Masculino , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/terapia , Rabdomiossarcoma/diagnóstico , Rabdomiossarcoma/terapiaRESUMO
Bone marrow transplantation (BMT) is the last chance of recovery for some children suffering from malignant hemopathy or congenital blood disease. BMT with related donor radically alters previous family relationships: each member of the nuclear family becomes actively involved. Parents and siblings all undergo HLA typing. Only 30% of those who would benefit from bone marrow transplantation are lucky enough to have an HLA matched related donor, brother or sister. Our retrospective study concerned related donors and their parents. This paper reports the parents study. It was carried out at Strasbourg University Hospital. Parents were invited to speak about the child's illness, the graft reasons and their own position to regarding the choice of donor. Semi-structured interviews were used and their content analysed. The results highlight the expression by the parents of the need to maintain some control over the action which will save their child and establish an other gift system to keep their parental status.
Assuntos
Atitude Frente a Saúde , Transplante de Medula Óssea/métodos , Pais/psicologia , Papel (figurativo) , Doadores de Tecidos/psicologia , Adolescente , Adulto , Transplante de Medula Óssea/mortalidade , Transplante de Medula Óssea/psicologia , Criança , Pré-Escolar , Comportamento de Escolha , Feminino , Teste de Histocompatibilidade , Humanos , Lactente , Recém-Nascido , Controle Interno-Externo , Masculino , Relações Pais-Filho , Estudos Retrospectivos , Taxa de SobrevidaAssuntos
Corticosteroides/farmacologia , Asparaginase/farmacologia , Fibrinogênio/análise , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Corticosteroides/uso terapêutico , Criança , Erwinia/enzimologia , Escherichia coli/enzimologia , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológicoRESUMO
A total of twenty-six patients with idiopathic thrombocytopenic purpura ITP refractory to corticosteroids were alternately allocated to undergo splenectomy alone (N = 12) or to receive a 5 day course of high dose immunoglobulin G i.v. immediately followed by splenectomy (N = 14). Although there were less initial failures after splenectomy in patients receiving IgG, the proportion of sustained complete remission at 1 and 2 years was identical in both groups. It is concluded that high dose IgG infusions do not improve the results of splenectomy in refractory ITP.
Assuntos
Imunoglobulina G/uso terapêutico , Púrpura Trombocitopênica/terapia , Esplenectomia , Adolescente , Corticosteroides/uso terapêutico , Adulto , Idoso , Terapia Combinada , Tolerância a Medicamentos , Feminino , Humanos , Imunoglobulina G/administração & dosagem , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Púrpura Trombocitopênica/tratamento farmacológico , Púrpura Trombocitopênica/cirurgiaRESUMO
Haemorragic cystitis is a well known complication of cyclophosphamide therapy. In the reported case, a 7 years old boy treated for lymphosarcoma, as an excretory urogram demonstrated important focal irregularity of the bladder wall. Cystoscopy revealed areas of important bullous oedema with generalized hyperemia. A biopsy disclosed normal urothelium raised by oedematous and congestive chorion and excluded a malignant tumor. Various kinds of endoscopic and surgical procedures are reported to control persisting hematuria after withdrawal of the cyclophosphamide treatment.
Assuntos
Ciclofosfamida/efeitos adversos , Cistite/induzido quimicamente , Linfoma não Hodgkin/tratamento farmacológico , Criança , Ciclofosfamida/uso terapêutico , Cistite/diagnóstico , Cistoscopia , Hematúria/induzido quimicamente , Hemorragia/induzido quimicamente , Humanos , Masculino , Neoplasias Faríngeas/tratamento farmacológico , Bexiga Urinária/patologia , UrografiaRESUMO
Left ventricular function in 21 patients treated by polychemotherapy including adriamycin (ADM) has been studied by repeated echocardiographic examination. The mean rate of circumferential, the ejection fraction, and the shortening fraction are the most significant data obtained by this investigation. They permit the detection of early damage of left ventricular performance which increases progressively, confirming the dose-dependent nature of the cardiomyopathy. Supervision of patients under ADM is necessary to recognize those who rapidly develop cardiomyopathy. In these cases, treatment interruption may be beneficial. In contrast, patients with little left ventricular damage can be treated by a total dosage of ADM superior to that actually recommended.
Assuntos
Doxorrubicina/efeitos adversos , Ecocardiografia , Cardiopatias/induzido quimicamente , Adolescente , Adulto , Idoso , Quimioterapia Combinada , Cardiopatias/fisiopatologia , Cardiopatias/prevenção & controle , Humanos , Pessoa de Meia-IdadeRESUMO
Three patients with malignant histiocytosis treated with combination chemotherapy are reported. Induction treatment included bleomycin, adriamycin, cyclophosphamide, vincristine and prednisone (BACOP). Complete response was obtained in one patient who is alive and well 32 months after diagnosis. A partial response was obtained in the second patient, who is alive and well 35 months after diagnosis. The third patient died with drug-induced agranulocytosis and sepsis.