Advances in Hematopoietic Cell Transplant for Pediatric AML Reduce Toxicity and Expand Access, but Relapse Remains a Problem

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John Perentesis, MD

John Horan, MD

One of the real successes in using hematopoietic cell transplantation for children with AML has been in developing better conditioning regimens and the reduction in regimen-related toxicity.

—John Horan, MD

Advances in allogeneic hematopoietic cell transplantation for children with acute myeloid leukemia (AML) have resulted in less toxic pretransplant conditioning regimens and expanded access to transplantation, but post-treatment leukemic relapse remains a big problem. The progress and continuing challenges were outlined at the opening Plenary Session of the second annual joint educational meeting of the Pediatric Blood and Marrow Transplant Consortium (PBMTC) and the American Society of Pediatric Hematology Oncology (ASPHO) in Chicago.

Better Conditioning Regimens

“One of the real successes” in using hematopoietic cell transplant for children with AML has been in developing better conditioning regimens and the “reduction in regimen-related toxicity,” noted John Horan, MD, Associate Professor of Pediatrics at Emory University School of Medicine in Atlanta. He reviewed the progression of conditioning regimens from total-body irradiation plus cyclophosphamide in the 1970s and 1980s, to oral busulfan (Myleran) and cyclophosphamide in the 1990s, and thereafter to intravenous busulfan (Busulfex)/cyclophosphamide. A 2013 study demonstrated the superiority of intravenous busulfan/cyclophosphamide over earlier regimens, showing significantly less nonrelapse mortality, a lower relapse rate at 1 year or more post-transplant, and better leukemia-free survival.1

A myeloablative regimen of intravenous busulfan and fludarabine has been associated with reduced toxicity but with survival and nonrelapse mortality similar to intravenous busulfan/cyclophosphamide. This combination is being investigated in clinical trial AAML 1031. A myeloablative regimen of high-dose treosulfan (an investigational alkylating agent) plus fludarabine also showed reduced toxicity and a low incidence of transplant-related mortality2 and is being studied in PBMTC ONC1101.

“Thought-provoking results” were provided by a study comparing reduced-intensity conditioning regimens and myeloablative conditioning in children with AML undergoing allogeneic hematopoietic cell transplant.3 However, no significant differences in overall survival, disease-free survival, relapse, or nonrelapse mortality were seen, Dr. Horan reported.

Trials using unrelated donors to expand access to transplantation have shown improvements in outcomes over time. Reductions in transplant-related mortality have been achieved through better human leukocyte antigen (HLA) matching, less toxic conditioning, and enhanced supportive care, Dr. Horan observed. Survival with well-matched unrelated donors is approaching that with matched related donors, he added.

Major Challenge

Relapse is “probably the biggest problem facing us,” Dr. Horan stated. There has been “no obvious decrease in relapse over the past 2 decades,” he pointed out, and gains in survival have been more modest than reductions in transplant-related mortality.

“Relapse is the major challenge,” agreed John Perentesis, MD, Director of the Division of Oncology and Cancer Programs at Cincinnati Children’s Hospital Medical Center. “Between one-quarter and one-third of patients struggle with relapse,” he said.

Important strategies being tested to prevent relapse after bone marrow transplant include enhancing the graft-vs-leukemia effect and targeted post-transplant chemotherapy with sorafenib (Nexavar) for FLT3-mutated blasts, and hypomethylating agents such as decitabine and azacitidine.

At high doses, decitabine and azacitidine “work like not very good chemotherapeutic drugs,” Dr. Perentesis said. “They have cytotoxicity. They kill the tumor cells, but they also produce a lot of toxicity to normal cells.” At low doses, they appear to reactivate cellular growth regulatory pathways, and potentially inhibit leukemic stem cell self-renewal and sensitivity to cytotoxic therapies.

In a recent small series of pediatric relapsed AML patients, three of eight patients achieved some form of a complete response with low-dose decitabine therapy,4 and several adult studies have indicated feasibility of post-SCT “maintenance” regimens incorporating low-dose decitabine or panobinostat (a histone deacetylase inhibitor).

Newer epigenetic modulators with potentially high-specificity targeting of the pathologic DOT1L-MLL axis in infant mixed-lineage leukemias or altered EZH2 activity in leukemia are under active investigation in pediatric AML, with the novel experimental drugs EPZ-5676 and EPZ-6438, respectively.

Surface Antigen–Targeted Therapies

Targeted agents are being used for AML in the transplant setting to both reduce minimal residual disease and address the problem of post-transplant relapse. One of the challenges is that “AML stem cells share features of hematopoietic progenitors that lead to drug resistance…. AML has a robust system to protect itself from toxic products such as chemotherapeutic agents,” Dr. Perentesis noted.

“CD33 is an AML cell surface target, one of several that has been of great interest. It is a good marker with significant expression of AML blasts, and it is also probably associated with prognostic risk factors,” Dr. Perentesis stated.

He cited a study that assessed CD33 expression levels by flow cytometry and found expression in over 99% of AML samples from adult patients. The study also found that targeting CD33 ex vivo using AMG 330, a CD33/CD3-bispecific T-cell engaging (BiTE) antibody, in primary AML samples led to T-cell recruitment and expansion, as well as highly potent antibody-mediated cytotoxicity, suggesting efficient therapeutic potential in vivo.5

Findings from another preclinical study cited by Dr. Perentesis suggest that SGN-CD33A, a novel CD33-targeting antibody-drug conjugate, “has CD33-directed antitumor activity and support clinical testing of this novel therapeutic in patients with AML.”6

This is an exciting time for new prospects to treat AML, as dozens of targeted drugs are in development, Dr. ­Perentesis said. These include next-generation drugs targeting FLT3-ITD and potential specificity against resistance mutations, new agents targeting the c-Kit and RAS/MEK axes, small molecules with more effective inhibition of the mTOR pathway, and new BLC2 inhibitors engineered to minimize throbocytopenia. “We’ve thought about targetable pathways for a long time,” he noted in closing, but cautioned, “it is likely that you actually have to hit the target directly.” ■

Disclosure: Drs. Horan and Perentesis reported no potential conflicts of interest.


1. Copelan EA, Hamilton BK, Avalos B, et al: Better leukemia-free and overall survival in AML in first remission following cyclophosphamide in combination with busulfan compared with TBI. Blood 122:3863-3870, 2013.

2. Nemecek ER, Guthrie KA, Sorror ML, et al: Conditioning with treosulfan and fludarabine followed by allogeneic hematopoietic cell transplantation for high-risk hematologic malignancies. Biol Blood Marrow Transplant 17:341-350, 2011.

3. Bitan M, He W, Zhang MJ, et al: Transplantation for children with acute myeloid leukemia: A comparison of outcomes with reduced intensity and myeloablative regimens. Blood 123:1615-1620, 2014.

4. Phillips CL, Davies SM, McMasters R, et al: Low dose decitabine in very high risk relapsed or refractory acute myeloid leukaemia in children and youg adults. Br J Haematol 161:406-410, 2013.

5. Krupka C, Kufer P, Kischel, R, et al: CD33 target validation and sustained depletion of AML blasts in long-term cultures by the bispecific T-cell-engaging antibody AMG 330. Blood 123:356-365, 2014.

6. Kung Sutherland MS, Walter RB, Jeffrey SC, et al: SGN-CD33A: A novel CD33-targeting antibody-drug conjugate using a pyrrolobenzodiazepine dimer is active in models of drug-resistant AML. Blood 122:1455-1463, 2013.