1,~. J Radrnrron Oncology Bml. Phys Prinled I” the lJ.S.A All rights reserved.

Vol.20,

pp. U-634

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I

??Editorial

WHAT

DOES TOTAL BODY IRRADIATION DO IN BONE MARROW TRANSPLANTS FOR LEUKEMIA?

ROBERT PETER GALE,’ ANNA BUTTURINI~ AND MORTIMER

M. BORTIN~

‘Department of Medicine, Division of Hematology-Oncology, UCLA School of Medicine, Los Angeles, CA 90024- 1678 USA; 2Department of Pediatrics, Division of Hematology and Oncology, University of Parma, Parma 43 100, Italy; and 3Statistical Center, International Bone Marrow Transplant Registry, Milwaukee, WI 53226 USA Almost

transplants have been per20,000 bone marrow formed in persons with leukemia since 1970 (4). Most received some form of total body irradiation as pre-transplant conditioning. In this editorial, we consider its role in transplants. There are three objectives of total body irradiation in bone marrow transplants in leukemia: provide adequate immune suppression to prevent rejection of donor hematopoietic stem cells, provide physical space for stem cells to engraft, and to eradicate leukemia cells. Few studies use radiation alone, so our comments refer predominately to persons receiving radiation with one or several myelosuppressive or immune suppressive drugs. Total body irradiation is an effective form of immune suppression. Doses of 8-l 5 Gy at dose-rates of OS-100 cGy/min in one or several fractions result in sustained engraftment in more than 98% of recipients of HLAidentical related transplants for leukemia (reviewed in 2, 20) and about 80-90% of recipients of HLA non-identical related or HLA-identical unrelated transplants (reviewed in 1, 3). Sometimes additional radiation was given, such as total lymphoid or spleen fields. No convincing data indicate that these increase the likelihood of engraftment. Although graft-failure (probably rejection) rates are low following total body radiation, it should not be assumed that radiation is the sole effective factor. As indicated, most recipients also receive immune suppressive drugs pre- and post-transplant such as cyclophosphamide and cyclosporine. Also, since graft failure is increased substantially following T-cell depleted transplants, T-cells in

the graft are presumably active in preventing rejection (10, 26). This adverse effect of T-cell depletion can be overcome by increasing radiation dose or dose-rate or by adding additional immune suppressive drugs (2 1, 29). It is also evident that residual recipient immune competent cells survive even the highest doses of radiation (13). For example, small numbers of blood cells of recipient origin are detected in lo-50% of transplant recipients following total body irradiation of 8- 15 Gy (25, 28). Persistence of recipient cells is not correlated with graft rejection. In summary, although total body irradiation is important in achieving long-term hematopoietic chimerism, other factors, like donor T-cells and post-transplant immune suppression, are important. Also, many transplant recipients are mixed chimeras of donor and recipient hematopoietic cells. These observations are of considerable import since they imply that it may not be necessary to eradicate recipient hematopoiesis (and presumably immunity) to achieve stable engraftment. Thus, from the perspective of immune suppression, it might be possible to decrease doses or dose-rates of total body irradiation. In some instances, such as untransfused persons with aplastic anemia, long-term engraftment is achievable in a high proportion of cases without use of radiation (15, 30). In leukemia, non-radiation containing regimens like busulfan and cyclophosphamide can achieve stable chimerism (15, 27, 30, 34). The second objective of total body irradiation is to provide space for donor stem cells to engraft. The need for space is well documented in animal models (35). This is

Reprint requests to: Robert Peter Gale, M.D. Ph.D., Division of Hematology-Oncology, Department of Medicine, UCLA School of Medicine, Los Angeles, CA 90024- 1678, USA. Acknowledgements-We thank Emanuel Maidenberg for technical assistance and Katharine Fry for typing the manuscript. Supported in part by grant CA23175 from the NCI, NIH, USPHS, DHHS; the Center for Advanced Studies in Leukemia; grant CA 40053 from the NCI, DHHS; contracts NOl-AI-62530 from the National Institute of Allergy and Infectious Diseases,

DHHS; B16-084-US from the Commission of European Communities; and grants from the Burroughs-Wellcome Foundation, Cutter Biologicals, Ambrose Monell Foundation, Elsa U. Pardee Foundation, RGK Foundation, Sandoz Research Institute, Joan and Jack Stein, the Swiss Cancer League, and Xoma Corporation. Robert Peter Gale is the Wald Foundation Scholar in Biomedical Communications. Accepted for publication 29 March 1990.

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readily accomplished in humans using total body irradiation doses greater than 5 Gy. The third objective of total body irradiation in bone marrow transplants for leukemia is to decrease or eradicate leukemia cells. Its use is based on several observations such as the radiation sensitivity of normal hematopoietic cells and leukemia cells in rilro. and similarities in the presumed mode of action of radiation and anti-leukemia drugs, particularly alkylating drugs. Also, radiation is effective in eradicating subclinical and clinically evident meningeal leukemia in persons with acute leukemia. However, it is worth noting that, save for chronic myelogenous leukemia and Burkitt lymphoma, alkylating drugs play a relatively minor role in leukemia treatment. Many different conditioning regimens are used in transplants for leukemia. Few persons received total body irradiation alone without anti-leukemia drugs (33). Although the relapse rate was high, several relapses were believed to be in donor cells. Consequently, it is not possible to calculate accurately the actuarial relapse rate associated with total body irradiation alone. Other conditioning regimens combine total body irradiation with various drugs singly or in combination, most commonly cyclophosphamide (for reviews see 2.20.22). Despite numerous reports of improved results, there are no convincing data that any of these regimens is superior to another or to total body irradiation alone. There are several ways to determine the anti-leukemia efficacy of total body radiation (combined with drugs). Since allogeneic bone marrow transplantation is associated with a substantial immune mediated anti-leukemia effect (termed graft-versus-leukemia or GvL). it is necessary to examine situations in which GvL reactions do not occur: examples include recipients of transplants from twins (syngeneic), recipients of allogeneic transplants without graft-versus-host disease (GvHD). recipients of T-cell depleted allografts, and autotransplant recipients (8, 9, 16, 17, 23, 3 1). We discuss several of these briefly by disease category and remission status. Bone marrow transplants in AML in first remission are associated with a low relapse rate, about 20% ( 16, 17,20). One might assume from this that total body irradiation is an effective anti-leukemia treatment. However, this notion is challenged by several observations. For example, twin transplants have a 50-60% relapse rate in this setting despite receiving comparable doses of total body irradiation (8, 23). In fact, the outcome of bone marrow transplants in twins with AML in first remission is probably not too different than chemotherapy alone without a transplant (9). Another point is that persons without GvHD and those receiving T-cell depleted transplants have an increased risk of leukemia relapse despite receiving similar total body irradiation and chemotherapy (8, 9, 23, 3 1). Finally, there is an extremely high relapse rate in autotransplant recipients-about 60% (reviewed in 18). This figure is similar to twin transplants and suggests that

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persistence of leukemia in the recipient (and not in the infused bone marrow) causes most (?all) relapses. Taken together, these data suggest that total body irradiation has only a partial role in eradicating leukemia in AML in first remission. One randomized trial compared different radiation schedules and doses (12 Gy in 6, 2 Gy fractions or 15.75 Gy in 7. 2.25 Gy fractions) reported different actuarial relapse rates, 64% versus 14% in 23 and 25 subjects, respectively (6). If correct. this implies that radiation is effective. However, the most impressive aspect of this study is the high relapse rate in the 12 Gy group rather than fewer relapses in the experimental group. For example. data from the International Bone Marrow Transplant Registry (IBMTR) in 201 comparable subjects receiving a similar radiation dose and schedule had a 24 ? 7 percent (95% confidence interval) probability of relapse. The most likely explanation of differences in the randomized trial is that it is not possible in these small studies to match the groups for factors influencing the risk of leukemia relapse like WBC. GvHD, and possibly leukemia subtype (20). Alternatively. the difference between this study and the IBMTR data may reflect the type of post-transplant immune suppression given. If so, this underscores the importance of factors other than radiation in eradicating leukemia. Another study that compared 10 Gy in a single fraction to I2 Gy in six fractions also showed more relapses in the 10 Gy cohort (7). Again this seems related to a higher than anticipated relapse rate in this group. Comparable data from the IBMTR indicate relapse rates of 24 + 7%) versus 23 + 8%,, respectively, in 487 subjects. Our notion that total body irradiation plays little if any role in leukemia eradication in AML is further supported by the observation that the anti-leukemia effect of bone marrow transplantation is independent of disease status, that is. risk adjusted leukemia relapse rates are similar for first remission, advanced leukemia, and persons never achieving remission (19). This situation would be unlikely if total body irradiation had a definite anti-leukemia effect in AML. The observation that results of transplants in AML in second remission or advanced disease are superior to chemotherapy can be explained by immune-mediated anti-leukemia effects rather than highdose radiation since the relapse rate in twins is very high. What of ALL? Here. the situation seems similar. Presently, there are no convincing data that bone marrow transplants are superior to chemotherapy in ALL except perhaps in adults in second remission. children in second remission in whom the initial remission was brief, and in adults and children with more advanced disease (2, 12. 17 ). However. most of this superior anti-leukemia effect seems to be associated with immune mechanisms like GvHD. Persons without GvHD and recipients of T-cell depleted transplants have high relapse rates (23). Autotransplants in ALL have very high relapse rates (18). In one study, use of hyperfractionated radiation was claimed to reduce relapse in children with ALL in second remission

TBI in bone marrow transplants 0 il. P. GALE

(5). This was not a randomized trial: some group sizes were small and there were other modifications such as giving cyclophosphamide post- rather than pre-radiation. Finally, let us examine the situation in CML. Here, non-T-cell depleted allogeneic transplants in chronic phase are associated with few relapses, less than 5% (22, 32). One might assume from these data that total body radiation is particularly effective in eradicating CML. However, the relapse rate rises substantially in persons without GvHD ( 1 l%), in T-cell depleted transplants (5070%) and in twin transplants (40-70%) (23). These data are superior to those achieved with chemotherapy, where all persons at risk die of leukemia, and suggest a 30-60% cure rate with high-dose radiation and chemotherapy. However, even in this setting it is not possible to know if total body radiation played any direct role in eliminating the leukemia, since similar results are achievable when high-dose busulfan is used instead of radiation (34). Autotransplants in CML almost always result in relapse ( I 1, 14). When there is an informative genetic marker, it seems that recurrence arises from persisting leukemia in the recipient rather than the reinfused bone marrow. One randomized trial of allograft transplants compared 12 versus 15.75 Gy total body radiation (6) (schedule as discussed). Leukemia relapse’rates were significantly different (24 vs. 0% in 38 and 40 subjects, respectively). However. again the difference seems to result from a high relapse rate in the 12 Gy cohort since data from the IBMTR in 135 comparable subjects indicate a relapse rate of only 3 + 5 percent. The data we review challenge the dogma that total body radiation is a very effective anti-leukemia modality. We do not question that it can rapidly decrease levels of leukemia cells. However, it seems unlikely that it cures many cases of leukemia not already cured by chemotherapy alone. The sole exception may be CML, but even here. superiority over conventional treatment cannot be definitively attributed to radiation. There is one situation in which total body radiation seems to be important in eradicating leukemia-T-cell depleted transplants. For example, both dose and fractionation (but not dose rate) affect the risk of relapse of

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T-cell depleted transplants (2 1). Again, it is not possible to know if this is a direct anti-leukemia effect of total body irradiation or whether radiation reduces leukemia cells to a level at which immune factors are effective. A similar argument applies to all modalities that cure leukemia. not only radiation. What, then, is the role of total body irradiation in bone marrow transplantation for leukemia? We see two functions. One is to allow engraftment of allogeneic bone marrow and immune cells derived from the graft. The latter is the basis of the GvL reaction, an important factor contributing to the effectiveness of bone marrow transplantation. The second role of total body irradiation is probably to reduce rather than eradicate leukemia cells. This is probably a requisite for other factors, such as GvL, to be effective. Our conclusions explain why rather different total body irradiation protocols involving a wide range of doses, doserates. and schedules may produce similar results. They also explain why some conditioning regimens without total body irradiation produce equivalent results. How can results of total body irradiation be improved? Until now, the major objective was to increase dose. Based on the data we present, we feel this may not always be desirable. For example, if recipient immune cells are not completely eliminated even with the highest doses oftotal body irradiation and if there is no correlation of this with graft-failure or relapse, why not decrease the dose of total body irradiation? Another direction is to study more carefully combinations of anti-leukemia drugs and total body irradiation so as to achieve a sufficient level of leukemia eradication for cure by GvL to be effective. This notion may explain why some total body irradiation schedules of less than 8 Gy given with drugs have no more relapses than higher doses (even doses up to 15 Gy) (24). We are bzlllislz on total body irradiation. We think it is a very effective immune suppressive agent and a good way to reduce levels of leukemia cells. However, it is time to consider that total body radiation may operate by mechanisms other than what is normally believed and that more is not always better. A careful re-examination is in order.

REFERENCES 1. Ash, R.: Horowitz, M. M.; Gale, R. P., et al. Outcome of allogeneic bone marrow transplantation from related donors other than HLA-identical siblings. Ann. Intern. Med. (In press). 2. Barrett. A. J.; Horowitz, M. M.: Gale, R. P.; Biggs, J. C.; Blume, K. G.; Camitta, B. M.; Dicke, K. A.; Gluckman, E.; Good, R. A.; Herzig, R. H.; Lee. M. B.; Marrnont, A. L.; Masaoka, T.: Ramsay, N. K. C.; Rimm. A. A.; Speck, B.; Zwaan. F. E.: Bortin, M. M. Marrow transplantation for acute lymphoblastic leukemia: factors affecting relapse and survival. Blood 74:862-87 I: 1989. 3. Beatty. P. G.; Di Bat-tolomeo, P.; Storb, R.; Clift. R. A.; Buckner, C. D.; Sullivan, K. M.; Doney. K.; Appelbaum,

F. R.; Anasetti, C.: Witherspoon. R.; Ciancarelli, M.; Hansen, J. A.; Thomas, E. D. Treatment of aplastic anemia with marrow grafts from donors other than HLA-genotypicallymatched siblings. Clin. Transplant. I : 117- 124; 1987. 4. Bortin, M. M.; Rimm, A. A. Increasing utilization of bone marrow transplantation: Results of 1985-1987 survey. Transplantation 48:453-458; 1989. 5. Brochstein, J. A.: Kernan, N. A.: Groshen, S.; Cinincione, C.; Shank, B.; Emanuel, D.: Laver, J.; O’Reilly, R. J. Allogeneic marrow transplantation after hyperfractionated total body irradiation and cyclophosphamide in children with acute leukemia. N. Engl. J. Med. 317: 1618; 1987. 6. Buckner, C. D.: Clift, R. A.; Appelbaum. F. R.; Storb, R.:

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What does total body irradiation do in bone marrow transplants for leukemia?

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