Congratulations! Mr. Xiaojun Huang has been elected as an academician of the Chinese Academy of Engineering.Huang Xiaojun, an expert in hematologic diseases, serves as the director of the Hematology Department at Peking University People’s Hospital and the head of the Hematology Disease Research Institute at Peking University. His outstanding contributions are primarily concentrated in the field of leukemia transplantation, where he introduced the “Beijing Protocol,” a bone marrow transplant plan that effectively addresses donor issues. This innovation has made a significant impact on the field, leading to his election as an academician on November 22, 2023.
Let’s revisit his lecture from the CC Forum eight years ago.
“I and my team have established and refined a novel system for hematopoietic stem cell transplantation to treat malignant blood diseases. I am honored and proud to announce that this approach has now become a mainstream international method for treating hematologic malignancies, propelling the industry’s development. According to 2014 data, Peking University People’s Hospital has become the world’s largest allogeneic hematopoietic stem cell transplant center and one of the most effective units in this field. I feel extremely honored and proud, and now I will share the story of the Beijing Protocol.”
“Is Leukemia Incurable?”
Speaking of leukemia, a familiar topic to many, one might believe it is incurable. But is leukemia truly incurable? Not at all! Whether through drug treatments or hematopoietic stem cell transplantation, there is a possibility to cure this disease.
This is a popular science topic, and hematopoietic stem cell transplantation remains one of the most effective treatments for many diseases. Hematopoietic stem cell transplantation is depicted in this diagram: we extract healthy hematopoietic stem cells and infuse them back into patients who have undergone pre-treatment, often referred to as conditioning, involving chemotherapy. The infused stem cells then rebuild the patient’s blood and immune system, ultimately curing the disease.
This entire process is known as hematopoietic stem cell transplantation. The prerequisite for hematopoietic stem cell transplantation is having a source of normal hematopoietic stem cells. This requirement has, in fact, posed a challenge to the development of hematopoietic stem cell transplantation over the years.
Traditional Challenges in Hematopoietic Stem Cell Transplantation
According to traditional theory, for hematopoietic stem cell transplantation to occur, the donor’s tissue type (HLA typing) must be a perfect match with that of the recipient. This typically limits the search for a match to siblings, where there’s only a 25% chance of finding a suitable donor. Moreover, with the prevalent trend of single-child families in China, the pool of potential stem cell donors has been diminishing. Consequently, both in China and globally, efforts have been made to explore non-relative donors as an alternative source of bone marrow. However, the challenge lies in the fact that the tissue types of non-relative donors are often significantly different, making it a rare occurrence.
Introduction of Haplotype Matching Scheme
Certainly, according to traditional theory, a perfect 100% match in tissue type (HLA typing) between the donor and recipient is required for hematopoietic stem cell transplantation. This typically limits the search for a match to siblings, where there’s only a 25% chance of finding a suitable donor. Moreover, with the prevalent trend of single-child families in China, the pool of potential stem cell donors has been diminishing. Consequently, both in China and globally, efforts have been made to explore non-relative donors as an alternative source of bone marrow. However, due to the significant differences in tissue types among non-relative donors, matching is often challenging and considered a rare event.
In response to this challenge, a breakthrough was achieved with the introduction of the haplotype matching scheme. This innovative approach allows for transplantation even when the donor and recipient have a partial match in their tissue types, expanding the pool of potential donors and significantly improving the chances of finding a suitable match for hematopoietic stem cell transplantation.
Therefore, based on this pattern, we can simplify the explanation: parents and children always have a haploidentical match, or what we can refer to as a partial match. However, haploidentical matching provides a promising avenue for solving the donor source issue. Nevertheless, as indicated by the data below, it comes with challenges such as graft rejection (the transplanted cells do not thrive), graft-versus-host disease (the transplanted cells not only attack the tumor but also harm normal tissues), and an overall survival rate that is only one-third of that achieved with a full match from siblings. Thus, while haploidentical matching is a research hotspot, it often becomes a restricted area due to these complexities, both domestically and internationally.
In the 1990s, attempts were already underway to address the challenges associated with haploidentical stem cell transplantation. I pondered why host-versus-graft disease occurs, and it became apparent that T cells, primarily responsible for graft rejection, played a pivotal role. T cells have the ability to combat both tumors and the host, offering resistance to the patient’s own body and infections. The foreign approach was to eliminate T cells, theoretically eliminating the issue of host resistance. However, this approach brought forth new problems, such as increased risks of infection, rejection, and relapse.
Despite some progress, this strategy did not achieve widespread adoption and popularity due to the associated complications. We also attempted a similar approach based on Western medical practices in the late 1990s. Given the influence of Western medicine in China, there was a tendency to trust Western methodologies. During that time, we experimented with a T-cell depletion method, but the results were not satisfactory. Therefore, we began contemplating whether, since removing T cells resolved the host-versus-graft problem, we could find a solution using a perspective rooted in Chinese culture.
The question we posed was whether we could temporarily control the function of T cells, preventing early host resistance. The idea was to introduce T cells into the patient, allow them time to adapt, and then release their functionality gradually. In this way, we aimed to avoid early host-versus-graft disease and enable the T cells to slowly combat tumors and infections. Our focus turned to Granulocyte Colony-Stimulating Factor (G-CSF).
Of course, as we tell this story today, much time has passed since these developments occurred.
G-CSF’s mechanisms are now well understood, but over a decade ago, we were conducting simple in vitro experiments. We didn’t have absolute confidence that it would work; instead, we thought it might. Here, I must share a story about the bond between me and the patients.
Building Trust Across Life and Death
Between 2001 and 2003, we performed a few cases, starting with possibly three or four in 2001 and more in 2002. When we began, our selection criteria were patients with relapsed leukemia. As many may know, if leukemia relapses and isn’t treated promptly, survival is usually limited to two or three months. I vividly remember our first case; it was a patient who had relapsed after undergoing autologous transplantation, and all other treatments had proven ineffective. I explained to him that while we were doing our best with medication, I estimated it might not be sufficient. The best solution would be an allogeneic transplant, but being an only child, he couldn’t find a suitable unrelated donor. He asked if he could consider using his father as a donor, but there was limited worldwide experience with such cases. I believed that inducing immune tolerance using G-CSF could be effective. The patient was understandably eager, and we engaged in discussions. However, when he expressed a firm desire to proceed, I found myself hesitating. I told him I wasn’t entirely sure about going through with it and that I only hoped it would work. So, open and honest communication was crucial, and the patient said, “Dr. Huang, you treated me in the years before this illness. I’ve already lived for over two years, and if I don’t try this, I won’t have a chance. Even if it doesn’t work, I think you’ve gained experience, so go ahead boldly!” With his encouragement, we proceeded according to our plan, and fortunately, it was successful in the end.
During this process, I was deeply moved because the patient’s desire for life and trust in me gave me the courage to take this step. Without his trust, I might have remained in the realm of in vitro experiments or even in imagination forever. Later, because of our ongoing interactions, the patient expressed deep gratitude and considered me his lifesaver. However, deep down, I have always wanted to say that, personally, I should be the one thanking him! Because with his life, he allowed me to achieve this innovative endeavor. So, on this CC Forum platform today, I want to express sincere gratitude to all the patients who have supported and trusted us in our journey.
As depicted in this graph, after our initial five cases in the first year, we expanded to 34 cases. While the graph may appear impressive, when the data was first presented internally in 2004 at a small meeting, I reported results from 58 cases. While our colleagues initially said it looked good and there seemed to be no issues, I knew they harbored doubts, with some questioning whether they truly believed in the results.
“Why isn’t it working after so many attempts?” they wondered. While some of them might have attempted similar procedures, I wasn’t sure if they had faithfully replicated our approach. In subsequent public presentations, around 2007 and 2008, I addressed this skepticism. I told them, “Challenging any new concept is normal, but remember one thing: I might lie to you, but I won’t lie to myself, and I can’t deceive the patients around me. Why? Because our data continues to show consistent improvement. If it were false, how could I sustain this deception for so long?” This data serves as a strong indicator of the procedure’s efficacy. Of course, this was just the first step, and subsequently, many within the country followed suit, eventually achieving similar outcomes.
International recognition of haplotypes
However, gaining international acceptance was an equally challenging task. The graph displayed here, depicting the difference between the high and low curves, illustrates that the transplants I conducted were more effective than conventional chemotherapy. It indicates that the results were comparable to those achieved with sibling donors. Both of these findings were published in the highest-tier international journals in our field, specifically in “Blood.” One article was published in 2011, another in 2013, and the last one in 2014. These results, published on an international platform, helped garner acceptance from the international community.
I remember very clearly in 2009 and 2010, I was invited twice to MD Anderson Cancer Center in the United States, which is the world’s largest transplant center. Of course, as we mentioned earlier, my allogeneic bone marrow transplant surpassed theirs in 2014. At that time, they had the highest expertise and the most significant volume. Despite this, they invited me to the United States to present my findings. While they were skeptical, they were also intrigued and wanted to hear more.
I presented my reports in 2009 and 2010. By 2012, a professor named Anderson approached me. He mentioned that when I first visited, he, without explicitly mentioning Dr. Champlin’s name, expressed doubt, saying he didn’t believe in my results. However, by 2011, Dr. Champlin himself published an article stating, “Now everybody has a donor!” After that, they began to believe. In fact, the leader of transplant in Europe, who had initially doubted the Beijing Protocol, admitted at the European Transplant Congress last year: “I used to be skeptical about Beijing’s approach, but now that Italy has replicated it, I believe!” This was a significant validation. So, it can be said that our work has led the leaders in the global field of hematology to accept that haploidentical transplantation is feasible.
The haplotype solves the problem of donor selection more effectively
However, this work is just getting started. Can it be further perfected? The first problem we addressed was the lack of donors. Now there are plenty of donors, but the question arises: which donor is the best?
The traditional thinking is that the more differences there are at a specific site, the less desirable it is. This is a common understanding. However, we must recognize that common understanding is essentially a bias of an era toward certain issues. It may not always be correct.
Looking at our results now, we can tell you that there is not much difference between matched and unmatched sites. What does make a difference? If we look at it overall, a donor who is a father is better than a mother, a male donor is better than a female donor, so I jokingly say that men have to bear more responsibility. Also, a younger donor is better than an older one. This information has been published in “Blood” as well.
A professor from Germany commented on the donor selection principles, saying, “The principles of donor selection demonstrated here will benefit at least 50% or more of those undergoing haploidentical transplants worldwide.” This shows that what we’ve demonstrated is significant. From initially proving its feasibility to showcasing donor selection principles, along with techniques for relapse prevention and various pre-treatment methods, our progress has been substantial.
Similarly, I have a story. My approach is different from others. One of the most renowned professors in Germany, on one occasion when he invited me to lecture in St. Petersburg, said, “I chaired the session primarily because of your presentation. But why did you choose a different approach, deviating from the step-by-step increase in cell numbers according to my method?” I replied, “Professor Kröger, if I followed your approach, you probably wouldn’t be here listening to my presentation today.” Thus, it’s clear that in 2013, an Italian team replicated my results. In 2015, the Beijing Protocol was formally presented at a conference in Beijing, and it has been included in many textbooks. After completing this work, the United States also adopted a new method, and its development has been robust. Currently, globally, the three mainstream methods of haploidentical transplantation are categorized as 1, 2, and 3, with the third method gradually losing effectiveness while the first and second remain strong.
“Beijing Plan” leads the world
Up to now, we still have the largest number and the best efficacy. In this graph, we can see that, due to the work on haploidentical transplantation, everyone now has a donor. So, I hope that from now on, people won’t say, “I want to undergo a transplant, but I don’t have a donor.” Almost everyone will have a donor, except in extreme cases. The problem now is not having a donor but rather which donor is better. How can we make the process more perfect and improve survival rates and quality of life? Therefore, many people are increasingly paying attention to the “Beijing Protocol” today.
Some colleagues in China say to me, “Dr. Huang, you are very fortunate,” and I do feel fortunate. From the beginning, I acknowledged my luck and felt proud. However, is it merely luck? I don’t think so. I believe it is crucial because we have ideals. I often ponder, what are ideals? Are they goals? Ideals are a kind of vague spiritual force! Because we have ideals, our goals become clearer, and our actions more resolute.
Because we have ideals, starting from medical school, we aimed to solve problems for patients. Because we have ideals, we aspire to address global medical challenges that have not been resolved. Because we have ideals, we’ve developed and formed a team with ideals, enabling us to fearlessly navigate the path of scientific exploration and maintain unwavering confidence.
I believe my story has come to an end. The story of the Beijing Protocol has just begun! Thank you, everyone!
