Safety of 20Gy Total Marrow Irradiation Based Conditioning Regimen for Hematopoietic Cell Transplantation with T Cell Adoptive Immunotherapy
Authors: Zorutti Francesco , Saldi Simonetta , Ruggeri Loredana , Viglione Valerio , Fulcheri Christian , Sembenico Rebecca , Caridi Matteo , Castaldo Anna , Mancusi Antonella , Zucchetti Claudio , Hui Susanta , Camilli Federico , Zei Tiziana , Iacucci Ostini Roberta , Jardini Enrico Karim , Hoxha Eni , Monaldi Antonella , Stein Anthony S. , Ingrosso Gianluca , Velardi Andrea , Martelli Massimo Fabrizio , Martelli Maria Paola , Aristei Cynthia , Carotti Alessandra , Pierini Antonio 
Published: December 2024

Introduction
Acute leukemia patients with chemorefractory active disease at the time of hematopoietic stem cell transplantation (HSCT) have high-risk of post-transplant relapse and a poor prognosis. Indeed, utility of HSCT has been questioned in this unfavorable subgroup of patients. We recently employed an immune-suppression free transplant platform that combines irradiation-based myeloablative conditioning regimen with regulatory and conventional T cell adoptive immunotherapy (Treg-Tcon HSCT). Such approach showed promising efficacy in patients with detectable disease at transplant (Pierini et al. Blood Advances 2021). In this study TMLI (total marrow and lymphoid irradiation) at the dose of 13,5 Gy in the bone marrow and 11,5 Gy in lymphoid organs has been used in the conditioning regimen in patients &gt;50 years old or unfit for TBI (total body Irradiation). TMLI can be adjusted to deliver doses up to 20 Gy to bone marrow while sparing off-target organs. Dose escalation of TMLI has been tested to reduce post-transplant leukemia relapse in high-risk leukemia patients without increasing organ toxicity (Wong JYC et al. Front Oncol. 2022). Here, we report outcomes of the first 10 patients with active disease at transplant that received 20Gy/11,5Gy TMLI in the conditioning regimen and Treg-Tcon HSCT.
Methods
Since June 2020, 10 patients with active disease at transplant were treated at our center with 20 Gy/11,5 Gy TMLI-based conditioning regimen and Treg-Tcon HSCT. TMLI was delivered in 5 days in 2 daily fractions by Helical Tomotherapy. Target volumes were skeletal bones for TMI (total dose 20 Gy) and major lymph node chains and spleen for TLI (total dose 11.5 Gy). Patients with acute lymphoblastic leukemia (ALL) also received 13.5 Gy to the brain. Chemotherapy (fludarabine, cyclophosphamide, thiotepa) was administered after TMLI and was followed by the infusion of a mega-dose (median 10.85x106/kg) of CD34+ donor progenitor cells, 2x106/kg donor Tregs and 1x106/kg donor Tcons. No post-transplant immune suppression was given.
Results
Patients' median age was 48 years (38-63). Six were affected by acute myeloid leukemia (AML), 3 by ALL, 1 by plasma cell leukemia. Eight patients had more than 5% bone marrow blast at transplant. Two patients (one with co-occurring Hodgkin lymphoma and AML, the other with T-ALL) were transplanted despite extramedullary active disease. Three patients received HLA-matched and 7 HLA-haploidentical Treg-Tcon HSCT. The exposure of individual off-target organs to radiation during TMLI was as it follows: bladder 10.4 ± 1.03 Gy, esophagus 13.88 ± 0.56 Gy, heart 8.47 ± 0.39 Gy, small bowel 7.67 ± 0.43, large bowel 8.94 ± 0.65, kidneys 6.65 ± 0.23 Gy, lens 3.38 ± 0.19 Gy, lungs 10.43 ± 0.23 Gy, oral cavity 7.17 ± 0.45 Gy, parotids 11.41 ± 1.01 Gy, rectum 7.21 ± 0.68 Gy, thyroid 10.14 ± 1.03 Gy. Oral mucositis was grade III in 1 patient, grade II in 7 patients and grade 0-I in 2 patients. Mucositis fully resolved in all of them. All the 10 patients engrafted. None of them was affected by veno-occlusive disease. Grade &gt;= 2 acute graft-versus-host disease (GvHD) occurred in only 1 patient (grade III intestinal) and fully resolved with a 3 months course of steroids and Ruxolitinib. No case of moderate/severe chronic GvHD was observed and no patient died because of non-relapse mortality. One patient with AML with t(3;3) and monosomy 7 relapsed 16 months after transplant and 9 out of 10 patients are alive and disease-free at a median follow up of 30 months (range 23-49).
Conclusions
TMI dose escalation up to 20 Gy is followed by acceptable toxicity that appears comparable to the one observed in historical patients that received 13,5 Gy. Indeed, mucositis was generally manageable, incidence of acute GvHD appears to be low and no life-threatening complications occurred in the 10 patients. No moderate/severe chronic GvHD was observed as previously reported in immune suppression free Treg-Tcon HSCT approach. In this small cohort of very high risk patients, disease control appears promising. To further test efficacy of such approach a phase II clinical study with 20 Gy TMLI-based Treg-Tcon HSCT for acute leukemia patients with detectable disease at transplant has been recently approved and is ongoing at our center.