Unrelated Cord Blood Transplantation For Infant Acute Leukemia Diagnosed Within 1 Year Of Age: Outcomes and Risk Factor Analysis On Behalf Of Eurocord and PDWP-EBMT
Authors: Ruggeri Annalisa , Volt Fernanda , Michel Gerard , Diaz de Heredia Cristina , Abecasis Manuel , Zecca Marco , Locatelli Franco , Vora Ajay J. , Yakouben Karima , O'Brien Tracey , Dini Giorgio , Cornish Jacqueline , Gluckman Eliane , Peters Christina , Rocha Vanderson , Dalle Jean-Hugues 
Published: October 2019

Infant acute leukemia has poor prognosis due to both chemo-resistance and toxicity in these very young patients (pts). Allogeneic stem cell transplantation (HSCT) is indicated for all pts with infant AML and ALL beyond first complete remission (CR). While some cooperative protocols exist for infant ALL with clear criteria for HSCT in CR1 pts, there is no international consensus for HSCT in infants with CR1 AML. In this population of low body weight pts, with aggressive disease, unrelated cord blood (UCB) is an attractive stem cell source due to high cell content and prompt donor availability.

We retrospectively analyzed 254 children with ALL (n=154) or AML (n=95) diagnosed within 1 year (y) of age (median age 5.7 months (range 0.03-12)). Median age at UCBT was 1.15 y (range 0.3-11). Pts received single-unit unrelated UCBT after myeloablative conditioning regimen (MAC) from 1995 to 2012 in EBMT centers.

Pts were transplanted in CR1 (n=135, 54%), CR2 (n=79, 32%) or more advanced disease (n=35, 14%). Data on cytogenetic at diagnosis were available for 182 pts (ALL=111, AML= 71), 24% were intermediate risk and 76% poor risk. For pts with ALL, 82 had chromosome 11 abnormalities defined as (t(4;11)-n=47, 11q23 abnormalities not otherwise specified-n=25, and others-n=10). For pts in CR1 median time from diagnosis to UCBT was 6 months (range 2.8- 20.7 months) and median duration of remission prior to transplant was 127 days (range 15-326 ).

CB units (21%) were identical to recipient, 57% had 1 HLA disparity (antigen level for HLA-A and B, allelic level for DRB1), and 22% had 2 HLA disparities. Median TNC dose at infusion was 9.4x107/kg (range 1- 18x107/kg). Most pts received busulfan (Bu) based conditioning (75%, n=186). The most frequent regimens were Bu+cyclophosphamide (Cy) (n=68), Bu+Cy+Melphalan (n=43), Bu+Cy+Fludarabine+Thiotepa (n=31). Thirty one pts received conditionings that included TBI. ATG was used in 79% of pts. GVHD prophylaxis consisted either of CSA±steroids or CSA±MMF in 72% and 11% of pts, respectively.

Median follow-up was 42 (range 3-170) months. Cumulative incidence (CI) of day 60 neutrophil recovery was 89±2%, with median time of 21 (range 7-55) days. CI of engraftment was 88% for those receiving TNC<9.4x107/kg, and 93% for pts receiving TNC>9.4x107/kg, p=0.006. At day 100, 90% of pts had full donor chimerism (data available for 73% of pts who engrafted). Of the 28 pts who had graft failure, 11 died within 30 days after UCBT, 7 had autologous recovery, and 10 received a subsequent HSCT (3 autologous, 7 allogeneic). Of the 7 pts with a second allo-HSCT, 4 are alive at a median of 2 years.

CI of day 100 acute GVHD (grade II-IV) was 39±3%, median time of onset was 18 days (range 6-100). Among 96 pts who experienced grade II-IV acute GVHD, 58 had grade II, 24 had grade III, and 14 had grade IV. CI of 1 y chronic GvHD was 10±3%.

CI of 1y TRM was 25±3%. CI of TRM was higher for infants transplanted for ALL than for AML (31% and 15% , respectively, p= 0.004. One hundred and fifteen pts died. The causes of death were relapse (n=55), infection (n=30), GvHD (n=9), or other transplant-related events (n=21).

CI of 4y relapse was 26±4%. It was 28% for pts transplanted for ALL and 21% for AML, p=0.32. CI of 4y relapse was 19%, 31% and 50% for pts transplanted in CR1, CR2 or more advanced disease, p=0.007. Age at diagnosis less than 3 months was associated with a trend for higher CI of relapse at 4y (36% versus 22%, p=0.06).

Leukemia-free-survival (LFS) at 4y was 49±3%; it was 40% and 69% for those transplanted for ALL and AML, respectively p=0.001. According to diagnosis and disease status, 4y LFS for ALL was: 50% for pts in CR1, 36% for CR2 and 0% for advanced disease, (p=0.001). For AML it was: 82% for pts in CR1, 58% for CR2 and 11% for advanced disease, (p=0.001). LFS was better for pts transplanted with a short delay from diagnosis to transplant (within 6 months of diagnosis, 60% versus 45%, p=0.01). For pts with chromosome 11 abnormalities, 4y LFS was 45%. In multivariable model, diagnosis of ALL (HR 1.8, p=0.004), advanced disease status at UCBT (HR 2.4, p<0.0001) and age at diagnosis less than 3 months (HR 1.5, p=0.02) were independently associated with worse LFS.

UCBT is a suitable option for infants with acute leukemia in remission. TRM was higher for ALL pts probably due to the intensity of pre transplant therapies. Contrarily to what is usually observed in children older than 1 year, in our study pts transplanted with UCB for AML had better prognosis than ALL recipients.

Disclosures:

No relevant conflicts of interest to declare.