Cord Blood Instead of Bone Marrow for HSCT for Blood Cancers

Liam Davenport

February 21, 2019

HOUSTON — The use of umbilical cord blood as a source of hematopoietic stem cells (HTCs) for transplants for patients with blood cancers has declined in recent years in the United States.

However, positive study findings that show it may have advantages over the use of unrelated donor bone marrow transplants should reverse that decline, argued a leading expert in the field.

Juliet N. Barker, MD, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, and Department of Medicine, Weill Cornell Medical College, New York City, chaired a session about cord blood transplantation here at the Transplantation and Cellular Therapy (TCT) 2019 conference.

Barker told Medscape Medical News she is confident that the use of cord blood for transplantation in patients with hematologic malignancies will start to increase again in the coming years.

"Although the number of cord blood transplants performed has retracted, in a way that has given the opportunity for the centers that are real advocates of cord blood to embrace it," she said.

Barker added that the "centers that are advocates for cord blood are very motivated to create consortiums."

She also noted she and her colleagues are to receive government funding to stop the use of cord blood "from collapsing," and they are working on establishing an international consortium of transplant centers and cord blood banks.

"It is also important to emphasize that there's a huge amount of research going on," she continued. "That helps to really both keep cord blood alive and demonstrate that it is a very useful stem cell source both for basic clinical transplantation as well as, for example, cellular therapy and regenerative medicine applications."

Among the new data presented here at the conference were studies showing reduced relapse and chronic graft versus host disease (GVHD) rates seen with cord blood versus other approaches, which could lead to cost savings down the line.

In addition, several studies presented here showed that, with the right techniques, cord blood can also achieve early results at least as good as, for example, unrelated donor (URD) transplants, and good results in the elderly.

Moreover, cord blood has huge advantages over other sources of HTCs, as it is available to patients from a much wider ethnic heritage and can be prepared for use extremely quickly.

Issues With Cord Blood Transplants

While opening the session, Barker commented that the decline in cord blood transplants in the United States in recent years may be because of issues with using this source.

Unit selection is more complicated than for URD or haploidentical transplants, and the cord blood units have a higher cost and are associated with longer hospital stays.

In addition, the early post-transplant period can be more complex than for other transplant types, but this has led to a "selective focus" by clinicians, who are not looking to the reduced risk of relapse or GVHD with cord blood.

Barker also noted that cord blood transplants are seen as a "last ditch" therapy and that the increase in ex vivo expansion before transplantation to achieve quicker hematopoietic recovery has been at the expense of the use of cord blood without expansion.

To reverse the decline in cord blood transplants, she said that the efficiency of cord blood searches needs to be improved, alongside cord blood inventories and unit selection.

It also needs to be made easier to perform cord blood transplants, which will require new technologies and novel clinical trials and collaborations.

While all of those steps are already underway, Barker said reducing the unit cost of cord blood would be advantageous, as would demonstrating cost-effectiveness by showing that the initial costs are offset by the long-term benefits.

Barker also emphasized that other sources of HTCs are not without their problems.

One of the major limitations of URD transplants is that, unless the patient is of northwestern or Eastern European heritage, it is likely that finding a donor will be difficult.

She said that individuals with Southern European, Asian, White Hispanic, African, and other heritages do not generally have an 8/8 unrelated donor, and the situation "is not improving."

This is because the US population is becoming more diverse, with donors aged younger than 35 years less likely to match patients of any age because of having a unique human leukocyte antigen (HLA) profile.

Moreover, not everyone has a haploidentical donor, with, again, individuals of African descent significantly less likely to have a haploidentical graft available than those of European descent.

Haploidentical transplants are also limited by the requirement that donors have to be medically, socially, and psychologically fit to donate, as well as the need to workup multiple haploidentical donors in case there is an issue with the donors. In addition, there is a lack of pediatric and older donors.

Barker pointed out that the prevention or treatment of relapse after allograft may not always work, especially if the patient is in full-blown relapse.

All this, Barker said, "makes the cord blood inventory very important."

It has the advantages of being much more widely available to non-northwestern European/non-Eastern European populations and having very rapid availability, often before patients are ready to receive the graft.

Multiple studies have also shown that the relapse rate in patients with minimal residual disease is lower after cord blood grafting than when using HLA-matched or mismatched unrelated donors.

However, this is set against the higher rate of early treatment-related mortality with cord blood transplantation.

Barker wondered aloud whether cord blood expansion was the answer to this issue.

She said that the requirements for success for a cord blood expansion technology are that it be logistically easy, have a high likelihood of improving myeloid recovery, and is cost-effective.

She also noted that it should be associated with improved survival or, at the very least, no adverse effects.

Although there are several technologies for cord blood expansion, she pointed out that none have yet fulfilled all the requirements for success.

To reduce treatment-related mortality without cord blood expansion, Barker suggested that this could be achieved with more efficient unit searches and better selection of units.

Also, there should be greater focus on preventing and treating acute GVHD and cytomegalovirus (CMV) infection, as well as pre-engraftment syndrome, among other strategies, she said.

Double-Unit Cord Transplants

Another approach is to perform double-unit cord blood transplants (dCBTs).

Barker pointed to research by Ioannis Politikos, MD, Memorial Sloan Kettering Cancer Center, New York City, presented here in Houston on that topic.

Their study compared dCBT with 8/8 HLA-matched related donor (MRD) or URD T-cell depleted transplants in 206 adults with myeloid malignancies who had a median age of approximately 50 years.

The results showed that dCBT was associated with significantly higher grade 2-4 acute GVHD than the other approaches, at 83% compared to 17% with MRD and 21% with URD transplants (P < .001).

Nevertheless, 3-year treatment-related mortality was not significantly different between groups, at 20%, 12%, and 8%, respectively (P = .20), nor was 3-year relapse, at 12%, 32%, and 24% (P = .08).

After a median follow-up of 3.1 years, 3-year progression-free survival (PFS) was also comparable between the groups, at 70% with dCBT, 63% with MRD, and 68% with URD.

Barker said these results show that double-unit grafts can be used to "safely transplant mismatched units in adults."

New Research With Positive Findings

New research, to be presented later during the conference, shows prophylaxis with letermovir (Prevymis, Merck) is highly efficacious in preventing CMV infection in adults receiving cord blood transplants.

Moreover, it is not associated with attributable toxicity and is cost-effective, making it the new standard of care, although Barker noted one issue is that it is not clear when the drug can be safely stopped.

These are not the only studies to be presented here that show the potential for cord blood as a source of HTCs.

A poster tackled one of the preconceptions clinicians can have about the use of cord blood in hematologic malignancies — the presumed increase in morbidity in elderly patients.

Shruti Singh, MD, Loyola University Medical Center, Maywood, Illinois, and colleagues studied 148 patients aged ≥ 60 years who underwent allogeneic stem cell transplant for hematological malignancies between 2005 and 2016.

The patients, who were considered a high-risk cohort, received umbilical cord-derived (UCB) transplants (n = 58), URD transplants (n = 69), or HLA-matched sibling donor (MRD) transplants (n = 57).

The results showed that median PFS was comparable for UCB and URD transplants, at 5.50 and 5.59 months, respectively, but was much higher for MRD transplants, at 18.3 months.

A similar picture was seen for median overall survival, at 6.64 months for UCB and 6.14 for URD versus 24.28 months for MRD transplants.

UCB patients were more likely to relapse or die than patients who had an MRD transplant, at a hazard ratio of 1.79 (P = .01), but there was no difference UCB and URD patients.

There were also no differences in incidence of acute GVHD between the groups. However, UCB was associated with significantly fewer cases of chronic GVHD than MRD, but not when compared with URD.

The team concludes that MRD "should remain the gold standard for donor course in the elderly high-risk population."

Co-author Patrick A. Hagen, MD, also from Loyola University Medical Center, told Medscape Medical News that he and his colleagues wanted to show that, in the absence of a matched donor, cord blood transplants "can be done safely and with similar outcomes to other alternate donor sources."

He added that, with the older, higher-risk patient population, a "big sticking point is we often don't have time to wait around for other donors, so if there is a good cord available and the patient is in remission, we want to try to show from our experience that they should be taken to transplant."

Hagen said that one of the challenges with cord blood versus haploidentical transplants is the concern about infectious complications, but he agreed with Barker that "they are overblown."

He underlined that "we need to work to get the complications decreased, and so we're doing some correlative and phase 1/2 studies to look at that," including using donor T-cell infusions to decrease infection rates.

Hagen said that he "actually agrees with a lot of the points" Barker made, and added: "There are challenges with cord blood, and the approach shouldn't be to abandon the ship. The approach should be we improve on the outcomes."

Barker said that, despite the encouraging results with cord blood, one of the main issues of stem cell transplantation in general is the poor disease-free survival.

She said that, if transplant A is associated with a 3-year disease-free survival of 36% and transplant B has a disease-free survival of 39%, the general response is "they are the same and I like B."

However, her interpretation is that the treatment "failed in the majority of patients in both arms, and we need to improve each arm."

No study funding declared. The authors have reported no relevant financial relationships.

2019 TCT Transplantation. Presented 20 February. Poster 312

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