Augmenting the Reduced Intensity Conditioning (RIC) Regimen of Fludarabine (FLU) and Melphalan (MEL) by Addition of Total Marrow and Lymph Node Irradiation (TMLI) Using Helical Tomotherapy in Patients (pts) with Advanced Hematological Malignancies.
Authors: Rosenthal Joseph , Wong Jeffrey , Stein Anthony , Bolotin Ellen , Karanes Chatchada , Popplwell Leslie , Nademanee Auayporn , Sahebi Firoozeh , O’Donnell Margaret , Delioukina Maria , Somlo George , Pawlowska Anna , Hitt Debbie , Shakhnovits Marianna , Forman Stephen 
Published: October 2019

Abstract
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). We developed a protocol to address the problem by augmenting the anti tumor efficacy of an RIC regimen with a limited increase in toxicity. We hypothesize that RIC consisting of Flu/Mel with 1200 cGY of TMLI radiation delivered using Tomotherapy Hi-Art systemis 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, defined as high-risk remission or marrow blasts ≤10%, were eligible. The RIC consisted of FLU 25 mg/m2/d × 5 days, MEL 140 mg/m2 for one day, and TMLI delivered at 150 cGy/fraction in 8 fractions over 4 days. Tacrolimus and sirolimus were used for prevention of GVHD. Supportive care was given according to our institution standard guidelines.
Results: There were 8 evaluable pts (median age: 52.4 yr, range 24.3–61.6 yr). The diagnoses were: AML (n=5), ALL, multiple myeloma, NHL (n=1, each). At the time of HSCT 6 patients (75%) had advanced disease: first relapse (n=1) induction failure (n=4) and progressive disease (n=1). Two pts (25%) were in complete remission. Mobilized peripheral blood stem cells from HLA-identical siblings (n=4) or matched unrelated donor (n=4) were used in all cases. The addition of TMLI was well tolerated with no grade 4 toxicities. Common radiation related toxicities by day +30 included: nausea grade 2 (n=2) grade 3 (n=6), emesis grade 2 (n=3) and grade 3 (n=2), mucositis grade 2 (n=1) and grade 3 (n=6) and fatigue grade 2 (n=3) grade 3 (n=2): Myeloid engraftment occurred in a median of 15 days post transplant (range: 11–21 days) and platelet engraftment was documented at a median of 15 days (range:10–18 days). Acute GvHD occurred in 6 pts for all (grade II, n=3, grade III, n=3). At a median of 150 days post HSCT, 7 pts are alive and with no evidence of disease. One pt died on Day + 57 post-transplant of multi-organ failure secondary to influenza virus type A infection.
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 will be conducted to further assess efficacy in pts with advanced hematological malignancies who are not eligible for RIC due to disease burden.