Toxicity of tretinoin in acute promyelocytic leukaemia

cultivated on blood agar that contained 5-7% rabbit blood. White colonies appeared and grew to about 1 5mm in diameter. Smears showed gram-negative rods measuring 0.5x1.0 flm and coccoid forms with a diameter of about 1 flm. The organisms stained poorly with alkaline methylene-blue solution but well with Giemsa’s method. They were sensitive only to amikacin and imipenem. In identifying these microorganisms we excluded the genus Haemobartonella as well as Anaplasma and Aegyptianella because organisms in these genera cannot be cultivated on a non-living medium. We also excluded Bartonella bacilliformis because patients had had no contact with the endemic regions in South America, the Phlebotomus fly vector was absent in the residential area of our patients, and they had no symptoms of Oroya fever or of verruga peruana. Therefore, we considered it not necessary to look for flagellae. Moreover, the electron micrograph of a thin section of the microorganisms from our culture revealed structures that morphologically resembled Grahamella organisms (figure, bottom). Therefore, we conclude that the organisms grown in the culture from the guineapigs are likely to be of the genus Grahamella, but we cannot prove that these organisms are the same as those observed in our patients. Further tests are necessary with specific antisera. We also do not know the relation between the intraerythrocytic elements found in blood smears of our patients to their diseases; the immune status of our patients is important in appreciating the role of a "new" opportunistic

pathogen. We gratefully acknowledge the editorial efforts and suggestions made Dr Julius P Kreier, Professor Emeritus of the Ohio State University, Ohio, USA.

by

Figure: Electron micrographs Top=blood smear from case 1. Bottom=from culture x 24500; W=cell wall, C=cytoplasmic mass, Cm=cytoplasmic membrane, LW=empty cell wall.

We have seen intraerythrocytic coccoidal elements in Giemsa-stained blood films from some patients in our hospital (figure, top). All patients were febrile, and some were anaemic but without signs of haemolysis (normal serum indirect bilirubin, urinary urobilinogen, and number of reticulocytes in blood). The raised temperature and anaemia were thought to be related to the underlying disease that led to hospital admission. We report 3 of these cases here. Case 1 was a female patient with varicella, scarlatina, and toxaemia. Group A P-haemolytic streptococci of the Ml Tl serotype, opacity factor negative (confirmed by the Central Public Health Laboratory in London, UK), were isolated from her throat. Case 2 was a 26-year-old male patient with hepatosplenomegaly, pancytopenia, and pleuropneumonia. He developed acute renal, respiratory, and cardiac insufficiency. He died 40 h after admission from generalised tuberculosis confirmed at necropsy. Case 3 was an elderly male patient who died with the diagnosis of generalised candidiasis confirmed at necropsy. All 3 patients came from rural areas or went to these areas visiting relatives so that contact with animals and their ectoparasites cannot be excluded. None of these patients mentioned direct contact with animals. In view of these patients’ severe underlying diseases, it is possible that their immune systems were compromised. Unfortunately, we do not have the relevant laboratory data. In order to confirm or reject our hypothesis that these were haemotropic bacteria, we inoculated blood from cases 1 and 3 into hearts of 2 healthy guineapigs and into the peritoneum of a further 2 animals. Before the experiment the guineapigs did not show any signs of anaemia; their red blood cells were normal. 3-4 weeks later coccoid forms, like those observed in the patients, appeared in the blood of all 4 inoculated animals. We then took a kidney of 1 animal with a sterile technique and minced it in saline. After centrifugation, the supernatant was

360

Vladimir Puntarić, Dražen Borčić, Danijela Bejuk, Branka Vrhovec, Josip Madić, Kristina Busch, Branko Richter University Hospital of Infectious Diseases "Dr Fran Mihaljević", 41000 Zagreb, Croatia; Institute of Pathology, Medical Faculty, University of Zagreb; Department of Microbiology and Infectious Diseases, Veterinary Faculty, University of Zagreb; Pliva, Pharmaceutical, Chemical, Food, and Cosmetic Industry, Zagreb; and institute of Microbiology, A Štampar School of Public Health, Zagreb 1 2 3 4 5

6

Kreier JP. Parasitic protozoa, vol IV. New York: Academic Press, 1977: 221-33. Krampitz HE, Kleinschmidt A. Grahamella Brumpt 1911: Biologische und morphologische Untersuchungen. Z Tropenmed 1960; 11: 336-52. Krampitz HE. Weitere Untersuchungen an Grahamella Brumpt 1911. Z Tropenmed 1962; 13: 34-53. Brumpt E. Précis de Parasitologie, sixième edition. Paris: Libraires de L’Académie de Médecine, 1949: 536. Kreier JP, Dominquez N, Krampitz HE, Gothe R, Ristić M. The hemotrophic bacteria: the families Bartonellaceae and Anaplasmataceae (Grahamella). In: Starr MP, Stolp H, Trüper HG, Balows A, Schlegel HG, eds. The prokaryotes: a handbook on habitats, isolation and identification of bacteria. Berlin: Springer-Verlag, 1981: 2193-97. Ristić M, Kreier JP. Genus II: Grahamella (ex Brumpt 1911) nom rev. In: Krieg NR, Holt JG, eds. Bergey’s manual of systematic bacteriology, vol 1. Baltimore: Williams & Wilkins, 1984: 718.

Toxicity of tretinoin in acute promyelocytic leukaemia SIR—Mahmoud and colleagues (Dec 4, p 1394) raise several important points about the safety of tretinoin in children with acute promyelocytic leukaemia (APL). They report a high incidence of severe adverse effects in 8 of 9 children treated with a daily oral dose of 45 mg/m2. Unfortunately, the plasma concentration of tretinoin and the excretion of its metabolites were not measured; this might have contributed to further understanding the pharmacokinetics of tretinoin in APL. It is well known that the maximum-tolerated dose of tretinoin is lower in children than in adults (60 vs 150 mg/m2 per day).1Fatal toxicity induced by tretinoin in children with APL has been reported.2 For unclear reasons, children are

substantially more sensitive than adults to the central nervous system effects of tretinoinand central nervous system toxicity is dose-limiting in children with cancer. Although neurotoxicity of tretinoin is dose dependent, the development of intracranial hypertension does not necessarily imply a high plasma drug concentration since the occurrence of pseudotumour cerebri during a period of low plasma drug concentrations has been reported in a female patient with APL.4 This suggests that other factors, such as an increased expression of cellular retinoic acid-binding proteins in normal body tissues, may contribute to the development of toxicity.4 Although most clinical experience with tretinoin administration in patients with APL has been obtained with a daily dose of 45 mg/m2, lower doses are effective.3 Castaigne and colleaguess have shown that a daily dose of 25 mg/m2 is adequate for the induction of complete remission in patients with APL, and that the pharmacokinetic data are similar to those obtained with 45 mg/m2. On the basis of these observations, children with APL should receive a fraction of the dose usually administered to adults until further doseresponse studies are conducted and this crucial safety issue is settled.

Bone marrow aspiration on day 35 revealed a hypocellular bone in complete remission, but molecular analysis by polymerase chain reaction still showed the PML/RAR fusion transcript. This result was regarded as indication for further marrow

chemotherapy.3 therapy nor leucopheresis are useful management of hyperleucocytosis; only early dexamethasone has resulted in some improvement.4 Thus, an increased leucocyte count in the presence of papilloedema prompted us to add short-time high-dose cytarabine which successfully prevented retinoic acid syndrome. Early additive chemotherapy with high-dose cytarabine might prevent tretinoin-induced hyperleucocytosis. Neither cessation of

in

Klaus Schmitt, Rudolf Schwarz, Gerald Tulzer, Otto Krieger, Andreas Zoubek, Helmut Gadner Children’s Hospital Linz, A-4020 Linz, Austria; Elisabethinen and St Anna Children’s Hosiptal, Vienna

1

2

J Forjaz de Lacerda Department of Haematology/Bone Marrow Transplantation Unit, University of Lisbon, Hospital, Lisbon, Portugal

3

1 Zurzroch R, Estey E, Talpaz M. All-trans retinoic acid: tolerance and biologic effects in myelodysplastic syndrome. J Clin Oncol 1993; 11: 1489-95. 2 Smith-Whitley K, Lange B. Fatal all-trans retinoic acid pneumonitis. Ann Intern Med 1993; 118: 472-73. 3 Warrell RP Jr, De Thé H, Wang Z-Y, Degos L. Acute promyelocytic leukemia. N Engl J Med 1993; 329: 177-89. 4 Muindi J, Frankel SR, Miller WH Jr, et al. Continuous treatment with all-trans retinoic acid causes a progressive reduction in plasma drug concentrations: implications for relapse and retinoid "resistance" in patients with acute promyelocytic leukemia. Blood 1992; 79: 299-303. 5 Castaigne S, Lefebvre PH, Rigal-Huguet F, et al. Lower all-trans retinoic acid (ATRA 25 mg/m2/day) are effective in acute promyelocytic leukemia (APL). Blood 1992; 80 (suppl 1): 360a.

4

Santa Maria

SIR—Mahmoud et al report that tretinoin toxicity in children with APL is frequent and recommend that tretinoin should be used cautiously. In their patients, retinoic acid syndrome was associated with hyperleucocytosis, which in our opinion can be prevented. More than 90% of patients with APL show features of disseminated intravascular coagulation and 20-40% die early of fatal haemorrhage when treated with chemotherapy alone.1,2 We report a child with APL and multiorgan failure who was successfully induced into remission with tretinoin. A 3-year-old girl with APL had the characteristic (15 ;17) translocation with a breakpoint on chromosome 17 in the region of the RAR alpha. Red blood cell count was 0-63 x 1012 /L, haemoglobin 21 g/dL, leucocyte count 4-6 x 109/L, (94% lymphocytes, 1% myelocytes, 2% erythroblasts, 3% blast cells), and platelets 10 x 109/L. Severe anaemia probably due to a concurrent parvovirus infection (IgM and IgG positive on day 5) led to hypoxic cardiac failure, pulmonary oedema, and acute renal failure. Respiratory function deteriorated and mechanical ventilation was required. She had mucosal bleeding and gross haematuria. Fibrinogen split products were 4-0 pg/dL. Tretinoin at 22 mg (45 mg/m2) per day was started. Bleeding stopped within 3 days. On day 5 the while cell count reached 10-6 x 109/L. Bilateral papilloedema as a symptom of increased intracranial pressure was noticed. To prevent further increase of leucocytes and progression to retinoic acid syndrome, cytotoxic chemotherapy was added. On days 6 and 7 of treatment the patient received 4 x 750 mg (1500 mg/m2) cytarabine every 12 h.- The leucocyte count decreased immediately and remained below 7 x 109/L until recovery.

the

Hospital, Linz;

Biondi A, Rambaldi A, Alcalay M, et al. RAR-alpha gene rearrangements as genetic marker for diagnosis and monitoring in acute promyelocytic leukemia. Blood 1991; 77: 1418-22. Humphries JE, Hess CE, Stewart FM. Acute promyelocytic leukemia: impact of hemorrhagic complications on response to induction chemotherapy and survival. South Med J 1990; 3: 1157-61. Lo Coco F, Diverio D, Pandolfi PP, et al. Molecular evaluation of residual disease as a predictor of relapse in acute promyelocytic leukaemia. Lancet 1992; 340: 1437-38. Frankel SR, Eardley A, Lauers G, Weiss M, Warrel RP. The retinoic acid syndrome in acute promyelocytic leukemia. Ann Intern Med 1992; 117: 292-96.

SIR—Of 9

cases

of APL treated

by Mahmoud

et

al with

tretinoin, 5 had pseudotumor cerebri, 3 retinoic acid (RA) syndrome, and 1 died of hyperleucocytosis, pseudotumour cerebri, and RA syndrome despite steroids and mechanical ventilation. Warrel et all reviewed recent progress in tretinoin treatment for APL. Frankel et al2 suggest early treatment of leucocytosis and RA syndrome with dexamethasone, 10 mg intravenously every 12 hours for 3 days. We report 2 patients with RA syndrome who recovered without use of steroids. A 47-year-old man was admitted to hospital because of gingival bleeding and melaena in September, 1993. His white blood cell (WBC) counts was 2-1 x 109jL, haemoglobin (Hb) was 6-6 g/dL, and platelet count was 6-0 x 109/L. Peripheral blood profile showed 89% pathological promyelocytes and Auer bodies in the cytoplasm. Coagulation studies showed disseminated intravascular coagulopathy, prothrombin time (PT) 13.5s, activated partial thromboplastin time (APTT) 37 0 s, and fibrinogen degradation product (FDP) 160 mg/mL. Chromosomal studies from bone marrow showed translocation of (15; 17). He was diagnosed as having APL, and was started on 80 mg/day tretinoin. On day 2, he complained of coughing, and had a fever of 37.6°C. On day 3, his WBC increased to 3-0 x 109/L, and the percentage of pathological promyelocytes decreased to 66%. Coagulation studies were improved (PT 11 -7 s, APTT 27 3 s, FDP 40 mg/mL). On day 4 he complained of dyspnoea and his body weight was 3 kg higher than on day 1. Chest radiograph showed mild bilateral pleural effusion; blood urea nitrogen and serum creatinine were increased. We thought that this event might be a sort of RA syndrome. He recovered with diuretics. A 69-year-old woman was admitted with severe diabetes mellitus and second relapse of APL. WBC count was 1.8 x 109/L, Hb was 5.0 g/dL, and platelet count was 10.0x109/L. Bone marrow chromosomes showed 81% deletion 15(q22). On day 5, she complained of dyspnoea and her chest radiograph showed the presence of pleural effusion and congestion. Blood gas analysis showed low arterial saturation with Pa02 67-9 mm Hg. She recovered with diuretics and vasodilators.

361

Our patients with RA syndrome recovered without steroids. Our findings do not clarify why they recovered only with the treatment for pulmonary congestion. Masaaki Yokokura, Kiyohiko Hatake, Norio Komatsu, Hitoshi Kajitani, Yasusada Miura Division of Hematology, Department of Internal Medicine, Jichi Medical School, 3311-1, Yakushiji, Minamikawachi, Kawachi, Tochigi, Japan

Warrel RP, de The H,

1 2

Wang Z-y, Degos L. Acute promyelocytic leukemia. N Engl J Med 1993; 329: 177-89. Frankel SR, Eardley A, Lanwers G, Weiss M, Warrel RP. The ’retinoic acid syndrome’ in acute promyelocytic leukemia. Ann Intern Med 1992; 117: 292-96.

Breastfeeding and HIV in African countries SIR—Ziegler (Dec 11, p 1437) in his review of the role of breastfeeding in vertical transmission of HIV, concludes that information about risk factors is incomplete, with which all would agree. He also says, that "in areas where many infants die of infectious diseases, some mothers might be able to bottle feed safely". This statement is true, but begs questions about how many and who. I disagree with two of Ziegler’s statements-that "many pregnant women with HIV are aware of their status at the time of delivery", and that a national under-five mortality of 100 is more realistic than the higher figures used by Hu and co-workers1 in their mathematical model about the relative mortality rates from HIV infection and from other illness in an impoverished community. In most countries in Africa HIV antibody testing is often limited to blood transfusion centres, and not to all of these. Moreover, in some communities where HIV is common, women are unaware that they are infected.2 Decisions about breastfeeding that are based on maternal awareness of their HIV status are of little value. Under-five mortality for sub-Saharan Africa in 1992 was 181.3 For several African countries the official rates have been revised upwards (table), and in 5 of the 8 countries the latest rates are as high or higher than they were 5 years earlier.3 Safe and effective artificial feeding also depends on factors such as availability of domestic water, mothers’ knowledge about the preparation of formula, the availability of the powder and the household cash to purchase it (table). In 1992 Hofvander (personal communication) examined in African countries the cost of commercial breast-milk substitute for a 3-month-old infant (800 mL/daily) and compared this with the daily wage of a hospital cleaner. The cost was 27-60% of the wage in Zimbabwe and Zambia and 217-900% in The Gambia and Uganda. For most women and children in Africa,

switch from the traditional pattern of formula feeding is clearly unrealistic. a

breastfeeding

to

about breastfeeding and HIV, and UNICEF state "where the primary causes of infant WHO deaths are infectious diseases and malnutrition ... breastfeeding should remain the standard advice given to women, including those who are known to be HIV-infected" .4 Ziegler is right to distinguish between recommendations for a population group and an individual mother. Guidelines are only applicable generally, and individual decisions should be made on the basis of the mother’s health and circumstances. Furthermore, recommendations that are appropriate for one group of women will influence others for whom they are not. Health workers should counsel mothers individually. Unfortunately HIV antibody results, personal information, and scientific knowledge are often unavailable to help make a balanced decision. Ultimately each woman has to decide, and she may be more influenced by distorted media reports (eg, a headline saying "HIV transmitted by breastfeeding")5 than the considered words of a Lancet commentary. In

a consensus statement

William A M

Cutting

Department of Child Life and Health, University of Edinburgh, Edinburgh EH9 1UW, UK 1

2

3 4

5

Hu

DJ, Heyward WL, Byers RH Jr, et al. HIV infection and breast feeding: policy implications through a decision analysis model. AIDS

1992; 6: 1505-13. Merson MH. Women with HIV: the global experience. (Speech and press release at the Second International Conference on HIV in Children and Mothers, Edinburgh, Sept 7, 1993.) Grant J. The state of the world’s children 1994, UNICEF report. New York: Oxford University Press, 1993. World Health Organization. Global programme on AIDS. Consensus statement from the WHO/UNICEF consultation on HIV transmission and breast-feeding. Geneva: WHO, 1992. Berer M, Ray S. Breast feeding: the unresolved dilemmas in women and HIV/AIDS. London: Pandora Press, 1993: 80-86.

SIR—Ziegler does not address all the practical difficulties for developing countries in the midst of an AIDS epidemic. Who will pay for the routine prenatal HIV testing, for the bottle feeding, and for milk-suppressing drugs? Furthermore, late transmission of HIV through breastfeeding has been documented.1

Breastfeeding, via lactational amenorrhoea, is still the most contraceptive in countries where modern familymethods are little used-so we could end up with the planning worst of two worlds, the death of a bottle-fed baby and a new pregnancy under way. The applicability for such countries of studies on HIV and breastfeeding looks remote (with the few exceptions noted by Ziegler). Studies of vaginal microbicides may be of more direct help. effective

A De

Clercq

Department of Obstetrics and Gynaecology, Centre Hospitalier de Kigali, BP 934, Kigali, Rwanda 1

Datta P, Embree JE, Kreiss JK, et al. Resumption of breast feeding in later childhood: a risk factor for mother to child human immunodeficiency virus type 1 transmission. Pediatr Infect Dis J 1992; 11: 974-76.

Vaginal microbicides and prevention of HIV infection *Under-flve mortality revised upwards between 1992 and 1993 UNICEF state of the world’s children reports. ORT=oral rehydration therapy, estimated % of all cases of diarrhoea treated with suitable ORT solution. From-The state of the world’s children, UNICEF reports 1990, 1991,1992,1993. New York: Oxford University Press, 1989, 1990, 1991, 1992.

Table: Factors relevant to safe artificial countries

362

feeding In 8 African

SIR-Lange and colleagues’ (Nov 27, p 1356) report of the WHO conference on vaginal microbicides against HIV omits one recommendation. This recommendation proposes development of a microbicide that is not also a spermicide. Individual couples or family planning agencies probably do not