Phase I Trial of Total Marrow and Lymphoid Irradiation Transplantation Conditioning in Patients with Relapsed/Refractory Acute Leukemia

Abstract

Current conditioning regimens provide insufficient disease control in relapsed/refractory acute leukemia (AL) patients undergoing hematopoietic stem cell transplantation (HSCT) with active disease. Intensification of chemotherapy and/or total body irradiation (TBI) is not feasible because of excessive toxicity. Total marrow and lymphoid irradiation (TMLI) allows for precise delivery and increased intensity treatment via sculpting radiation to sites with high disease burden or high risk for disease involvement, while sparing normal tissue. We conducted a phase I trial in 51 patients (age: 16–57 years) with relapsed/refractory AL undergoing HSCT (matched related, matched unrelated, or one-allele mismatched unrelated) with active disease, combining escalating doses of TMLI (range 1200–2000 cGy) with cyclophosphamide (CY) and etoposide (VP16). The maximum tolerated dose was declared at 2000 cGy since TMLI simulation studies indicated that >2000 cGy might deliver doses toxic for normal organs at or exceeding those delivered by standard TBI. The post transplant non-relapse mortality (NRM) rate was only 3.9% (95% CI: 0.7–12.0) at day +100 and 8.1% (95% CI: 2.5–18.0) at one year. The cumulative incidence of grade II–IV acute GVHD was 43.1% (95% CI: 29.2–56.3) and for grade III–IV was 13.7% (95% CI: 6.9–27.3). The day +30 complete remission rate for all patients was 88% and was 100% for those treated at 2000 cGy. The overall one-year survival was 55.5% (95% CI: 40.7–68.1). The TMLI/CY/VP16 conditioning regimen is well tolerated at TMLI doses up to 2000 cGy with a low 100 day and 1 year NRM rate and no increased risk of GVHD with higher doses of radiation.

Dose Escalation of Total Marrow Irradiation in High-Risk Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

“…We interpret these varying results to suggest that delivering irradiation prior to chemotherapy might allow for safer irradiation escalation. In support of this, Stein and coworkers have recently reported in abstract form, the escalation of TMI to 20 Gy followed by cyclophosphamide and etoposide 30 . It is also worth noting that their dose escalation strategy (to 20 Gy) used 2 Gy/fraction and thus an increase in BED of 68% relative to conventional TBI (BED ratio 1.7).…”

Advances in adult acute lymphoblastic leukemia therapy

“…The study included 16 patients with active ALL, and the TMLI dose was escalated safely to 2000 cGy. The study showed encouraging results, with 1-year NRM and OS of 8% and 55%, respectively [82].…”

Haploidentical hematopoietic SCT using helical tomotherapy for total-body irradiation and targeted dose boost in patients with high-risk/refractory acute lymphoblastic leukemia

“…Stein A, et al recently also conducted a phase I trial for TMLI in 51 patients with relapsed/refractory acute leukemia undergoing allo-HSCT. Their results indicated that TMLI is safe up to a total dose of 20 Gy and radiation to off-target critical organs is lower than typically delivered by TBI [32]. Wong JY et al further carried out an autologous HSCT trial in 13 patients with multiple myeloma (MM) with high dose melphalan, followed 6 weeks later by TMI to skeletal bone using HT, and a separate allo-HSCT trial in eight patients (5 AML, 1 ALL, 1 NHL, 1 MM) treated with TMLI + splenic irradiation to 12 Gy using HT combined with fludarabine/melphalan.…”