266 TESTS FOR M.T.F. ACTIVITY
*K.L.H. in jjtg,
M.T.F.
in
no.
of cells, C. albicans
ter) as dilution. tErythema (E) and induration (1) positive
antigen (C.A.) (Hollis-
if reactions were 5 mm or ’
in diameter. t1 x 108 cells.
more
of 0.2 ml applied to both inguinal regions (0-1 ml K.L.H. plus 0.1ml adjuvant). The mice were injected every 15 days for 2 months and killed 10 days after the last injection. The spleens were separated and the pool of lymphocytes obtained was adjusted to 2x108, 1x108, and 2x107 cells/ml. Lymphocytes were also obtained from non-immunised mice and adjusted to 1x108 cells/ml. The murine transfer factor (M.T.F.) was prepared as for the human material.3 Twenty-one healthy subjects, not sensitised to K.L.H., were injected with M.T.F. The course of test injections is shown in the table; eight individuals who were anergic to Candida albicans were tested with candida antigen (Hollister) as well. Injections of antigen and M.T.F. were simultaneous; saline was given where only K.L.H., candida antigen, or M.T.F. was being given. Diameters of erythema and induration were read at 48 h, a diameter of 5 mm or more being considered positive. The results (see table) show that M.T.F. is active and apparently specific in man, at least for K.L.H. Application of a different antigen from the immunogenic one (i.e., candida) had no effect. M.T.F. doses of at least 1x10* cells seem to be required, and results also seemed to vary with the amount of antigen administered. Should these findings be confirmed the door would be open to possible therapeutic applications since transfer factor for clinical use could be raised in laboratory animals.
Immunology Unit, Laboratorio F. Echevarne,
Barcelona-9, Spain
J. M. VICH J. V. GARCIA-CALDERÓN P. ENGEL P. A. GARCIA-CALDERÓN
SURVIVAL AFTER RELAPSE IN ACUTE MYELOID LEUKÆMIA
SIR,-The U.C.L.A. Bone-marrow Transplantation Team, in their report on the treatment of resistant acute leukaemia by the SCARI chemotherapy/radiotherapy regimen followed by transplantation of allogeneic bone-marrow,’ compared the results with those obtained in an apparently comparable (control) group of patients treated by chemotherapy only. 5 of the 3. Lawrence, H. S. Ad. Immuno. 1969, 11, 229. 1. U.C.L.A. Bone-marrow Transplant Team. Lancet, 1977, ii,
1197.
33 patients who received bone-marrow transplants (B.M.T. group) were in remission 1-2 Zyears later, whereas none of the 37 controls survived longer than 13 months. It is not clear whether the two groups were strictly comparable in two important respects. Firstly, the controls might have had much less intensive therapy than SCARI, a regimen so intensive that the bone-marrow would be unlikely to recover unless a graft were successful. Did the controls receive the most intensive treatment, short of total-body irradiation, that could be safely administered without the support of a marrow graft? Secondly, there were proportionately more acute lymphoblastic leukaemia (A.L.L.) patients (33%) in the B.M.T. group than in the controls (24%); the A.L.L. patients in the control group had all relapsed for the second time, and may well have had more resistant disease than at least 4 of the 11 A.L.L. patients in the B.M.T. group who were in their first relapse. A central feature of the U.C.L.A. results is the survival of 5 patients beyond one year. How many of the 5 had A.L.L. and were any of them treated for their first relapse? This is important because acute myeloid leukaemia (A.M.L.) and A.L.L. are so different in their biology and response to cytotoxic drugs. Could the superior results in the B.M.T. group be accounted for by A.L.L. patients in their first relapse, and by less than maximal chemotherapy in the control group? We would also like to
know how many of the 3 patients who received bone-marrow from identical twins were among the 5 patients who survived more than a year; syngeneic B.M.T. is a far less complex procedure than allogeneic transplantation. In A.M.L.,
prolonged survival after first relapse is uncomhappened in 5 adult patients out of 150 treated
mon, but it has
this unit since 1970. Their mean age was 37; 4 were The duration of the first remission was 6-48 months, and survival after first relapse ranged from 1 to more than 4 years (2 more than 1 year, 2 more than 3 years, 1 more than 4 years). 4 patients are still alive, 2 in complete remission (1 has had no treatment for more than 2 years) and 2 have lately relapsed and been put on re-induction therapy. 3 patients relapsed more than once; 1, with hypergranular promyelocytic leukaemia, died after the third relapse. All 5 received cytarabine or 5-azacytidine, thioguanine, and an anthracycline in various combinations, and the maintenance therapy varied. 1 patient received "late intensification" as recommended by Freireich et al .2 These 5 patients with relapsed A.M.L. have survived at least as long as the U.C.L.A. B.M.T. survivors, and considerably longer than any in the U.C.L.A. controls, although their disease-free survival is not as good as in the U.C.L.A. B.M.T. group. on
women.
The results from Los Angeles,’ Seattleand Basleshow that relapse of acute leukaemia after total-body irradiation and B.M.T., though infrequent, does occur in patients who survive the complications of the procedure. Long survival after first relapse can also be obtained in patients with A.M.L. without recourse to B.M.T. We cannot yet conclude that transplantation of allogeneic bone-marrow, when available, is necessary for the ideal management of all patients with relapsed acute leukaemia. Future studies on the treatment of relapsed acute leukeemia by B.M.T. should include simultaneous control groups of patients treated as vigorously as possible but without B.M.T., and specify the cytological type of the leukaemia in every case. It might then be possible to assess the real value of B.M.T. in the management of this difficult group of disorders. M.R.C. Leukæmia Unit, Royal Postgraduate Medical London W12 0HS
D. CATOVSKY School,
J. M. GOLDMAN D. A. G. GALTON
2. Freireich, E. J., and others. Archs intern. Med. 1976, 136, 1417. 3. Thomas, E. D., Weiden, P. L. Wld J. Surg. 1977, 1, 197. 4. Speck, B., Cornu, P., Nissen, C., Groff, P., Weber, W., Sartorius, J. Paper read at 2nd international symposium on Therapy of Acute Leukæmias, held in Rome, in 1977.
267
"This letter has been shown
to
Dr
RESULT OF PLATELET THERAPY
Gale, whose reply fol-
lows.-ED. L.
SIR,-I should like
to several important points the M.R.C. Leukaemia Unit. 2 of colleagues the long-term survivors had A.L.L. 1 was transplanted after a second relapse. The second failed to achieve an initial remission. Thus, transplantation of less-resistant A.L.L. does not seem a likely explanation of our results. Since our approach was to perform transplants only in patients unresponsive to intensive chemotherapy, those transplanted after a first relapse may have had more resistant dosage than those transplanted after a second or subsequent relapse. The 3 twins fared similarly to the 30 allograft recipients; 1 is a long-term survivor and 2 died, 1 of recurrent leukaemia and 1 of a late interstitial
raised by
our
to
respond
at
pneumonitis (day +224). The question of whether the transplant cohort received more intensive therapy than the non-transplant cohort is not easily answered. Non-transplant patients received maximally tolerated conventional and experimental chemotherapy and the vast majority died of marrow aplasia with and without residual leukaemia. 3 patients who received SCARI without total-body irradiation also failed to achieve a remission and died of marrow aplasia. The 5 long-term survivors reported by Dr Catovsky and his colleagues are of interest. Unfortunately, our experience has been less favourable. As Catovsky et al. point out, the diseasefree survival in the long-term was less than that of the transplant cohort. The object of our study was to determine the feasibility of achieving long-term disease-free survival in "resistant" acute leukaemia using intensive chemoradiotherapy and bone-marrow transplantation. I should like to re-emphasise the experimental nature of this approach. It is noteworthy that resistant leukaemia was responsible for treatment failure in only 24% of patients while immunological problems (graft-versus-host disease and interstitial pneumonitis) accounted for three-quarters of late deaths. Inroads into these immunological problems could significantly improve long-term survival. U.C.L.A. Bone Marrow Transplant Team, Department of Microbiology and Immunology, Center for the Health Sciences, Los Angeles, California 90024, U.S.A.
ROBERT PETER GALE
PLATELET PROPHYLAXIS IN ACUTE NON-LYMPHOBLASTIC LEUKÆMIA many treatment centres, the thrombocytopenia patients with acute leukaemia by induction chemotherapy is routinely managed by the transfusion of platelets when the platelet-count falls below a predetermined level. Since platelets are expensive and often difficult to obtain, we have compared the effect of this routine platelet prophylaxis with the effect of giving platelets for specific indications onlynamely, clinically significant bleeding and a very rapid decline in the platelet-count. Of 31 successive patients, 17 randomly selected patients were given platelet transfusions from random donors whenever the platelet-count was
*K.L.H. in jjtg,
M.T.F.
in
no.
of cells, C. albicans
ter) as dilution. tErythema (E) and induration (1) positive
antigen (C.A.) (Hollis-
if reactions were 5 mm or ’
in diameter. t1 x 108 cells.
more
of 0.2 ml applied to both inguinal regions (0-1 ml K.L.H. plus 0.1ml adjuvant). The mice were injected every 15 days for 2 months and killed 10 days after the last injection. The spleens were separated and the pool of lymphocytes obtained was adjusted to 2x108, 1x108, and 2x107 cells/ml. Lymphocytes were also obtained from non-immunised mice and adjusted to 1x108 cells/ml. The murine transfer factor (M.T.F.) was prepared as for the human material.3 Twenty-one healthy subjects, not sensitised to K.L.H., were injected with M.T.F. The course of test injections is shown in the table; eight individuals who were anergic to Candida albicans were tested with candida antigen (Hollister) as well. Injections of antigen and M.T.F. were simultaneous; saline was given where only K.L.H., candida antigen, or M.T.F. was being given. Diameters of erythema and induration were read at 48 h, a diameter of 5 mm or more being considered positive. The results (see table) show that M.T.F. is active and apparently specific in man, at least for K.L.H. Application of a different antigen from the immunogenic one (i.e., candida) had no effect. M.T.F. doses of at least 1x10* cells seem to be required, and results also seemed to vary with the amount of antigen administered. Should these findings be confirmed the door would be open to possible therapeutic applications since transfer factor for clinical use could be raised in laboratory animals.
Immunology Unit, Laboratorio F. Echevarne,
Barcelona-9, Spain
J. M. VICH J. V. GARCIA-CALDERÓN P. ENGEL P. A. GARCIA-CALDERÓN
SURVIVAL AFTER RELAPSE IN ACUTE MYELOID LEUKÆMIA
SIR,-The U.C.L.A. Bone-marrow Transplantation Team, in their report on the treatment of resistant acute leukaemia by the SCARI chemotherapy/radiotherapy regimen followed by transplantation of allogeneic bone-marrow,’ compared the results with those obtained in an apparently comparable (control) group of patients treated by chemotherapy only. 5 of the 3. Lawrence, H. S. Ad. Immuno. 1969, 11, 229. 1. U.C.L.A. Bone-marrow Transplant Team. Lancet, 1977, ii,
1197.
33 patients who received bone-marrow transplants (B.M.T. group) were in remission 1-2 Zyears later, whereas none of the 37 controls survived longer than 13 months. It is not clear whether the two groups were strictly comparable in two important respects. Firstly, the controls might have had much less intensive therapy than SCARI, a regimen so intensive that the bone-marrow would be unlikely to recover unless a graft were successful. Did the controls receive the most intensive treatment, short of total-body irradiation, that could be safely administered without the support of a marrow graft? Secondly, there were proportionately more acute lymphoblastic leukaemia (A.L.L.) patients (33%) in the B.M.T. group than in the controls (24%); the A.L.L. patients in the control group had all relapsed for the second time, and may well have had more resistant disease than at least 4 of the 11 A.L.L. patients in the B.M.T. group who were in their first relapse. A central feature of the U.C.L.A. results is the survival of 5 patients beyond one year. How many of the 5 had A.L.L. and were any of them treated for their first relapse? This is important because acute myeloid leukaemia (A.M.L.) and A.L.L. are so different in their biology and response to cytotoxic drugs. Could the superior results in the B.M.T. group be accounted for by A.L.L. patients in their first relapse, and by less than maximal chemotherapy in the control group? We would also like to
know how many of the 3 patients who received bone-marrow from identical twins were among the 5 patients who survived more than a year; syngeneic B.M.T. is a far less complex procedure than allogeneic transplantation. In A.M.L.,
prolonged survival after first relapse is uncomhappened in 5 adult patients out of 150 treated
mon, but it has
this unit since 1970. Their mean age was 37; 4 were The duration of the first remission was 6-48 months, and survival after first relapse ranged from 1 to more than 4 years (2 more than 1 year, 2 more than 3 years, 1 more than 4 years). 4 patients are still alive, 2 in complete remission (1 has had no treatment for more than 2 years) and 2 have lately relapsed and been put on re-induction therapy. 3 patients relapsed more than once; 1, with hypergranular promyelocytic leukaemia, died after the third relapse. All 5 received cytarabine or 5-azacytidine, thioguanine, and an anthracycline in various combinations, and the maintenance therapy varied. 1 patient received "late intensification" as recommended by Freireich et al .2 These 5 patients with relapsed A.M.L. have survived at least as long as the U.C.L.A. B.M.T. survivors, and considerably longer than any in the U.C.L.A. controls, although their disease-free survival is not as good as in the U.C.L.A. B.M.T. group. on
women.
The results from Los Angeles,’ Seattleand Basleshow that relapse of acute leukaemia after total-body irradiation and B.M.T., though infrequent, does occur in patients who survive the complications of the procedure. Long survival after first relapse can also be obtained in patients with A.M.L. without recourse to B.M.T. We cannot yet conclude that transplantation of allogeneic bone-marrow, when available, is necessary for the ideal management of all patients with relapsed acute leukaemia. Future studies on the treatment of relapsed acute leukeemia by B.M.T. should include simultaneous control groups of patients treated as vigorously as possible but without B.M.T., and specify the cytological type of the leukaemia in every case. It might then be possible to assess the real value of B.M.T. in the management of this difficult group of disorders. M.R.C. Leukæmia Unit, Royal Postgraduate Medical London W12 0HS
D. CATOVSKY School,
J. M. GOLDMAN D. A. G. GALTON
2. Freireich, E. J., and others. Archs intern. Med. 1976, 136, 1417. 3. Thomas, E. D., Weiden, P. L. Wld J. Surg. 1977, 1, 197. 4. Speck, B., Cornu, P., Nissen, C., Groff, P., Weber, W., Sartorius, J. Paper read at 2nd international symposium on Therapy of Acute Leukæmias, held in Rome, in 1977.
267
"This letter has been shown
to
Dr
RESULT OF PLATELET THERAPY
Gale, whose reply fol-
lows.-ED. L.
SIR,-I should like
to several important points the M.R.C. Leukaemia Unit. 2 of colleagues the long-term survivors had A.L.L. 1 was transplanted after a second relapse. The second failed to achieve an initial remission. Thus, transplantation of less-resistant A.L.L. does not seem a likely explanation of our results. Since our approach was to perform transplants only in patients unresponsive to intensive chemotherapy, those transplanted after a first relapse may have had more resistant dosage than those transplanted after a second or subsequent relapse. The 3 twins fared similarly to the 30 allograft recipients; 1 is a long-term survivor and 2 died, 1 of recurrent leukaemia and 1 of a late interstitial
raised by
our
to
respond
at
pneumonitis (day +224). The question of whether the transplant cohort received more intensive therapy than the non-transplant cohort is not easily answered. Non-transplant patients received maximally tolerated conventional and experimental chemotherapy and the vast majority died of marrow aplasia with and without residual leukaemia. 3 patients who received SCARI without total-body irradiation also failed to achieve a remission and died of marrow aplasia. The 5 long-term survivors reported by Dr Catovsky and his colleagues are of interest. Unfortunately, our experience has been less favourable. As Catovsky et al. point out, the diseasefree survival in the long-term was less than that of the transplant cohort. The object of our study was to determine the feasibility of achieving long-term disease-free survival in "resistant" acute leukaemia using intensive chemoradiotherapy and bone-marrow transplantation. I should like to re-emphasise the experimental nature of this approach. It is noteworthy that resistant leukaemia was responsible for treatment failure in only 24% of patients while immunological problems (graft-versus-host disease and interstitial pneumonitis) accounted for three-quarters of late deaths. Inroads into these immunological problems could significantly improve long-term survival. U.C.L.A. Bone Marrow Transplant Team, Department of Microbiology and Immunology, Center for the Health Sciences, Los Angeles, California 90024, U.S.A.
ROBERT PETER GALE
PLATELET PROPHYLAXIS IN ACUTE NON-LYMPHOBLASTIC LEUKÆMIA many treatment centres, the thrombocytopenia patients with acute leukaemia by induction chemotherapy is routinely managed by the transfusion of platelets when the platelet-count falls below a predetermined level. Since platelets are expensive and often difficult to obtain, we have compared the effect of this routine platelet prophylaxis with the effect of giving platelets for specific indications onlynamely, clinically significant bleeding and a very rapid decline in the platelet-count. Of 31 successive patients, 17 randomly selected patients were given platelet transfusions from random donors whenever the platelet-count was
