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Treatment of graft failure after bone marrow transplantation
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Pergamon
Leukemia Research Vol. 18, No. 11, pp. 875 876. 1994. Elsevier Science Ltd Printed in Great Britain (1145-2126/94 $7.00 + 0.00
0145-2126(94)00084-0
LETTER TO THE EDITORS TREATMENT OF GRAFT FAILURE AFTER BONE MARROW TRANSPLANTATION (Received 3 June 1994. Accepted 7 June 1994)
Table 1. Cases of graft failure No. 1 2 3 4 5 6
Disease
Age
Sex
CML CP AML 1st CR AML early relapse 2nd BMT CML CP AML 1st CR NHL leukemic
45 18 40
M M F
45 33 24
F F F
First nadir Day Day Day Day Day Day Day
Engrafted peak
7 (144) 8 (13) 8 (14) 5 (5) 7 (51) 10 (89) 3 (27)
Day Day Day Day Day Day
35 (24,740) 17 (1030) 49 (3530) 56 (9230) 35 (10,400) 17 (1370)
Rejection nadir Day Day Day Day Day Day Day
50 (720) 31 (90) 62 (100) 70 (1120) 118 (340) 20 (800) 43 (230)
Response Day Day Day Day Day Day Day
143 (4520) 131 (3030) 89 (80) 115 (2570) 132 (2180) 37 (4430) 60 (9550)
( ): Count of peripheral blood leukocytes/~d We have treated six patients with graft failure after B M T with IL-lfl and G-CSF. In all these patients full recovery of marrow was obtained as shown in Table 1. Five out of six patients showed transient engraftment with leukocyte count over 1000, which then decreased markedly. They were diagnosed as undergoing rejection. In patient 6 WBC count was 230 even on day 43 after autologous BMT. She was treated under the diagnosis of primary engraftment
failure. All these patients had been treated with GCSF or M-CSF, which had been shown to accelerate hematopoietic recovery after B M T [1-3]. In patient 3 cytokine treatment was started earlier at a leukocyte count of 1120, because it was her second BMT following the failure of the first to engraft. All these patients showed marrow recovery with the cytokine treatment shown in Table 2. We decided to administer IL-lfl which from previous
Table 2. Treatment courses Before rejection Patient 1
Daily G-CSF
Patient 2 Patient 3
Daily G-CSF Daily G-CSF
Patient 4 Patient 5 Patient 6
Daily G-CSF Daily M-CSF Daily G-CSF
Treatment course G-CSF + steroid pulse + donor buffy coat transfusion --~ daily IL-lfi --~ engraftment. G-CSF + GM-CSF + Epo + IL-lfl --~ host marrow recovered G-CSF + M-CSF + IL-1/3 + donor buffy coat transfusion --~ 1st rejection -+ re-transplant ~ 2nd rejection ~ IL-lfl + G-CSF 4 days off 3 days on engraftment IL-lfl --~ engraftment M-CSF + IL-lfl ~ engraftment IL-lfl+ daily G-CSF --~ IL-lfi+ G-CSF 4 days off 3 days on engraftment
* Months from last BMT. 875
Diseasefree survival* 31+ 36+ 2{}+ 5 13+ 11+
876
Letter to the Editors
studies was expected to be effective for marrow failure [4-5]. It was initially administered at a dose of 10,000 U / d a y and elevated to 30,000 U/day. In patients 1, 2, 4 and 5, the addition of IL-lfl resulted in an increase in granulocytes and withdrawal of IL-lfl resulted in a decrease in granulocytes. In patients 3 and 6 the combination of IL-lfl and daily G-CSF showed a downward trend after a transient increase in granulocytes, however the level of granulocytes could be maintained by changing the daily administration of G-CSF to intermittent administration of 4 days off and 3 days on. In all patients cytokines could be tapered off with sustained grafts. Five patients out of 6 are alive disease-free at the end of May 1994. Patient 5 died of interstitial pneumonitis during the fifth month. We consider that the following regimen could prove to be promising for treatment of engraftment failure after BMT. l. IL-lfl daily. 2. Stop G-CSF for 4 days. 3. Re-administer G-CSF intermittently.
References 1. Masaoka T., Takaku F., Kato S., Moriyama Y., Kodera Y., Kanamaru A., Shimosaka A., Shibata H. & Nakamura H. (1989) Recombinant human granulocyte colony-stimulating factor in allogeneic bone marrow transplantation. Expl Hemat. 17, 1047. 2. Schuening G. F., Storb R., Goehle S., Graham Th. C.,
Hackman R., Mori M., Souza L. M. & Appelbaum F. R. (1990) Recombinant human granulocyte colonystimulating factor accelerates hematopoietic recovery after DLA-identical littermate marrow transplantation in dogs. Blood 76, 636. 3. Masaoka T., Shibata H., Ohno R., Katoh S., Harada M., Motoyoshi K., Takaku F. & Sakuma A. (1990) Double-blind test of human urinary macrophage colonystimulating factor for allogeneic and syngeneic bone marrow transplantation: effectiveness of treatment and 2 year follow-up for relapse of leukemia. Br. J. Haemat. 76, 501. 4. Farrar W. L., Mizel S. B. & Farrar J. J. (1980) Participation of lymphocyte activating factor (interleukin-1) in the induction of cytotoxic T-cell responses. J. Immun. 124, 1371. 5. Hermann F., Oster W., Meuer S. C., Lindemann A. & Mertelsmann R. H. (1988) Interleukin-1 stimulates Tlymphocytes to produce granulocyte-macrophage colony-stimulating factor. J. clin. Invest. 81, 1415. Takafumi Yokota Akihiro Tsuboi Yuu Okajima Yusuke Oji Yasuhiro Moriyama Toyoshi Tatekawa Takahiro Karasuno Nobuhiko Tominanga Hirofumi Tejima Akira Hiraoka Hiroyuki Nakamura and Tohru Masaoka Fifth Internal Medicine Center for Adult Diseases 1-3-3 Nakamichi 1-chome higashinari-ku, Osaka 537 Japan
Pergamon
Leukemia Research Vol. 18, No. 11, pp. 875 876. 1994. Elsevier Science Ltd Printed in Great Britain (1145-2126/94 $7.00 + 0.00
0145-2126(94)00084-0
LETTER TO THE EDITORS TREATMENT OF GRAFT FAILURE AFTER BONE MARROW TRANSPLANTATION (Received 3 June 1994. Accepted 7 June 1994)
Table 1. Cases of graft failure No. 1 2 3 4 5 6
Disease
Age
Sex
CML CP AML 1st CR AML early relapse 2nd BMT CML CP AML 1st CR NHL leukemic
45 18 40
M M F
45 33 24
F F F
First nadir Day Day Day Day Day Day Day
Engrafted peak
7 (144) 8 (13) 8 (14) 5 (5) 7 (51) 10 (89) 3 (27)
Day Day Day Day Day Day
35 (24,740) 17 (1030) 49 (3530) 56 (9230) 35 (10,400) 17 (1370)
Rejection nadir Day Day Day Day Day Day Day
50 (720) 31 (90) 62 (100) 70 (1120) 118 (340) 20 (800) 43 (230)
Response Day Day Day Day Day Day Day
143 (4520) 131 (3030) 89 (80) 115 (2570) 132 (2180) 37 (4430) 60 (9550)
( ): Count of peripheral blood leukocytes/~d We have treated six patients with graft failure after B M T with IL-lfl and G-CSF. In all these patients full recovery of marrow was obtained as shown in Table 1. Five out of six patients showed transient engraftment with leukocyte count over 1000, which then decreased markedly. They were diagnosed as undergoing rejection. In patient 6 WBC count was 230 even on day 43 after autologous BMT. She was treated under the diagnosis of primary engraftment
failure. All these patients had been treated with GCSF or M-CSF, which had been shown to accelerate hematopoietic recovery after B M T [1-3]. In patient 3 cytokine treatment was started earlier at a leukocyte count of 1120, because it was her second BMT following the failure of the first to engraft. All these patients showed marrow recovery with the cytokine treatment shown in Table 2. We decided to administer IL-lfl which from previous
Table 2. Treatment courses Before rejection Patient 1
Daily G-CSF
Patient 2 Patient 3
Daily G-CSF Daily G-CSF
Patient 4 Patient 5 Patient 6
Daily G-CSF Daily M-CSF Daily G-CSF
Treatment course G-CSF + steroid pulse + donor buffy coat transfusion --~ daily IL-lfi --~ engraftment. G-CSF + GM-CSF + Epo + IL-lfl --~ host marrow recovered G-CSF + M-CSF + IL-1/3 + donor buffy coat transfusion --~ 1st rejection -+ re-transplant ~ 2nd rejection ~ IL-lfl + G-CSF 4 days off 3 days on engraftment IL-lfl --~ engraftment M-CSF + IL-lfl ~ engraftment IL-lfl+ daily G-CSF --~ IL-lfi+ G-CSF 4 days off 3 days on engraftment
* Months from last BMT. 875
Diseasefree survival* 31+ 36+ 2{}+ 5 13+ 11+
876
Letter to the Editors
studies was expected to be effective for marrow failure [4-5]. It was initially administered at a dose of 10,000 U / d a y and elevated to 30,000 U/day. In patients 1, 2, 4 and 5, the addition of IL-lfl resulted in an increase in granulocytes and withdrawal of IL-lfl resulted in a decrease in granulocytes. In patients 3 and 6 the combination of IL-lfl and daily G-CSF showed a downward trend after a transient increase in granulocytes, however the level of granulocytes could be maintained by changing the daily administration of G-CSF to intermittent administration of 4 days off and 3 days on. In all patients cytokines could be tapered off with sustained grafts. Five patients out of 6 are alive disease-free at the end of May 1994. Patient 5 died of interstitial pneumonitis during the fifth month. We consider that the following regimen could prove to be promising for treatment of engraftment failure after BMT. l. IL-lfl daily. 2. Stop G-CSF for 4 days. 3. Re-administer G-CSF intermittently.
References 1. Masaoka T., Takaku F., Kato S., Moriyama Y., Kodera Y., Kanamaru A., Shimosaka A., Shibata H. & Nakamura H. (1989) Recombinant human granulocyte colony-stimulating factor in allogeneic bone marrow transplantation. Expl Hemat. 17, 1047. 2. Schuening G. F., Storb R., Goehle S., Graham Th. C.,
Hackman R., Mori M., Souza L. M. & Appelbaum F. R. (1990) Recombinant human granulocyte colonystimulating factor accelerates hematopoietic recovery after DLA-identical littermate marrow transplantation in dogs. Blood 76, 636. 3. Masaoka T., Shibata H., Ohno R., Katoh S., Harada M., Motoyoshi K., Takaku F. & Sakuma A. (1990) Double-blind test of human urinary macrophage colonystimulating factor for allogeneic and syngeneic bone marrow transplantation: effectiveness of treatment and 2 year follow-up for relapse of leukemia. Br. J. Haemat. 76, 501. 4. Farrar W. L., Mizel S. B. & Farrar J. J. (1980) Participation of lymphocyte activating factor (interleukin-1) in the induction of cytotoxic T-cell responses. J. Immun. 124, 1371. 5. Hermann F., Oster W., Meuer S. C., Lindemann A. & Mertelsmann R. H. (1988) Interleukin-1 stimulates Tlymphocytes to produce granulocyte-macrophage colony-stimulating factor. J. clin. Invest. 81, 1415. Takafumi Yokota Akihiro Tsuboi Yuu Okajima Yusuke Oji Yasuhiro Moriyama Toyoshi Tatekawa Takahiro Karasuno Nobuhiko Tominanga Hirofumi Tejima Akira Hiraoka Hiroyuki Nakamura and Tohru Masaoka Fifth Internal Medicine Center for Adult Diseases 1-3-3 Nakamichi 1-chome higashinari-ku, Osaka 537 Japan