A Safer Conditioning Regimen for Patients With Bone Marrow Failure and Short Telomeres?

A study of patients with bone marrow failure (BMF) and short telomeres found that a conditioning regimen that eliminates radiation and DNA-alkylating agents led to successful engraftment and could spare patients from the toxicities associated with standard conditioning regimens.

Removing the “necessary evils” of DNA-alkylating agents and radiation could enable transplant in patients with high-risk comorbidities, according to lead author Suneet Agarwal, MD, PhD, from Dana-Farber/Boston Children’s Cancer & Blood Disorders Center and Harvard Medical School, who presented the results as a late-breaking abstract at the 2019 Transplantation & Cellular Therapy Meeting.

“Radiation and/or DNA-alkylating agents have been used to achieve myeloid engraftment since the inception of allogeneic hematopoietic cell transplantation (HCT),” Dr. Agarwal told ASH Clinical News. If these preparative regimens can be avoided, he said, so can the potential toxicities that accompany them.

For this study, researchers hypothesized that in patients with BMF and short telomeres, hematopoietic and immune cells have a replicative disadvantage that facilitates engraftment of healthy donor cells without the need for DNA-alkylating agents and radiation, he explained.

Investigators enrolled 20 patients with BMF (age range = 1.7-31.5 years at time of HCT) who were treated at one of seven institutions between August 2012 and October 2018. All participants had dyskeratosis congenita (DC) or lymphocyte telomere length below the first percentile, determined by flow cytometry fluorescent in situ hybridization. The pre-HCT preparative regimen consisted of fludarabine and alemtuzumab, and patients received cyclosporine A and mycophenolate mofetil as graft-vs.-host disease (GVHD) prophylaxis.

The primary endpoint of the study was donor myeloid engraftment, defined as an absolute neutrophil count ≥500 cells/µL by 42 days post-HCT and donor chimerism greater than 50 percent by 100 days post-HCT.

Eighteen patients received unrelated donor grafts (15 matched and 3 single-allele mismatched).

Primary myeloid engraftment was achieved in 19 of 20 patients (95%) at a median of 22 days post-HCT (range 1-35 days). The single patient who had primary graft failure was observed to have DC-related liver disease and hypersplenism, the researchers noted. A splenectomy was performed at 47 days post-HCT, which “promptly revealed donor myeloid engraftment,” they wrote.

Of the remaining 19 patients, 16 had sustained myeloid engraftment at a median post-HCT follow-up of 21 months (range = 1-74 months).

Three patients experienced secondary graft failure, two of whom had early graft rejection but underwent successful repeat HCT using higher-intensity regimens. The third patient maintained high donor chimerism after primary engraftment but developed severe neutropenia in the setting of multiple viral reactivations and died of a fungal infection 90 days post-HCT. Another patient died as a result of DC-related gastrointestinal complications at 19 months post-HCT.

Although it is difficult to compare the post-HCT outcomes observed in this single-arm trial with other approaches, Dr. Agarwal said that the mortality rates at 100 days post-HCT and overall survival “appear to be superior to other regimens.” Also, “engraftment appears to be non-inferior, despite the complete omission of alkylators and radiation.”

Four patients developed chronic GVHD, classified as limited (involving only localized skin and/or liver) in three patients and extensive (generalized skin or limited disease plus involvement of other organs) in one patient. These patients were treated successfully with limited courses of topical or oral steroids, and “none of the 16 patients who engrafted durably under the protocol regimen had acute GVHD, despite the fact that 90 percent had unrelated donors,” Dr. Agarwal added.

“Long-term follow-up will be important to assess whether avoiding the damaging effects of radiation and alkylating agents slowed the progression or prevented other life-threatening problems, such as cancer and lung and liver disease, to which these patients are predisposed,” he concluded.

He also noted that because this protocol was limited to HCT recipients with related or unrelated donors, human leukocyte antigen 7/8 or 8/8 matches, and bone marrow grafts, “we need to develop the best approach for patients who don’t have such donors and for patients with myelodysplastic syndromes/acute myeloid leukemia due to an underlying telomere disease.”

The authors report no relevant conflicts of interest.


Agarwal S, Myers KC, Antin JH, et al. Hematopoietic cell transplantation without radiation or DNA alkylating agents in bone marrow failure with short telomeres. Abstract LBA2. Presented at the Transplantation & Cellular Therapy Meetings of ASBMT and CIBMTR, February 24, 2019; Houston, TX.