Total marrow and lymphoid irradiation as conditioning in haploidentical transplant with posttransplant cyclophosphamide

Abstract

Posttransplant cyclophosphamide (PTCy) platform has shown low rates of graft-versus-host disease (GVHD) and nonrelapse mortality (NRM) after haploidentical hematopoietic cell transplantation (HaploHCT). However, because of the limited disease control, relapse rate remains a major cause of treatment failure in high-risk patients. Total marrow and lymphoid irradiation (TMLI) allows for delivery of high radiation to bone marrow and other targeted structures, without increasing off-target radiation exposure and toxicity to end organs. In this phase 1 trial, 31 patients with high-risk and/or active primary refractory leukemias or myelodysplastic syndrome underwent peripheral blood stem cell HaploHCT with TMLI, fludarabine, and cyclophosphamide as the conditioning regimen. Radiation dose was escalated in increments of 200 cGy (1200-2000 cGy). GVHD prophylaxis was PTCy with tacrolimus/mycophenolate mofetil. Grade 2 toxicities by the Bearman scale were mucositis (n = 1), hepatic (n = 3), gastrointestinal (n = 5), and cardiac (n = 2). One patient (1800 cGy) experienced grade 3 pulmonary toxicity (dose-limiting toxicity). At a follow-up duration of 23.9 months for the whole cohort; 2-year NRM was 13%. Cumulative incidence of day 100 grade 2 to 4 and 3 to 4 acute GVHD was 52% and 6%, respectively. Chronic GVHD at 2 years was 35%. For patients treated with 2000 cGy, with a median follow-up duration of 12.3 months, 1-year relapse/progression, progression-free survival, and overall survival rates were 17%, 74%, and 83%, respectively. In conclusion, HaploHCT-TMLI with PTCy was safe and feasible in our high-risk patient population with promising outcomes.

Total marrow irradiation (TMI): Addressing an unmet need in hematopoietic cell transplantation - a single institution experience review

“…Attempts to add standard 9 Gy TBI to a RIC regimen to reduce relapse rates resulted in unacceptable toxicities ( 6 ). Organ sparing targeted radiotherapy such as TMLI is needed ( 11 , 15 , 38 , 39 ), specifically for older patients with limited HCT options, who present frequently with more aggressive and chemo-resistant disease, are unable to tolerate standard myeloablative regimens ( 40 , 41 ), and where reduced intensity conditioning (RIC) regimens can be associated with increased relapse rates ( 37 ).…”

“…Al Malki et al. evaluated the addition of dose escalated TMLI to an established PTCy conditioning regimen ( 39 ) to further reduce relapse rates without contributing to NRM or GVHD. The target structures were bone and bone marrow, major lymph node regions and spleen.…”

“…More recently TMLI strategies at this center have been extended to other patient populations. Dose escalated TMLI has been added to a PTCy GVHD reduction regimen in R/R acute leukemia patients undergoing HCT with a haplo-identical donor with promising low relapse rates achieved without an increase in GVHD or NRM ( 39 ). This approach warrants further investigation given the initial promising results and rapid expansion of haplo-identical HCT.…”

“…These strategies while reducing GVHD can reduce the graft versus leukemia (GVL) effects, potentially resulting in higher relapse rates, as demonstrated in patients with AML undergoing haplo-identical donor HCT with RIC conditioning regimens and PTCy (59). Al Malki et al evaluated the addition of dose escalated TMLI to an established PTCy conditioning regimen (39) to further reduce relapse rates without contributing to NRM or GVHD. The target structures were bone and bone marrow, major lymph node regions and spleen.…”

Role of radiotherapy in treatment of extramedullary relapse following total marrow and lymphoid irradiation in high-risk and/or relapsed/refractory acute leukemia

“…All patients underwent pre-transplant conditioning with high-dose chemotherapy and TMLI. Patients received one of four chemotherapy regimens on a per protocol basis, with regimens including busulfan/etoposide (VP-16), fludarabine/ cyclophosphamide (CTX), fludarabine/melphalan, or VP-16/ CTX (3,4,(17)(18)(19)(20). For all five trials, tacrolimus and sirolimus were administered for graft-versus-host disease (GVHD) prophylaxis.…”