Bone Marrow Transplantation (2011) 46, 475–484 & 2011 Macmillan Publishers Limited All rights reserved 0268-3369/11 www.nature.com/bmt REVIEW TBI during BM and SCT: review of the past, discussion of the present and consideration of future directions CE Hill-Kayser, JP Plastaras, Z Tochner and E Glatstein Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA TBIhasbeenusedwidelyinthesettingofBMToverthe described survivors of accidental irradiation who received past 3 decades. Early research demonstrated feasibility matched marrow infusions.7 Clinical and animal research and efficacy in the myeloablative setting, in preparation continued over the next decade, in parallel with the first for allogenic BMT and later for autologous stem cell development of clinical measures to support patients with rescue. As experience with TBI increased, its dual roles of decreased marrow function: these included antibiotic and myeloablation and immunosuppression came to be recog- antifungal agents, parenteral nutrition and blood transfusion nized. Toxicity associated with myeloablative TBI remains technology that prolonged survival during the acute pretrans- significant, and this treatment is generally reserved for plant and post transplant phases of treatment. In the 1970s, younger patients with excellent performance status. Reduced several groups demonstrated strong clinical results in leukemic intensity conditioning regimens may be useful to provide patients receiving allogeneic BMT following chemoradiation8– immunosuppression for patients who are not candidates for 11 (Table 1). At this time, BMT were limited to patients with a myeloablative treatment. Efforts to reduce toxicity through sibling or related donor found to be histocompatible based on protection of normal tissue using methods of normal tissue human leukocyte antigen (HLA) typing. blocking and use of TLI, rather than TBI, continue. In the As survival rates after hematological malignancies future, modalities such as helical tomotherapy, proton radio- increased with use of BMT, attention turned to methods therapy and radioimmunotherapy, may have roles in delivery of reducing toxicity and expanding potential therapeutic of radiation to the BM and lymphoid structures with reduced value. Single, large-fraction treatment was associated with normal tissue toxicity. With further investigation, these death due to toxicity, most notably pneumonitis.12 Several efforts may expand the therapeutic ratio associated with TBI, groups reported on methods of reduction of risk of lung allowing safer delivery to a broader range of patients. toxicity, including fractionated treatment and use of lung- Bone Marrow Transplantation (2011) 46, 475–484; blocking devices. Unrelated donor transplants were under- doi:10.1038/bmt.2010.280; published online 29 November 2010 taken for patients without matched, related donors. Keywords: TBI; autologous stem cell rescue; reduced Finally, largely to address problems identifying donors, as intensity conditioning; TLI; TRM well as higher side-effect profiles for patients receiving unrelated donor marrow, research in the 1980s led to development of autologous SCT techniques. These allowed patients to receive their own stem cells with no concern for immunocompatibility13–16 (Table 1). Introduction and historical perspective Understanding of the extremely important role of BMT in treatment of potentially fatal conditions culminated in Interest in the use of radiation as part of BMT arose in the receipt of the 1990 Nobel Prize in Physiology and Medicine mid-twentieth century. With the use of radioactive substances by Dr E Donnell Thomas for his work on ‘Organ and Cell came the recognition that death from exposure to low-dose Transplantation in the Treatment of Human Disease.’ The TBI was commonly due to marrow failure. Animal studies use of TBI as a part of conditioning regimens for this type subsequently demonstrated the potential role of hematological of treatment continues in the modern era, and appears to 1–5 infusions as rescue therapy after BM damage or eradication. provide benefit over conditioning with chemotherapy alone The first examples of humans surviving supralethal TBI in the in many settings17–20 (Table 1). Although huge amounts of setting of leukemia with the use of BM infusion and grafting progress have been made with regard to optimal BMT 6 were published in 1965. During the same year, other groups methods in the past 50 years, myriad questions regarding technique and outcome remain. Correspondence: Dr CE Hill-Kayser, Department of Radiation Onco- logy, University of Pennsylvania School of Medicine, 3400 Spruce Street, Goals of TBI 2 Donner, Philadelphia, PA 19146, USA. E-mail: [email protected] Received and accepted 6 October 2010; published online 29 November TBI may be given as a part of BMT with therapeutic goals 2010 that are single or multifold. The first uses of TBI were with TBI in BMT CE Hill-Kayser et al 476 Table 1 Influential studies examining the role of TBI in BMT Study lead author No. of Population type Comment and year of patients publication Early human studies Mathe´et al.6 10 ALL Described regimen of 8 Gy TBI delivered in 2 fractions with allogeneic marrow transplantation; 3/10 patients experienced CR. 7/10 died within 30 days of BMT. Andrews et al.7 5 Accidental exposure Described survivors of accidental irradiation after treatment with allogeneic marrow infusion Benefit of TBI in the allogenic BMT setting Thomas et al.9 100 AML/ALL Examined 100 patients surviving advanced leukemia treated with TBI and BMT, and demonstrated that patient condition at the time of BMT influenced outcomes. Thomas et al.10 19 ANLL Described improved outcomes in AML after first remission, using HLA-matched donors. Demonstrated importance of low-leukemic cell burden, patient clinical condition and HLA-matching. Thomas et al.11 22 ALL Demonstrated improved outcomes in patients undergoing BMT in remission compared with those in relapse. Recommended BMT before terminal relapse for patients with HLA-identical sibling donors. Ringde´n et al.17 1060 ALL/AML Retrospective comparison of patients treated with Bu/Cy vs TBI/Cy BMT regimens; demonstrated improved outcomes with TBI in ALL patients only. Davies et al.18 627 Pediatric ALL Demonstrated improved survival for children with ALL treated with TBI/Cy vs Bu/Cy for HLA-identical allogenic BMT. Kro¨ger et al.19 50 CML Demonstrated similar antitumor efficacy of Bu/Cy and TBI/Cy regimens for unrelated BMT, but showed higher incidence of liver and bladder toxicity with Bu/Cy. Shi-Xia et al20 3172 Leukemia Meta-analysis demonstrating improved DFS with TBI/Cy over Bu/Cy in ALL and AML. Lower TRM was seen in all groups with TBI/Cy compared with Bu/Cy. Benefit of TBI in the autologous BMT setting Ravindranath 232 Pediatric AML Demonstrated lower relapse rate after autologous BMT with TBI compared with intensive et al.13 consolidation chemotherapy in childhood AML. TRM was increased in BMT group. Vaidya et al.14 31 Pediatric ALL Long-term follow-up of childhood ALL patients in second remission treated with autologous BMT with TBI, in absence of matched sibling donor. Demonstrated improved survival compared with historic controls after relapsed ALL. Dusenberry 35 AML Demonstrated improved outcomes with TBI/Cy over Bu/Cy for patients with relapsed AML et al.15 undergoing autologous BMT. Toxicity reduction: fractionation and dose-rate Altschuler et al.21 108 ALL Demonstration of low risk of pneumonitis with fractionated TBI (11 Gy in 5 fractions) Kim et al.24 22 ALL/AML/CML Demonstrated increased death from pneumonitis with higher dose rate TBI. Shank et al.28 76 ALL/ANLL Demonstrated reduced incidence of pneumonitis (18 vs 50%) with 13.2 Gy in 11 fractions compared with 10 Gy in a single fraction. Thomas et al.29 53 ANLL Demonstrated survival advantage after 12 Gy in 6 fractions compared with 10 Gy in 1 fraction Reduced-intensity conditioning regimens Giralt et al.35 15 AML/MDS Demonstrated feasibility of RIC regimens in patients ineligible for myelablative regimens. McSweeney 45 450 years, various Demonstrated usefulness of graft vs tumor effect in patients not eligible for myeloablative et al.36 malignancies therapy; utilized mycophenolate mofetil for GVHD prophylaxis Sorror et al.37 144 Various malignancies Retrospective analysis demonstrating decreased incidence of grade III–IV toxicities in patients undergoing RIC vs myeloablative therapy. Higher pretransplant comorbidity scores were correlated with increased toxicity and mortality. Mielcarek et al.38 96 Various malignancies Retrospective analysis demonstrating decreased acute GVHD after RIC vs myeloablative regimens, but described association of RIC with ‘late-onset GVHD.’ Baron et al.39 322 Various malignancies Showed potential improved graft vs tumor outcomes in patients with chronic GVHD after RIC, which was not apparent in association with acute GVHD. Kahl et al.40 834 Various malignancies Described improved outcomes after RIC for patients with low-grade disease (CLL, MM, NHL) compared with those with advanced myeloid/lymphoid disease. Baron et al.41 21 CML Demonstrated concern for increased risk of graft rejection in CML. Marks et al.42 1521 ALL Demonstrated higher relapse but similar age-adjusted survival in ALL patients treated with RIC vs myeloablative regimens. Underscored importance of PS and age in decisions regarding TBI regimen. Abbreviations: ANLL ¼ acute nonlymphoblastic leukemia; Bu/Cy ¼ busulfan/cytoxan; DFS