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

Anthony Stein, Joycelynne Palmer, Ni-Chun Tsai, Monzr M Al Malki, Ibrahim Aldoss, Haris Ali, Ahmed Aribi, Len Farol, Chatchada Karanes, Samer Khaled, An Liu, Margaret O'Donnell, Pablo Parker, Anna Pawlowska, Vinod Pullarkat, Eric Radany, Joseph Rosenthal, Firoozeh Sahebi, Amandeep Salhotra, James F Sanchez, Tim Schultheiss, Ricardo Spielberger, Sandra H Thomas, David Snyder, Ryotaro Nakamura, Guido Marcucci, Stephen J Forman, Jeffrey Wong, Anthony Stein, Joycelynne Palmer, Ni-Chun Tsai, Monzr M Al Malki, Ibrahim Aldoss, Haris Ali, Ahmed Aribi, Len Farol, Chatchada Karanes, Samer Khaled, An Liu, Margaret O'Donnell, Pablo Parker, Anna Pawlowska, Vinod Pullarkat, Eric Radany, Joseph Rosenthal, Firoozeh Sahebi, Amandeep Salhotra, James F Sanchez, Tim Schultheiss, Ricardo Spielberger, Sandra H Thomas, David Snyder, Ryotaro Nakamura, Guido Marcucci, Stephen J Forman, Jeffrey Wong

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.

Keywords: Acute lymphoblastic leukemia; Acute myeloid leukemia; Relapsed/refractory; Total marrow and lymphoid irradiation.

Conflict of interest statement

Financial Disclosure Statement

All other authors declare no competing financial interests.

Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1. Treatment Schema
Figure 1. Treatment Schema
TMLI was delivered in 8–10 fractions b.i.d. over 4–5 days with total targeted dose ranging from 1200–2000 cGy. VP16 = etoposide; CY = cyclophosphamide. *Adjusted body weight, **Ideal body weight, ***A window of 1–2 days is allowed for stem cell availability. Interval between CY and stem cell infusion must be >48 hrs.
Figure 2. Dose Distribution Map for Patient…
Figure 2. Dose Distribution Map for Patient Treated at MTD
TMLI was delivered at 2000 cGy to bone and lymph nodes (excluding mesenteric lymph nodes and Waldeyer ring) and 1200 cGy to liver, spleen, and brain. Doses delivered are coded according to the colors indicated in the legend.
Figure 3. TMLI Median Organ Dose (D50)…
Figure 3. TMLI Median Organ Dose (D50) by Phase I Dose Levels
Dose levels and number of patients at each dose level are indicated in the legend. The doses plotted are averaged for the patients at each dose level. N=51 total patients treated.

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