Phase I Trial of Escalated Doses of Targeted Marrow Radiation Delivered by Tomotherapy Combined with Etoposide and Cyclophosphamide; An Allogeneic HCT Preparative Regimen for Patients with Advanced Leukemia

Overall survival (OS) for acute leukemia in relapse (RL) or induction failure (IF) treated with HCT is 16–19% (Duval et al., JCO 2010). While randomized studies have shown a dose response relationship, with higher doses of radiation resulting in decreased relapse, this benefit is offset by increased treatment related mortality.

To explore the safety and tolerability of targeted radiation treatment in the context of HCT, a phase I trial is being conducted in which escalated doses of targeted whole body radiation is delivered to marrow bearing and lymphoid areas, while sparing non hematopoietic (vital) organs. The transplant preparative regimen is as follows: tomotherapy on days −10 to −6; etoposide 60mg/kg [adj bw] on day −5 with cyclophosphamide 100mg/kg [ideal bw] on day −3. The radiation dose was started at 1200cGy delivered in 150 cGy fractions twice a day. As part of the design, the dose of radiation was escalated in increments of 150 cGy until 1500 cGy and then 100 cGy incrementally using cohorts of three until ultimately dose limiting toxicity is reached according to the Bearman and CTCAE 3.0 (for hematologic toxicity) scales. Liver and brain dose was kept at 1200 cGy. Normal organs received 17–62% of the marrow dose (lung 47%, esophagus 35% and oral cavity 28%). All patients received peripheral blood stem cells on day 0. GVHD prophylaxis consisted of tacrolimus and sirolimus.

To date, a total of 26 patients have been transplanted; from 3/14/2008 to 2/9/2012. Additional patient characteristics are as follows:

Age median 33y (20–54y)

AML n=12, ALL Ph- n=10, ALL Ph+ n=2, Biphenotypic n=2

Disease status at HCT, 1RL n=9, 2RL n=2, IF n=15

Cytogenetic risk: intermediate n=13, unfavorable n=8 and information not available n=5

KPS at HCT median 80 (70–100)

Donor source sibling n=13, HLA matched related n=6, mismatched (1 allele) unrelated n=7

WBC at HCT median 1.9 (0.1–14.9)

blasts (blood) at HCT median 0.5% (0–85%)

blasts (marrow) at HCT median 46% (10–85%)

Two patients presented with extramedullary disease at time of HCT.

With a median follow-up for alive patients of 16.1 months (5.3–47.7), the OS and cumulative incidence of relapse/progression at 1 year are 55% (95%CI: 44–65) and 34.6% (95%CI: 17.1–52.9) respectively. Five patients have been treated at 1600 cGy, the current dose level being tested, without reaching DLT. Twenty-two patients (85%) achieved CR at their day 30 post transplant evaluation. Twelve (46%) of patients developed acute GvHD; 5(42%) of these developed grades 3–4. The day 30 and day 100 NRM was 0% and 8% respectively. The most common toxicity across the dose levels tested is grade 2 stomatitis (Bearman Scale). Causes of death were disease progression/persistent disease n=10, GvHD n=2 and infection n=1.

These results are encouraging and suggest that 1) doses of targeted whole body, marrow and lymphoid radiation delivered by Tomotherapy can be safely escalated to 1600 cGy in combination with etoposide and cyclophosphamide (DLT not reached and dose escalation continues); and that 2) a reduction in relapse/progression compared to published reports can be achieved without increasing NRM in this high risk population.

No relevant conflicts of interest to declare.