- Email: [email protected]
HOW SHOULD ACUTE LYMPHOBLASTIC LEUKAEMIA RELAPSING AFTER BONE-MARROW TRANSPLANTATION BE TREATED?
1188
Repetition of the UVR after chemotherapy produced an increase in 25(OH)D3 to a peak slightly higher than before but there
was no
increase in
serum or
urine calcium. Serum
1,25(OH)2D3 increased slightly but remained well within the normal range (fig 1). The increase in 1,25(OHhD3 was again positively related to the increase in serum 25(OH)D3 (r= 0’ 9; p<0. 02) but the relation between these 2 metabolites showed a much less steep regression line than before chemotherapy (fig 2).
metabolism and the production of a hypercalcaemic factor which we have been unable to separate from 1,25(OH)2D3 itself. The work was supported by Regional Health Authority.
a
research grant from the North Western
Correspondence should be addressed to M. D., Department Royal Infirmary, Manchester M13 9WL.
of Medicine;
REFERENCES
AF, Horst R, Deftos LJ, Cadman EC, Lang R, Broadus AE. Biochemical evaluation of patients with cancer-associated hypercalcaemia. N Engl JMed 1980,
1. Stewart
Discussion
Hypercalcaemia with raised serum 1,25(OH)2D3 has been reported in 6 patients with various lymphomas.2,3 In 5 cases of non-Hodgkin’s lymphoma these abnormalities were corrected by treatment of the lymphoma. In the 6th patient, a case of Hodgkin’s lymphoma, no post-treatment data were given. The present report is the first to describe spontaneous correction of hypercalcaemia and the first in which both the hypercalcaemia and raised 1,25(OH)2D3 levels have been shown to be dependent upon the prevailing serum concentration of substrate, 25(OH)D3. In normal individuals renal synthesis of 1,25(OH)2D3 is under tight control and serum levels of 1,25(OHhD3 are generally unrelated to precursor 25(OH)D3 at normal serum concentrations.’In the present case regulation of the synthesis of 1,25(OH)2D3 was lost and synthesis appeared to be related to the Hodgkin’s disease since reduction in the mass of Hodgkin’s tissue was followed by an inability to produce excess 1,25(OH)2D3. The Hodgkin’s tissue may have been synthesising 1,25(OH)2D3 in a way similar to that proposed for sarcoidosis where there is evidence for extrarenal synthesis of 1,25(OH)2D3 by the sarcoid tissue. 14 In these circumstances the extrarenal production of 1,25(OH)2D3 and the accompanying hypercalcaemia would suppress both the secretion of parathyroid hormone and the relan lahydroxylase enzyme. The subnormal 1,25(OH)2D3 and the increased iPTH observed after chemotherapy suggest that the initial hypercalcaemia resulted from extrarenal 1,25(OH)2D3 production; the changes in NcAMP are compatible with this theory. Alternatively the Hodgkin’s tissue might have produced a trophic substance that increased the renal synthesis of 1,25(OH)2D3. It is difficult to explain the subnormal 1,25(OH)2D3 and increased iPTH after chemotherapy if the 1 a-hydroxylase enzyme had not previously been suppressed. Humoral hypercalcaemia in malignancy is usually associated with raised NcAMP and 1,25(OH)2D3 and iPTH.1 In the present case no evidence for a humoral factor acting on the kidney through the adenylate cyclase system has been found. It seems unlikely therefore that synthesis of 1,25(OH)2D3 was occurring in the kidney. There have been many claims for the extrarenal synthesis of 1,25(OH)2D3 in vitro and at least one metabolite of vitamin D has been shown to be synthesised in vitro, to have the same chromatographic behaviour as 1,25(OH)2D3, and to crossreact in the 1,25(OH)2D3 assay.15 We used 3 different assay systems to measure 1,25(OH)2D3 when its concentration was raised and they all produced similar results. The samples were also run in 3 different HPLC systems including one (system 3) which separates 1,25(OH)2D3 from 19-nor-10keto-25-hydroxyvitamin D3is but in each similar concentrations of 1,25(OH)2D3 were found. It is extremely likely then that this material is 1,25(OH)2D3 and that this patient’s hypercalcaemia was caused by altered vitamin D
suppressed
303: 1377-83. NA, McGuire SL, Zerwekh JE, Frenkel EP, Pak CYC. Hypercalcaemia associated with increased serum calcitriol levels in three patients with lymphoma. Ann Intern Med 1984; 100: 1-7. 3. Rosenthal M, Insogna KL, Godsall JW, Smaldone L, Waldron JA, Stewart AF. Elevations in circulating 1,25 dihydroxyvitamin D in three patients with lymphoma associated hypercalcaemia. J Clin Endocrinol Metab 1984, 60: 29-33 4. Davies M, Mawer EB, Adams PH. Vitamin D metabolism and the response to 1,25 dihydroxycholecalciferol m osteoporosis. J Clin Endocrinol Metab 1977, 45: 199-208. 5. Walton RJ, Bijvoet OLM. Nomogram for derivation of renal threshold phosphate concentration. Lancet 1975; ii: 309-10. 6. Davies M, Adams PH, Berry JL, Lumb GA, et al. Familial hypocalciuric hypercalcaemia: Observations on vitamin D metabolism and parathyroid function Acta Endocrinol 1983, 104: 210-15. 7. Broadus AE, Mahaffey JE, Bartter FC, Neer RM. Nephrogenous cyclic adenosine monophosphate as a parathyroid function test. J Clin Invest 1977; 60: 771-83. 8. Mawer EB, Backhouse J, Hill LF, Lumb GA, et al. Vitamin D metabolism and parathyroid function in man. Clin Sci 1975; 48: 349-65. 9. Davies M, Mawer EB, Hann JT, Stephens WP, Taylor JL Vitamin D prophylaxis in the elderly. A simple effective method suitable for large populations Age Ageing (in
2. Breslau
press) 10. Mawer EB, Hann JT, Berry JL, Davies M. Vitamin D metabolism in patients intoxicated with ergocalciferol. Clin Sci 1985, 68: 135-41 11. Fraher LJ, Adami S, Clemens TL, Jones G, O’Riordan JLH Radioimmunoassay of 1,25 dihydroxyvitamin D2, studies on the metabolism of vitamin D2 in man. Clin Endocrinol 1983; 19: 151-66. 12. Remhardt TA, Horst RL, OrfJW, Hollis BW. A microassay for 1,25 dihydroxyvitamin D not requiring high pressure liquid chromatography: Application to clinical studies. J Clin Endocrinol Metab 1984, 58: 91-98. 13. Haussler MR, McCain TA Basic and clinical concepts related to vitamin D metabolism and action. N Engl J Med 1977, 297: 974-83. 14. Adams JS, Sharma OP, Gacad MA, Singer FR. Metabolism of 25 hydroxyvitamin D3 by cultured pulmonary alveolar macrophages in sarcoidosis. J Clin Invest 1983, 72: 1856-60. 15. Lester GE, Horst RL, Napoli JL. Formation of 19-nor-10-keto-25-hydroxyvitamin D3 in cultured mammalian cells. Biochem Biophys Res Commun 1984, 120: 919-25
HOW SHOULD ACUTE LYMPHOBLASTIC LEUKAEMIA RELAPSING AFTER BONE-MARROW TRANSPLANTATION BE TREATED?
A. J.
BARRETT
R. JOSHI C. TEW
Department of Haematology, Charing Cross and Westminster Medical School, Westminster Hospital, Horseferry Road, London SW1P 2AP
patients given bone-marrow transplantation (BMT) for acute lymphoblastic leukaemia (ALL) relapsed between day 75 and day 1126 after BMT. 19 patients were given leukaemic induction treatment with standard combination chemotherapy. 7 patients achieved a sustained remission, of whom 5 are alive in remission 88-1240 days after relapse; the 2 others died during a second BMT. 2 of the remaining 14 obtained partial remission but all 14 ultimately died with relapsed leukaemia. A favourable outcome for ALL relapsing after BMT was predicted by the pace of the disease: the 5 survivors had an interval between diagnosis and first relapse of more than 2 years and a disease-free period after BMT of 500 days or
Summary
more.
21 of 63
These results indicate that further conventional
chemotherapy should be used rather than a second marrow transplant to prolong disease-free survival in patients with ALL relapsing after BMT.
1189 Introduction RELAPSE of leukaemia after bone-marrow transplantation (BMT) is a continuing problem, occurring in up to 20% of patients with acute myeloblastic leukaemia (AML) and up to2 50% of patients with acute lymphoblastic leukaemia (ALL).2
Assuming that BMT is the most effective and intensive form of antileukaemia treatment available, it would be logical to treatment to be ineffective. Although patients do receive further chemotherapy and radiotherapy for relapsed disease after BMT, no firm conclusions as to the efficacy of treatment have been drawn. In a series of 63 patients transplanted for ALL 21 relapsed.3
receiving prednisolone and azathioprine in low doses to control mild chronic skin GVHD. Relapse was diagnosed by means ofbonemarrow aspiration and lumbar puncture or biopsy. Where possible, marker studies were carried out on leukaemia cells to identify the nature of the relapse, and chromosome analysis (6 patients) was done in order to determine whether the relapse was in the donor or recipient cells. Results
expect any further many
We describe here the results of leukaemia reinduction patients and discuss the indications for further active antileukaemia treatment in the patients who treatment in 19
relapsed. Patients and Methods The 21 patients studied received bone-marrow transplants between 1979 and 1983. The transplant procedure has been described in full previously.4 All patients received a combination chemotherapy pre-graft schedule which included vincristine and daunorubicin 50 mg/m2 x 2, or prednisolone and arabinoside 300 mg/m2 twice daily x 4 and VM26 200 mg/m x 2, or cyclophosphamide 60 mg/kgx 2. Whole-body irradiation was given to a total dose of 9 - 5 Gy delivered by a linear accelerator or a cobalt source at a dose rate of less than 3 cGy/min. For prevention of graftversus-host-disease (GVHD) 2 patients received methotrexate and the remainder cyclosporin for over 100 days. 16 patients required a short course of methylprednisolone for acute skin GVHD, and 9 required treatment for chronic skin GVHD. At the time of relapse 2 patients were in hospital with problems associated with BMT, and no treatment was considered. The remaining 19 patients were well and fully active, although 4 were
either
cytosine
Relapse Characteristics Relapse occurred 75-1126 days after BMT. The characteristics of the patients and the nature of their relapse are shown in the table. 16 patients had common ALL, 3 null ALL, and 3 T lymphoblastic ALL. In 16 instances where marker studies were carried out the relapse was found to have the characteristics of the original leukaemia. In 6 patients where donor-recipient sex differed and satisfactory chromosome preparations were obtained the relapse was identified as occurring in recipient cells. Treatment 2 patients in poor general health were not considered for active leukaemia treatment, and both died from complications associated with relapsed leukaemia. 19 patients were treated for their relapse with vincristine, prednisolone, and other agents including daunorubicin, VM26, cytosine arabinoside, and vindesine. Patients with central-nervous-system disease received weekly methotrexate alternating with cytosine arabinoside by lumbar puncture or from an Ommaya reservoir. Testicular relapse was treated with orchidectomy at diagnosis or with 12 Gy radiation to both testes. 8 patients failed to achieve remission and died of leukaemia 9-22 days (median 32 days) after relapse. 9
DETAILS OF PATIENT AND RESULTS OF TREATMENT
BM = bone
C-ALL = common ALL. F=fast. S=slow.
marrow.
Rel=retapse.
T-ALL = T-lymphoblastic ALL.
N-ALL = null ALL. CNS = central
nervous
system. Inf= infection. R = remission.
1190
radiotherapy badly.5 Nevertheless, using high-dose melphalan and retransplantation have been reported in AML,6 and occasional patients with ALL have been reported to respond
chemotherapy modest
and
successes
favourably to chemotherapy.’
Actuarial survival of patients with ALL
relapsing after BMT. Day 0 =day ofpost-BMT relapse. Dashes indicate follow-up of survivors.
patients achieved a remission and 2 a partial remission. They survived for 80-621 days (median 216 days). 4 subsequently relapsed (including 2 patients who had achieved only partial remission). The 7 remaining patients achieved a sustained remission with relative ease. They tolerated induction treatment well, with pancytopenias of normal duration following chemotherapy. In 3 patients chronic GVHD improved greatly. BMT was attempted in 2 of these patients. 1 died in remission of infection associated with severe gastrointestinal mucositis resulting from intermediate-dose cytosine arabinoside 1 day before BMT. 1 patient was given BMT from her original donor after melphalan 180 mg/m2. She died in remission of severe acute gastrointestinal and liver GVHD on day 27 after BMT. 5 patients survive in remission. 2 have stopped maintenance treatment, 1 after 2 years and 1 after 6 months, when pulmonary fibrosis and
multiple pneumothoraces developed, possibly associated with methotrexate. All 5 surviving patients are active and at work or school. The actuarial survival for the 19 treated patients is 26% (see figure).
of Outcome after Treatment The interval between diagnosis and first relapse (ie, either before or after BMT, depending on the remission status at the time of grafting) was used as an indication of the rapidity of
Prediction
leukaemic
recurrence.
An interval of more than 2 years
was
designated "slow" disease and less than 2 years "fast" disease. 6 of 9 patients with slow disease and 3 of 10 with fast disease achieved a remission. The only long-term survivors are 5 patients with slow disease. The chance of obtaining remission was also related to the duration of the leukaemiafree period following BMT. Thus, of 12 patients with treated relapses occurring before 500 days only 3 achieved remission, whereas 6 of 7 patients relapsing after 500 days achieved remission. The only survivors belong to the latter group. In general patients with isolated bone-marrow relapse fared better: 6 of 10 such patients achieved remission, compared with 2 of 8 presenting with disease of the marrow and extramedullary sites. Isolated testicular relapse in 1 patient was successfully treated with orchidectomy and intensive
chemotherapy. Discussion
Leukaemic relapse after BMT has a gloomy prognosis.’1 Most BMT reports do not give details of the management of relapsing patients, and a planned approach to their treatment has not been clearly defined. It is generally assumed that a second BMT offers the only hope of achieving a further remission and that patients in relapse withstand intensive
Since there is often considerable pressure by the patient or the patient’s family to continue active treatment when relapse occurs after BMT, we have adopted a policy of attempting or recommending further remission induction in transplanted patients with relapsing ALL. With this approach 19 of 21 patients received active treatment and 7 of them achieved sustained remissions. 5 patients are still alive in remission with a good quality of life. 3 of these patients have now had a longer period of remission than the interval between BMT and relapse. It is possible to identify a group of ALL patients relapsing after BMT who should receive further treatment since they are likely to achieve long remissions. They are, in general, patients with an interval between diagnosis and first relapse of more than 2 years (slow disease) who have solitary relapses in either bone marrow or testes and have had a disease-free interval since BMT of over 500 days. A striking feature of this series was the relative ease with which remission was reinduced with conventional chemotherapy. Conversely, both patients in whom a second BMT was attempted died from complications of drug toxicity and GVHD, suggesting that a second BMT may carry a much greater risk. The prolonged survival of the untransplanted patients achieving remission therefore discourages us from attempting retransplantation in ALL patients achieving remission. These results emphasise that despite a considerable heterogeneity of response to treatment in ALL, each patient’s leukaemia remains consistent in its responsiveness to treatment. Thus, slow disease remains controllable with conventional chemotherapeutic approaches, even after BMT. It could be argued that in this type of ALL prolonged maintenance treatment and not BMT is the treatment of choice. An alternative approach would be to use standard maintenance treatment after BMT in slow-disease ALL, which, paradoxically, though eminently controllable, may be impossible to cure.8 Conversely, fast ALL requires intensive treatments such as BMT to achieve a prolonged disease-free period and possible cure. Patients in this category who relapse after BMT could be considered in the future for further intensive treatment and BMT, but our inability to achieve second remissions in this type of ALL makes their outlook poor. We thank the Leukaemia Research Fund of Great Britain for generous support of the bone-marrow transplantation programme, the haematologists for referring patients to us, our nursing and technical staff for their skilled care and support, and Karen Camacho for typing the manuscript.
Correspondence should be addressed to A. J.
B.
REFERENCES 1. Farbstem
MJ, Blume KG. In: Blume KG, Petz LD, eds Clinical bone
marrow
transplantation. New York: Churchill Livingstone, 1984: 287. 2. Gale RP. Current status of bone marrow transplantation in acute leukaemia Transplant Proc 1979; 11: 1920. 3. Barrett AJ, Joshi R, Giangrande P, et al. Factors determining relapse and survival after bone marrow transplantation for acute lymphoblastic leukaemia. Proceedings of 11th European Bone Marrow Transplant Group meeting Exp Haematol(in press) 4. Barrett AJ, Kendra JR, Saleem NJ, et al. Bone marrow transplantation for acute lymphoblastic leukaemia. In: Gale RP, ed. Recent advances in bone marrow transplantation. New York: AR Liss, 1983. 115-22. 5. Wright SE, Thomas ED, Buckner CD. Experience with second marrow transplants Exp Haematol 1976; 4: 221.
1191
Preliminary Communication HIGH-DENSITY LIPOPROTEIN CHOLESTEROL IN DIFFERENTIAL DIAGNOSIS OF SENILE DEMENTIA
JOHN R. ROY† J. MUCKLE* Departments of Pathology* and Psychiatry, &dag er; McMaster University; and Southam Laboratories* and Geriatric Psychiatry Service,† Chedoke Hospital Division, Chedoke-McMaster Hospitals, THOMAS
Hamilton, Ontario, Canada of Levels Summary high-density lipoprotein cholesterol were found to be significantly lower in 5 men with multi-infarct dementia than in 12 men with senile dementia of the Alzheimer type. The large difference between the groups suggests that levels of highdensity lipoprotein cholesterol may be useful in differential diagnosis of these two kinds of senile dementia. The finding also supports the theory that multi-infarct dementia may be a complication of atherosclerosis. INTRODUCTION
A REDUCED level of high-density lipoprotein cholesterol (HDLC) is associated with major strokel-4 as well as other complications of atherosclerosis, such as myocardial infarctionS-12,lS and peripheral vascular disease. 12-16
Hachinski
et
al17 concluded that multi-infarct dementia
caused by multiple emboli originating from extracerebral arteries affected by atheromatous disease, or the heart. This suggests that levels of HDLC in atheromatous cardiovascular based (ACV)-MID might be reduced, compared with those in dementia resulting from other disorders. There have been no reports on blood lipids in either MID or the much commoner senile dementia of the Alzheimer type (SDAT), and we have started a number of such studies. The present report is of a preliminary finding of a considerable difference in HDLC levels between a small group of men with MID and another group with SDAT. Our results seem to support Hachinski’s theory.
(MID)
was
usually
SUBJECTS AND METHODS We studied 17 consecutive men who presented at the Geriatric Psychiatry Ambulant Outpatient Clinic for Early Dementia, Chedoke Hospital Division of Chedoke-McMaster Hospitals. On the basis of Roth criteria 18, 19 and DSM III criteria20 SDAT was diagnosed in 12 patients and MID in 5 patients by J. R. R. He was by means of heparin-manganese chloride precipitation22 then
series. All subjects in the SDAT group had a Hachinski score2l of less than 4, whereas the 5 men in the MID group had scores greater than 4. Each subject was weighed at first attendance, and blood for laboratory investigations was collected in 7 ml evacuated tubes
6
Lumley HS, Powles RA, Morgenstern GR, et al. Pseudosyngeneic transplantation as a treatment for recurrent leukaemia following allogeneic bone marrow transplantation. In: Touraine JL, Gluckman E, Griscelli C, eds. Bone marrow transplantation in Europe, II. Amsterdam: Excerpta Medica, 1981: 24-28. 7. Koch PA, Serota FT, Elkins WL, et al. Achievement of remission with chemotherapy in acute lymphoblastic leukaemia following bone marrow transplantation. Proc Am Soc Clin Oncol 1979; 20: 307. WG, Nesbit ME, Ramsay NKC, et al. Intensive therapy followed by bone marrow transplantation for patients with acute lymphoblastic leukaemia in second or subsequent remission: Determination of prognostic factors (a report from the Unversity of Minnesota Bone Marrow Transplantation Team). Blood 1983; 61:
8 Woods
1182.
Plasma HDLC levels (mmol/1) and body-weights (kg) for the subjects. SDAT shown as circles, MID as crosses. Weights for 1 and I with MID were missing from the patient records.
subject with SDAT
("Vacutainers", Becton-Dickinson, Mississauga, Ontario, Canada) each containing 10,5 mg of tripotassium edetic acid and 0 - 0 14 mg potassium sorbate. Portions of plasma for HDLC determination were then removed and processed by laboratory technologists who had no knowledge of the clinical source of the coded samples or of the diagnoses. HDL fraction supernatants were prepared within 2 h by means of heparin-manganese chloride precipitation 22 then divided into portions and immediately stored at -70°C. Analysis done within 6 weeks. Cholesterol--was’ estimated in a "Centrifichem 400" (Union Carbide Corporation, Pleasantville, New York, USA) centrifugal fast spectrophotometric analyser with the use of the standard Boehringer-Mannheim "CHOD-PAP" enzymatic method after Stahler et a123 as modified by Siede1.24 The overall coefficient of variation for this method is usually in the range of 3-5%. Clinical data and HDLC values were compared after assessment of the series of 17 subjects. was
RESULTS
The means and ranges of HDLC levels were significantly <0 - 001) lower in the MID group (mean =0-94 mmol/1, range =0-88-0-98 mmol/1, SEM=0-02 mmol/1) to the extent that there was no overlap with the SDAT group mmol/l, mmol/1, range = 1 -11 -1’68 (mean =1-37 SEM=0-06mmol/1) (see figure). A fairly strong negative correlation between weight and HDLC level was evident for all 17 subjects when considered =0-39). This together (r=-0-624, 2p=<0-02, association was near 0 for each group by itself, significant for neither, and the 4 body-weight values available for men with MID were distributed widely over the range (see figure). The age distribution of both groups was somewhat, but nearly equally, skewed towards the younger end of the range, whereas the body-weight distribution was slightly skewed towards the lower end of the range in the SDAT group only.
(2p
=
Repetition of the UVR after chemotherapy produced an increase in 25(OH)D3 to a peak slightly higher than before but there
was no
increase in
serum or
urine calcium. Serum
1,25(OH)2D3 increased slightly but remained well within the normal range (fig 1). The increase in 1,25(OHhD3 was again positively related to the increase in serum 25(OH)D3 (r= 0’ 9; p<0. 02) but the relation between these 2 metabolites showed a much less steep regression line than before chemotherapy (fig 2).
metabolism and the production of a hypercalcaemic factor which we have been unable to separate from 1,25(OH)2D3 itself. The work was supported by Regional Health Authority.
a
research grant from the North Western
Correspondence should be addressed to M. D., Department Royal Infirmary, Manchester M13 9WL.
of Medicine;
REFERENCES
AF, Horst R, Deftos LJ, Cadman EC, Lang R, Broadus AE. Biochemical evaluation of patients with cancer-associated hypercalcaemia. N Engl JMed 1980,
1. Stewart
Discussion
Hypercalcaemia with raised serum 1,25(OH)2D3 has been reported in 6 patients with various lymphomas.2,3 In 5 cases of non-Hodgkin’s lymphoma these abnormalities were corrected by treatment of the lymphoma. In the 6th patient, a case of Hodgkin’s lymphoma, no post-treatment data were given. The present report is the first to describe spontaneous correction of hypercalcaemia and the first in which both the hypercalcaemia and raised 1,25(OH)2D3 levels have been shown to be dependent upon the prevailing serum concentration of substrate, 25(OH)D3. In normal individuals renal synthesis of 1,25(OH)2D3 is under tight control and serum levels of 1,25(OHhD3 are generally unrelated to precursor 25(OH)D3 at normal serum concentrations.’In the present case regulation of the synthesis of 1,25(OH)2D3 was lost and synthesis appeared to be related to the Hodgkin’s disease since reduction in the mass of Hodgkin’s tissue was followed by an inability to produce excess 1,25(OH)2D3. The Hodgkin’s tissue may have been synthesising 1,25(OH)2D3 in a way similar to that proposed for sarcoidosis where there is evidence for extrarenal synthesis of 1,25(OH)2D3 by the sarcoid tissue. 14 In these circumstances the extrarenal production of 1,25(OH)2D3 and the accompanying hypercalcaemia would suppress both the secretion of parathyroid hormone and the relan lahydroxylase enzyme. The subnormal 1,25(OH)2D3 and the increased iPTH observed after chemotherapy suggest that the initial hypercalcaemia resulted from extrarenal 1,25(OH)2D3 production; the changes in NcAMP are compatible with this theory. Alternatively the Hodgkin’s tissue might have produced a trophic substance that increased the renal synthesis of 1,25(OH)2D3. It is difficult to explain the subnormal 1,25(OH)2D3 and increased iPTH after chemotherapy if the 1 a-hydroxylase enzyme had not previously been suppressed. Humoral hypercalcaemia in malignancy is usually associated with raised NcAMP and 1,25(OH)2D3 and iPTH.1 In the present case no evidence for a humoral factor acting on the kidney through the adenylate cyclase system has been found. It seems unlikely therefore that synthesis of 1,25(OH)2D3 was occurring in the kidney. There have been many claims for the extrarenal synthesis of 1,25(OH)2D3 in vitro and at least one metabolite of vitamin D has been shown to be synthesised in vitro, to have the same chromatographic behaviour as 1,25(OH)2D3, and to crossreact in the 1,25(OH)2D3 assay.15 We used 3 different assay systems to measure 1,25(OH)2D3 when its concentration was raised and they all produced similar results. The samples were also run in 3 different HPLC systems including one (system 3) which separates 1,25(OH)2D3 from 19-nor-10keto-25-hydroxyvitamin D3is but in each similar concentrations of 1,25(OH)2D3 were found. It is extremely likely then that this material is 1,25(OH)2D3 and that this patient’s hypercalcaemia was caused by altered vitamin D
suppressed
303: 1377-83. NA, McGuire SL, Zerwekh JE, Frenkel EP, Pak CYC. Hypercalcaemia associated with increased serum calcitriol levels in three patients with lymphoma. Ann Intern Med 1984; 100: 1-7. 3. Rosenthal M, Insogna KL, Godsall JW, Smaldone L, Waldron JA, Stewart AF. Elevations in circulating 1,25 dihydroxyvitamin D in three patients with lymphoma associated hypercalcaemia. J Clin Endocrinol Metab 1984, 60: 29-33 4. Davies M, Mawer EB, Adams PH. Vitamin D metabolism and the response to 1,25 dihydroxycholecalciferol m osteoporosis. J Clin Endocrinol Metab 1977, 45: 199-208. 5. Walton RJ, Bijvoet OLM. Nomogram for derivation of renal threshold phosphate concentration. Lancet 1975; ii: 309-10. 6. Davies M, Adams PH, Berry JL, Lumb GA, et al. Familial hypocalciuric hypercalcaemia: Observations on vitamin D metabolism and parathyroid function Acta Endocrinol 1983, 104: 210-15. 7. Broadus AE, Mahaffey JE, Bartter FC, Neer RM. Nephrogenous cyclic adenosine monophosphate as a parathyroid function test. J Clin Invest 1977; 60: 771-83. 8. Mawer EB, Backhouse J, Hill LF, Lumb GA, et al. Vitamin D metabolism and parathyroid function in man. Clin Sci 1975; 48: 349-65. 9. Davies M, Mawer EB, Hann JT, Stephens WP, Taylor JL Vitamin D prophylaxis in the elderly. A simple effective method suitable for large populations Age Ageing (in
2. Breslau
press) 10. Mawer EB, Hann JT, Berry JL, Davies M. Vitamin D metabolism in patients intoxicated with ergocalciferol. Clin Sci 1985, 68: 135-41 11. Fraher LJ, Adami S, Clemens TL, Jones G, O’Riordan JLH Radioimmunoassay of 1,25 dihydroxyvitamin D2, studies on the metabolism of vitamin D2 in man. Clin Endocrinol 1983; 19: 151-66. 12. Remhardt TA, Horst RL, OrfJW, Hollis BW. A microassay for 1,25 dihydroxyvitamin D not requiring high pressure liquid chromatography: Application to clinical studies. J Clin Endocrinol Metab 1984, 58: 91-98. 13. Haussler MR, McCain TA Basic and clinical concepts related to vitamin D metabolism and action. N Engl J Med 1977, 297: 974-83. 14. Adams JS, Sharma OP, Gacad MA, Singer FR. Metabolism of 25 hydroxyvitamin D3 by cultured pulmonary alveolar macrophages in sarcoidosis. J Clin Invest 1983, 72: 1856-60. 15. Lester GE, Horst RL, Napoli JL. Formation of 19-nor-10-keto-25-hydroxyvitamin D3 in cultured mammalian cells. Biochem Biophys Res Commun 1984, 120: 919-25
HOW SHOULD ACUTE LYMPHOBLASTIC LEUKAEMIA RELAPSING AFTER BONE-MARROW TRANSPLANTATION BE TREATED?
A. J.
BARRETT
R. JOSHI C. TEW
Department of Haematology, Charing Cross and Westminster Medical School, Westminster Hospital, Horseferry Road, London SW1P 2AP
patients given bone-marrow transplantation (BMT) for acute lymphoblastic leukaemia (ALL) relapsed between day 75 and day 1126 after BMT. 19 patients were given leukaemic induction treatment with standard combination chemotherapy. 7 patients achieved a sustained remission, of whom 5 are alive in remission 88-1240 days after relapse; the 2 others died during a second BMT. 2 of the remaining 14 obtained partial remission but all 14 ultimately died with relapsed leukaemia. A favourable outcome for ALL relapsing after BMT was predicted by the pace of the disease: the 5 survivors had an interval between diagnosis and first relapse of more than 2 years and a disease-free period after BMT of 500 days or
Summary
more.
21 of 63
These results indicate that further conventional
chemotherapy should be used rather than a second marrow transplant to prolong disease-free survival in patients with ALL relapsing after BMT.
1189 Introduction RELAPSE of leukaemia after bone-marrow transplantation (BMT) is a continuing problem, occurring in up to 20% of patients with acute myeloblastic leukaemia (AML) and up to2 50% of patients with acute lymphoblastic leukaemia (ALL).2
Assuming that BMT is the most effective and intensive form of antileukaemia treatment available, it would be logical to treatment to be ineffective. Although patients do receive further chemotherapy and radiotherapy for relapsed disease after BMT, no firm conclusions as to the efficacy of treatment have been drawn. In a series of 63 patients transplanted for ALL 21 relapsed.3
receiving prednisolone and azathioprine in low doses to control mild chronic skin GVHD. Relapse was diagnosed by means ofbonemarrow aspiration and lumbar puncture or biopsy. Where possible, marker studies were carried out on leukaemia cells to identify the nature of the relapse, and chromosome analysis (6 patients) was done in order to determine whether the relapse was in the donor or recipient cells. Results
expect any further many
We describe here the results of leukaemia reinduction patients and discuss the indications for further active antileukaemia treatment in the patients who treatment in 19
relapsed. Patients and Methods The 21 patients studied received bone-marrow transplants between 1979 and 1983. The transplant procedure has been described in full previously.4 All patients received a combination chemotherapy pre-graft schedule which included vincristine and daunorubicin 50 mg/m2 x 2, or prednisolone and arabinoside 300 mg/m2 twice daily x 4 and VM26 200 mg/m x 2, or cyclophosphamide 60 mg/kgx 2. Whole-body irradiation was given to a total dose of 9 - 5 Gy delivered by a linear accelerator or a cobalt source at a dose rate of less than 3 cGy/min. For prevention of graftversus-host-disease (GVHD) 2 patients received methotrexate and the remainder cyclosporin for over 100 days. 16 patients required a short course of methylprednisolone for acute skin GVHD, and 9 required treatment for chronic skin GVHD. At the time of relapse 2 patients were in hospital with problems associated with BMT, and no treatment was considered. The remaining 19 patients were well and fully active, although 4 were
either
cytosine
Relapse Characteristics Relapse occurred 75-1126 days after BMT. The characteristics of the patients and the nature of their relapse are shown in the table. 16 patients had common ALL, 3 null ALL, and 3 T lymphoblastic ALL. In 16 instances where marker studies were carried out the relapse was found to have the characteristics of the original leukaemia. In 6 patients where donor-recipient sex differed and satisfactory chromosome preparations were obtained the relapse was identified as occurring in recipient cells. Treatment 2 patients in poor general health were not considered for active leukaemia treatment, and both died from complications associated with relapsed leukaemia. 19 patients were treated for their relapse with vincristine, prednisolone, and other agents including daunorubicin, VM26, cytosine arabinoside, and vindesine. Patients with central-nervous-system disease received weekly methotrexate alternating with cytosine arabinoside by lumbar puncture or from an Ommaya reservoir. Testicular relapse was treated with orchidectomy at diagnosis or with 12 Gy radiation to both testes. 8 patients failed to achieve remission and died of leukaemia 9-22 days (median 32 days) after relapse. 9
DETAILS OF PATIENT AND RESULTS OF TREATMENT
BM = bone
C-ALL = common ALL. F=fast. S=slow.
marrow.
Rel=retapse.
T-ALL = T-lymphoblastic ALL.
N-ALL = null ALL. CNS = central
nervous
system. Inf= infection. R = remission.
1190
radiotherapy badly.5 Nevertheless, using high-dose melphalan and retransplantation have been reported in AML,6 and occasional patients with ALL have been reported to respond
chemotherapy modest
and
successes
favourably to chemotherapy.’
Actuarial survival of patients with ALL
relapsing after BMT. Day 0 =day ofpost-BMT relapse. Dashes indicate follow-up of survivors.
patients achieved a remission and 2 a partial remission. They survived for 80-621 days (median 216 days). 4 subsequently relapsed (including 2 patients who had achieved only partial remission). The 7 remaining patients achieved a sustained remission with relative ease. They tolerated induction treatment well, with pancytopenias of normal duration following chemotherapy. In 3 patients chronic GVHD improved greatly. BMT was attempted in 2 of these patients. 1 died in remission of infection associated with severe gastrointestinal mucositis resulting from intermediate-dose cytosine arabinoside 1 day before BMT. 1 patient was given BMT from her original donor after melphalan 180 mg/m2. She died in remission of severe acute gastrointestinal and liver GVHD on day 27 after BMT. 5 patients survive in remission. 2 have stopped maintenance treatment, 1 after 2 years and 1 after 6 months, when pulmonary fibrosis and
multiple pneumothoraces developed, possibly associated with methotrexate. All 5 surviving patients are active and at work or school. The actuarial survival for the 19 treated patients is 26% (see figure).
of Outcome after Treatment The interval between diagnosis and first relapse (ie, either before or after BMT, depending on the remission status at the time of grafting) was used as an indication of the rapidity of
Prediction
leukaemic
recurrence.
An interval of more than 2 years
was
designated "slow" disease and less than 2 years "fast" disease. 6 of 9 patients with slow disease and 3 of 10 with fast disease achieved a remission. The only long-term survivors are 5 patients with slow disease. The chance of obtaining remission was also related to the duration of the leukaemiafree period following BMT. Thus, of 12 patients with treated relapses occurring before 500 days only 3 achieved remission, whereas 6 of 7 patients relapsing after 500 days achieved remission. The only survivors belong to the latter group. In general patients with isolated bone-marrow relapse fared better: 6 of 10 such patients achieved remission, compared with 2 of 8 presenting with disease of the marrow and extramedullary sites. Isolated testicular relapse in 1 patient was successfully treated with orchidectomy and intensive
chemotherapy. Discussion
Leukaemic relapse after BMT has a gloomy prognosis.’1 Most BMT reports do not give details of the management of relapsing patients, and a planned approach to their treatment has not been clearly defined. It is generally assumed that a second BMT offers the only hope of achieving a further remission and that patients in relapse withstand intensive
Since there is often considerable pressure by the patient or the patient’s family to continue active treatment when relapse occurs after BMT, we have adopted a policy of attempting or recommending further remission induction in transplanted patients with relapsing ALL. With this approach 19 of 21 patients received active treatment and 7 of them achieved sustained remissions. 5 patients are still alive in remission with a good quality of life. 3 of these patients have now had a longer period of remission than the interval between BMT and relapse. It is possible to identify a group of ALL patients relapsing after BMT who should receive further treatment since they are likely to achieve long remissions. They are, in general, patients with an interval between diagnosis and first relapse of more than 2 years (slow disease) who have solitary relapses in either bone marrow or testes and have had a disease-free interval since BMT of over 500 days. A striking feature of this series was the relative ease with which remission was reinduced with conventional chemotherapy. Conversely, both patients in whom a second BMT was attempted died from complications of drug toxicity and GVHD, suggesting that a second BMT may carry a much greater risk. The prolonged survival of the untransplanted patients achieving remission therefore discourages us from attempting retransplantation in ALL patients achieving remission. These results emphasise that despite a considerable heterogeneity of response to treatment in ALL, each patient’s leukaemia remains consistent in its responsiveness to treatment. Thus, slow disease remains controllable with conventional chemotherapeutic approaches, even after BMT. It could be argued that in this type of ALL prolonged maintenance treatment and not BMT is the treatment of choice. An alternative approach would be to use standard maintenance treatment after BMT in slow-disease ALL, which, paradoxically, though eminently controllable, may be impossible to cure.8 Conversely, fast ALL requires intensive treatments such as BMT to achieve a prolonged disease-free period and possible cure. Patients in this category who relapse after BMT could be considered in the future for further intensive treatment and BMT, but our inability to achieve second remissions in this type of ALL makes their outlook poor. We thank the Leukaemia Research Fund of Great Britain for generous support of the bone-marrow transplantation programme, the haematologists for referring patients to us, our nursing and technical staff for their skilled care and support, and Karen Camacho for typing the manuscript.
Correspondence should be addressed to A. J.
B.
REFERENCES 1. Farbstem
MJ, Blume KG. In: Blume KG, Petz LD, eds Clinical bone
marrow
transplantation. New York: Churchill Livingstone, 1984: 287. 2. Gale RP. Current status of bone marrow transplantation in acute leukaemia Transplant Proc 1979; 11: 1920. 3. Barrett AJ, Joshi R, Giangrande P, et al. Factors determining relapse and survival after bone marrow transplantation for acute lymphoblastic leukaemia. Proceedings of 11th European Bone Marrow Transplant Group meeting Exp Haematol(in press) 4. Barrett AJ, Kendra JR, Saleem NJ, et al. Bone marrow transplantation for acute lymphoblastic leukaemia. In: Gale RP, ed. Recent advances in bone marrow transplantation. New York: AR Liss, 1983. 115-22. 5. Wright SE, Thomas ED, Buckner CD. Experience with second marrow transplants Exp Haematol 1976; 4: 221.
1191
Preliminary Communication HIGH-DENSITY LIPOPROTEIN CHOLESTEROL IN DIFFERENTIAL DIAGNOSIS OF SENILE DEMENTIA
JOHN R. ROY† J. MUCKLE* Departments of Pathology* and Psychiatry, &dag er; McMaster University; and Southam Laboratories* and Geriatric Psychiatry Service,† Chedoke Hospital Division, Chedoke-McMaster Hospitals, THOMAS
Hamilton, Ontario, Canada of Levels Summary high-density lipoprotein cholesterol were found to be significantly lower in 5 men with multi-infarct dementia than in 12 men with senile dementia of the Alzheimer type. The large difference between the groups suggests that levels of highdensity lipoprotein cholesterol may be useful in differential diagnosis of these two kinds of senile dementia. The finding also supports the theory that multi-infarct dementia may be a complication of atherosclerosis. INTRODUCTION
A REDUCED level of high-density lipoprotein cholesterol (HDLC) is associated with major strokel-4 as well as other complications of atherosclerosis, such as myocardial infarctionS-12,lS and peripheral vascular disease. 12-16
Hachinski
et
al17 concluded that multi-infarct dementia
caused by multiple emboli originating from extracerebral arteries affected by atheromatous disease, or the heart. This suggests that levels of HDLC in atheromatous cardiovascular based (ACV)-MID might be reduced, compared with those in dementia resulting from other disorders. There have been no reports on blood lipids in either MID or the much commoner senile dementia of the Alzheimer type (SDAT), and we have started a number of such studies. The present report is of a preliminary finding of a considerable difference in HDLC levels between a small group of men with MID and another group with SDAT. Our results seem to support Hachinski’s theory.
(MID)
was
usually
SUBJECTS AND METHODS We studied 17 consecutive men who presented at the Geriatric Psychiatry Ambulant Outpatient Clinic for Early Dementia, Chedoke Hospital Division of Chedoke-McMaster Hospitals. On the basis of Roth criteria 18, 19 and DSM III criteria20 SDAT was diagnosed in 12 patients and MID in 5 patients by J. R. R. He was by means of heparin-manganese chloride precipitation22 then
series. All subjects in the SDAT group had a Hachinski score2l of less than 4, whereas the 5 men in the MID group had scores greater than 4. Each subject was weighed at first attendance, and blood for laboratory investigations was collected in 7 ml evacuated tubes
6
Lumley HS, Powles RA, Morgenstern GR, et al. Pseudosyngeneic transplantation as a treatment for recurrent leukaemia following allogeneic bone marrow transplantation. In: Touraine JL, Gluckman E, Griscelli C, eds. Bone marrow transplantation in Europe, II. Amsterdam: Excerpta Medica, 1981: 24-28. 7. Koch PA, Serota FT, Elkins WL, et al. Achievement of remission with chemotherapy in acute lymphoblastic leukaemia following bone marrow transplantation. Proc Am Soc Clin Oncol 1979; 20: 307. WG, Nesbit ME, Ramsay NKC, et al. Intensive therapy followed by bone marrow transplantation for patients with acute lymphoblastic leukaemia in second or subsequent remission: Determination of prognostic factors (a report from the Unversity of Minnesota Bone Marrow Transplantation Team). Blood 1983; 61:
8 Woods
1182.
Plasma HDLC levels (mmol/1) and body-weights (kg) for the subjects. SDAT shown as circles, MID as crosses. Weights for 1 and I with MID were missing from the patient records.
subject with SDAT
("Vacutainers", Becton-Dickinson, Mississauga, Ontario, Canada) each containing 10,5 mg of tripotassium edetic acid and 0 - 0 14 mg potassium sorbate. Portions of plasma for HDLC determination were then removed and processed by laboratory technologists who had no knowledge of the clinical source of the coded samples or of the diagnoses. HDL fraction supernatants were prepared within 2 h by means of heparin-manganese chloride precipitation 22 then divided into portions and immediately stored at -70°C. Analysis done within 6 weeks. Cholesterol--was’ estimated in a "Centrifichem 400" (Union Carbide Corporation, Pleasantville, New York, USA) centrifugal fast spectrophotometric analyser with the use of the standard Boehringer-Mannheim "CHOD-PAP" enzymatic method after Stahler et a123 as modified by Siede1.24 The overall coefficient of variation for this method is usually in the range of 3-5%. Clinical data and HDLC values were compared after assessment of the series of 17 subjects. was
RESULTS
The means and ranges of HDLC levels were significantly <0 - 001) lower in the MID group (mean =0-94 mmol/1, range =0-88-0-98 mmol/1, SEM=0-02 mmol/1) to the extent that there was no overlap with the SDAT group mmol/l, mmol/1, range = 1 -11 -1’68 (mean =1-37 SEM=0-06mmol/1) (see figure). A fairly strong negative correlation between weight and HDLC level was evident for all 17 subjects when considered =0-39). This together (r=-0-624, 2p=<0-02, association was near 0 for each group by itself, significant for neither, and the 4 body-weight values available for men with MID were distributed widely over the range (see figure). The age distribution of both groups was somewhat, but nearly equally, skewed towards the younger end of the range, whereas the body-weight distribution was slightly skewed towards the lower end of the range in the SDAT group only.
(2p
=