Risks for Healthy PBSC Donors? One Family’s Powerful Experience

By Jane Langille

A few weeks ago, I wrote to Dr. Paul Knoepfler after reading his book Stem Cells: An Insider’s Guide because I was intrigued by his stem cell theory of aging. I wondered if his theory might mean that someone who mobilized and donated hematopoietic cells might be shortening their own lifetime supply. After exchanging emails about my daughter’s experience, he invited me to contribute a guest blog as he felt that the complexity of her experience as a donor and the questions I was raising would be of interest to the stem cell community.

Peripheral blood stem cell (PBSC) donation is a miraculous treatment that provides people with high-risk forms of blood cancers and other immune diseases a last chance for a cure when other treatment options are exhausted.

As of December 2012, the number of hematopoietic stem cell transplants worldwide passed the 1 million mark, a remarkable accomplishment reported in a retrospective study published recently in The Lancet Haematology. Data collected by the Worldwide Network for Bone and Marrow Transplantation showed that across 75 countries, 42% of hematopoietic stem cell transplants (HSCTs) were allogeneic and 58% were autologous.

The preparation for cancer patients prior to receiving a donation is brutal. Their immune system is wiped out with high doses of chemotherapy and/or radiation therapy so their body is ready for an infusion of healthy, donated hematopoietic stem cells that hopefully find their way into niches in the bone marrow where they divide and produce healthy blood cells. The human leucocyte antigen (HLA) match between the donor and recipient must be as close as possible to minimize the risk of rejection.

It’s a remarkable treatment that helps many critically ill people. But what are the short and long-term risks for healthy donors?

Those were the questions I was contemplating in the spring of 2013 when my daughter Katherine, 22 at the time, turned up as a perfect match for an unknown patient in the bone marrow registry. I was worried about her decision to donate from two different perspectives: as her mom; and as a health journalist.

Short-term issues

As her Mom, I was proud that Katherine had a big heart and the courage to donate a gift of life to a complete stranger. According to some reports, only about half of the people who are identified as matches in the bone marrow registry follow through. This was the child who had to be bear-hugged for childhood vaccines, so I was surprised she was volunteering for a procedure that would mean self-injecting a growth factor drug, twice a day for four days, followed by leukapheresis, which requires being tethered to blood filtering equipment with cannula in both arms for hours.

I also wondered how she would manage the stress, given that the donation was squeezed in between grad school interviews, final exams and her thesis presentation in her final year of university. The information provided by Canadian Blood Services’ OneMatch Stem Cell and Marrow Network said that donors would feel tired and achy for 5-7 days and there were possible complications of spleen rupture, but those symptoms would return to normal fairly quickly after donation was completed.

Long-term worry

As a health journalist, I had another worry. I didn’t like that the growth-factor drug she had to inject for four days prior to donation had an unproven safety profile among healthy donors and was an off-label use. The consent forms said, “No long-term safety information is available.”

The FDA approved the drug Neupogen in 1991. The drug contains the active ingredient filgrastim, a granulocyte colony-stimulating factor. The FDA approval and subsequent updates show that Neupogen was approved for autologous use among cancer patients, with no mention of allogeneic use by healthy donors. There is also no mention of healthy donors in the prescribing information.

Neupogen

A 2007 paper in the British Journal of Haematology mentions that since 1997, the US National Marrow Donor Program has maintained an Investigational New Drug application for the manufacture of PBSC products from unrelated donors and that “it is unknown whether filgrastim increases or decreases an individual’s risk of developing cancer” but added, “based on limited long-term data from healthy people…no long-term risks have been found so far.” Not exactly reassuring.

The only prospective trial I could find assessing the safety of filgrastim-mobilized stem cell donation and PBSC leukapheresis among healthy donors is currently underway and will not be completed until January 2022. The description says that filgrastim is “not a licensed indication,” and mentions that data collection began in February 1997.

The decision to donate

So the crux of the decision came down to this: should she risk an unproven drug treatment so that she could give a complete stranger another chance at life?

As a 22-year old adult, it was Katherine’s personal decision to follow through. She self-injected filgrastim twice a day and had the usual symptoms of bone aches, headache, and fatigue. She donated over two days, tethered to the apheresis machine for about 5 hours each day in a room where the other 10 treatment chairs were filled with cancer patients receiving chemotherapy and plasma treatments.

Kat-OneMatch-Donation-2

It was an odd juxtaposition for everyone involved, but the equipment and staff were located there. A second day is not always required, but it turned out that the recipient was apparently 15 kg (33 lbs.) larger than she was and the target collection calculation depends on body weight.

After her donation days, she traveled by train back to her university town three hours away to study for final exams and work on her thesis presentation. Three weeks later, she had an enlarged spleen scare, which prompted a visit to her local hospital ER via ambulance and had to restrict her activity to prevent a ruptured spleen. The donation hospital in Toronto then requested she travel back for a check a couple of weeks later. By then, thankfully, her spleen was back to normal size. She was well enough to do a karate grading a few weeks later and over the last two years, has had no complications.

At the one-year mark, she contacted OneMatch to find out if it would be possible to exchange contact information with the recipient, as the rules allow for that if both donor and recipient agree. She learned that the recipient lives in a country where there is a two-year restriction on information exchange. She doesn’t really want to know the recipient, but someday would like to know how they fared with her gift and if it made a difference.

There’s no question I’m proud she followed through with a donation. Even better — she’s proud. Katherine says, “In any case, I’m happy to know that my gift likely brought hope to the recipient and their family.”

The stem cell theory of aging

Dr. Knoepfler provided some helpful perspective about how a one-time mobilization of stem cells might affect a donor’s long-term health. He said, “In principle, boosting production of stem cells for a PBSC donation could have long-term effects. My feeling in the grand scheme of life is that a short-term, one-time mobilization of PBSC is unlikely to have a lasting effect on an otherwise healthy young person. Given the massive turnover in blood cells (something like a trillion blood cells are replaced per week for each of us), our hematopoietic stem cells have got to be very robust and for the dozens of times in our lives when we get sick enough to mount a major immune response, our stem cells are mobilized repeatedly each time.”

Bottom line

Is it admirable to donate and give someone else a chance at life? Of course! But I wish donors could have more information on how the procedure might affect them in both the short and long term, to understand more about what they are risking in order to help someone else. Here’s hoping that the study currently underway finds minimal risks for donors. In the meantime, it was great to get some perspective and reassurance from a scientist working in the stem cell field.

Jane Langille is a health journalist and mom based near Toronto, ON, Canada.

New biotech Semma Therapeutics joins ViaCyte & Betalogics in stem cell Diabetes arena

Semma Therapeutics

Semma’s technology director Felicia Pagliuca, with CEO Robert Millman. Boston Globe Picture

A new biotech startup, Semma Therapeutics, announced that it seeks to fight diabetes via translating technology from the lab of Doug Melton at Harvard to the clinic.

Another major player in cell therapy-based arena for Diabetes is most likely good news for patients.

Quoted in the Boston Globe, there is a good deal of enthusiasm about the potential of this kind of therapeutic approach:

“This would be a huge breakthrough,” said Dr. George L. King, a Harvard Medical School professor and research director at Joslin Diabetes Center. “It could cure diabetes.”

Semma TherapeuticsSemma will have to compete with ViaCyte and Betalogics, which could prove challenging given, for example, that ViaCyte already has an ongoing FDA-approved clinical trial. Still Semma has raised more than $40 million, which is a good start, and this capital came from some known bio-investment players:

“Sensing a business opportunity at the juncture of stem cells and diabetes, venture firms MPM Capital, Fidelity Biosciences of Cambridge, and Arch Venture Partners of Chicago are teaming with Minneapolis-based medical technology giant Medtronic plc to back Semma in the company’s first round of financing.”

Two of the leaders of Semma are former Melton lab postdoc Felicia Pagliuca, and CEO Robert Millman. Pagliuca was first author on a high-profile Melton lab paper in Cell published just about half a year ago and post-pub reviewed on this blog.

The Semma website has more information.

Why the name Semma?

I’m not sure.

There is a SEMMA acronym in high-tech:

Sample, Explore, Modify, Model, Assess.

It’ll be exciting to see how Semma performs and more broadly how cell therapy-based approaches to Diabetes evolve. I view Semma coming on the scene as a positive.

Lisa Ikemoto Guest Piece on Human Germline Genetic Modification

lisa ikemotoLisa C. Ikemoto, Professor, U.C. Davis School of Law

I have been following the reports about genetic editing technology with concern. The fact that some scientists are calling for moratoria on gene editing of human embryos heartens me. Frankly, I had little confidence that any group of scientists could bring themselves to call for limits on research. The call for a moratorium is as much a game changer as the technology itself. It creates an opportunity for research transparency and open exchange between the scientific community and the lay public. Germline modification raises a wide range of scientific, social and ethical issues that we have only begun to consider. The call for a moratorium puts those issues front and center and, if implemented, gives us valuable time for consideration.

In the meantime, as Paul Knoepfler has pointed out, we need is a practical plan for proceeding. His ABCD plan proposes use of SCROs for approval and oversight of in vitro research. The use of existing oversight mechanisms makes sense, although in practice, both IRB and SCRO review is only as rigorous as local institutional culture allows. SCRO review is a decentralized oversight mechanism through which research standards are subject to variable interpretation. However, as Knoepfler points out, SCROs are already in place.

As a bioethics scholar and teacher, I find the bioethics training appealing, fascinating, and daunting, given the wide range of potential issues. I’m glad to see that Knoepfler has flagged sourcing of human oocytes as one issue. In the fertility context, human oocyctes are procured through a largely unregulated and rapidly expanding market. The process of soliciting young women to provide oocytes for others’ use is often degrading and expresses eugenic ideals. (See my recent blogpost here). Federal guidelines and a few state laws prohibit payment to research donors. But I worry that the notion of free market individualism used to explain treating women as sources of raw materials and exposing healthy young women to the risks of ovarian stimulation and oocyte retrieval is being used in research, as well. Do we really want to superimpose market thinking on human beings, in the name of science?

I would hope that bioethics training would take the concerns of disability rights activists seriously. Genetic modification is a form of genetic selection. We have a long, bad history of mis-using human genetic selection. Genetic selection technology use can, and probably will, expand the list of conditions and traits considered undesirable. As the list expands, so will the therapeutic justification for genetic modification. The most important concern is that as the list expands, acceptance of persons with disabilities will narrow. The Americans with Disabilities Act has effected important legal and social changes for people with disabilities, and the Genetic Information Nondiscrimination Act provides some protection against genetic discrimination. But neither limits the use of genetic selection. While this concern applies most obviously to in vivo research, it starts with in vitro research agendas.

The Scientist’s Garden: Spring Has Sprung

the scientist's gardenIn celebrate the start of Spring yesterday, here are some pics from my garden. I have so little time I kind of neglect it, but sometimes it all turns out anyway.

Above you can see the edge of one of the beds with over-wintered & self-reseeded sweet alyssum in white and purple. Intermixed I have tulips and miniature carnations, with the latter surviving the winter. The climate in Davis, CA can be very mild in the winter and this year that was especially true. I like the combinationof purple and white overall. To the right of the flowers are various veggies that grew over the winter and are now exploding including lettuce, beets, dill, carrots, and cilantro.

more scientists garden

Here you can see all kinds of flowers in a gardening riot mixed with veggies.

Then below is a nice sunrise viewed from the garden. Got to stop working on one’s grant early in the morning and go outside sometimes.garden sunset

Practical Plan for Managing Human Germline Genetic Modification

CRISPR-Cas9 gene editing technology is a game changer on many levels both inside and soon outside the lab. There is a growing sense of urgency amongst biomedical scientists to take a proactive approach to current and future use of CRISPR technology in human germ cells and embryos.

These concerns have been heightened by rumors of multiple papers currently in various stages of peer review that will reportedly describe CRISPR-mediated gene editing of human embryos. A number of scientists and scientific organizations have recently come out with policy statements on human germline genetic modification: Lanphier, et al. NatureBaltimore, et al. Science, and ISSCR.

I’ve outlined a proposed plan (see figure below) that I call ABCD for simplicity to try to practically manage the situation with human germline genetic modification. This plan shares a few key features with some of those already proposed by others, but in some ways it is different or more specific. This ABCD idea is just a possible plan coming from one person (me) with the intention of positively adding to the overall dialogue.ABCD Plan Human Germline Modification

My view is that in vitro research on genetically modified human germ cells and early embryos–with appropriate training and oversight–is ethical and can in fact be of great value. Such work will provide new, valuable information about gene editing itself and early human development, fertility, and more. Therefore, such research should not be prohibited, but should only be conducted under certain conditions.

For example, the In vitro studies of genetically modified human germ cells and embryos would require appropriate approval and oversight. This is the A part of the plan. Given the urgency in terms of timing on this issue, it seems impractical to create new committees from scratch solely for this purpose. Thus, I propose that standing SCRO committees have the authority and responsibility to regulate genetically modified germ cell and embryo-related work. They already are the ones overseeing similar research now. The human germ cell and embryo CRISPR work would have to have a compelling justification to get SCRO approval.

Researchers proposing to the relevant SCRO or similar committee to conduct research related to human genetic modification of germ cells or embryos must also receive bioethics training, which is the B part of the plan. This is particularly important because of the complicated bioethical issues that this unique kind of work raises and such training would serve to provide a strong educational component. Bioethical issues to be discussed would include the human germ cell modification itself, the specific concerns over outcomes if the work were applied in vivo, and other aspects such as the sourcing of human oocytes. As to that last issue, in vitro CRISPR human genetic modification research could substantially increase the research demand for human eggs.

The C part of the plan is clarity. Both the public and scientists would greatly benefit from education and openness in this area. Transparency and outreach in lay terms is essential for public trust. Research on human germline genetic modification, including those manuscripts potentially currently in review, should be published in open access format to make the data fully available to society as a whole. No pay walls here. This area of research is too important and charged to block access.

The D part of the plan is don’t extend the work to vivo applications involving implantation of genetically modified human embryos. There should be a moratorium on this step given the major ethical and safety issues involved. Whether such a moratorium could ever be lifted is unclear and would depend on what the data that come in the next few years teaches us. Practically speaking the questions of how such a moratorium would work or be enforced are tough ones, especially if one intends to extend it internationally.

With these ABCD guidelines in place the goal would be that innovative, valuable research in this area could proceed in a responsible and ethical manner, while minimizing the risk of negative outcomes.

Within just a year or two the knowledge base regarding CRISPR-based gene editing will be vastly increased. Further, in the same timeline additional next-generation CRISPR approaches will improve accuracy and introduce further refinements in the technology. Plans for managing germline human genetic modification may need to evolve as well. The ongoing dialogue that has ramped up recently already shows signs of having very positive impact and is likely to continue to do so as it proceeds.