scholarly journals Total Body Irradiation Forever? Optimising Chemotherapeutic Options for Irradiation-Free Conditioning for Paediatric Acute Lymphoblastic Leukaemia

2021 ◽  
Vol 9 ◽  
Author(s):  
Khalil Ben Hassine ◽  
Madeleine Powys ◽  
Peter Svec ◽  
Miroslava Pozdechova ◽  
Birgitta Versluys ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukaemia ◽  
Lymphoblastic Leukaemia ◽  
Total Body Irradiation ◽  
Alkylating Agents ◽  
Phase Iii ◽  
Therapeutic Window ◽  
Therapeutic Drug ◽  
Hematopoietic Stem ◽  
Early Results ◽  
Total Body

Total-body irradiation (TBI) based conditioning prior to allogeneic hematopoietic stem cell transplantation (HSCT) is generally regarded as the gold-standard for children >4 years of age with acute lymphoblastic leukaemia (ALL). Retrospective studies in the 1990's suggested better survival with irradiation, confirmed in a small randomised, prospective study in the early 2000's. Most recently, this was reconfirmed by the early results of the large, randomised, international, phase III FORUM study published in 2020. But we know survivors will suffer a multitude of long-term sequelae after TBI, including second malignancies, neurocognitive, endocrine and cardiometabolic effects. The drive to avoid TBI directs us to continue optimising irradiation-free, myeloablative conditioning. In chemotherapy-based conditioning, the dominant myeloablative effect is provided by the alkylating agents, most commonly busulfan or treosulfan. Busulfan with cyclophosphamide is a long-established alternative to TBI-based conditioning in ALL patients. Substituting fludarabine for cyclophosphamide reduces toxicity, but may not be as effective, prompting the addition of a third agent, such as thiotepa, melphalan, and now clofarabine. For busulfan, it's wide pharmacokinetic (PK) variability and narrow therapeutic window is well-known, with widespread use of therapeutic drug monitoring (TDM) to individualise dosing and control the cumulative busulfan exposure. The development of first-dose selection algorithms has helped achieve early, accurate busulfan levels within the targeted therapeutic window. In the future, predictive genetic variants, associated with differing busulfan exposures and toxicities, could be employed to further tailor individualised busulfan-based conditioning for ALL patients. Treosulfan-based conditioning leads to comparable outcomes to busulfan-based conditioning in paediatric ALL, without the need for TDM to date. Future PK evaluation and modelling may optimise therapy and improve outcome. More recently, the addition of clofarabine to busulfan/fludarabine has shown encouraging results when compared to TBI-based regimens. The combination shows activity in ALL as well as AML and deserves further evaluation. Like busulfan, optimization of chemotherapy conditioning may be enhanced by understanding not just the PK of clofarabine, fludarabine, treosulfan and other agents, but also the pharmacodynamics and pharmacogenetics, ideally in the context of a single disease such as ALL.

Pulmonary toxicity following total body irradiation for acute lymphoblastic leukaemia: The Ottawa Hospital Cancer Centre (TOHCC) experience

2015 ◽  
Vol 15 (1) ◽  
pp. 54-60
Author(s):  
R. K. Ujaimi ◽  
N. Isfahanian ◽  
D. J. La Russa ◽  
R. Samant ◽  
C. Bredeson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukaemia ◽  
Lymphoblastic Leukaemia ◽  
Total Body Irradiation ◽  
Pulmonary Toxicity ◽  
Conditioning Regimen ◽  
Cancer Centre ◽  
Ottawa Hospital ◽  
Radiation Induced ◽  
Total Body

AbstractPurposeTo review the incidence of clinically significant pulmonary toxicity following total body irradiation (TBI) as a part of the conditioning regimen for acute lymphoblastic leukaemia (ALL) patients undergoing bone marrow transplantation (BMT) at The Ottawa Hospital Cancer Centre.MethodsThis is a retrospective review of ALL patients who received TBI in The Ottawa Hospital Bone Marrow Transplant Program (TOH-BMT) as part of their conditioning regimen from 1991 to 2011 inclusive. The patients were treated using a locally developed translating-couch irradiation technique. We have analysed all available data for the first 100 days following TBI to determine the incidence of radiation-induced pulmonary toxicities.ResultsOf the total 622 patients undergoing TBI during the specified period, 88 had ALL. Median age at BMT was 30 years and the conditioning regimens varied. A total of 74 (84%) patients received 12 Gy/6 F/BID of TBI. A total of 55 (63%) patients have died, 32 (36%) within the 1st year after BMT. In the 1st year, pulmonary events were reported for 24 (27%) patients, and the follow-up notes were unavailable for seven (8%). Pulmonary toxicities were reported as the cause of death for six patients, five (6%) within the 1st year. It is estimated that the total number of deaths in the 1st year possibly attributed to radiation-induced lung injury was four (4·5%). Eight (9%) patients had symptoms suggestive of non-lethal grade 2–3 radiation-induced pneumonitis.ConclusionsTBI continues to be an important component of the conditioning regimen for ALL patients undergoing BMT, and the incidence of radiation-induced pulmonary injury, using our technique and lung dose, is comparable to the published literature.

scholarly journals Total Body Irradiation in Haematopoietic Stem Cell Transplantation for Paediatric Acute Lymphoblastic Leukaemia: Review of the Literature and Future Directions

2021 ◽  
Vol 9 ◽  
Author(s):  
Bianca A. W. Hoeben ◽  
Jeffrey Y. C. Wong ◽  
Lotte S. Fog ◽  
Christoph Losert ◽  
Andrea R. Filippi ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Acute Lymphoblastic Leukaemia ◽  
Lymphoblastic Leukaemia ◽  
Total Body Irradiation ◽  
Haematopoietic Stem Cell Transplantation ◽  
Conditioning Regimen ◽  
Haematopoietic Stem Cell ◽  
Total Body

Total body irradiation (TBI) has been a pivotal component of the conditioning regimen for allogeneic myeloablative haematopoietic stem cell transplantation (HSCT) in very-high-risk acute lymphoblastic leukaemia (ALL) for decades, especially in children and young adults. The myeloablative conditioning regimen has two aims: (1) to eradicate leukaemic cells, and (2) to prevent rejection of the graft through suppression of the recipient's immune system. Radiotherapy has the advantage of achieving an adequate dose effect in sanctuary sites and in areas with poor blood supply. However, radiotherapy is subject to radiobiological trade-offs between ALL cell destruction, immune and haematopoietic stem cell survival, and various adverse effects in normal tissue. To diminish toxicity, a shift from single-fraction to fractionated TBI has taken place. However, HSCT and TBI are still associated with multiple late sequelae, leaving room for improvement. This review discusses the past developments of TBI and considerations for dose, fractionation and dose-rate, as well as issues regarding TBI setup performance, limitations and possibilities for improvement. TBI is typically delivered using conventional irradiation techniques and centres have locally developed heterogeneous treatment methods and ways to achieve reduced doses in several organs. There are, however, limitations in options to shield organs at risk without compromising the anti-leukaemic and immunosuppressive effects of conventional TBI. Technological improvements in radiotherapy planning and delivery with highly conformal TBI or total marrow irradiation (TMI), and total marrow and lymphoid irradiation (TMLI) have opened the way to investigate the potential reduction of radiotherapy-related toxicities without jeopardising efficacy. The demonstration of the superiority of TBI compared with chemotherapy-only conditioning regimens for event-free and overall survival in the randomised For Omitting Radiation Under Majority age (FORUM) trial in children with high-risk ALL makes exploration of the optimal use of TBI delivery mandatory. Standardisation and comprehensive reporting of conventional TBI techniques as well as cooperation between radiotherapy centres may help to increase the ratio between treatment outcomes and toxicity, and future studies must determine potential added benefit of innovative conformal techniques to ultimately improve quality of life for paediatric ALL patients receiving TBI-conditioned HSCT.

scholarly journals Total Body Irradiation or Chemotherapy Conditioning in Childhood ALL: A Multinational, Randomized, Noninferiority Phase III Study

2020 ◽  
pp. JCO.20.02529
Author(s):  
Christina Peters ◽  
Jean-Hugues Dalle ◽  
Franco Locatelli ◽  
Ulrike Poetschger ◽  
Petr Sedlacek ◽  
...  
Keyword(s):  
Total Body Irradiation ◽  
Lymphoblastic Leukemia ◽  
Stopping Rule ◽  
Phase Iii ◽  
Unrelated Donor ◽  
Open Label ◽  
Hematopoietic Stem ◽  
Childhood All ◽  
Total Body

PURPOSE Total body irradiation (TBI) before allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients with acute lymphoblastic leukemia (ALL) is efficacious, but long-term side effects are concerning. We investigated whether preparative combination chemotherapy could replace TBI in such patients. PATIENTS AND METHODS FORUM is a randomized, controlled, open-label, international, multicenter, phase III, noninferiority study. Patients ≤ 18 years at diagnosis, 4-21 years at HSCT, in complete remission pre-HSCT, and with an HLA-compatible related or unrelated donor were randomly assigned to myeloablative conditioning with fractionated 12 Gy TBI and etoposide versus fludarabine, thiotepa, and either busulfan or treosulfan. The noninferiority margin was 8%. With 1,000 patients randomly assigned in 5 years, 2-year minimum follow-up, and one-sided alpha of 5%, 80% power was calculated. A futility stopping rule would halt random assignment if chemoconditioning was significantly inferior to TBI (EudraCT: 2012-003032-22; ClinicalTrials.gov: NCT01949129 ). RESULTS Between April 2013 and December 2018, 543 patients were screened, 417 were randomly assigned, 212 received TBI, and 201 received chemoconditioning. The stopping rule was applied on March 31, 2019. The median follow-up was 2.1 years. In the intention-to-treat population, 2-year overall survival (OS) was significantly higher following TBI (0.91; 95% CI, 0.86 to 0.95; P < .0001) versus chemoconditioning (0.75; 95% CI, 0.67 to 0.81). Two-year cumulative incidence of relapse and treatment-related mortality were 0.12 (95% CI, 0.08 to 0.17; P < .0001) and 0.02 (95% CI, < 0.01 to 0.05; P = .0269) following TBI and 0.33 (95% CI, 0.25 to 0.40) and 0.09 (95% CI, 0.05 to 0.14) following chemoconditioning, respectively. CONCLUSION Improved OS and lower relapse risk were observed following TBI plus etoposide compared with chemoconditioning. We therefore recommend TBI plus etoposide for patients > 4 years old with high-risk ALL undergoing allogeneic HSCT.

scholarly journals Total Body Irradiation for Hematopoietic Stem Cell Transplantation: What Can We Agree on?

2021 ◽  
Vol 28 (1) ◽  
pp. 903-917
Author(s):  
Mitchell Sabloff ◽  
Steven Tisseverasinghe ◽  
Mustafa Ege Babadagli ◽  
Rajiv Samant
Keyword(s):  
Cell Transplantation ◽  
Total Body Irradiation ◽  
Hematopoietic Cell Transplantation ◽  
Conditioning Regimen ◽  
Late Toxicity ◽  
Hepatic Function ◽  
Vascular Supply ◽  
Entire Body ◽  
Hematopoietic Stem ◽  
Total Body

Total body irradiation (TBI), used as part of the conditioning regimen prior to allogeneic and autologous hematopoietic cell transplantation, is the delivery of a relatively homogeneous dose of radiation to the entire body. TBI has a dual role, being cytotoxic and immunosuppressive. This allows it to eliminate disease and create “space” in the marrow while also impairing the immune system from rejecting the foreign donor cells being transplanted. Advantages that TBI may have over chemotherapy alone are that it may achieve greater tumour cytotoxicity and better tissue penetration than chemotherapy as its delivery is independent of vascular supply and physiologic barriers such as renal and hepatic function. Therefore, the so-called “sanctuary” sites such as the central nervous system (CNS), testes, and orbits or other sites with limited blood supply are not off-limits to radiation. Nevertheless, TBI is hampered by challenging logistics of administration, coordination between hematology and radiation oncology departments, increased rates of acute treatment-related morbidity and mortality along with late toxicity to other tissues. Newer technologies and a better understanding of the biology and physics of TBI has allowed the field to develop novel delivery systems which may help to deliver radiation more safely while maintaining its efficacy. However, continued research and collaboration are needed to determine the best approaches for the use of TBI in the future.

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