Transplants el pt

Matching Made Simple

Date: December 17, 2024

by Chaya Venkat

Is a Bone Marrow Transplant in Your Future?

If you are a relatively young CLL patient (I am not going to stick my foot in my mouth by defining "relatively young" any more precisely!), and you have a poor prognostic version of CLL (IgVH unmutated, ATM (11q) deleted, p53 (17p) deleted, ZAP-70 positive, any or all of the above), it is well worth your time to check out bone marrow transplants. Please read the ASH highlights article we just published, to get the latest thinking on the subject (ASH 2024 Highlights).You may not think so right now, but a bone marrow (same thing as a stem cell) transplantation may be your best bet, and sooner than you think. Allogeneic or "allo-" transplants are all the rage. This is where a healthy donor's stem cells are used to replace your own cancer riddled ones in your bone marrow. In this article I would like to take out some of the mystery surrounding the subject of finding a "matched" donor. This is the first step in exploring transplant options and, as in all things medical, this area is lousy with jargon. But don't let that stop you. It is just a bunch of short-hand that doctors use. Have you heard the phrase "if you cannot dazzle them with your brilliance, baffle them with your b.s."? Jargon has been around for as long as human civilization, a way of telling apart those that are the in-crowd and those that are merely riff-raff. Sort of like the silly secret handshakes at the Raccoon Lodge, the ones known only to the members of the exclusive club. Once you get past the jargon, the information behind donor-patient matching is pretty straightforward.

Matching HLA

Most of us know that if you ever need blood transfusions, it had better be blood from a donor that has been matched to your particular blood type. Matching bone marrow stem cells is more complex. The match has to be made on the basis of "HLA" (Human Leukocyte Antigen). Depending on the transplant team you use, the matching of HLA between you and your donor may be made on a 6 point, 8 point or 10 point basis. HLA typing is increasingly done using DNA techniques. It is a lot more complex than simple blood typing and it can take a week or two to get back the results. And I am sure you will not be surprised to hear, it is more expensive as well.

Telling apart friend from foe is very important business if you are a cell. How else will the body know which cell to kill and which one to protect? HLA is the system of markers found on nearly every cell in the body that aid the immune system in telling apart “self” from “non-self”. The genetic coding for HLA is found in a series of genes on the short arm of chromosome 6. Variations in these genes make it possible to have thousands of different possible combinations. In older times, HLA testing was performed by simple blood tests (serologic tests), but with the advent of molecular technologies, we can now look at cellular DNA and define ever more diversity in the HLA types.

Here is one dilemma that transplant specialists (and their patients) face: slicing and dicing the HLA subtypes ever more accurately means we are able to tell apart very subtle differences between the HLA typing between different human beings. The good news is that better matching of the HLA type between donor and patient makes for better transplants, less complications of graft-versus-host disease (GvHD), and better outcome. The bad news is that when we get more picky, it also becomes a lot harder to find that perfect match. I have no doubt that if we keep raising the bar on our definition of a perfect match, a time will come when we each have an entirely unique HLA type, the only one in the whole entire world with just that specific type, sort of like your unique fingerprint. No other individual will be a perfect match. With that dilemma in mind, a consensus is emerging not to go too far in the search for perfection but settle for a match that does a good enough job and at the same time leaves a reasonably high chance of finding a suitable donor. I for one like this pragmatic approach to things.

Some of the transplant centers in this country use a ten point scale, based on five antigens called HLA-A, HLA-B, HLA-C, HLA-DR and HLA-DQ. The first three (A, B and C) are called type 1 antigens and the second bunch (DR and DQ) are called type 2. Generally, the type 1 seem to be measured by low resolution techniques while the type 2 seem to be measured by more fancy high resolution tests. Some centers use a six point scale based only on HLA-A, HLA-B and HLA-DR. Below is a very recent abstract (and link where you can read the full text article for free) that describes why it is important to include the HLA-C in the mix. These authors think HLA-A, -B, -C, and -DR mismatch can have significant adverse clinical effects and can have an impact on survival after unrelated donor BMT. HLA-C should clearly be included in the HLA matching process.

Abstract:

Blood Journal Article (Free full-text)

Blood. 2024 Oct 1;104(7):1923-30.

Impact of HLA class I and class II high-resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome.

Flomenberg N, Baxter-Lowe LA, Confer D, Fernandez-Vina M, Filipovich A, Horowitz M, Hurley C, Kollman C, Anasetti C, Noreen H, Begovich A, Hildebrand W, Petersdorf E, Schmeckpeper B, Setterholm M, Trachtenberg E, Williams T, Yunis E, Weisdorf D.

Department of Medicine and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107

Outcome of unrelated donor marrow transplantation is influenced by donor-recipient matching for HLA. Prior studies assessing the effects of mismatches at specific HLA loci have yielded conflicting results. The importance of high-resolution matching for all HLA loci has also not been established. We therefore examined the effects of HLA matching (low or high resolution or both) on engraftment, graft-versus-host disease (GVHD), and mortality in 1874 donor-recipient pairs retrospectively typed at high resolution for HLA-A, -B, -C, -DRB1, -DQ, and -DP. Mismatches at HLA-A, -B, -C, and -DRB1 each had similar adverse effects on mortality. Only HLA-A mismatches demonstrated significant adverse effects on GVHD. These adverse effects on outcome were more evident in transplants with low-resolution versus only high-resolution mismatches. Mismatches for HLA-DQ or -DP did not significantly affect outcome. When high-resolution mismatches at HLA-A, -B, -C, and -DRB1 were considered together, adverse effects on survival and GVHD were observed. We therefore conclude that matching for HLA-C should be incorporated into algorithms for unrelated donor selection. High-resolution mismatches at HLA-A, -B, -C, and -DRB1 adversely affect outcome, but less so than low-resolution mismatches. When clinical circumstances allow, high-resolution class I typing may help optimize donor selection and improve outcome.

PMID: 15191952
____________

All in the Family

All of us inherit ½ of our entire genetic make-up from our mothers and the other ½ from our fathers, and this is true for our HLA type as well. In other words, you have a double set of HLAs, one set from your dad and one from your mom. Using the set of five HLA antigens, let us assume that you inherited from your mom HLA-A5, HLA-B18, HLA-C25, HLA-DR3 and HLA-DQ5, and from your father you got A7, B36, C17, DR9 and DQ6. Your HLA type based on these 5 antigens can be represented as:

A5 B18 C25 DR3 DQ5	(from mother)
A7 B36 C17 DR9 DQ6	(from father)

Now lets talk about your wife. Below is her HLA type, again one set comes from her mother and one from her father.

A9 B7 C12 DR14 DQ2	(from mother)
A16 B4 C25 DR4 DQ7	(from father)

Your children can have any one of the four combinations, as shown below.

A5 B18 C25 DR3 DQ5		A5 B18 C25 DR3 DQ5		A7 B36 C17 DR9 DQ6		A7 B36 C17 DR9 DQ6
A9 B7 C12 DR14 DQ2		A16 B4 C25 DR4 DQ7		A16 B4 C25 DR4 DQ7		A9 B7 C12 DR14 DQ2

Since there are a large number of each type of HLA antigen, you can see that a huge number of combinations are possible in humans. In other words, the best place to look for a perfectly matched bone marrow donor is within your own family. Brothers and sisters will more likely match than other relatives, such as parents, children, or cousins. Therefore, for each full sibling, you have a one in four (25%) chance of a full match. Below are the odds of finding a perfectly matched donor, depending on the number of full siblings you have. The larger the number of brothers and sisters, the better the chances of having a completely matched donor. (For those of you who are into the math of calculating probabilities, the chance of having a matching donor is 1-(3/4)ⁿ, where n is the number of siblings).

Number of Siblings		Probability
One		25%
Two		44%
Three		58%
Four		68%
Five		76%
Six		82%
Seven		87%
Eight		90%
Nine		92%
Ten		94%

Matched, Unrelated Donors (MUD)

What if you do not have any brothers or sisters, or you are unlucky and none of them match your HLA type, or you have been less than generous with your Christmas and birthday gifts over the years? You are then stuck with depending on the kindness of strangers, looking for a match from an unrelated donor. You realize right away that the chance of matching with a perfect stranger are less likely. Several public and private bone marrow banks have volunteers on their rolls, people whose HLA types are on file. With your own HLA typing in hand, you can walk the complex maze of trying to find a donor whose profile matches yours. Since there are far more Caucasian donors in this country's bone marrow donor lists, your chances of getting a good match are better if you are a standard issue Caucasian yourself. The more exotic your lineage, the poorer your chances of finding a perfectly matched donor. Below are the rough odds, based on your ethnicity. Remember, finding a match on the bone marrow registry of volunteers is just the first step. It then becomes necessary to chase down the donor and make sure he or she is still willing and able to make the donation. This is not always the case: a lot can happen between the time a donor puts his or her name down on the list of volunteers and the time when the actual call comes in for him or her to step up and make good on the promise.

Ethnicity		Probability
Caucasian		52.4%
African American		8%
Asian/Pacific Islander		6.5%
Hispanic		8.5%
Native American		1.2%
Multi-Racial		2.2%
Unknown		21.1%

As things stand right now, only about 30% of patients looking for a matched unrelated donor are able to find suitable matches. The other 70% are out of luck.

The Advantages (and Disadvantages) of Using Umbilical Cord Blood in Adult Bone Marrow Transplants

There is one more source of good quality stem cells for bone marrow transplants, most often just thrown away as so much trash. I am talking about the blood in the placenta and umbilical cord that accompanies each birth. After the baby is born, the umbilical cord is tied off and cut, separating this very real link between baby and mother. There can be anywhere from 50 - 100 ml of blood in the placenta and umbilical cord and it is chock full of baby stem cells ready to start their proliferative careers. As we highlighted in our ASH article (ASH 2024 Highlights), there are several very good advantages to using cord blood in bone marrow transplants — and a few disadvantages as well.

• Harvesting umbilical cord blood poses no risk to mother or child.
• On the other hand, an adult bone marrow donor must undergo mobilization, which means getting shots of Neupogen and leukapharesis. The process is described in prior articles (Primer on Bone Marrow Stem Cell Transplants).
• Umbilical cord blood can be typed and stored in cryogenic freezers, ready for use as soon as it is needed.
• Contacting bone marrow donors listed in the National Marrow Donor Bank can take weeks. Often, it is not possible to locate the volunteer, and upon testing the volunteer may turn out to have some infection or condition that prevents him or her being a donor.
• Insurance companies seem to have no problem with cord blood transplants. In fact the cost of obtaining a matching cord blood is often less than that of harvesting marrow from adult donors.
• Because the stem cells in cord blood are more "primitive" (less set in their ways) than those in adult bone marrow, cord blood transplants have less risk of acute graft versus host disease (GVHD). This makes it possible to perform transplants with less than perfect matches of type.
• The other side of the coin, because the stem cells in cord blood are more primitive, the engraftment process takes longer with cord blood. This may leave the patient vulnerable to a fatal infection for a longer period of time.
• A typical cord blood harvest only contains enough stem cells to transplant children or small adults (~100 pounds by weight). There is a lot of evidence that says it is important to have enough stem cells in the transplant, based on the recipient's weight.
• The very nature of cord blood means you cannot go back for a re-fill from the same donor (baby) in those instance that the first transplant does not "take" and you want to get a booster shot with more stem cells.
• Several researchers are exploring ways of growing huge armies of stem cells from cord blood. As the technology is perfected down the road, they may be able to give you an expanded version of the original cord blood and at the same time hold back some of it in reserve, in case a booster infusion is needed later.
• Another approach is to use two units of cord blood (from two babies) for each adult transplant. The abstract below from ASH 2024 spells out the details. The University of Minnesota is at the cutting edge of this approach. I enjoyed listening to Dr. John Wagner's presentation. The abstract is rather dense in statistics and jargon, but well worth slogging through. I have highlighted the juicy parts for your convenience.
• If you already have your HLA typing done, you can go to the Public HLA Search website of the National Cord Blood Program and check out, for free, a first pass look at potential cord blood matches. The match is done on a six point basis, using HLA-A. HLA-B and HLA-DR antigens. Remember, with cord blood, 5 out of 6 is very much acceptable!
• Costs: while the cord blood is obtained pretty much free of charge by the various public and private banks, there is a cost associated with careful screening and testing of the cord blood (for infectious diseases, HLA typing, etc.) cryogenic freezing and saving of the cord blood, not to mention salaries, profit, overheads, etc. Here is a PDF with the fee schedule charged by the University of Colorado cord blood bank. I am not sure about the costs of the testing, but I understand the cost of the actual cord blood is covered by most insurance companies. This company rep also told me they will cut you a "deal", give you a good price on the second cord if you buy the first one from them. Wow! Roughly speaking, one unit of cord blood costs $17,000.
• You can read more about cord blood, frequently asked questions and answers, on the website of the National Cord Blood Program: http://www.nationalcordbloodprogram.org/qa/.

Abstract:

Non-Myeloablative Umbilical Cord Blood Transplantation (UCBT): Low Transplant-Related Mortality in 59 High-Risk Adults.

Juliet N. Barker, Daniel J. Weisdorf, Todd E. Defor, John E. Wagner. Blood and Marrow Transplant Program, University of Minnesota Medical School, Minneapolis, MN, USA

Conventional allogeneic HSC transplantation is limited by lack of rapidly available, HLA-matched donors & excess transplant-related mortality (TRM) in high-risk adults. Therefore, we investigated the combined use of unrelated donor UCB, utilizing 2 units to augment graft cell dose, with non-myeloablative (NMA) conditioning in adults with advanced or high-risk hematologic malignancy. From 10/01 to 3/04, 59 consecutive adults [median age 49 years (range 19-60), median weight 78 kg (range 53-114)] received NMA UCB UCBT. Patients were eligible if: age >45 years (n=43; 73%); &/or extensive prior therapy (n=25; 42%, inc. 14 prior transplants); &/or serious co-morbidity (n=18; 31%). Patients received cyclophosphamide 50 mg/kg (day-6), fludarabine 200 mg/m2 (40 mg/m2 days-6 to -2), & 200 cGy TBI (day-1), with cyclosporine-A to at least day 100 & mycophenolate mofetil to day 30. Twelve patients without recent chemotherapy also received ATG during conditioning. Patients received either single (n=14) or double (n=45) UCB units with a median total infused cell dose of 3.4 x 107 NC/kg (range 1.1-5.7). Of the 104 units used, 61 were 4/6, 35 were 5/6 & 8 were 6/6 HLA-A,B,DRB1-antigen matched with the recipient. Of 58 evaluable patients, neutrophil recovery to >0.5 x 109/l occurred at a median of 8 days (range 5-32) with a cumulative incidence of sustained donor engraftment of 89% (95%CI: 81-97). In patients with sustained donor engraftment the median BM chimerism was 85% (range 8-100) at day 21, 100% (range 72-100) at day 100, & 100% (range 87-100) at 1 year after transplant. Four patients had primary graft failure & 2 had secondary graft rejection. Of the 44 patients with a prior autograft or chemotherapy within 3 months prior to UCBT, 43 (98%) achieved sustained engraftment as compared to 9/14 (64%) patients who had no chemotherapy or whose chemotherapy was at least 4 months prior to UCBT. The cumulative incidences of grade II-IV & III-IV acute GVHD were 63% (95%CI: 49-77) & 25% (95%CI: 1436) at day 100, & chronic GVHD was 28% (95%CI: 16-40) at 1 year. TRM (Editor's note: TRM stands for treatment related mortality) was 19% (95%CI: 9-29) at day 180, & relapse/progression was 33% (95%CI: 20-46) at both 1 & 2 years. Regression of relapsed or persistent disease has been seen in patients with MDS (n=2), CML (n=1), intermediate and low grade NHL/CLL (n=11), Hodgkins disease (n=1) & myeloma (n=1). With a median follow-up of 16 months (range 4-30), the probability of overall & progression-free survival was 52% (95%CI: 39-65) & 37% (95%CI: 24-50) at 1 year, & 44% (95%CI: 30-58) & 37% (95%CI: 24-50) at 2 years, with no difference in outcome between single & double unit recipients. Notably, day 180 TRM in patients aged >45 years was 14% (95%CI: 4-24), & in those with extensive prior therapy was 24% (95%CI: 8-40). Serious co-morbidity, however, was associated with a higher day 180 TRM of 44% (95%CI: 20-68)(p<0.01). Despite HLA disparity & NMA conditioning, (Editor's note: NMA stands for non-myeloablative or "mini" transplant) NMA UCBT (UCBT stands for umbilical cord blood transplant) is associated with prompt neutrophil recovery, a high incidence of sustained engraftment & relatively low TRM in older or extensively pre-treated adults. Further, a graft-vs-malignancy effect is suggested in both myeloid & lymphoid malignancies. Extended follow-up confirms that the progression-free survival is reasonable given the high-risk nature of this patient population. This approach allows transplantation to be offered to many adults who would otherwise be ineligible based on lack of donor &/or inability to tolerate conventional conditioning.

ASH 2024 Abstract #825 appears in Blood, Volume 104, issue 11, November 16, 2024

Additional Reading

Below are a number of very recent abstracts from top rated researchers and transplant centers. If you are interested in reading the full text articles, write to us at and we will help you locate the articles. Where full length articles are available free of charge, I have provided the URL links. The first two abstracts are from the 2024 ASH Education program and not only can you read the full texts free of charge, they have a wealth of additional articles available free in the reference section. If a bone marrow transplant is a possibility in your case, it is time to start collecting your own library of good reference articles on the subject, make yourself familiar with the terminology, the jargon and statistics, names of the researchers who are at the cutting edge of the technology, and transplant teams that are cited most often by their peers. The abstracts below will give you a good place to start. Happy reading!

Abstracts:

Article from ASH Education Book 2024.

Hematology (Am Soc Hematol Educ Program). 2024;:392-421.

Non-myeloablative transplantation.

Maloney DG, Sandmaier BM, Mackinnon S, Shizuru JA.

Fred Hutchinson Cancer Research Center, Seattle, WA 98104

The concept of utilizing enhanced immunosuppression rather than myeloablative cytotoxic conditioning has allowed the engraftment of allogeneic stem cells from related and unrelated donors with lower early transplant-related mortality (TRM) and morbidity. This approach shifts tumor eradication to the graft-vs-host immune response directed against minor histocompatibility antigens expressed on tumor cells. This is not without risk, as the long-term effects of graft-versus-host disease (GVHD), it's treatment, or resulting complications and immunodeficiency may be life threatening. However, this approach does allow the application of a potentially curative procedure to elderly or medically infirm patients who would not tolerate high-dose conditioning regimens. Section I, by Dr. Sandmaier, describes the current use of nonmyeloablative regimens and matched related or unrelated donors for the treatment of patients with CLL, CML, acute leukemia, MDS, lymphoma, and myeloma. In Section II, Dr. Maloney discusses the use of cytoreductive autologous followed by planned non-myeloablative allografts as treatment for patients with myeloma or NHL. This tandem transplant approach has a lower TRM than conventional high dose allografting. The nonmyeloablative allograft may allow the graft-versus-tumor (GVT) immune response to eradicate the minimal residual disease that causes nearly all patients with low-grade NHL or myeloma to relapse following autologous transplantation. In Section III, Dr. Mackinnon discusses the risks and benefits of T cell depletion strategies to prevent acute GVHD, while retaining GVT activity by planned donor lymphocyte infusions. Finally, in Section IV, Dr. Shizuru discusses the relationship between GVHD and GVT activity. Future studies, employing a greater understanding of these issues and the separation of GVHD from GVT activity by immunization or T cell cloning, may allow nonmyeloablative allogeneic transplantation to be safer and more effective.

PMID: 12446434
____________

Article in ASH Education Book 2024.

Hematology (Am Soc Hematol Educ Program). 2024;:354-71

Stem cell transplantation (cord blood transplants).

Chao NJ, Emerson SG, Weinberg KI.

Allogeneic stem cell transplantation is an accepted treatment modality for selected malignant and non-malignant diseases. However, the ability to identify suitably matched related or unrelated donors can be difficult in some patients. Alternative sources of stem cells such as cord blood provide a readily available graft for such patients. Data accumulated over the past several years have demonstrated that the use of cord blood is an accepted source of stem cells for pediatric patients. Since the cell numbers of hematopoietic progenitors in cord blood is limited and the collection can occur only in a single occasion, its use in adult patients can be more problematic. Here, new developments in the use of cord blood for adults and studies aimed at expansion of cord blood cells and immune reconstitution are described. In Section I, Dr. Nelson Chao describes the early data in cord blood transplantation in adult patients. The patient outcomes are reviewed and analyzed for various factors such as cell dose, HLA typing, and patient selection that could have contributed to the final outcome of these adult patients. Myeloablative as well as nonmyeloablative approaches are presented. Discussion of the various benefits and risks are presented. More recent data from multiple single institutions as well as larger registry data comparisons are also provided. Analyses of these studies suggest methods to improve on the outcome. These newer data should lead to a logical progression in the use of cord blood cells in adult patients. In Section II, Dr. Stephen Emerson describes the historical efforts associated with expansion of hematopoietic stem cells, specifically with cord blood cells. These efforts to expand cord blood cells continue with novel methods. Moreover, a better understanding of stem cell biology and signaling is critical if we are to be able to effectively expand these cells for clinical use. An alternative, more direct, approach to expanding stem cells could be achieved by specific genetic pathways known or believed to support primitive HSC proliferation such as Notch-1 receptor activation, Wnt/LEF-1 pathway induction, telomerase or the Homeobox (Hox) gene products. The clinical experience with the use of expanded cord blood cells is also discussed. In Section III, Dr. Kenneth Weinberg describes immune reconstitution or lack thereof following cord blood transplantation. One of the hallmarks of successful hematopoietic stem cell transplantation is the ability to fully reconstitute the immune system of the recipient. Thus, the relationship between stem cell source and the development of T lymphocyte functions required for protection of the recipient from infection will be described, and cord blood recipients will be compared with those receiving other sources of stem cells. T cell development is described in detail, tracking from prethymic to postthymic lymphocytes with specific attention to umbilical cord blood as the source of stem cells. Moreover, a discussion of the placenta as a special microenvironment for umbilical cord blood is presented. Strategies to overcome the immunological defects are presented to improve the outcome of these recipients.

PMID: 15561692
____________

Blood. 2024 Oct 1;104(7):1923-30. Epub 2024 Jun 10.

Impact of HLA class I and class II high-resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome.

Flomenberg N, Baxter-Lowe LA, Confer D, Fernandez-Vina M, Filipovich A, Horowitz M, Hurley C, Kollman C, Anasetti C, Noreen H, Begovich A, Hildebrand W, Petersdorf E, Schmeckpeper B, Setterholm M, Trachtenberg E, Williams T, Yunis E, Weisdorf D.

Department of Medicine and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107

Outcome of unrelated donor marrow transplantation is influenced by donor-recipient matching for HLA. Prior studies assessing the effects of mismatches at specific HLA loci have yielded conflicting results. The importance of high-resolution matching for all HLA loci has also not been established. We therefore examined the effects of HLA matching (low or high resolution or both) on engraftment, graft-versus-host disease (GVHD), and mortality in 1874 donor-recipient pairs retrospectively typed at high resolution for HLA-A, -B, -C, -DRB1, -DQ, and -DP. Mismatches at HLA-A, -B, -C, and -DRB1 each had similar adverse effects on mortality. Only HLA-A mismatches demonstrated significant adverse effects on GVHD. These adverse effects on outcome were more evident in transplants with low-resolution versus only high-resolution mismatches. Mismatches for HLA-DQ or -DP did not significantly affect outcome. When high-resolution mismatches at HLA-A, -B, -C, and -DRB1 were considered together, adverse effects on survival and GVHD were observed. We therefore conclude that matching for HLA-C should be incorporated into algorithms for unrelated donor selection. High-resolution mismatches at HLA-A, -B, -C, and -DRB1 adversely affect outcome, but less so than low-resolution mismatches. When clinical circumstances allow, high-resolution class I typing may help optimize donor selection and improve outcome.

PMID: 15191952
____________

Blood. 2024 Oct 5; [Epub ahead of print]

Transplantation of two partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy.

Barker JN, Weisdorf DJ, Defor TE, Blazar BR, McGlave PB, Miller JS, Verfaillie CM, Wagner JE.

Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, MN, USA; Division of Medical Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN

Limited umbilical cord blood (UCB) cell dose compromises the outcome of adult UCB transplantation. Therefore, to augment graft cell dose, we evaluated the safety of the combined transplantation of two partially HLA-matched UCB units. Twenty-three patients with high-risk hematologic malignancy [median age 24 years (range: 13-53)] received two UCB units [median infused dose 3.5 x 10(7) NC/kg (range 1.1-6.3)] after myeloablative conditioning. All evaluable patients (n = 21) engrafted at a median of 23 days (range 15-41). At day 21, engraftment was derived from both donors in 24% and a single donor in 76%, with one unit predominating in all patients by day 100. While neither nucleated or CD34+ cell dose, nor HLA-A,B,DRB1 match, predicted which unit would predominate, the predominating unit had a significantly higher CD3+ dose (p < 0.01). Incidences of grade II-IV and III-IV acute GVHD were 65% (95%CI: 42-88%) and 13% (95%CI: 0-26%), respectively. Disease-free survival was 57% (95%CI: 35-79) at one year, with 72% (95%CI: 49-95) of patients alive if transplanted in remission. Therefore, transplantation of 2 partially HLA-matched UCB units is safe, and may overcome the cell dose barrier that limits the use of UCB in many adults and adolescents.

PMID: 15466923
____________

Blood. 2024 Sep 30; [Epub ahead of print]

Comparative outcome of non-myeloablative and myeloablative allogeneic hematopoietic cell transplantation for patients greater than fifty years of age.

Alyea EP, Kim HT, Ho VT, Cutler C, Gribben J, DeAngelo DJ, Lee SJ, Windawi S, Ritz J, Stone RM, Antin JH, Soiffer RJ.

Departments of Medical Oncology and Biostatistical Science, Dana-Farber Cancer Institute, Boston, MA

Non-myeloablative stem cell transplantation (NST) is increasingly utilized in older patients. The impact of the shift from myeloablative to NST upon relapse, transplant complications, and outcome has yet to be fully examined. We performed a retrospective analysis of 152 patients older than age 50 receiving NST or myeloablative transplantation. 71 patients received non-myeloablative conditioning, fludarabine (30 mg/m(2)/day x 4) and intravenous busulfan (0.8 mg/kg/d x 4). 81 patients received myeloablative conditioning, primarily cyclophosphamide and TBI. NST patients were more likely to have unrelated donors (58% vs 36%, p=0.009), prior transplant (25% vs 4%, p=<0.0001), and active disease at transplantation (85% vs. 59%, p=<0.001). Despite the adverse characteristics, overall survival was improved in the NST group at 1 (51% vs 39%) and 2 (39% vs. 29%) years (p = 0.056). There was no difference in progression free survival (2 year, 27% vs. 25%, p =0.24). Incidence of 2-4 GVHD was similar, (28% vs. 27%). Non-relapse mortality was lower for NST patients (32% vs. 50%, p=0.01), but relapse was higher (46% vs. 30%, p=0.052). Our experience suggests that, in patients over age 50, NST with fludarabine and low dose busulfan leads to an overall outcome at least as good as myeloablative therapy.

PMID: 15459007
____________