title: 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 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 range, 16 to 57 years) with relapsed/refractory acute leukemia undergoing HSCT (matched related, matched unrelated, or 1-allele mismatched unrelated) with active disease, combining escalating doses of TMLI (range, 1200 to 2000 cGy) with cyclophosphamide (CY) and etoposide (VP16). The maximum tolerated dose was declared at 2000 cGy, as TMLI simulation studies indicated that >2000 cGy might deliver doses toxic for normal organs at or exceeding those delivered by standard TBI. The post-transplantation nonrelapse mortality (NRM) rate was only 3.9% (95% confidence interval [CI], .7 to 12.0) at day +100 and 8.1% (95% CI, 2.5 to 18.0) at 1 year. The cumulative incidence of grades II to IV acute graft-versus-host disease (GVHD) was 43.1% (95% CI, 29.2 to 56.3) and for grade III and IV, it was 13.7% (95% CI, 6.9 to 27.3). The day +30 complete remission rate for all patients was 88% and was 100% for those treated at 2000 cGy. The overall 1-year survival was 55.5% (95% CI, 40.7 to 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.
authors.affiliation: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California; Gehr Family Center for Leukemia Research, City of Hope, Duarte, California. Electronic address: astein@coh.org.
authors.forename: Anthony
authors.initials: A
authors.lastname: Stein
authors.affiliation: Department of Biostatistics, City of Hope, Duarte, California.
authors.forename: Joycelynne
authors.initials: J
authors.lastname: Palmer
authors.affiliation: Department of Biostatistics, City of Hope, Duarte, California.
authors.forename: Ni-Chun
authors.initials: NC
authors.lastname: Tsai
authors.affiliation: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California; Gehr Family Center for Leukemia Research, City of Hope, Duarte, California.
authors.forename: Monzr M
authors.initials: MM
authors.lastname: Al Malki
authors.affiliation: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California; Gehr Family Center for Leukemia Research, City of Hope, Duarte, California.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Aldoss
authors.affiliation: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California; Gehr Family Center for Leukemia Research, City of Hope, Duarte, California.
authors.forename: Haris
authors.initials: H
authors.lastname: Ali
authors.affiliation: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California; Gehr Family Center for Leukemia Research, City of Hope, Duarte, California.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Aribi
authors.affiliation: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California; Southern California Kaiser Permanente Bone Marrow Transplant Program, Los Angeles, California.
authors.forename: Len
authors.initials: L
authors.lastname: Farol
authors.affiliation: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California; Gehr Family Center for Leukemia Research, City of Hope, Duarte, California.
authors.forename: Chatchada
authors.initials: C
authors.lastname: Karanes
authors.affiliation: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California; Gehr Family Center for Leukemia Research, City of Hope, Duarte, California.
authors.forename: Samer
authors.initials: S
authors.lastname: Khaled
authors.affiliation: Department of Radiation Oncology, City of Hope, Duarte, California.
authors.forename: An
authors.initials: A
authors.lastname: Liu
authors.affiliation: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California; Gehr Family Center for Leukemia Research, City of Hope, Duarte, California.
authors.forename: Margaret
authors.initials: M
authors.lastname: O'Donnell
authors.affiliation: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California; Gehr Family Center for Leukemia Research, City of Hope, Duarte, California.
authors.forename: Pablo
authors.initials: P
authors.lastname: Parker
authors.affiliation: Department of Pediatrics, City of Hope, Duarte, California.
authors.forename: Anna
authors.initials: A
authors.lastname: Pawlowska
authors.affiliation: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California; Gehr Family Center for Leukemia Research, City of Hope, Duarte, California.
authors.forename: Vinod
authors.initials: V
authors.lastname: Pullarkat
authors.affiliation: Department of Radiation Oncology, City of Hope, Duarte, California.
authors.forename: Eric
authors.initials: E
authors.lastname: Radany
authors.affiliation: Department of Pediatrics, City of Hope, Duarte, California.
authors.forename: Joseph
authors.initials: J
authors.lastname: Rosenthal
authors.affiliation: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California; Southern California Kaiser Permanente Bone Marrow Transplant Program, Los Angeles, California.
authors.forename: Firoozeh
authors.initials: F
authors.lastname: Sahebi
authors.affiliation: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California; Gehr Family Center for Leukemia Research, City of Hope, Duarte, California.
authors.forename: Amandeep
authors.initials: A
authors.lastname: Salhotra
authors.affiliation: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California.
authors.forename: James F
authors.initials: JF
authors.lastname: Sanchez
authors.affiliation: Department of Radiation Oncology, City of Hope, Duarte, California.
authors.forename: Tim
authors.initials: T
authors.lastname: Schultheiss
authors.affiliation: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California; Southern California Kaiser Permanente Bone Marrow Transplant Program, Los Angeles, California.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Spielberger
authors.affiliation: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California.
authors.forename: Sandra H
authors.initials: SH
authors.lastname: Thomas
authors.affiliation: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California; Gehr Family Center for Leukemia Research, City of Hope, Duarte, California.
authors.forename: David
authors.initials: D
authors.lastname: Snyder
authors.affiliation: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California; Gehr Family Center for Leukemia Research, City of Hope, Duarte, California.
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Nakamura
authors.affiliation: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California; Gehr Family Center for Leukemia Research, City of Hope, Duarte, California.
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.affiliation: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Forman
authors.affiliation: Department of Radiation Oncology, City of Hope, Duarte, California.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Wong
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D001853:Bone Marrow / Q000528:radiation effects*; D003520:Cyclophosphamide / Q000627:therapeutic use; D004307:Dose-Response Relationship, Radiation; D005047:Etoposide / Q000627:therapeutic use; D005260:Female; D006086:Graft vs Host Disease / Q000209:etiology; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods; D006801:Humans; D007938:Leukemia / Q000401:mortality / Q000628:therapy*; D015182:Lymphatic Irradiation; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D016879:Salvage Therapy / Q000379:methods; D016019:Survival Analysis; D019172:Transplantation Conditioning / Q000379:methods*; D055815:Young Adult
chemical_list: D005047:Etoposide; D003520:Cyclophosphamide
keywords: Acute lymphoblastic leukemia; Acute myeloid leukemia; Relapsed/refractory; Total marrow and lymphoid irradiation