Adding Total Marrow and Lymph Node Irradiation (TMLI) Using Helical Tomotherapy to Reduced Intensity Conditioning (RIC) Regimen of Fludarabine (FLU) and Melphalan (MEL) in Patients (pts) with Advanced Hematological Malignancies.
Authors: Rosenthal Joseph , Wong Jeffrey Y. , Somlo George , Snyder David , O’Donnell Margaret , Stein Anthony , Nademanee Ayurporn , Delioukina Maria , Popplewell Leslie , Parker Pablo , Spielberger Ricardo , Sahebi Firoozeh , Karanes Chatchada , Hitt Debbie , Naeem Hossameldin , Dagis Andrew , Forman Stephen 
Published: October 2019

In an attempt to augment the anti-tumor efficacy of RIC, while maintaining a low-toxicity profile, we added TMLI to FLU/MEL. The concept of reduced-intensity conditioning regimen was developed in an effort to reduce transplant related morbidity and mortality in older pts or those with compromised organ function (COF). Previous studies showed that RIC with FLU/MEL followed by hematopoietic stem cell transplantation (HSCT) may result in long-term survival for a fraction of pts with hematologic malignancies; however, pts with advanced disease at the time of transplant do poorly (Giralt, Biol. Blood Marrow Transplant, 13:884, 2007). Attempts to augment RIC with total body irradiation (TBI) at 900 cGY have shown that the regimen, while well tolerated in children, was too toxic in older pts and the study had to be discontinued (Petropoulos et al. Bone Marrow Transplant. 37:463, 2006). This trial was developed to examine the possibility of augmenting the anti-tumor efficacy of an RIC regimen without significantly increasing the toxicity. We hypothesize that RIC consisting of Flu/Mel with 1200 cGY of TMLI radiation delivered using Tomotherapy Hi-Art system is safe, well tolerated, and may improve outcome in pts with advanced hematological malignancies.

Patients and Methods: Pts, older than 50 years of age, or with COF with advanced disease status; high-risk remission and marrow blasts 10%, were eligible. The RIC consisted of FLU 25 mg/m2/d x 5 days, MEL 140 mg/m2 for one day, and TMLI delivered at 150 cGy/fraction in 8 fractions over 4 days along with FLU. Supportive care and treatment for prevention of GVHD were given according to our institution standard guidelines.

Results: There were 16 evaluable pts (median age: 50.8 yr range 24.3–65.7 yr). The diagnoses were: AML (n=10), ALL (n=3), NHL (n=2), multiple myeloma (n=1),. At the time of HSCT 9 patients (56%) had advanced disease: 1st or 2nd relapse (n=3) induction failure (n=5) and progressive disease (n=1). Seven pts (44%) were in complete remission. Mobilized peripheral blood stem cells from HLA-identical siblings (n=7) or matched unrelated donor (n=9) were used in all cases. Transplant-related toxicities by day +30 included: nausea grade 2 (n=4) grade 3 (n=12), emesis grade 2 (n=6) and grade 3 (n=4), mucositis grade 2 (n=2) and grade 3 (n=14) and fatigue grade 2 (n=6) grade 3 (n=4). Myeloid engraftment occurred at a median of 15 days post transplant (range: 10–19 days) and platelet engraftment was documented at a median of 16 days (range:10–19 days). Acute GvHD grade II-IV occurred in 38.5% of patients (grade II (31%) and grade III in 7.5%). Extensive chronic GVHD was documented in 3 patients (19%). Five patients expired; 3 of relapsed disease, 1 with a secondary malignancy, and 2 of transplant related mortality. At a median of 12 month overall survival and disease-free survival are 81% (95% CI, 51%–93%), and 59% (95% CI,23%–82%), respectively.

Conclusion: The addition of a third agent, TMLI at a dose of 1200 cGy to traditional RIC with FLU/MEL appears to be safe and tolerable. A study is ongoing to further assess efficacy in pts with advanced hematological malignancies who are not eligible for RIC due to disease burden.