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PROGNOSIS IN T PROLYMPHOCYTIC LEUKAEMIA
381
SECONDARY LEUKAEMIA IN LYMPHOMA PATIENTS statements with which The assertion that "there is little evidence of an increase in any acute leukaemia in patients treated with radiotherapy alone" overlooks the 20 of 216 patients with Hodgkin’s disease reviewed by us,the 7 of 189 patients with nonHodgkin’s lymphoma and chronic lymphocytic leukaemia reported by O’Donnell et al,2 and the 5 patients with lymphoma described by Michels et al,3 all of whom were treated with radiation only and had secondary acute non-lymphocytic leukaemia. Furthermore, there3 are many published cases of breast cancer4 and other solid tumours3 who were treated with radiotherapy alone and in whom acute
SIR,-Your Nov 23 editorial makes three
we
disagree.
leukaemia developed. You state that "treatment is seldom successful; complete remissions or cures are rare". Using high-dose cytarabine, Preisler et al5 achieved 8 complete and 2 partial remissions in 11 patients with secondary acute leukaemia. Similar but less striking results have since been described by Vaughn et al6 and by Duane et af who reported, respectively, 50% and 41% complete remission induction rates in secondary acute leukaemia. Back in 1978, 5 of 6 patients with acute leukaemia secondary to treatment of lymphoma entered
complete remission.8 Finally, the claim by Valagussa et al,9 cited in your editorial, that "chemotherapy for Hodgkin’s disease that does not rely on alkylating agents (eg, the ABVD regimen) has so far not been associated with an increased risk of AML" is no longer true. Reports of acute leukaemia after ABVD (adriamvcin, bleomycin, vinblastine, dacarbazine) are beginning to appearlaand more can be expected as more follow-up with this recently introduced regimen is obtained. Queens Hospital Center Affiliation of Long Island Jewish Medical Center, Jamaica, NY 11432, USA; and Health Sciences Center, SUNY at Stony Brook
FRED ROSNER HANS W. GRÜNWALD
1. Grünwald
HW, Rosner F. Acute myeloid leukemia following treatment of Hodgkin’s disease Cancer 1982, 50: 676-83. 2. O’Donnell JF, Brerton HD, Greco FA, Gralnick HR, Johnson RE. Acute nonlymphocytic leukemia and acute myeloproliferative syndrome following radiation therapy for non-Hodgkin’s lymphoma and chronic lymphocytic leukemia: clinical studies Cancer 1979; 44: 1930-38. 3. Michels SD, McKenna RW, Arthur DC, Brunning RD. Therapy related acute myeloid leukemia and myelodysplastic syndrome a clinical and morphologic study of 65 cases Blood 1985, 65: 1364-72. 4. Fisher B, Rockette H, Fisher ER, Wickerham DL, Redmond C, Brown A. Leukemia in breast cancer patients following adjuvant chemotherapy or postoperative radiation the NSABP experience. J Clin Oncol 1985; 3: 1640-58. 5. Preisler HD, Early AP, Raza A, Vlahides G, Marinello MJ, Stein AM, Browman G. Therapy of secondary acute nonlymphocytic leukemia with cytarabine. N Engl J Med 1983; 308: 21-23. 6. Vaughn WP, Karp JE, Burk PJ. Effective chemotherapy of acute myelocytic leukemia occurring after alkylating agent or radiation therapy for prior malignancy. J Clin Oncol 1983; 1: 204-07. 7. Duane SF, Peterson BA, Bloomfield CD, Michels SD, Hurd DD. Response to therapyassociated acute nonlymphocytic leukemia to intensive induction chemotherapy. Med Pediator Oncol 1985; 13: 207-13. 8. Beltran G, Stuckey WJ. Therapy of secondary acute nonlymphocytic leukemia. N Engl
trimethyl derivatives of compounds identified as 2-(hydroxymethylthio)benzothiazole (upper) and 2,5-dichloroxylenol (lower).
Mass spectra from
ketoacids were increased. Moreover, gas chromatography/mass spectrometry revealed large amounts of penicillin derivatives (5,5’-dimethyl- 2-thiazolin carboxylic acid, phenylmalonic acid, and phenylacetylglycine) and a metabolite not previously detected in urine, N-lactyltyrosine. In the infusion fluid we found two unknown compounds, tentatively identified as 2,5-dichloroxylenol and 2-(hydroxyethylthio)benzothiazole (figure). Suspecting a defect in the metabolism of organic acids we treated the patient with large doses of riboflavin. The clinical symptoms and organic aciduria disappeared within a few hours. On day 30 severe renal failure developed, leading to death within a week. Necropsy revealed extensive dilatation of the intralobular bile ducts, suggesting inspissated bile syndrome. The other two patients showed a similar clinical course, responding to riboflavin but with complete remission. At 6 months of age they are in good health. These observations may be compatible with a transient defect in the flavoprotein component of the respiratory chain which transfers electrons from NADH-dehydrogenase to coenzyme Q. Although the specific course of the disease remains obscure, further study of the secondary effects of contaminants after prolonged exposure are needed in very low birthweight infants on total parenteral nutrition. Other series of aminoacids and organic acids should be screened in premature infants on long-term infusion therapy to evaluate more fully the dangers of these contaminants. Dr L Willems-Instituut,
3610 Diepenbeek, Belgium Neonatal
Centre, Clinique Nôtre-Dame,
Charleroi
BAUDOUIN FRANCOIS LUC LEYSSENS PATRICK GERARD ALAIN BACHY ORESTE BATTISTI
9.
J Med 1983; 308: 1295. Valagussa P, Santoro A, Bellini FF, Franchi F, Banfi A, Bonadonna G. Absence of treatment-induced second neoplasms after ABVD in Hodgkin’s disease. Blood 1982;
59: 488-94. 10. Amadori S, Papa G, Anselmo AP, Fidani P, Mandelli F, Biagini C. Acute promyelocytic leukemia following ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) and radiotherapy for Hodgkin’s disease Cancer Treat Rep 1983; 67: 603-04.
PROGNOSIS IN T PROLYMPHOCYTIC LEUKAEMIA
SIR,-Dr Pandolfi (Dec 14, p 1367) and Dr Catovsky (Oct 26, 945) and their colleagues state that T prolymphocytic leukaemias (TPLL) carry a gloomy prognosis. Over a six year period we have studied three cases of TPLL (and eighty-two patients with B chronic lymphocytic leukaemia) and two of the three patients had protracted courses. Case1 (F, 58).-This patient was referred to us in July, 1976, because of lymphocytosis (48 x 109/1). She had no symptoms. T cell disease was diagnosed on the basis of E rosette formation, and this was later shown to be T8+ PLL. Lymphocytosis of 6 - 0 x 109 /1 and of 8’5x10/1 had been noted 30 and 19 months previously, p
382 months (doubling time about 70 days). Shortly before a routine check-up he was admitted with bronchopneumonia and died. Between his first abnormal lymphocyte count and his death 8 years elapsed. Case 3 (F, 74).-This patient presented with a 5 week history of vague ill-health. Her white cell count was 734 x 109/1 (virtually all prolymphocytes ofT4+ phenotype). Skin infiltration was present. No blood counts had been done during the 10 years before presentation. After deoxycoformycin therapy her T4 subset had a doubling time of 11-13 days. When Galton et al2 described prolymphocytic leukaemia as a well-defined clinical entity they suggested that "the evolution of the disease before presentation with symptoms may well be slow". The data in two of our three cases confirm this and also show that effective therapy can lead to long periods of good health. We may expect to start finding cases of TPLL earlier in their course as wellpatient check-ups increase in number. It would be a mistake to give a very poor prognosis to such patients immediately.
next 7 .
YEARS
Fig 1-Case November,
1: lymphocyte count between 1979.
January, 1974, and
- - - represents estimated duration of raised lymphocyte level before first
Haematology Department, City Hospital, Belfast BT9 7AD
GERALDINE MARKEY T. C. M. MORRIS D. ALEXANDER ANNE KYLE J. H. ROBERTSON
count.
Morris TCM, Robertson JH, Markey G, Alexander HD. Successful remission induction with deoxycoformycin in elderly patients with T helper prolymphocytic leukaemia. Br J Haematol (in press). 2. Galton DAG, Goldman JM, Wiltshaw E, Catovsky D, Henry K, Goldenberg GJ. Prolymphocytic leukaemia. Br J Haematol 1974; 27: 7-23. 1.
El’Agnaf MR, Ennis KE,
ETHYLENE OXIDE HYPERSENSITIVITY IN DIALYSIS PATIENTS
Fig
2-Case 2:
lymphocyte
count
between October, 1977, and
November, 1985. DCF= deoxycoform
ycin.
started with chlorambucil and but her count rose to 110 x 109/1 and no response occurred. She responded to abdominal radiotherapy in October, 1977, and she then remained well although with rising lymphocyte count (doubling time 150 days or so). A second course of abdominal radiotherapy was given in September, 1979, but shortly afterwards a typical "1’homme rouge" appearance developed and she died in November, 1979, of pneumococcal septicaemia. Her (disease had been present for 5 years and 10 months and her lymphocyte count was probably abnormal for 1 year before the initial count of 6 x 109/1. Apart from the two brief periods before radiotherapy treatments she denied any symptoms. Case 2 (M, 81).-This patient had lymphocytosis noted 6 years before he presented with symptoms and had TPLL (T4 +) + diagnosed (fig 2). After treatment his lymphocyte count and T4 subset remained normal for 15 months and then rose slowly over the
respectively (fig 1). then
Treatment
was
cyclophosphamide/vincristine/prednisone (CVP)
SiR,-In your issue of Dec 21/28 two teams from West Germany discuss risks associated with the use of ethylene oxide (EtO) to sterilise dialysis equipment. Professor Bommer and colleagues found antibodies to EtO in 42% of dialysis patients, 63% of those with antibodies having anaphylactoid reactions. EtO antibodies were detected by a protease-release test, said to correspond to the histamine-release test. The histamine-release test is specific for basophil activation. Proteases, by contrast, are present in other types of white blood cell and may be released by mechanisms other than IgE-mediated stimulation. Bommer et al coupled EtO to bovine rather than human serum albumin (HSA). Atopies may be sensitised to bovine albumin, so protease release from leucocytes on incubation with EtO coupled with HSA may be more specific for EtO hypersensitivity. We screened 100 dialysis patients for EtO antibodies using a radioallergosorbent test (RAST) (’PhadebasRAST’; Pharmacia) and found few (only 9%) to be positive (more than 0 -8% binding),as have others.3,4 We did histamine-release tests in the 9 EtO-RAST positive patients. Whole blood was incubated for 40 min at 37°C with serial dilutions of EtO-HSA. 2 patients released histamine at EtO-HSA concentrations ranging from 0-001 to 1-00 ).tg/ml in a dosedependent fashion. The patient with the highest EtO-RAST (37’5% binding) and with clinical hypersensitivity had a positive histamine-release test; the patient with the second highest EtORAST (7-27o) but no anaphylactoid reactions had a borderline result; and the other 7 patients (EtO-RAST below 3 -5%) were symptomless and had negative histamine-release tests. These data suggest that IgE-mediated release of histamine in response to the multivalent hapten EtO is one of the immunological pathways leading to anaphylaxis during dialysis. In another study 10 EtO-RAST positive patients without anaphylactic reactions were exposed to EtO-sterilised cuprammonium rayon dialysers. They had a significantly stronger generation of C3a and C5a than the controls and a drop in platelet counts corresponding to the degree of complement activation.5 IgEmediated hypersensitivity may not explain all haemodialysisassociated anaphylactoid symptoms.
SECONDARY LEUKAEMIA IN LYMPHOMA PATIENTS statements with which The assertion that "there is little evidence of an increase in any acute leukaemia in patients treated with radiotherapy alone" overlooks the 20 of 216 patients with Hodgkin’s disease reviewed by us,the 7 of 189 patients with nonHodgkin’s lymphoma and chronic lymphocytic leukaemia reported by O’Donnell et al,2 and the 5 patients with lymphoma described by Michels et al,3 all of whom were treated with radiation only and had secondary acute non-lymphocytic leukaemia. Furthermore, there3 are many published cases of breast cancer4 and other solid tumours3 who were treated with radiotherapy alone and in whom acute
SIR,-Your Nov 23 editorial makes three
we
disagree.
leukaemia developed. You state that "treatment is seldom successful; complete remissions or cures are rare". Using high-dose cytarabine, Preisler et al5 achieved 8 complete and 2 partial remissions in 11 patients with secondary acute leukaemia. Similar but less striking results have since been described by Vaughn et al6 and by Duane et af who reported, respectively, 50% and 41% complete remission induction rates in secondary acute leukaemia. Back in 1978, 5 of 6 patients with acute leukaemia secondary to treatment of lymphoma entered
complete remission.8 Finally, the claim by Valagussa et al,9 cited in your editorial, that "chemotherapy for Hodgkin’s disease that does not rely on alkylating agents (eg, the ABVD regimen) has so far not been associated with an increased risk of AML" is no longer true. Reports of acute leukaemia after ABVD (adriamvcin, bleomycin, vinblastine, dacarbazine) are beginning to appearlaand more can be expected as more follow-up with this recently introduced regimen is obtained. Queens Hospital Center Affiliation of Long Island Jewish Medical Center, Jamaica, NY 11432, USA; and Health Sciences Center, SUNY at Stony Brook
FRED ROSNER HANS W. GRÜNWALD
1. Grünwald
HW, Rosner F. Acute myeloid leukemia following treatment of Hodgkin’s disease Cancer 1982, 50: 676-83. 2. O’Donnell JF, Brerton HD, Greco FA, Gralnick HR, Johnson RE. Acute nonlymphocytic leukemia and acute myeloproliferative syndrome following radiation therapy for non-Hodgkin’s lymphoma and chronic lymphocytic leukemia: clinical studies Cancer 1979; 44: 1930-38. 3. Michels SD, McKenna RW, Arthur DC, Brunning RD. Therapy related acute myeloid leukemia and myelodysplastic syndrome a clinical and morphologic study of 65 cases Blood 1985, 65: 1364-72. 4. Fisher B, Rockette H, Fisher ER, Wickerham DL, Redmond C, Brown A. Leukemia in breast cancer patients following adjuvant chemotherapy or postoperative radiation the NSABP experience. J Clin Oncol 1985; 3: 1640-58. 5. Preisler HD, Early AP, Raza A, Vlahides G, Marinello MJ, Stein AM, Browman G. Therapy of secondary acute nonlymphocytic leukemia with cytarabine. N Engl J Med 1983; 308: 21-23. 6. Vaughn WP, Karp JE, Burk PJ. Effective chemotherapy of acute myelocytic leukemia occurring after alkylating agent or radiation therapy for prior malignancy. J Clin Oncol 1983; 1: 204-07. 7. Duane SF, Peterson BA, Bloomfield CD, Michels SD, Hurd DD. Response to therapyassociated acute nonlymphocytic leukemia to intensive induction chemotherapy. Med Pediator Oncol 1985; 13: 207-13. 8. Beltran G, Stuckey WJ. Therapy of secondary acute nonlymphocytic leukemia. N Engl
trimethyl derivatives of compounds identified as 2-(hydroxymethylthio)benzothiazole (upper) and 2,5-dichloroxylenol (lower).
Mass spectra from
ketoacids were increased. Moreover, gas chromatography/mass spectrometry revealed large amounts of penicillin derivatives (5,5’-dimethyl- 2-thiazolin carboxylic acid, phenylmalonic acid, and phenylacetylglycine) and a metabolite not previously detected in urine, N-lactyltyrosine. In the infusion fluid we found two unknown compounds, tentatively identified as 2,5-dichloroxylenol and 2-(hydroxyethylthio)benzothiazole (figure). Suspecting a defect in the metabolism of organic acids we treated the patient with large doses of riboflavin. The clinical symptoms and organic aciduria disappeared within a few hours. On day 30 severe renal failure developed, leading to death within a week. Necropsy revealed extensive dilatation of the intralobular bile ducts, suggesting inspissated bile syndrome. The other two patients showed a similar clinical course, responding to riboflavin but with complete remission. At 6 months of age they are in good health. These observations may be compatible with a transient defect in the flavoprotein component of the respiratory chain which transfers electrons from NADH-dehydrogenase to coenzyme Q. Although the specific course of the disease remains obscure, further study of the secondary effects of contaminants after prolonged exposure are needed in very low birthweight infants on total parenteral nutrition. Other series of aminoacids and organic acids should be screened in premature infants on long-term infusion therapy to evaluate more fully the dangers of these contaminants. Dr L Willems-Instituut,
3610 Diepenbeek, Belgium Neonatal
Centre, Clinique Nôtre-Dame,
Charleroi
BAUDOUIN FRANCOIS LUC LEYSSENS PATRICK GERARD ALAIN BACHY ORESTE BATTISTI
9.
J Med 1983; 308: 1295. Valagussa P, Santoro A, Bellini FF, Franchi F, Banfi A, Bonadonna G. Absence of treatment-induced second neoplasms after ABVD in Hodgkin’s disease. Blood 1982;
59: 488-94. 10. Amadori S, Papa G, Anselmo AP, Fidani P, Mandelli F, Biagini C. Acute promyelocytic leukemia following ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) and radiotherapy for Hodgkin’s disease Cancer Treat Rep 1983; 67: 603-04.
PROGNOSIS IN T PROLYMPHOCYTIC LEUKAEMIA
SIR,-Dr Pandolfi (Dec 14, p 1367) and Dr Catovsky (Oct 26, 945) and their colleagues state that T prolymphocytic leukaemias (TPLL) carry a gloomy prognosis. Over a six year period we have studied three cases of TPLL (and eighty-two patients with B chronic lymphocytic leukaemia) and two of the three patients had protracted courses. Case1 (F, 58).-This patient was referred to us in July, 1976, because of lymphocytosis (48 x 109/1). She had no symptoms. T cell disease was diagnosed on the basis of E rosette formation, and this was later shown to be T8+ PLL. Lymphocytosis of 6 - 0 x 109 /1 and of 8’5x10/1 had been noted 30 and 19 months previously, p
382 months (doubling time about 70 days). Shortly before a routine check-up he was admitted with bronchopneumonia and died. Between his first abnormal lymphocyte count and his death 8 years elapsed. Case 3 (F, 74).-This patient presented with a 5 week history of vague ill-health. Her white cell count was 734 x 109/1 (virtually all prolymphocytes ofT4+ phenotype). Skin infiltration was present. No blood counts had been done during the 10 years before presentation. After deoxycoformycin therapy her T4 subset had a doubling time of 11-13 days. When Galton et al2 described prolymphocytic leukaemia as a well-defined clinical entity they suggested that "the evolution of the disease before presentation with symptoms may well be slow". The data in two of our three cases confirm this and also show that effective therapy can lead to long periods of good health. We may expect to start finding cases of TPLL earlier in their course as wellpatient check-ups increase in number. It would be a mistake to give a very poor prognosis to such patients immediately.
next 7 .
YEARS
Fig 1-Case November,
1: lymphocyte count between 1979.
January, 1974, and
- - - represents estimated duration of raised lymphocyte level before first
Haematology Department, City Hospital, Belfast BT9 7AD
GERALDINE MARKEY T. C. M. MORRIS D. ALEXANDER ANNE KYLE J. H. ROBERTSON
count.
Morris TCM, Robertson JH, Markey G, Alexander HD. Successful remission induction with deoxycoformycin in elderly patients with T helper prolymphocytic leukaemia. Br J Haematol (in press). 2. Galton DAG, Goldman JM, Wiltshaw E, Catovsky D, Henry K, Goldenberg GJ. Prolymphocytic leukaemia. Br J Haematol 1974; 27: 7-23. 1.
El’Agnaf MR, Ennis KE,
ETHYLENE OXIDE HYPERSENSITIVITY IN DIALYSIS PATIENTS
Fig
2-Case 2:
lymphocyte
count
between October, 1977, and
November, 1985. DCF= deoxycoform
ycin.
started with chlorambucil and but her count rose to 110 x 109/1 and no response occurred. She responded to abdominal radiotherapy in October, 1977, and she then remained well although with rising lymphocyte count (doubling time 150 days or so). A second course of abdominal radiotherapy was given in September, 1979, but shortly afterwards a typical "1’homme rouge" appearance developed and she died in November, 1979, of pneumococcal septicaemia. Her (disease had been present for 5 years and 10 months and her lymphocyte count was probably abnormal for 1 year before the initial count of 6 x 109/1. Apart from the two brief periods before radiotherapy treatments she denied any symptoms. Case 2 (M, 81).-This patient had lymphocytosis noted 6 years before he presented with symptoms and had TPLL (T4 +) + diagnosed (fig 2). After treatment his lymphocyte count and T4 subset remained normal for 15 months and then rose slowly over the
respectively (fig 1). then
Treatment
was
cyclophosphamide/vincristine/prednisone (CVP)
SiR,-In your issue of Dec 21/28 two teams from West Germany discuss risks associated with the use of ethylene oxide (EtO) to sterilise dialysis equipment. Professor Bommer and colleagues found antibodies to EtO in 42% of dialysis patients, 63% of those with antibodies having anaphylactoid reactions. EtO antibodies were detected by a protease-release test, said to correspond to the histamine-release test. The histamine-release test is specific for basophil activation. Proteases, by contrast, are present in other types of white blood cell and may be released by mechanisms other than IgE-mediated stimulation. Bommer et al coupled EtO to bovine rather than human serum albumin (HSA). Atopies may be sensitised to bovine albumin, so protease release from leucocytes on incubation with EtO coupled with HSA may be more specific for EtO hypersensitivity. We screened 100 dialysis patients for EtO antibodies using a radioallergosorbent test (RAST) (’PhadebasRAST’; Pharmacia) and found few (only 9%) to be positive (more than 0 -8% binding),as have others.3,4 We did histamine-release tests in the 9 EtO-RAST positive patients. Whole blood was incubated for 40 min at 37°C with serial dilutions of EtO-HSA. 2 patients released histamine at EtO-HSA concentrations ranging from 0-001 to 1-00 ).tg/ml in a dosedependent fashion. The patient with the highest EtO-RAST (37’5% binding) and with clinical hypersensitivity had a positive histamine-release test; the patient with the second highest EtORAST (7-27o) but no anaphylactoid reactions had a borderline result; and the other 7 patients (EtO-RAST below 3 -5%) were symptomless and had negative histamine-release tests. These data suggest that IgE-mediated release of histamine in response to the multivalent hapten EtO is one of the immunological pathways leading to anaphylaxis during dialysis. In another study 10 EtO-RAST positive patients without anaphylactic reactions were exposed to EtO-sterilised cuprammonium rayon dialysers. They had a significantly stronger generation of C3a and C5a than the controls and a drop in platelet counts corresponding to the degree of complement activation.5 IgEmediated hypersensitivity may not explain all haemodialysisassociated anaphylactoid symptoms.