History in the making

Stem cell transplants have been making headlines and changing lives for 65 years

The science of haematopoietic stem cell transplantation has greatly improved over the last half century, but there’s still much more work to be done.

In 1956, a New York doctor transplanted bone marrow from one twin to another; who was suffering from leukaemia. It was the first ever successful bone marrow transplant. Now – over 65 years later – more than 100,000 hematopoietic stem and progenitor cell transplantation (HSCT) procedures are expected to be performed worldwide this year alone.

Thanks to a steady stream of innovations in HSCT, the rate and quality of these life-saving transplants have increased dramatically in the last few decades, offering improved prognoses to patients with a wide range of haematologic diseases and cancer. And many more patients who were once passed over for HSCT because of their advanced age are now being offered transplants. Furthermore, the number of autologous stem cell transplants performed in patients over age 60 quintupled between 2000 and 2018.

While there are many different innovations that have driven the growth of HSCT, improvements in the precise enumeration of viable CD34-positive hematopoietic stem and progenitor cells have played a major role. The enumeration of these cells is critical to determine the viability and potency of cells used in HSCT, thereby increasing the likelihood of successful engraftment.

As HSCT continues to evolve, there are still challenges to be solved, such as lab errors in cell enumeration and lab-to-lab variability in procedures and results. Increased automation is helping to lower these hurdles, but it will be incumbent upon leaders in the field to standardise effective methods and procedures, and harmonise best practices worldwide, ensuring that patient who undergoes HSCT has a high chance of success.

To better understand the current HSCT landscape, it’s helpful to review just how far this field has come in the last half-century. It was the late 1950s when researchers first demonstrated that a cellular component of bone marrow could regenerate healthy cells in cancer patients who had received high doses of radiation. Over the next two decades, a small number of patients received either autologous transplants or allogeneic transplants from bone marrow donors.

It wasn’t until the 1980s that the enumeration of CD34-positive haematopoietic cells became feasible. Three studies led to the development of monoclonal antibodies that could bind to cells that form most colony-forming units for myeloid and erythroid progenitor lineages. That pioneering work gave rise to all of the antibodies that are used today to enumerate CD34-positive cells.

The number of HSCTs rose dramatically in the 1980s and 1990s, with the majority being autologous transplants. There was also a shift away from bone marrow and towards peripheral blood as the primary source of transplanted cells. At the same time, improvements in supportive care made HSCT more tolerable, likely driving the increase in older patients undergoing the procedure.

While all of this is good news for patients, the improvement in outcomes is even more encouraging. Five-year survival rates for HSCT recipients have increased steadily since 1993, while the probability of patients relapsing before dying has dropped, according to the American Society for Transplantation and Cellular Therapy.

Further enhancement of HSCT patient outcomes is certainly within reach, provided the ability to enumerate CD34-positive cells continues to improve. CD34-positive cell quantities vary by source but are especially low in peripheral blood: less than 0.1%, vs. 1% to 3% in bone marrow. While mobilisation schemes can increase these numbers, accurate enumeration is key to ensure successful engraftment.

Automation can increase flexibility, helping laboratory managers adjust their protocols to meet changing guidelines, and it can greatly reduce manual, error-prone processes. But studies have shown that standardising enumeration procedures – and improving the training protocols used in laboratories that perform enumeration – is vital.

One survey carried out within a few years of the original ISHAGE guideline release found that 43% of labs that said they followed the guidelines were not set up properly to do so, and the failure rate of CD34 enumeration doubled when incorrect ISHAGE protocols were used.

Given how critical it is to harvest large populations of viable stem cells for successful transplantations, the HSCT field should work towards harmonising international guidelines and standards for enumeration.

HSCT has provided hope to so many patients in the 65 years that have passed since one twin saved the life of another. Let’s build on that progress and continue to support innovations that boost every patient’s shot at a cure.