ANTI-IFN-α TTTRES DURING INTERFERON THERAPY
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1521 infiltrates and an increase in osteoblasts. 21 months after the start of the treatment, he is being given IFN three times weekly. His ESR and blood count are normal and the exophthalmos and skin changes have disappeared. The liver and spleen enlargement are reduced and his general condition is excellent. The osteolytic lesions show radiological signs of healing. Case 2.-This boy presented with several cranial osteolytic lesions and seborrhoeic skin changes at 11 months of age. He was treated with prednisolone and vinblastine and responded well; treatment was discontinued after 6 months. At 4 years osteolytic changes recurred, with large tender swellings. Since his twin brother had responded to IFN this boy was given daily injections of IFN-x (1-3 million IU). After 9 months the swellings have . disappeared and there are no signs of involvement of other organs. Although spontaneous remissions may occur, even in multisystem LCH,4 the outcome is usually fatal in stage IV disease. 2 Our case 1 had stage IV LCH and was very ill when IFN treatment began. There was obvious clinical improvement and a slow but steady haematological response. Apart from steroids (which were phased out) no other drugs were given. There was a transient hair loss but no other side-effects of IFN were observed. An immunological abnormality (suggesting suppressor-cell deficiency) may have a role in LCH since thymic extract has led to restoration of immunological normality and a clinical response in some patients.s Purified human histiocytosis X cells secrete interleukin-1 and prostaglandin E2 spontaneously in vitro and this may be a mechanism for the osteolysis and other local tissue lesions. The effects of IFN-a on these two possible mechanisms are unknown. However, IFN-a does enhance natural killer (NK) cell killing of tumour and virus-infected cells and suppresses NK cell killing of normal cells,7 so interferon may be enhancing NK cell killing of transformed Langerhans cells and/or suppressing NK cell killing of other normal target cells, thus reversing the formation of LCH infiltrates and preventing tissue damage. Our experience indicates that extended treatment with IFN-cx is effective and well tolerated; in view of the poor prognosis of stage IV LCH we suggest that IFN-&agr; should be included in future clinical studies. Departments of Paediatrics, Oncology, and Pathology, Akademiska Sjukhuset, S-751 85 Uppsala, Sweden AKE M. JAKOBSON ANDERS KREUGER HANS HAGBERG CHRISTER SUNDSTROM 1 Grundy P, Ellis R. Histiocytosis X: a review of the etiology, pathology, staging, and therapy. Med Pediatr Oncol 1986; 14: 45-50. 2. Greenberger JS, Crocker AC, Vawter G, et al. Results of treatment of 127 patients with systemic histiocytosis (Letterer-Siwe syndrome, Schuller-Christian syndrome and multifocal eosmophilic granuloma). Medicine 1981; 60: 311-38. 3 Broadbent V, Pritchard J Histiocytosis X—current controversies Arch Dis Child 1985; 60: 605-07. 4. Broadbent V, Davies EG, Heaf D, et al. Spontaneous remission of multisystem histiocytosis X. Lancet 1984; i: 253-54. 5 Osband ME, Lipton JM, Lavin P, et al. Histiocytosis X Demonstration of abnormal immunity, T-cell histamine H2-receptor deficiency, and successful treatment with thymic extract N Engl J Med 1981; 304: 146-53. 6. Arenzana-Seisdedos F, Barbey S, Virelizier JL, et al. Histiocytosis X: Purified (T6+) cells from bone granuloma produce interleukin 1 and prostaglandin E2 in culture J Clin Invest 1986; 77: 326-29. 7. Johnson HM. Interferon-mediated modulation of the immune system In- Pfeffer LM, ed. Mechanisms of interferon actions: Vol II. Boca Raton, Florida. CRC Press, 1987: 59-77. ANTI-IFN-&agr; TTTRES DURING INTERFERON THERAPY SIR,-Dr von Wussow and colleagues (Sept 12, p,635) report neutralising recombinant interferon-alpha2a (rIFN-&agr;2a) antibodies (anti-IFN) in 5 of 25 treated patients with chronic myelogenous leukaemia. The presence of antibodies was associated with a lack of response or relapse during treatment. In several trials1.2 we have treated 42 patients, who had chronic hepatitis B with high viral replication levels (HBV-DNA and HBeAg positive), with rIFN-ot2, administered intramuscularly at doses ranging from 2-5 to 20 MUfm2 of body surface, two or three times weekly over six months. Anti-IFN was measured monthly by a competitive ELISA and a biological neutralisation assay3 in serum samples obtained 72 h after the last dose of IFN. Anti-IFN developed in 7 patients (17%). 1 patient (treated with 2-5 MU) lost HBV-DNA during the second month of therapy, had anti-IFN one month later, but remained HBV-DNA negative. A second patient (20 MU) had anti-IFN one month after the start of treatment. At the second month, HBV-DNA became undetectable and the patient later seroconverted to anti-HBe. At the end of treatment, HBV-DNA became positive again, concomitantly with the highest anti-IFN level (titre 1/105). Finally, HBV-DNA became undetectable at the 15th month. During the fourth month of therapy, another patient (18 MU) had anti-IFN antibodies when HBV-DNA was still positive. This patient had a herpes zoster infection five months after the start of treatment, but the infection was not related to the anti-IFN levels. The other four patients, treated with 10, 10, 5, and 25 MU had serum antibodies at the second, third, fourth, and fifth months of therapy, respectively, when they were HBV-DNA positive, these patients did not lose their HBV-DNA. Therapy was not discontinued in any patient despite the development of anti-IFN, and the symptoms due to interferon therapy (such as "flu-like syndrome" and weight loss) disappeared in the presence of anti-IFN. No patient had immune complex- associated illness. The development of anti-IFN among patients who previously became HBV-DNA negative will not influence the response to treatment, but if HBV-DNA remains positive at that time, efficacy is usually poor. Thus it is advisable to stop interferon treatment in patients who become HBV-DNA negative after the development of anti-IFN, because increasing levels of such antibodies in serum are related to a risk of viral reactivation. Department of Gastroenterology, Fundación Jiménez Diaz, 28040 Madnd, Spam LUIS INGLADA JUAN CARLOS PORRES FAUSTINO LA BANDA IGNACIO MORA VICENTE CARREÑO 1. Carreño V, Porres JC, Mora I, et al Prolonged (six months) treatment of chronic hepatitis B virus infection with recombinant leukocyte A interferon. Liver (in press). 2. Porres JC, Carreño V, Mora I, et al A controlled study of recombinant alpha-interferon in chronic hepatitis B virus infection· Serological and histological changes. J Hetatol 1987; 5: S187 3 Kawade Y, Watanabe Y Neutralization of interferon by antibody: Appraisals of methods of determining and expressing the neutralization titre J Int Res 1984: 4: 571-84. ACUTE LEUKAEMIA DURING PREGNANCY SIR,-In 1978, The Lancet reported on the successful treatment of acute leukaemia in a pregnant woman.’ A healthy child was delivered. There have been several reports of cytostatic therapy preceding conception but the management of acute leukaemia during pregnancy is still under debate We report here the outcome in four such cases. Case 1.—In September, 1982, a 33-year-old woman was admitted with a white cell count (WCC) of 31 000/µl, most of them leukaemic blasts. The diagnosis was acute myeloblastic leukaemia (AML). The patient was 16 weeks’ pregnant. 1 week later induction therapy with TAD-9 (thioguanine, cytarabine, daunorubicin)3 was started but no reduction in leukaemic blasts was achieved. 5 weeks later a second course was given, again without success. No further therapy was given at that time. Monitoring by ultrasound revealed no fetal abnormalities or growth retardation. On Dec 4 (week 30) a baby girl weighing 1180 g (slightly below average for a 30-week fetus) was bom. She is now 5 years old and has developed normally and remains in excellent health. Examination of the placenta revealed myeloblastic infiltration. This might have caused the premature rupture of the membranes. The puerperium was complicated by sepsis, which responded to broad-spectrum antibiotics. However, further chemotherapy failed to achieve a complete remission, and the mother died in April, 1983. Case 2.-In September, 1985, a 29-year-old woman was referred to us with a 5-week history of fatigue and weakness. Her WCC was 12 600/µl (46% leukaemic blasts) and AML was diagnosed. She was 23 weeks’ pregnant. TAD-9 induction therapy was started and platelet transfusions and packed red blood cells were given. 2 ½ weeks later a complete remission was achieved. Fetal monitoring revealed no abnormalities. At the patient’s request labour was not
Transcript of ANTI-IFN-α TTTRES DURING INTERFERON THERAPY
1521
infiltrates and an increase in osteoblasts. 21 months after the start ofthe treatment, he is being given IFN three times weekly. His ESRand blood count are normal and the exophthalmos and skin changeshave disappeared. The liver and spleen enlargement are reducedand his general condition is excellent. The osteolytic lesions showradiological signs of healing.
Case 2.-This boy presented with several cranial osteolyticlesions and seborrhoeic skin changes at 11 months of age. He wastreated with prednisolone and vinblastine and responded well;treatment was discontinued after 6 months. At 4 years osteolyticchanges recurred, with large tender swellings. Since his twinbrother had responded to IFN this boy was given daily injections ofIFN-x (1-3 million IU). After 9 months the swellings have
. disappeared and there are no signs of involvement of other organs.Although spontaneous remissions may occur, even in
multisystem LCH,4 the outcome is usually fatal in stage IV disease. 2Our case 1 had stage IV LCH and was very ill when IFN treatment
began. There was obvious clinical improvement and a slow butsteady haematological response. Apart from steroids (which werephased out) no other drugs were given. There was a transient hairloss but no other side-effects of IFN were observed.An immunological abnormality (suggesting suppressor-cell
deficiency) may have a role in LCH since thymic extract has led torestoration of immunological normality and a clinical response insome patients.s Purified human histiocytosis X cells secrete
interleukin-1 and prostaglandin E2 spontaneously in vitro and thismay be a mechanism for the osteolysis and other local tissue lesions.The effects of IFN-a on these two possible mechanisms are unknown.However, IFN-a does enhance natural killer (NK) cell killingof tumour and virus-infected cells and suppresses NK cell killing ofnormal cells,7 so interferon may be enhancing NK cell
killing of transformed Langerhans cells and/or suppressing NKcell killing of other normal target cells, thus reversing the formationof LCH infiltrates and preventing tissue damage. Our experienceindicates that extended treatment with IFN-cx is effective and well
tolerated; in view of the poor prognosis of stage IV LCH we suggestthat IFN-&agr; should be included in future clinical studies.
Departments of Paediatrics,Oncology, and Pathology,
Akademiska Sjukhuset,S-751 85 Uppsala, Sweden
AKE M. JAKOBSONANDERS KREUGERHANS HAGBERGCHRISTER SUNDSTROM
1 Grundy P, Ellis R. Histiocytosis X: a review of the etiology, pathology, staging, andtherapy. Med Pediatr Oncol 1986; 14: 45-50.
2. Greenberger JS, Crocker AC, Vawter G, et al. Results of treatment of 127 patientswith systemic histiocytosis (Letterer-Siwe syndrome, Schuller-Christian
syndrome and multifocal eosmophilic granuloma). Medicine 1981; 60: 311-38.3 Broadbent V, Pritchard J Histiocytosis X—current controversies Arch Dis Child
1985; 60: 605-07.4. Broadbent V, Davies EG, Heaf D, et al. Spontaneous remission of multisystem
histiocytosis X. Lancet 1984; i: 253-54.5 Osband ME, Lipton JM, Lavin P, et al. Histiocytosis X Demonstration of abnormal
immunity, T-cell histamine H2-receptor deficiency, and successful treatment withthymic extract N Engl J Med 1981; 304: 146-53.
6. Arenzana-Seisdedos F, Barbey S, Virelizier JL, et al. Histiocytosis X: Purified (T6+)cells from bone granuloma produce interleukin 1 and prostaglandin E2 in culture JClin Invest 1986; 77: 326-29.
7. Johnson HM. Interferon-mediated modulation of the immune system In- Pfeffer
LM, ed. Mechanisms of interferon actions: Vol II. Boca Raton, Florida. CRCPress, 1987: 59-77.
ANTI-IFN-&agr; TTTRES DURING INTERFERONTHERAPY
SIR,-Dr von Wussow and colleagues (Sept 12, p,635) reportneutralising recombinant interferon-alpha2a (rIFN-&agr;2a) antibodies(anti-IFN) in 5 of 25 treated patients with chronic myelogenousleukaemia. The presence of antibodies was associated with a lack of
response or relapse during treatment.In several trials1.2 we have treated 42 patients, who had chronic
hepatitis B with high viral replication levels (HBV-DNA andHBeAg positive), with rIFN-ot2, administered intramuscularly atdoses ranging from 2-5 to 20 MUfm2 of body surface, two or threetimes weekly over six months. Anti-IFN was measured monthly bya competitive ELISA and a biological neutralisation assay3 in serumsamples obtained 72 h after the last dose of IFN.Anti-IFN developed in 7 patients (17%). 1 patient (treated with
2-5 MU) lost HBV-DNA during the second month of therapy, hadanti-IFN one month later, but remained HBV-DNA negative. Asecond patient (20 MU) had anti-IFN one month after the start oftreatment. At the second month, HBV-DNA became undetectableand the patient later seroconverted to anti-HBe. At the end oftreatment, HBV-DNA became positive again, concomitantly withthe highest anti-IFN level (titre 1/105). Finally, HBV-DNA becameundetectable at the 15th month. During the fourth month oftherapy, another patient (18 MU) had anti-IFN antibodies whenHBV-DNA was still positive. This patient had a herpes zosterinfection five months after the start of treatment, but the infectionwas not related to the anti-IFN levels. The other four patients,treated with 10, 10, 5, and 25 MU had serum antibodies at thesecond, third, fourth, and fifth months of therapy, respectively,when they were HBV-DNA positive, these patients did not losetheir HBV-DNA.
Therapy was not discontinued in any patient despite the
development of anti-IFN, and the symptoms due to interferontherapy (such as "flu-like syndrome" and weight loss) disappearedin the presence of anti-IFN. No patient had immune complex-associated illness.The development of anti-IFN among patients who previously
became HBV-DNA negative will not influence the response totreatment, but if HBV-DNA remains positive at that time, efficacyis usually poor. Thus it is advisable to stop interferon treatment inpatients who become HBV-DNA negative after the development ofanti-IFN, because increasing levels of such antibodies in serum arerelated to a risk of viral reactivation.
Department of Gastroenterology,Fundación Jiménez Diaz,28040 Madnd, Spam
LUIS INGLADA
JUAN CARLOS PORRESFAUSTINO LA BANDAIGNACIO MORAVICENTE CARREÑO
1. Carreño V, Porres JC, Mora I, et al Prolonged (six months) treatment of chronichepatitis B virus infection with recombinant leukocyte A interferon. Liver (inpress).
2. Porres JC, Carreño V, Mora I, et al A controlled study of recombinant
alpha-interferon in chronic hepatitis B virus infection· Serological and histologicalchanges. J Hetatol 1987; 5: S187
3 Kawade Y, Watanabe Y Neutralization of interferon by antibody: Appraisals ofmethods of determining and expressing the neutralization titre J Int Res 1984: 4:571-84.
ACUTE LEUKAEMIA DURING PREGNANCY
SIR,-In 1978, The Lancet reported on the successful treatmentof acute leukaemia in a pregnant woman.’ A healthy child wasdelivered. There have been several reports of cytostatic therapypreceding conception but the management of acute leukaemiaduring pregnancy is still under debate We report here the outcomein four such cases.
Case 1.—In September, 1982, a 33-year-old woman was
admitted with a white cell count (WCC) of 31 000/µl, most of themleukaemic blasts. The diagnosis was acute myeloblastic leukaemia(AML). The patient was 16 weeks’ pregnant. 1 week later inductiontherapy with TAD-9 (thioguanine, cytarabine, daunorubicin)3 wasstarted but no reduction in leukaemic blasts was achieved. 5 weekslater a second course was given, again without success. No furthertherapy was given at that time. Monitoring by ultrasound revealedno fetal abnormalities or growth retardation. On Dec 4 (week 30)a baby girl weighing 1180 g (slightly below average for a 30-weekfetus) was bom. She is now 5 years old and has developed normallyand remains in excellent health. Examination of the placentarevealed myeloblastic infiltration. This might have caused thepremature rupture of the membranes. The puerperium wascomplicated by sepsis, which responded to broad-spectrumantibiotics. However, further chemotherapy failed to achieve acomplete remission, and the mother died in April, 1983.
Case 2.-In September, 1985, a 29-year-old woman was referredto us with a 5-week history of fatigue and weakness. Her WCC was12 600/µl (46% leukaemic blasts) and AML was diagnosed. Shewas 23 weeks’ pregnant. TAD-9 induction therapy was started andplatelet transfusions and packed red blood cells were given. 2 ½weeks later a complete remission was achieved. Fetal monitoringrevealed no abnormalities. At the patient’s request labour was not
