Total body irradiation-based myeloablative conditioning for acute lymphoblastic leukaemia patients undergoing allogeneic haematopoietic stem cell transplantation: the best way to prevent relapse in a real-world scenario

To the Editor,

For patients affected by Philadelphia chromosome-negative (PH−) acute lymphoblastic leukaemia (ALL) with diagnostic high-risk (HR) features and for those with minimal residual disease (MRD) persistency during paediatric-inspired therapeutic approaches, the best outcome success depends on the subsequent allogeneic haematopoietic stem cell transplantation (allo-HSCT), ¹ while in PH+ ALL-patients, the benefit from allo-HSCT seems doubtful in case of MRD negativity. ² For what concern the optimal conditioning regimen, the total body irradiation (TBI)-driven efficiency benefit has been not clearly demonstrated when allo-HSCT was performed in ALL-patients with diagnostic standard-risk features and in first complete remission (CR1) using lower than 12 Gy-TBI dose. ³ It was also recently reported that high-dose TBI (12 Gy) was associated with better survival and lower relapse rate if compared with busulfan-based conditioning regimen. ⁴ However, the latter evidence^3,4 comes from two large prospective randomized clinical trials with different study populations (adult ALL-patients allotransplanted in CR1 ³ and paediatric ALL-patients allotransplanted not only in CR1 ⁴ ). Therefore, in a real-world scenario, we retrospectively collected data from allotransplanted ALL-patients comparing those who performed a high dose (i.e. 12 Gy) TBI-based allo-HSCT, with those who underwent a TBI-free myeloablative conditioning to investigate the TBI-impact on adult ALL allotransplanted patients’ outcomes.

Post-allotransplantation outcomes have been reported in Table 1. The patient characteristics and Cox-regression analyses of factors with impact on overall survival (OS), relapse and transplant-related mortality (TRM) have been detailed in Supplemental Table S1 and S2, respectively. See also Supplemental Materials for details about myeloablative conditioning regimens and Statistics.

Table 1.

Post-allotransplant outcomes in ALL-patients according to complete remission (1 vs ⩾2) at transplant.

Study population	No. patients	5-Year OS (%)			5-Year CIR (%)			1-Year TRM (%)
		CR1	CR ⩾ 2	p	CR1	CR ⩾ 2	p	CR1	CR ⩾ 2	p
Whole group	60	55	32	0.006	34	70	0.025	11	19	ns
TBI-based	26	57	41	0.097	12	52	0.036	13	9	ns
Bu-based	34	39	30	ns	47	80	0.005	9	23	ns

ALL, acute lymphoblastic leukaemia; Bu, busulfan; CIR, cumulative incidence of relapse; CR1, first complete remission; CR⩾2, second or subsequent CR; OS, overall survival; TBI, total body irradiation; TRM, transplant-related mortality.

Bold values denote statistical significance at the p<0.05 level.

As already reported, ⁵ in our study population the OS lack of benefit by TBI doesn’t seem due to the excess of TRM (Supplemental Table S2), but to the consistent number of subsequent to second CR-patients at allotransplant (18%). In fact, when analysing only TBI-based allotransplants, CR1 showed a trend in favour of better OS-outcome (5-year OS: 57% (CR1) vs 41% (CR⩾2), Table 1) thus confirming the exclusive OS-benefit from CR1 when the conditioning regimen was a TBI-based one. As expected, ⁶ in multivariate analysis, relapse-risk was lower in patients undergoing TBI-based approach (HR = 0.349, Supplemental Table S2). Of note, in our study population, TBI-based conditioning regimen was TBI-Cy in 100% of the cases; consequently, in accordance with recently published data reporting a protective effect against relapse by TBI-Cy, ⁷ the prevalent TBI-impact on relapse (rather than on OS) was expected. The contribution of TBI on cumulative incidence of relapse (CIR) seemed to equal the CR1 achievement before allotransplant, being the 5-year CIR 47% (in CR1) and 52% (in CR ⩾ 2) in non-TBI and in TBI-based conditioning regimen (Table 1), respectively, Therefore, our data confirm that CR1 hierarchically remains the treatment goal to impact OS, while TBI appears crucial to maximize the prevention of relapse (5-year CIR rate of 12%) in a real-world scenario.

However, we must recognize that the flow cytometry-MRD negativity CR1 achievement (47% of our transplants, see Supplemental Materials) at the time of allotransplant inevitably could have impacted the choice to or not to transplant those ALL-patients if they had been followed according to an MRD-driven curative strategy (i.e. not HR patients by diagnostic features). ¹ In fact, the sequential chemo-immune antineoplastic approach has demonstrated the most promising outcomes in MRD persistency, ⁸ paving the way to a long-term survival even without allo-HSCT^8,9 for MRD negative ALL-patients without adverse diagnostic features. ¹ On the other hand, the crucial role of TBI-based myeloablative conditioning in CR1 remains ¹⁰ thus suggesting how the choice to adopt a TBI-sparing approach in curing ALL-patients should depend on a careful evaluation of the balance between TRM and relapse-risk.

Supplemental Material

sj-docx-1-tah-10.1177_20406207251314612 – Supplemental material for Total body irradiation-based myeloablative conditioning for acute lymphoblastic leukaemia patients undergoing allogeneic haematopoietic stem cell transplantation: the best way to prevent relapse in a real-world scenario

Supplemental material, sj-docx-1-tah-10.1177_20406207251314612 for Total body irradiation-based myeloablative conditioning for acute lymphoblastic leukaemia patients undergoing allogeneic haematopoietic stem cell transplantation: the best way to prevent relapse in a real-world scenario by Mario Delia, Vito Pier Gagliardi, Francesco Tarantini, Corinne Contento, Daniela Di Gennaro, Olga Battisti, Camilla Presicce, Immacolata Attolico, Paola Carluccio, Francesco Albano and Pellegrino Musto in Therapeutic Advances in Hematology

Supplemental Material

sj-docx-2-tah-10.1177_20406207251314612 – Supplemental material for Total body irradiation-based myeloablative conditioning for acute lymphoblastic leukaemia patients undergoing allogeneic haematopoietic stem cell transplantation: the best way to prevent relapse in a real-world scenario

Supplemental material, sj-docx-2-tah-10.1177_20406207251314612 for Total body irradiation-based myeloablative conditioning for acute lymphoblastic leukaemia patients undergoing allogeneic haematopoietic stem cell transplantation: the best way to prevent relapse in a real-world scenario by Mario Delia, Vito Pier Gagliardi, Francesco Tarantini, Corinne Contento, Daniela Di Gennaro, Olga Battisti, Camilla Presicce, Immacolata Attolico, Paola Carluccio, Francesco Albano and Pellegrino Musto in Therapeutic Advances in Hematology

Supplemental Material

sj-docx-3-tah-10.1177_20406207251314612 – Supplemental material for Total body irradiation-based myeloablative conditioning for acute lymphoblastic leukaemia patients undergoing allogeneic haematopoietic stem cell transplantation: the best way to prevent relapse in a real-world scenario

Supplemental material, sj-docx-3-tah-10.1177_20406207251314612 for Total body irradiation-based myeloablative conditioning for acute lymphoblastic leukaemia patients undergoing allogeneic haematopoietic stem cell transplantation: the best way to prevent relapse in a real-world scenario by Mario Delia, Vito Pier Gagliardi, Francesco Tarantini, Corinne Contento, Daniela Di Gennaro, Olga Battisti, Camilla Presicce, Immacolata Attolico, Paola Carluccio, Francesco Albano and Pellegrino Musto in Therapeutic Advances in Hematology