- Email: [email protected]
DISCREPANT BONE-MARROW ASPIRATIONS IN LEUKÆMIA
557
only at the conversion of V.L.D.L.
and L.D.L. but also earlier in
the metabolic cascade. Division of Clinical Medicine, Victoria Infirmary, Glasgow G42 9TY
D. BALLANTYNE
University Department of Pathological BiochemistryFIONA C. BALLANTYNE
Royal Infirmary,
P. STROMBERG
Glasgow
Welsh National School of Medicine and University Hospital of Wales, Cardiff CF4 4XW
SYNCHRONISATION OF CELL PHASE IN TREATMENT OF LEUKÆMIA well established that the majority of cells in untreated patients with leukxmia are in the resting (Go) phase of mitosisl-3 with a small proportion of cells continually reentering the mitotic cycle.4,5 Recent advances in the induction treatment of leukaemia have usually included the drugs daunorubicin or doxorubicin, ,which destroy cells by inhibiting D.N.A. synthesis.6.7 By the spleen colony assay, a striking increase in cell kill has been demonstrated when these drugs are given after cytosine arabinoside.8 Although the exact mechanism of this cell kill is unknown, one explanation is that cytosine arabinoside partially synchronises the leukxmia cell in cell cycle, killing cells in S-phase and blocking others at the Gi S interface where the cell kill of daunorubicin and doxorubicin is greatest.8 Partial synchronisation of cells in S-phase has been demonstrated in patients with acute leukaemia,9.1O and it has been suggested that further improvements in leukaemia chemotherapy might be possible if treatment schedules were designed to make use of these findings. Studies" in patients with acute myelogenous leukxmia (A.M.L.) have demonstrated that synchrony of D.N.A. synthesis was maximum six days after the start of cytosine-arabinoside treatment. We have adopted a similar approach in a series of 32 unselected adults with previously untreated acute non-lymphoid leukaemia presenting in South Wales in an 18-months period. 30 patients had A.M.L. or its variant, acute myelomonocytic leukaemia, and 2 had acute promyelocytic leukxmia. 1 patient who had A.M.L. also had a history ofpolycythsemia many years previously. 12 patients were male and 20 female; and the age range was 15-73 years (mean 49). Each patient received cytosine arabinoside (400 mg/m2) in a saline infusion over 72 hours (days 1-3) and on day 5, at a time when synchronisation could be expected to be near maximum, patients were given doxorubicin (40 mg/m2). Treatment was repeated with intervals of 10-14 days between day 1 of each course until patients reached remission as judged by established criteria.12 3 patients received only one course (including a patient who entered an early remission), but others received 2-8 (mean 3-8) courses. Transfusions of blood and platelets were given when needed, and infectious complications were treated with intravenous gentamicin or tobramycin and intravenous lincomycin. Granulocyte transfusions from related donors or patients with chronic granulocytic leukxmia were given to any patient whose infection did not respond to antibiotics. The complete-remission rate was 34.5%, which is similar to our remission-rate in adults given daunorubicin and
SIR,-It is
now
1 Mauer, A. M., Fisher, V Nature, 1962, 193, 1085. 2. Mauer, AM., Fisher, VBlood, 1966, 28, 428. 3 Gavosto, F., Pileri, A , Bachi, G., Pegoraro, I.. Nature, 1964, 203, 92. 4 Gabutti, V., Pileri, A., Tarocco, R. P., Gavosto, F., Cooper, E. H. ibid. 1969, 224, 375. 5. Saunders, E F., Mauer, A. M J clin. Invest. 1969, 48, 1299. 6. Lampkin, B. C., Nagao, T , Mauer, A. M. ibid. 1971, 50, 2204. 7 Stryckmans, P. A., Manaster, J, La Chapelle, F., Socquet, M. ibid. 1973, 52, 1973. 8 Edelstein, M., Vietti, T , Valerioff, F Cancer Res. 1973, 34, 293. 9. Vogler, W. R., Cooper, L E , Groth, D. P. Cancer, 1974, 33, 603 10. Lampkin, B. C., McWilliams, N. B., Mauer, A. M., Flessa, H. C., Hake, D A., Fisher, V. Br J Hœmat. 1976, 32, 29. 11 Smith, I. E., Mehta, A., Powles, R. L , McElwain, T. J. ibid 1976, 33, 613. 12 M R C Working Party on Evaluation of Different Methods of Leukæmia. Br med J. 1963, i, 7.
Therapy
arabinoside together." It is possible that cells synchronised in S-phase using cytosine arabinoside may be more effectively killed by a combination of drugs, and preliminary evidence" suggests that daunorubicin and doxorubicin given sequentially on days 6 and 7 may improve remission-rates. Further studies of treatment schedules which attempt to use synchronisation of cells are needed before final conclusions can be drawn.
cytosine
in
Morriston Swansea
J. A. WHITTAKER S. AD, AL-ISMAIL
Hospital, M. KHURSHID
DISCREPANT BONE-MARROW ASPIRATIONS IN LEUKÆMIA
SIR,-Reports of Dr Hann and others (June 4, p. 1215) and Professor Jacobs (Aug. 13, p. 355) highlight the difficulties in deciding the remission/relapse status of patients being treated for leukxmia. No doubt Professor Jacobs’ suggestion of regular marrow aspiration at two separate sites will improve the accuracy of diagnosis, but recurrence elsewhere in the marrow and at extramedullary sites will still escape detection. Mathe et al.l in an extensive histological and cytological survey of 31 patients with leukxmia (mainly lymphoblastic) in "complete remission" found residual leukxmia cells in 12, but only 4 of these were detected by a series of six marrow punctures at different sites. Such an extensive programme of investigations involving multiple biopsies might be acceptable for a special purpose-e.g., in deciding whether treatment should finally be stopped-but could hardly be part of routine management. A further problem is that, particularly in acute myeloid leukxmia, interpretation of the borderline marrow smear is subjective and imprecise. The patient is usually said to be in remission if less than 5% of the marrow cells are blast forms and none are recognisable as leukaemia cells. The counting in
non-homogeneous substance like marrow is high, not possible to say on morphological grounds whether myeloblasts are normal or leukaemic. These difficulties of interpretation explain some of the varying results obtained in different trials and at different centres using apparently identical treatments. For these reasons I have adopted a different approach to the problem, and am currently evaluating the usefulness of whitecell-concentrate examination. Two of the relapses in Mathe’s series were detected by this method, but the pick-up rate might be higher in myeloblastic leukaemia, and Willoughby and Whitelaw2 have demonstrated that it is possible to predict the development of leukxmia in cases of refractory anaemia by this technique. With this method it is technically easy to examine the white cells from a large volume of blood and to detect small error
a
however, and it is often
numbers of abnormal cells, without discomfort or inconvenience to the patient. Leukaemic cells may be shed into the blood from extramedullary sites as well as from the marrow, and the presence of a few myeloblasts in the peripheral blood is probably of greater significance than the same cells in the marrow (their normal habitat). This technique deserves further assessment as an aid in the diagnosis of remission/relapse and may even enable these long-suffering patients to be
spared some marrow aspirations. General
Hospital,
Steelhouse Lane,
Birmingham 13.
B4 6NH
ANDREW POLLOCK
Ansari, B. M., Thompson, E. N., Whittaker, J. A., Br. J. Hœmat. 1975, 31, 269.
1. Mathé, G., Schwarzenberg, L., Mery, A. M., Cattan, A., Schneider, M., Amiel, J. L., Schlumberger, J. R., Poisson, J., Wajcner, G. Br. med. J. 1966, i, 640. 2 Willoughby, M. L. N., Whitelaw, J. W in Proceedings of the Tenth Congress of the International Society for Hæmatology, Stockholm; p. A33. 1964.
only at the conversion of V.L.D.L.
and L.D.L. but also earlier in
the metabolic cascade. Division of Clinical Medicine, Victoria Infirmary, Glasgow G42 9TY
D. BALLANTYNE
University Department of Pathological BiochemistryFIONA C. BALLANTYNE
Royal Infirmary,
P. STROMBERG
Glasgow
Welsh National School of Medicine and University Hospital of Wales, Cardiff CF4 4XW
SYNCHRONISATION OF CELL PHASE IN TREATMENT OF LEUKÆMIA well established that the majority of cells in untreated patients with leukxmia are in the resting (Go) phase of mitosisl-3 with a small proportion of cells continually reentering the mitotic cycle.4,5 Recent advances in the induction treatment of leukaemia have usually included the drugs daunorubicin or doxorubicin, ,which destroy cells by inhibiting D.N.A. synthesis.6.7 By the spleen colony assay, a striking increase in cell kill has been demonstrated when these drugs are given after cytosine arabinoside.8 Although the exact mechanism of this cell kill is unknown, one explanation is that cytosine arabinoside partially synchronises the leukxmia cell in cell cycle, killing cells in S-phase and blocking others at the Gi S interface where the cell kill of daunorubicin and doxorubicin is greatest.8 Partial synchronisation of cells in S-phase has been demonstrated in patients with acute leukaemia,9.1O and it has been suggested that further improvements in leukaemia chemotherapy might be possible if treatment schedules were designed to make use of these findings. Studies" in patients with acute myelogenous leukxmia (A.M.L.) have demonstrated that synchrony of D.N.A. synthesis was maximum six days after the start of cytosine-arabinoside treatment. We have adopted a similar approach in a series of 32 unselected adults with previously untreated acute non-lymphoid leukaemia presenting in South Wales in an 18-months period. 30 patients had A.M.L. or its variant, acute myelomonocytic leukaemia, and 2 had acute promyelocytic leukxmia. 1 patient who had A.M.L. also had a history ofpolycythsemia many years previously. 12 patients were male and 20 female; and the age range was 15-73 years (mean 49). Each patient received cytosine arabinoside (400 mg/m2) in a saline infusion over 72 hours (days 1-3) and on day 5, at a time when synchronisation could be expected to be near maximum, patients were given doxorubicin (40 mg/m2). Treatment was repeated with intervals of 10-14 days between day 1 of each course until patients reached remission as judged by established criteria.12 3 patients received only one course (including a patient who entered an early remission), but others received 2-8 (mean 3-8) courses. Transfusions of blood and platelets were given when needed, and infectious complications were treated with intravenous gentamicin or tobramycin and intravenous lincomycin. Granulocyte transfusions from related donors or patients with chronic granulocytic leukxmia were given to any patient whose infection did not respond to antibiotics. The complete-remission rate was 34.5%, which is similar to our remission-rate in adults given daunorubicin and
SIR,-It is
now
1 Mauer, A. M., Fisher, V Nature, 1962, 193, 1085. 2. Mauer, AM., Fisher, VBlood, 1966, 28, 428. 3 Gavosto, F., Pileri, A , Bachi, G., Pegoraro, I.. Nature, 1964, 203, 92. 4 Gabutti, V., Pileri, A., Tarocco, R. P., Gavosto, F., Cooper, E. H. ibid. 1969, 224, 375. 5. Saunders, E F., Mauer, A. M J clin. Invest. 1969, 48, 1299. 6. Lampkin, B. C., Nagao, T , Mauer, A. M. ibid. 1971, 50, 2204. 7 Stryckmans, P. A., Manaster, J, La Chapelle, F., Socquet, M. ibid. 1973, 52, 1973. 8 Edelstein, M., Vietti, T , Valerioff, F Cancer Res. 1973, 34, 293. 9. Vogler, W. R., Cooper, L E , Groth, D. P. Cancer, 1974, 33, 603 10. Lampkin, B. C., McWilliams, N. B., Mauer, A. M., Flessa, H. C., Hake, D A., Fisher, V. Br J Hœmat. 1976, 32, 29. 11 Smith, I. E., Mehta, A., Powles, R. L , McElwain, T. J. ibid 1976, 33, 613. 12 M R C Working Party on Evaluation of Different Methods of Leukæmia. Br med J. 1963, i, 7.
Therapy
arabinoside together." It is possible that cells synchronised in S-phase using cytosine arabinoside may be more effectively killed by a combination of drugs, and preliminary evidence" suggests that daunorubicin and doxorubicin given sequentially on days 6 and 7 may improve remission-rates. Further studies of treatment schedules which attempt to use synchronisation of cells are needed before final conclusions can be drawn.
cytosine
in
Morriston Swansea
J. A. WHITTAKER S. AD, AL-ISMAIL
Hospital, M. KHURSHID
DISCREPANT BONE-MARROW ASPIRATIONS IN LEUKÆMIA
SIR,-Reports of Dr Hann and others (June 4, p. 1215) and Professor Jacobs (Aug. 13, p. 355) highlight the difficulties in deciding the remission/relapse status of patients being treated for leukxmia. No doubt Professor Jacobs’ suggestion of regular marrow aspiration at two separate sites will improve the accuracy of diagnosis, but recurrence elsewhere in the marrow and at extramedullary sites will still escape detection. Mathe et al.l in an extensive histological and cytological survey of 31 patients with leukxmia (mainly lymphoblastic) in "complete remission" found residual leukxmia cells in 12, but only 4 of these were detected by a series of six marrow punctures at different sites. Such an extensive programme of investigations involving multiple biopsies might be acceptable for a special purpose-e.g., in deciding whether treatment should finally be stopped-but could hardly be part of routine management. A further problem is that, particularly in acute myeloid leukxmia, interpretation of the borderline marrow smear is subjective and imprecise. The patient is usually said to be in remission if less than 5% of the marrow cells are blast forms and none are recognisable as leukaemia cells. The counting in
non-homogeneous substance like marrow is high, not possible to say on morphological grounds whether myeloblasts are normal or leukaemic. These difficulties of interpretation explain some of the varying results obtained in different trials and at different centres using apparently identical treatments. For these reasons I have adopted a different approach to the problem, and am currently evaluating the usefulness of whitecell-concentrate examination. Two of the relapses in Mathe’s series were detected by this method, but the pick-up rate might be higher in myeloblastic leukaemia, and Willoughby and Whitelaw2 have demonstrated that it is possible to predict the development of leukxmia in cases of refractory anaemia by this technique. With this method it is technically easy to examine the white cells from a large volume of blood and to detect small error
a
however, and it is often
numbers of abnormal cells, without discomfort or inconvenience to the patient. Leukaemic cells may be shed into the blood from extramedullary sites as well as from the marrow, and the presence of a few myeloblasts in the peripheral blood is probably of greater significance than the same cells in the marrow (their normal habitat). This technique deserves further assessment as an aid in the diagnosis of remission/relapse and may even enable these long-suffering patients to be
spared some marrow aspirations. General
Hospital,
Steelhouse Lane,
Birmingham 13.
B4 6NH
ANDREW POLLOCK
Ansari, B. M., Thompson, E. N., Whittaker, J. A., Br. J. Hœmat. 1975, 31, 269.
1. Mathé, G., Schwarzenberg, L., Mery, A. M., Cattan, A., Schneider, M., Amiel, J. L., Schlumberger, J. R., Poisson, J., Wajcner, G. Br. med. J. 1966, i, 640. 2 Willoughby, M. L. N., Whitelaw, J. W in Proceedings of the Tenth Congress of the International Society for Hæmatology, Stockholm; p. A33. 1964.