Low dose systemic or intralesional meglumine antimoniate treatment for American tegumentary leishmaniasis results in low lethality, low incidence of relapse, and low late mucosal involvement in a referral centre in Rio de Janeiro, Brazil (2001-2013).

BACKGROUND: American tegumentary leishmaniasis (ATL) is a non-lethal parasitic disease that presents with cutaneous (CL) and mucosal (ML) clinical forms. ATL treatment aims at healing the lesions and preventing the development of the late mucosal form. Systemic meglumine antimoniate (MA) therapy with 10-20 mg Sb5+/kg/day is the first choice of treatment. However, alternative therapies using 5 mg Sb5+/kg/day or intralesional (IL) MA are the usual regimens at the National Institute of Infectious Diseases (NIID), Rio de Janeiro, Brazil. OBJECTIVES: To evaluate lethality and the incidence of relapse and development of late ML in CL patients treated at NIID from 2001 until 2013. METHODS: Data were recovered from records of all ATL patients diagnosed during that period. FINDINGS: Out of 777 patients, 753 were treated with MA (96.9%). Of those, 89.1% received alternative therapy of 9.9% IL and 79.2% systemic 5 mg Sb5+/kg/day. Some patients required 1-3 additional courses of treatment, thus making a total of 997 courses; 85.2% of them were subjected to alternative therapies. Lethality was 0.1%, relapse incidence 5.8%, and late ML incidence 0.25%. As a final outcome for the 777 patients, 95.9% were cured, 0.1% died and 4.0% were not able to follow-up. MAIN CONCLUSIONS: Alternative MA schedules resulted in low lethality without increase of relapse or late ML incidence.

Comparison of parasite load by qPCR and histopathological changes of inner and outer edge of ulcerated cutaneous lesions of cutaneous leishmaniasis.

BACKGROUND: Cutaneous leishmaniasis (CL) is an infectious vector-borne disease caused by protozoa of the Leishmania genus that affects humans and animals. The distribution of parasites in the lesion is not uniform, and there are divergences in the literature about the choice of the better sampling site for diagnosis-inner or outer edge of the ulcerated skin lesion. In this context, determining the region of the lesion with the highest parasite density and, consequently, the appropriate site for collecting samples can define the success of the laboratory diagnosis. Hence, this study aims to comparatively evaluate the parasite load by qPCR, quantification of amastigotes forms in the direct exam, and the histopathological profile on the inner and outer edges of ulcerated CL lesions. METHODS: Samples from ulcerated skin lesions from 39 patients with confirmed CL were examined. We performed scraping of the ulcer inner edge (base) and outer edge (raised border) and lesion biopsy for imprint and histopathological examination. Slides smears were stained by Giemsa and observed in optical microscopy, the material contained on the smears was used to determine parasite load by quantitative real-time PCR (qPCR) with primers directed to the Leishmania (Viannia) minicircle kinetoplast DNA. The histopathological exam was performed to evaluate cell profile, tissue alterations and semi-quantitative assessment of amastigote forms in inner and outer edges. PRINCIPAL FINDINGS: Parasite loads were higher on the inner edge compared to the outer edge of the lesions, either by qPCR technique (P<0.001) and histopathological examination (P< 0.003). There was no significant difference in the parasite load between the imprint and scraping on the outer edge (P = 1.0000). CONCLUSION/SIGNIFICANCE: The results suggest that clinical specimens from the inner edge of the ulcerated CL lesions are the most suitable for both molecular diagnosis and direct parasitological examination.

Comparative study of amplification systems in immunoenzyme assays for the diagnosis of American tegumentary leishmaniasis.

We compared the accuracy and reliability of three amplification systems for enzyme immunoassays in the detection of specific IgG antibodies for the diagnosis of cutaneous leishmaniasis caused by Leishmania (Viannia) braziliensis in patients from an endemic area in Rio de Janeiro, Brazil. Partially soluble antigens obtained from the promastigote forms of L. (V.) braziliensis were used. For development of the reaction, two chromogens, 1,2-orthophenylenediamine (OPD) and 3,3',5,5'-tetramethylbenzidine (TMB), and a fluorogen, 4-methylumbelliferylphosphate (MUP), were tested. The performance of each system was compared using the following parameters: accuracy, intraclass correlation coefficient (ICC), and area under the receiver operating characteristic (ROC) curve. Sensitivity was the same (97.4%) for all systems. The reliability was excellent (ICC = 98.6, 98.7, and 99.1%) and specificity was 93.7, 95.8, and 97.4% for OPD, MUP, and TMB, respectively, showing no statistical significance. Despite the absence of differences in the performance of the three systems, the use of TMB is suggested because of its operational advantages, such as low cost compared with fluorogens, easy manipulation, greater stability, and lower toxicity.

Visceral leishmaniasis in Brazil: scenarios and challenges for the surveillance and control

Adaptation of the vector and displacement of infected dogs to previously disease-free areas challenges visceral leishmaniasis (VL) control, and leads to geographic dispersion and occurrence in urban and peri-urban areas. Continuous VL control measures over time must be applied with a wide geographic reach, along with better diagnosis practices and timely treatment. The high case-fatality of human VL in areas of recent introduction and its growing association with HIV impose the need for an early diagnosis, treatment and the adoption of active search for human and canine cases incorporated into the routine of periodic home visits by health professionals. The increasing on public rejection of canine euthanasia as a control measure, the limitations of canine therapy with the current available drugs, and the controversies regarding available vaccines for canine protection are discussed. Good prospects on the insecticide-impregnated collars as an effective control measure are emphasized.

Favorable responses to treatment with 5 mg Sbv/kg/day meglumine antimoniate in patients with American tegumentary leishmaniasis acquired in different Brazilian regions.

INTRODUCTION: Favorable responses in American tegumentary leishmaniasis (ATL) patients to treatment with 5 mg Sbv/kg/day meglumine antimoniate (MA) has been reported in Rio de Janeiro, but little is known regarding the therapeutic response to low doses in patients from other locations. METHODS: A retrospective review of medical records was conducted to compare the therapeutic response to 5 mg Sbv/kg/day MA treatment among 36 patients who acquired ATL in Brazilian states other than Rio de Janeiro (OS group) and 72 patients from Rio de Janeiro (RJ group). RESULTS: One course of 5 mg Sbv/kg/day MA cured 72.8% of 81 cutaneous (CL) and 66.6% of 27 mucosal (ML) leishmaniasis-infected patients: 70% in the CL/RJ group, 81% in the CL/OS group, 50% in the ML/RJ group, and 80% in the ML/OS group. After up to two additional treatment courses at the same dose, 88.9% and 85.2% of the CL and ML patients were cured, respectively. Adverse events were observed in 40% of patients in the CL/RJ group, 57% of the CL/OS group, 58% of the ML/RJ group, and 80% of the ML/OS group. No significant differences were observed in the cure rates or adverse effects between the RJ and OS groups. No patients required permanent discontinuation of treatment due to adverse events. CONCLUSIONS: Patients with ATL acquired in both RJ and OS may respond to low-dose MA. While high-dose MA should remain the standard treatment for ATL, low-dose MA might be preferred when toxicity is a primary concern.

Spatial distribution and effects of land use and cover on cutaneous leishmaniasis vectors in the municipality of Paracambi, Rio de Janeiro, Brazil

ABSTRACT The municipality of Paracambi (Rio de Janeiro, Brazil) reports sporadic cases of American cutaneous leishmaniasis (ACL). Previous studies detected Nyssomyia intermedia (Diptera: Psychodidae) as the main vector in the region, but its spatial distribution and the presence of other vector species have not been evaluated. This study aims at filling this knowledge gap, by studying the ecology of sand flies, their spatiotemporal distribution, and correlation with land use/cover. Two campaigns of monthly sand fly collections using light traps and manual captures were conducted in 1992-1994 and 2001-2003. Females were dissected to detect natural Leishmania infections. The spatial distribution of sand flies was assessed using kernel density maps. Correlations with land use/cover were evaluated by extracting satellite imagery data around the capture points. A total of 17,232 sand flies from 13 species were captured. Medically important species included Ny. intermedia, Migonemyia migonei, Pintomyia fischeri and Ny. whitmani. No Leishmania-infected females were detected. Highest densities were detected in the peri-urban areas Cascata and Sabugo, and in rural areas São José and Mutirão. Ny. intermedia had statistically significant correlations with pasture and agricultural areas. Present results strengthened that Ny. intermedia and Mg. migonei are the main local ACL vectors. Correlations with land use evidence the association between ACL and anthropic environmental change.

Low versus high dose of antimony for American cutaneous leishmaniasis: A randomized controlled blind non-inferiority trial in Rio de Janeiro, Brazil.

BACKGROUND: Although high dose of antimony is the mainstay for treatment of American cutaneous leishmaniasis (ACL), ongoing major concerns remain over its toxicity. Whether or not low dose antimony regimens provide non-inferior effectiveness and lower toxicity has long been a question of dispute. METHODS: A single-blind, non-inferiority, randomized controlled trial was conducted comparing high dose with low dose of antimony in subjects with ACL treated at a referral center in Rio de Janeiro, an endemic area of Leishmania (Viannia) braziliensis transmission. The primary outcome was clinical cure at 360 days of follow-up in the modified-intention-to-treat (mITT) and per-protocol (PP) populations. Non-inferiority margin was 15%. Secondary objectives included occurrence of epithelialization, adverse events and drug discontinuations. This study was registered in ClinicalTrials.gov: NCT01301924. RESULTS: Overall, 72 patients were randomly assigned to one of the two treatment arms during October 2008 to July 2014. In mITT, clinical cure was observed in 77.8% of subjects in the low dose antimony group and 94.4% in the high dose antimony group after one series of treatment (risk difference 16.7%; 90% CI, 3.7-29.7). The results were confirmed in PP analysis, with 77.8% of subjects with clinical cure in the low dose antimony group and 97.1% in the high dose antimony group (risk difference 19.4%; 90% CI, 7.1-31.7). The upper limit of the confidence interval exceeded the 15% threshold and was also above zero supporting the hypothesis that low dose is inferior to high dose of antimony after one series of treatment. Nevertheless, more major adverse events, a greater number of adverse events and major adverse events per subject, and more drug discontinuations were observed in the high dose antimony group (all p<0.05). Interestingly, of all the subjects who were originally allocated to the low dose antimony group and were followed up after clinical failure, 85.7% achieved cure after a further treatment with local therapy or low dose of antimony. CONCLUSIONS: Compared with high dose, low dose of antimony was inferior at the pre-specified margin after one series of treatment of ACL, but was associated with a significantly lower toxicity. While high dose of antimony should remain the standard treatment for ACL, low dose antimony treatment might be preferred when toxicity is a primary concern.

Standardization of intralesional meglumine antimoniate treatment for cutaneous leishmaniasis.

INTRODUCTION:: Intralesional treatment for cutaneous leishmaniasis has been applied for over 30 years at the Oswaldo Cruz Foundation, Rio de Janeiro, with good therapeutic results and without relevant systemic toxicity. METHODS: Meglumine antimoniate was injected subcutaneously, using a long medium-caliber needle (for example, 30mm × 0.8mm); patients received 1-3 injections, with 15-day intervals. RESULTS: The technique is described in detail sufficient to enable replication. CONCLUSIONS:: The treatment of cutaneous leishmaniasis with intralesional meglumine antimoniate is a simple, effective, and safe technique, which may be used in basic healthcare settings.

Retrospective study of 151 patients with cutaneous leishmaniasis treated with meglumine antimoniate.

We retrospectively analyzed a series of 151 cases of cutaneous leishmaniasis treated between 1967 and 1982. One-hundred-and-thirty-nine (92%) patients presented with active lesions and were treated with daily doses of meglumine antimoniate: 81 adults received a 5-ml vial IM and 58 children received 1 to 5 ml. Forty-five (32.4%) patients underwent continuous treatment with meglumine antimoniate for 25 to 116 days without rest intervals, and 94 (67.6%) intermittent treatment with 2 to 5 series of meglumine antimoniate. Intermittent series could include schedules of daily IM applications for 10 to 25 days each and intervals varying from 10 to 60 days. Antimony dose was calculated for 66 (47.5%) patients and ranged from 3.9 to 28.7 Sb5+/kg/day. Of these, 35 patients received > or =10 mg and 31 patients < 10 mg Sb5+/kg/day. Median time of healing was longer for lesions on the legs and feet -- 67.5 days versus 48.7 days (p < 0.001) for other sites. However, there were no significant differences in the median time of healing between adults and children, intermittent and continuous regimens or high and low antimony doses. Fifty-one patients were reassessed 5 to 14 years after treatment and showed no evidence of disease. These results support further investigation (clinical trials) on treatment using low doses of antimony.

[Prevalence of canine infection from endemic areas of American cutaneous leishmaniasis in Paracambi District, Rio de Janeiro State, between 1992 and 1993]. / Prevalência da infecção canina em áreas endêmicas de leishmaniose tegumentar americana, do município de Paracambi, Estado do Rio de Janeiro, no período entre 1992 e 1993.

In the district of Paracambi, State of Rio de Janeiro an epidemiological survey for American tegumentary leishmaniasis in canine population was carried out in endemic localities. A total of 179 dogs was registered and 138 (77.1%) examined for their clinical aspects, development of delayed hypersensitivity (DHS) with Imunoleish(R) antigen and serological responses by indirect immunofluorescent reaction and enzyme-linked immunosorbent assay. In 9 (6.5%) dogs with active cutaneous lesions or suspect scars, 66.7% were caused by Leishmania sp; 44.4% produced infection in hamsters and showed growth in culture media, which was considered to be compatible with the species of Leishmania braziliensis complex. The molecular characterization (isoenzyme and KDNA restriction profiles) defined two strains with similar profiles for L. (Viannia) braziliensis. The prevalence of canine infection estimated by the cutaneous test, IFR and ELISA was 10.1%, 16.7% and 27.8%, respectively. The presence of clinical / sub-clinical form of ATL in canine population associated with human infections suggested that the dog can act as source of infection as well as for dissemination of the disease.

Identification of Leishmania (Leishmania) chagasi isolated from healthy skin of symptomatic and asymptomatic dogs seropositive for leishmaniasis in the municipality of Rio de Janeiro, Brazil.

Euthanasia of seropositive dogs has been one of the principal measures adopted by the Program for the Control of Leishmaniasis in Brazil for many years. However, its efficacy is currently being questioned. We obtained intact skin samples from 20 Leishmania-reactive dogs from the municipality of Rio de Janeiro that had been referred for euthanasia. The promastigote forms of Leishmania were isolated in culture from 18 of these animals. Fourteen of these isolates were identified as Leishmania (Leishmania) chagasi by isoenzyme electrophoresis; seven of these were from asymptomatic dogs and seven were from symptomatic animals with visceral leishmaniasis. In conclusion, cutaneous parasitism is found in the intact skin of dogs naturally infected with L. (L.) chagasi, irrespective of the presence or absence of clinical signs suggestive of visceral leishmaniasis.

[Immediate and generalized reaction to Montenegro skin test]. / Ocorrência de reação imediata generalizada à intradermorreação de Montenegro.

The authors describe for the first time a case of immediate and generalized reaction to Montenegro skin test with merthiolated antigen. This reaction consisted of generalized cutaneous rash with pruritus, and was treated with oral bromethazine. The pruritus disappeared an hour after medication and the rash 12 hours later.

[Absence of Lutzomyia longipalpis in some endemic visceral leishmaniasis areas in Rio de Janeiro municipality]. / Ausência da Lutzomyia longipalpis em algumas áreas de ocorrência de leishmaniose visceral no Município do Rio de Janeiro.

The first autochthonous case of human visceral leishmaniasis (VL) in the Municipality of Rio de Janeiro was diagnosed in 1977. Since 1980, 54 autochthonous cases have been diagnosed in various locations, and since 1993 some 17 autochthonous human cases have been reported. Eight of these occurred in the neighborhood of Barra de Guaratiba and the others were distributed in the following neighborhoods: Camorim, Colônia, Grota Funda, Grumari, Ilha de Guaratiba, and Carapiá. From September 1996 to December 1999, phebotomine sandfly captures were performed at 18 sites on the mountainsides of the Pedra Branca Massif, in the Municipality, and a total of 18,303 specimens were collected, with a predominance of L. intermedia (87.33%), L. migonei (6.59%), L. longipalpis (3.10%), and L. firmatoi (1.90%). The species L. longipalpis predominated in Barra de Guaratiba (46.80%) and was absent from the other six locations where VL cases also occurred, suggesting the participation of other species like L. migonei and L. firmatoi, belonging to the same paraphyletic group of the vector species, in the VL transmission chain in the region.

Leishmaniose visceral: cenários epidemiológicos e desafios / Visceral leishmaniasis: epidemiological scenarios and challenges

Um retrospecto histórico e epidemiológico da leishmaniose visceral (LV) no mundo e no Brasil e possíveis cenários dependentes de condicionantes ambientais, biológicos e sociais ressalta estratégias de vigilância e controle, enfatizando: associação de procedimentos com continuidade; conquistas e controvérsias em diagnóstico, tratamento, vacinação e uso de coleira com deltametrina, no cão; e ineficácia da terapêutica canina com as drogas disponíveis, mas boas perspectivas da vacina, na proteção individual, e da coleira impregnada, no controle coletivo. Considera a situação epidemiológica potencializada pela galopante urbanização da LV e sua dispersão geográfica, salientando desafios de controle por deslocamento do vetor e do cão infectado a novas áreas através do transporte rodoviário e ferroviário, e conflitos de rejeição à eutanásia canina. Alerta sobre a alta letalidade da LV humana em áreas de instalação recente e por associação crescente com HIV, impondo diagnóstico e tratamento precoces, para evitar agravamento clínico e óbitos, e adoção da busca ativa de casos humanos e caninos incorporada à rotina das visitações domiciliares periódicas da Estratégia Saúde da Família, para detecção de febre prolongada e outros sinais de LV e o encaminhamento a unidades de Saúde. Admite que a introdução do cão infectado em áreas indenes continuará um grande desafio.(AU)

A historical and epidemiological retrospect of visceral leishmaniasis (VL) in the world and in Brazil, and possible scenarios dependent of environmental, biological and social conditions stands out strategies of surveillance and control, emphasizing the association of procedures with continuity; conquests and controversies in diagnosis, treatment, vaccination and use of deltametrin collar in the dog; and ineffectiveness of canine therapy with available drugs, but good vaccine prospects, in individual protection, and impregnated collar, in collective control. It considers the epidemiological situation potentiated by the galloping urbanization of VL and its geographical dispersion, highlighting control challenges by moving the vector and the infected dog to new areas through road and rail transport, and conflicts of rejection to canine euthanasia. Alert on the high lethality of human LV in areas of recent installation and by increasing association with HIV, imposing early diagnosis and treatment, to avoid clinical worsening and death, and adoption of the active search of human and canine cases incorporated into the routine of the periodic home visits of the Family Health Strategy to detect prolonged fever and other signs of LV and referral to health units. Introducing the infected dog into free transmission areas will remain a major challenge.(AU)

Leishmaniose visceral: cenários epidemiológicos e desafios / Visceral leishmaniasis: epidemiological scenarios and challenges

Um retrospecto histórico e epidemiológico da leishmaniose visceral (LV) no mundo e no Brasil e possíveis cenários dependentes de condicionantes ambientais, biológicos e sociais ressalta estratégias de vigilância e controle, enfatizando: associação de procedimentos com continuidade; conquistas e controvérsias em diagnóstico, tratamento, vacinação e uso de coleira com deltametrina, no cão; e ineficácia da terapêutica canina com as drogas disponíveis, mas boas perspectivas da vacina, na proteção individual, e da coleira impregnada, no controle coletivo. Considera a situação epidemiológica potencializada pela galopante urbanização da LV e sua dispersão geográfica, salientando desafios de controle por deslocamento do vetor e do cão infectado a novas áreas através do transporte rodoviário e ferroviário, e conflitos de rejeição à eutanásia canina. Alerta sobre a alta letalidade da LV humana em áreas de instalação recente e por associação crescente com HIV, impondo diagnóstico e tratamento precoces, para evitar agravamento clínico e óbitos, e adoção da busca ativa de casos humanos e caninos incorporada à rotina das visitações domiciliares periódicas da Estratégia Saúde da Família, para detecção de febre prolongada e outros sinais de LV e o encaminhamento a unidades de Saúde. Admite que a introdução do cão infectado em áreas indenes continuará um grande desafio.

A historical and epidemiological retrospect of visceral leishmaniasis (VL) in the world and in Brazil, and possible scenarios dependent of environmental, biological and social conditions stands out strategies of surveillance and control, emphasizing the association of procedures with continuity; conquests and controversies in diagnosis, treatment, vaccination and use of deltametrin collar in the dog; and ineffectiveness of canine therapy with available drugs, but good vaccine prospects, in individual protection, and impregnated collar, in collective control. It considers the epidemiological situation potentiated by the galloping urbanization of VL and its geographical dispersion, highlighting control challenges by moving the vector and the infected dog to new areas through road and rail transport, and conflicts of rejection to canine euthanasia. Alert on the high lethality of human LV in areas of recent installation and by increasing association with HIV, imposing early diagnosis and treatment, to avoid clinical worsening and death, and adoption of the active search of human and canine cases incorporated into the routine of the periodic home visits of the Family Health Strategy to detect prolonged fever and other signs of LV and referral to health units. Introducing the infected dog into free transmission areas will remain a major challenge.

Treatment of cutaneous leishmaniasis with intralesional meglumine antimoniate at a primary care unit in Brazil / Tratamento da leishmaniose cutânea com antimoniato de meglumina intralesional em uma unidade básica de saúde

O antimoniato de meglumina (AM) intralesional (IL), por via subcutânea, é recomendado para o tratamento da leishmaniose cutânea (LC). A frequente falta de recursos nas unidades básicas de saúde costuma dificultar o monitoramento de efeitos adversos, o manuseio de comorbidades e o uso de medicamentos de segunda linha. São relatados seis casos de LC tratados com AM IL (devido a contraindicações ou efeitos adversos ao AM por via sistêmica) em uma unidade básica de saúde. As infiltrações com AM IL foram administradas quinzenalmente até a epitelização das lesões cutâneas, que ocorreu em todos os casos. Eczema local de intensidade moderada foi o único efeito adverso observado em um paciente. O AM IL se revelou um tratamento simples, eficiente e seguro para LC.

Favorable responses to treatment with 5 mg Sbv/kg/day meglumine antimoniate in patients with American tegumentary leishmaniasis acquired in different Brazilian regions

Abstract INTRODUCTION: Favorable responses in American tegumentary leishmaniasis (ATL) patients to treatment with 5 mg Sbv/kg/day meglumine antimoniate (MA) has been reported in Rio de Janeiro, but little is known regarding the therapeutic response to low doses in patients from other locations. METHODS: A retrospective review of medical records was conducted to compare the therapeutic response to 5 mg Sbv/kg/day MA treatment among 36 patients who acquired ATL in Brazilian states other than Rio de Janeiro (OS group) and 72 patients from Rio de Janeiro (RJ group). RESULTS: One course of 5 mg Sbv/kg/day MA cured 72.8% of 81 cutaneous (CL) and 66.6% of 27 mucosal (ML) leishmaniasis-infected patients: 70% in the CL/RJ group, 81% in the CL/OS group, 50% in the ML/RJ group, and 80% in the ML/OS group. After up to two additional treatment courses at the same dose, 88.9% and 85.2% of the CL and ML patients were cured, respectively. Adverse events were observed in 40% of patients in the CL/RJ group, 57% of the CL/OS group, 58% of the ML/RJ group, and 80% of the ML/OS group. No significant differences were observed in the cure rates or adverse effects between the RJ and OS groups. No patients required permanent discontinuation of treatment due to adverse events. CONCLUSIONS: Patients with ATL acquired in both RJ and OS may respond to low-dose MA. While high-dose MA should remain the standard treatment for ATL, low-dose MA might be preferred when toxicity is a primary concern.

Low dose systemic or intralesional meglumine antimoniate treatment for American tegumentary leishmaniasis results in low lethality, low incidence of relapse, and low late mucosal involvement in a referral centre in Rio de Janeiro, Brazil (2001-2013)

BACKGROUND American tegumentary leishmaniasis (ATL) is a non-lethal parasitic disease that presents with cutaneous (CL) and mucosal (ML) clinical forms. ATL treatment aims at healing the lesions and preventing the development of the late mucosal form. Systemic meglumine antimoniate (MA) therapy with 10-20 mg Sb5+/kg/day is the first choice of treatment. However, alternative therapies using 5 mg Sb5+/kg/day or intralesional (IL) MA are the usual regimens at the National Institute of Infectious Diseases (NIID), Rio de Janeiro, Brazil. OBJECTIVES To evaluate lethality and the incidence of relapse and development of late ML in CL patients treated at NIID from 2001 until 2013. METHODS Data were recovered from records of all ATL patients diagnosed during that period. FINDINGS Out of 777 patients, 753 were treated with MA (96.9%). Of those, 89.1% received alternative therapy of 9.9% IL and 79.2% systemic 5 mg Sb5+/kg/day. Some patients required 1-3 additional courses of treatment, thus making a total of 997 courses; 85.2% of them were subjected to alternative therapies. Lethality was 0.1%, relapse incidence 5.8%, and late ML incidence 0.25%. As a final outcome for the 777 patients, 95.9% were cured, 0.1% died and 4.0% were not able to follow-up. MAIN CONCLUSIONS Alternative MA schedules resulted in low lethality without increase of relapse or late ML incidence.