Newsletter - March 2013

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Case report of a stem cell transplant supported by expanded MSC

Erik J. Woods, Ph.D. W. Scott Goebel, M.D., Ph.D.

Erik J. Woods, Ph.D., &
W. Scott Goebel, M.D., Ph.D.,
Cook General BioTechnology LLC

This case report describes a novel stem cell transplant that we performed for a girl with Fanconi anemia. Children with Fanconi anemia have genetic defects that prevent normal DNA repair. The disease leads to bone marrow failure, and also to acute leukemia and solid tumors. The only long-term solution for the marrow failure is a transplant with normal blood-forming stem cells, either from a bone marrow donor or a cord blood donor. The very first cord blood transplant in the world was performed in 1988 for a child with Fanconi anemia.

Our Fanconi anemia patient received a transplant of blood-forming stem cells from her brother's bone marrow. In an effort help her recover faster from her transplant, we also gave her Mesenchymal Stem Cells (MSC) that were extracted from her brother's bone marrow and cultured in a laboratory to expand the number of cells before infusion. The beneficial characteristics of MSC support this therapeutic approach.

Mesenchymal Stem Cells can be derived from most adult tissues including bone marrow, fat, skin and dental pulp, as well as post-natal tissues like the umbilical cord and placenta. MSC can function both as regenerative and medicinal cells. Some cord blood banks now routinely offer parents the opportunity to store MSC from cord tissue along with their baby's cord blood. Hence MSC from cord tissue are becoming a readily available resource for therapy.

Researchers hope that co-transplants with MSC can reduce the time it takes a stem cell transplant to "engraft" and replace the patient's blood and immune system. This behavior relies on the medicinal capacity of MSC: they serve a transient role supporting the healing behavior of other cells in the patient's body, and then the MSC leave the patient's system. The co-transplanted MSC might reduce the risk of stem cell transplants, both by decreasing the dangerous time period before the donor cells begin to grow, and also by avoiding graft-versus-host disease (GVHD) where the donor immune cells attack the patient.

It was suggested in a previous issue of this newsletter that MSC from cord tissue could be co-transplanted with cord blood, using both cell types from a single donor. Our case report provides proof of this concept, because our patient received blood-forming stem cells and expanded MSC from a single donor.

Before treating our first patient, we demonstrated the feasibility of co-transplants with MSC in a mouse model of Fanconi anemia. We found that the MSC enhanced blood stem cell engraftment (1). This result enabled us to apply for a single patient clinical study. The transplant was conducted under both FDA and IRB approval, and the results were presented by Dr. Goebel at the AABB 2012 annual meeting in the featured plenary session (2).

Our patient's transplant was supported by a joint industry-academic cooperation in Indianapolis, USA. The donor's bone marrow was harvested at Indiana University about two months prior to the transplant. A portion of the bone marrow was taken to the laboratory of Cook General BioTechnology, where MSC were expanded for clinical dose production. The transplant took place at Riley Hospital for Children.

The patient's transplant proceeded in phases. The first dose of MSC was infused one day before the bone marrow transplant. Following the transplant, three weekly doses of MSC were infused. A standard drug regimen was used to prevent GVHD. The patient tolerated the MSC infusions without any complications. Engraftment (defined as neutrophil count over 500) occurred 12 days after the bone marrow transplant, as compared to the typical 14-17 days following a bone marrow transplant without MSC. She is now more than one year beyond the stem cell transplant, is no longer taking any immune suppressive drugs, has normal blood counts, and has not had serious infections. Despite an increased risk for GVHD in Fanconi anemia patients, this patient has not had GVHD. Lab analysis shows that her blood system is made of 100% donor cells.

Co-transplantation with MSC offers hope for similar patients at high risk of engraftment failure and/or GVHD. The bone marrow transplant described here could be seamlessly translated to a cord blood transplant. We are excited to continue this work and look forward to the possibility of transplants using cord blood and cord tissue-derived MSC from the same donor in future studies targeting Fanconi anemia and other diseases.

Given the clinical potential of MSC, cord tissue banking should always be considered in combination with cord blood banking. It is possible that cord tissue MSC, due to their post-natal nature, could be more potent than MSC from other sources, including bone marrow. In addition to co-transplantation with blood forming stem cells, MSC could be useful to treat heart disease, rheumatoid arthritis, wounds, and sports injuries. The wide range of possible uses for these cells justifies serious consideration of banking cord tissue-derived MSC on their own. Many private banks offer this service at a significantly lower cost than cord blood banking.

The use of MSC, regardless of their origin, will be subjected to FDA regulation. There are no currently approved clinical uses of MSC in the United States. The use of these cells must be done as part of an approved clinical study, but there are a number of options to gain access to these potential therapies. If you would like to bank MSC from cord tissue, please ask your bank how they plan to help you navigate the FDA requirements for the use of your cells.

Dr. Erik J. Woods, Ph.D. co-founded Cook General BioTechnology LLC to apply techniques he developed in cryopreservation, enhanced cell culture and tissue engineering from a practical perspective. Dr. Woods has continued to extend his research to clinically relevant applications, including unique methods for GMP cell processing and associated devices. He holds multiple patents, has published numerous scientific articles, reviews and book chapters. Dr. Woods is the current President-elect of the Society for Cryobiology. Genesis Bank is the family cell banking service of Cook General BioTechnology. For more information about banking cord blood and cord tissue, contact info@thegenesisbank.com.

Dr. W. Scott Goebel, M.D., Ph.D has served as Medical Director of the Genesis Bank at Cook General BioTechnology since its inception. He is a member of the Pediatric Stem Cell Transplantation Program at Riley Hospital for Children in Indianapolis, where he has personally performed more than 40 cord blood transplants in pediatric patients. Dr. Goebel is currently an investigator at the Herman B. Wells Center for Pediatric Research and an assistant professor of pediatrics at the Indiana University School of Medicine, where his research has included treatment of genetic disorders by transplantation of gene-corrected hematopoietic stem cells, as well as studies on long-term engraftment of stem cells.

References

  1. Mesenchymal stem/progenitor cells promote the reconstitution of exogenous hematopoietic stem cells in Fancg-/- mice in vivo
    Yan Li, Shi Chen, Jin Yuan, Yanzhu Yang, Jingling Li, Jin Ma, Xiaohua Wu, Marcel Freund, Karen Pollok, Helmut Hanenberg, W. Scott Goebel, and Feng-Chun Yang
    Blood 2009 113(10):2342-2351; doi:10.1182/blood-2008-07-168138 (Full text)
  2. Transfusion, Volume 52, issue s3, September 2012, page 13A; abstract P6-030A
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Haplo-Cord Transplants

(cord blood transplants supported by half-matched bone marrow)

Mi Kwon, M.D.

Mi Kwon, M.D., Hospital General Universitario Gregorio Marañon, Madrid, Spain

When a patient needs a stem cell transplant, the physician's goal is to find donor stem cells that match the patient's Human Leukocyte Antigens, also known as HLA type. The ideal donor is a sibling who is an exact match, but only about 30% of patients can find a matching donor in their family. The next best thing is a matching unrelated donor (MUD) of bone marrow. But here too, not all patients can find a match. It is especially difficult for patients of African descent or mixed ancestry to find matching bone marrow donors. At this point, the next step is to look for a cord blood donation that is a close enough match.

Cord blood transplants have both advantages and disadvantages for patients. Their biggest advantage is that the HLA types do not have to match exactly between the donor and patient. Studies have shown that, when looking at the 6 most important HLA types, cord blood transplants with only 4 of 6 HLA match are just as successful as bone marrow transplants that are 6 of 6 matched, in terms of long-term patient survival. Another advantage of cord blood stem cells is that they can be available in much less time than it takes to activate a registered bone marrow donor. But the biggest disadvantage of cord blood transplants is that it takes longer for the stem cells from cord blood donations to "engraft", so that the patient's immune system recovers. That is very dangerous because, while waiting for engraftment, the patient has no ability to fight disease and is at risk of a fatal infection.

At the Hospital General Universitario Gregorio Marañon, in Madrid, our research on cord blood transplants is focused on ways to combine cord blood stem cells with other donated stem cells so that patients will receive a full cell dose and will have faster engraftment. In this way we hope to push back the frontier of cord blood transplantation, and make the procedure both safer and available to more patients.

Our group has developed a strategy called "dual" or "haplo-cord" transplants: patients receive stem cells from a single cord blood unit combined with stem cells from the bone marrow of a donor who is "haploidentical" to the patient. A haploidentical donor is one who is a half-match. A haplotype is a series of genes that are close together on a chromsone and are usually inherited as a group. People inherit half their HLA types from their mother and half from their father. But since the HLA types are grouped into haplotypes, another way of looking at it, is that we receive one haplotype from the mother and one from the father. Thus, each parent is by definition a haploidentical matching donor, and 90% of people can find a haploidentical donor among their relatives. It is not difficult to find a haploidentical donor in a registry of bone marrow donors.

It has been known for many years that haploidentical bone marrow donors are not close enough matches for successful stem cell transplants; there is a strong chance the patient will experience graft failure or terrible graft versus host disease. However, when matching cord blood cells are given together with haploidentical donor cells in a haplo-cord transplant, the two stem cell sources support each other and produce a better outcome than either alone.

Haplo-cord transplants have been shown to reduce the patient's engraftment time, because the haploidentical donor cells engraft faster than the cord blood cells. However, this engraftment is transient, and only acts as a bridge - eventually the stem cells from the cord blood donor take over, replace the haploidentical donor cells, and engraft permanently.

Our group conducted the first clinical trial to compare outcomes of haplo-cord transplants versus MUD bone marrow transplants, for patients diagnosed with high-risk leukemias. In this study, 25 patients received traditional MUD bone marrow transplants and 20 patients received haplo-cord transplants. The median time for bone marrow engraftment was similar in the two groups, 16 days for MUD and 14 days for halo-cord. Incidents of serious post-transplant infection were also similar between the two groups.

The key result of the study was that outcome measures were comparable between the two groups of patients: haplo-cord transplants are just as good as traditional MUD bone marrow transplants for long-term survival. These outcome measures include overall survival, disease-free survival, and toxic-related deaths.

A second study result which is also very important was that the haplo-cord patient group had significantly less graft versus host disease, only 5% in the haplo-cord group versus 40% in the MUD group. Graft versus host disease is a major complication after any transplants with donor cells, and can seriously compromise the quality of life experienced by transplant survivors.

Taking the two results together, our study showed that haplo-cord transplants are just as good as traditional MUD bone marrow transplants for ensuring patient survival, and can be better than MUD transplants for patient quality of life post-transplant. Haplo-cord transplants confer the best qualities of both bone marrow and cord blood transplants: they have the shorter engraftement time of bone marrow transplants and the lower incidence of graft versus host disease of cord blood transplants.

In the future, we hope that more of our colleagues will adopt the haplo-cord option for their patients who lack a bone marrow donor or who require urgent transplantation. Haplo-cord transplants merit broader exploration through clinical trials for different hematologic diseases.

Mi Kwon was born in South Korea but grew up in Buenos Aires, where she received an M.D. degree from the Faculty of Medicine of the Universidad de Buenos Aires, Argentina. She is now a consultant physician at the Stem Cell Transplant Unit of Hospital General Universitario Gregorio Marañon, in Madrid, Spain. The unit performs both autologous and allogeneic stem cell transplants and has extensive experience with alternative donor sources for transplantation. Hospitals in Madrid lead the world in research on haplo-cord transplants. Dr. Kwon is also currently pursuing a Ph.D., based on research into the genetics of leukemia and cord blood transplantation.

Reference

  • Single Cord Blood Combined with HLA-Mismatched Third Party Donor Cells: Comparable Results to Matched Unrelated Donor Transplantation in High-Risk Patients with Hematologic Disorders
    Mi Kwon, Pascual Balsalobre, David Serrano, A. Pérez Corral, Ismael Buño, Javier Anguita, Jorge Gayoso, Jose Luis Diez-Martin
    BBMT 19(1): 143-149, January 2013 (Abstract)
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BMT InfoNet

Susan K. Stewart

Susan K. Stewart was in the prime of her life when, at age 38, she was told she had leukemia and needed a bone marrow transplant. "I was stunned", recalls Stewart. "I had no idea what a bone marrow transplant was or even why bone marrow was important."

Twenty-three years later, Stewart now heads BMT InfoNet (Blood & Marrow Transplant Information Network) which provides bone marrow, stem cell and cord blood transplant patients and their families with information and emotional support so that they can make informed decisions about whether or not to undergo a transplant.

"When I was diagnosed with leukemia, I didn't know anyone who had a bone marrow transplant. All the information given to me about the procedure was orally, meeting with doctors. Most of it went in one ear and out the other."

Her experience prompted her to write a series of newsletters and then two patient handbooks to explain - in clear, simple terms - what's involved in undergoing a transplant. More than 75,000 copies of the books have been distributed to patients and family members thus far, and many patients refer to the books as their "BMT bible".

books and support publications

Since its inception in 1990, BMT InfoNet has expanded its patient services. Through their web site, www.bmtinfonet.org, BMT offers access to books about transplantation, a peer support program called Caring Connections, an online Transplant Directory with details about more than 250 transplant centers in the U.S. and Canada, and helpful videos about what to expect before, during and after transplant.

"Most recently our focus has been on helping transplant survivors who continue to face health and emotional challenges many years after transplant", says Stewart. The group will be hosting its 5th national Celebrating a Second Chance at Life Survivorship Symposium in Costa Mesa, CA April 20-21, 2013 and expects 300-500 survivors and family members to attend.

"I know, first hand, the challenges transplant patients and survivors face", says Stewart. "Our mission is to help patients and families better manage both the medical and emotional challenges they face before, during and after treatment. It's very rewarding work." To learn more go to www.bmtinfonet.org or phone 888-597-7674.
(click on banner below to go to symposium registration page)

Celebrating a Second Chance at Life 2013