Successful Umbilical Cord Blood Transplantation in Relapsed B-Cell Acute Lymphoblastic Leukemia after Chimeric Antigen Receptors Therapy
Authors: Liu Fang , Zhu Xiaofan , Guo Ye , Chen Xiaojuan , Ruan Min 
Published: October 2019

Abstract
Chimeric antigen receptors (CARs) therapy targeting CD19, a cell surface molecule found in most B-cell leukemias and lymphomas, has been the most successful therapeutic T-cell engineering to treat refractory or relapsed B-cell acute lymphoblastic leukemia. After achieving a second complete remission (CR) by CARs therapy, patients then have opportunities for allogeneic hematopoietic cell transplantation (allo-HCT) to be cured. However, in many patients, especially children and adolescent, a HLA-matched sibling or unrelated donor is often unavailable in China. Umbilical cord blood grafts require less strict genetic matching and are more readily available, has been identified as an alternative donor source for transplantation. However, umbilical cord blood transplantation (UCBT) following CARs therapy in relapsed B-cell Acute Lymphoblastic Leukemia (ALL) has rarely been reported before. What is the efficacy and safety by this type of transplantation? Here, we performed a successful UCBT following CARs therapy in a 9-year-old relapsed and chemo-refractory B-ALL girl.
The girl was diagnosed as common B-ALL in July 2015 and suffered bone marrow relapse in August 2017. She was refractory to reinduction chemotherapy and got CR2 after CARs therapy. Unfortunately, her minimal residual disease (MRD) became positive again after 1month of CARs therapy. Stem cell transplantation is emergent. The girl didn't have matched related or unrelated donors, so a suitable umbilical cord blood graft was found with a matching of 4/6 alleles. Pretransplantation conditioning consisted of fludarabine 30 mg/m2 daily from days − 8 to − 5, busulfan 4 mg/kg daily from days − 7 to − 4, cyclophosphamide 60 mg/kg daily from days − 3 to - 2. Prophylaxis for acute graft versus host disease (GVHD) included cyclosporine A (CsA) and mycophenolate mofetil. She received one UCB unit on January 4, 2018. The infused cell doses of total nuclear cells (TNCs) and CD34+cells were 6.6 × 107/kg and 0.8 × 105/kg, respectively. Granulocyte colony-stimulating factor was given intravenously at a dose of 5 μg/kg on day 6 after transplantation and on each day thereafter until the WBC remained above 2.0 × 109/L for three consecutive days. The last follow up time was July 15, 2018.
During the period of granulocytopenia, the patient didn't suffer obvious infections. The neutrophil count increased to over 0.5 × 109/L on day +15 and exceeded 1.0 × 109/L on day +16. The self- sustained platelet count exceeded 20 × 109/L on day +39. Hematopoietic chimerism was determined by quantitative PCR based on the amplification of short tandem repeat (STR) markers. Peripheral blood samples were obtained from the donor and the recipient before UCBT and from the recipient at 7 d, 14 d, 1 month, 2 months, 3 months and 6 months post-transplant. A complete donor chimera (100% donor DNA) was detected at 14 d, 1 month, 2 months, 3 months and 6 months following transplantation. Only grade I acute GVHD but no chronic GVHD occurred. Her MRD detected by flow cytometry kept negative since 2 months after transplantation.
Thus, UCB transplantation following CARs therapy in relapsed and chemo-refractory B-ALL also appears to be an alternative donor source with successful engraftment, excellent graft versus leukemia (GVL) effect associated with no to mild GVHD. Unrelated UCB is an excellent alternative stem cell source for these patients especially for children.

Disclosures
No relevant conflicts of interest to declare.