1. HAPLOIDENTICAL STEM CELL TRANSPLANT
Zeina Al-Mansour, MD
Assistant Professor
Hematology/Bone Marrow Transplant
Loyola University Medical Center
May 21st, 2016

2. OUTLINE Introduction HLA Antigens & HLA Matching
Donor Options, Selection & Eligibility
How Haplo-SCT Works
Advantages of this approach
Outcomes
Who Should Consider Haplo-SCT
Summary

3. INTRODUCTION
Allogeneic Stem Cell Transplant (Allo-SCT) is a potentially curative therapy for a wide variety of malignant and non- malignant hematologic disorder.
Stem cell: mother of all types of blood cells, divides and differentiates to give rise to all types of blood cells.
Obtained from the bone marrow or peripheral blood of a related or unrelated donor
Given the small family sizes in developed nations and the 25 percent likelihood that any sibling is fully HLA-matched to the patient, an HLA-matched sibling can be found for only approximately 30 percent of patients. For patients who lack an HLA-matched sibling, alternative sources of donor grafts include suitably HLA-matched adult unrelated donors, umbilical cord blood stem cells, and partially HLA-mismatched, or HLA-haploidentical, related donors. The decision of which donor source to utilize depends, to a large degree, upon the clinical situation and the approaches employed at the individual transplant center.
The major challenge of HLA-haploidentical HCT is intense bi-directional alloreactivity leading to high incidences of graft rejection and graft-versus-host disease (GVHD). Advances in graft engineering and in pharmacologic prophylaxis of GVHD have reduced the risks of graft failure and GVHD after HLA-haploidentical HCT, and have made this stem cell source a viable alternative for patients lacking an HLA-matched sibling.
This topic will discuss the advantages and disadvantages of HLA-haploidentical HCT and the selection of an HLA-haploidentical donor. A general approach to donor selection for allogeneic HCT is discussed separately.

4. HLA Antigens
HLAs are proteins — or markers — found on most cells in the body.
The immune system uses these markers to recognize cells that belong in the body versus those that do not.

5. HLA Matching HLA matching basics
Half of your HLA markers are inherited from your mother and half from your father. Each brother and sister has a 25%, or 1 in 4, chance of matching you, if you have the same mother and father. It is highly unlikely that other family members will match you. Under very rare circumstances, family members other than siblings may be tested.
About 70%, or 7 out of 10, patients who need a transplant do not have a suitable donor in their family. If you do not have a donor in your family, your transplant team may look for an unrelated donor or cord blood unit for you on Be The Match Registry. When a search is done on the Be The Match Registry, it includes a search of more than 22.5 million potential adult donors and more than 601,000 cord blood units on lists from around the world. 

6. The above figure represents the genetic basis for donor selection
The above figure represents the genetic basis for donor selection. Every person has two sets of HLA antigens (haplotypes) which are located on chromosome 6; one set is derived from the father and one from the mother. These are shown in different colors, reflecting the vast HLA diversity among human subjects.   For any given mother and father there are four equally possible sets of HLA antigens in their children. On average, only one out of every four siblings (25 percent) will be fully HLA matched with the patient requiring the transplantation, here shown in the black box. Two out of every four siblings (50 percent) will be haplotype matches only.   Note that all of the patient's children and both of the patient's parents will only be haplotype matches. It is unlikely that any of the patient's parents, children, or first cousins will be full HLA matches unless the involved families happen to have very common haplotypes or there has been intermarrying among their families.

7. Role of HLA Matching
Increases the likelihood of a successful transplant
Improves engraftment—when the donated cells start to grow and make new blood cells in you.
Reduces the risk of complications after transplant, especially graft-versus-host disease (GVHD).
GVHD is a potentially serious complication.
Occurs when the immune cells, which are part of the donated marrow or cord blood, attack your body.
Normally, we look for a donor who matches a patient's tissue type, specifically their human leukocyte antigen (HLA) tissue type. HLAs are proteins — or markers — found on most cells in the body. The immune system uses these markers to recognize cells that belong in the body versus those that do not. The closer the match between a patient's HLA markers and the donor’s, the better for the patient. In most cases of sickle cell disease, for example, doctors looked for a nearly full match prior to bone marrow transplantation. This was extremely difficult because in many cases, the person with the closest match, such as a sibling, may also have carried the sickle cell gene. The Hopkins procedure requires just a half-match, meaning that a patient’s parents or children could be suitable donors. With this option, doctors estimate that more than half of sickle cell patients, and nearly all patients with other blood cancers or autoimmune disorders, have potential matches.

8. DONOR OPTIONS Matched sibling donor Matched unrelated donor
Alternative options:
Half-matched related donor  HAPLOIDENTICAL
Cord blood transplant

9. DONOR SELECTION
Normally, we look for a donor who matches a patient's tissue type, specifically their human leukocyte antigen (HLA) tissue type.
The closer the match between a patient's HLA markers and the donor’s, the better for the patient.
The chances that each full sibling is a donor is only 1 in 4 (or 25%)
Given the small family sizes in developed nations, an HLA- matched sibling can be found for only approximately 1/3 of patients.
For patients who lack an HLA-matched sibling, alternative sources of donor grafts include suitably HLA-matched adult unrelated donors, umbilical cord blood stem cells, and partially HLA-mismatched, or HLA-haploidentical, related donors. The decision of which donor source to utilize depends, to a large degree, upon the clinical situation and the approaches employed at the individual transplant center.
The major challenge of HLA-haploidentical HCT is intense bi-directional alloreactivity leading to high incidences of graft rejection and graft-versus-host disease (GVHD). Advances in graft engineering and in pharmacologic prophylaxis of GVHD have reduced the risks of graft failure and GVHD after HLA-haploidentical HCT, and have made this stem cell source a viable alternative for patients lacking an HLA-matched sibling.
This topic will discuss the advantages and disadvantages of HLA-haploidentical HCT and the selection of an HLA-haploidentical donor. A general approach to donor selection for allogeneic HCT is discussed separately.

10. DONOR ELIGIBILITY
Criteria to consider in selecting the optimal donor include:
Donor Health
Age
Gender
HLA Mismatch
Relation to patient
Blood type

11. HAPLOIDENTICAL SCT Requires just a half-match of the HLA antigens.
Potential HLA-haploidentical donors include biological parents, biological children, and full or half siblings
With this option, we estimate that nearly all patients who need allo-SCT have potential matches.

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13. HOW HAPLO-SCT WORKS
3 days after transplant, a patient is given a high dose of a drug called cyclophosphamide, which “re-boots” the immune system.
The cyclophosphamide spares the donor's stem cells and allows them to establish new blood cells and a new immune system.
The budding immune system is re-trained to see the patient's body as friend, preventing the patient from rejecting the transplanted bone marrow.
The budding immune system is re-trained to see the patient's body as friend, preventing the patient from rejecting the transplanted bone marrow. Doctors speculate the procedure works because with a higher level of mismatch between the donor and recipient, the immune system reacts more strongly against the cancer and lowers the chance of relapse, explains Dr. Ephraim Fuchs, associate professor of oncology, who helped develop the procedure.
Normally, doctors look for a donor who matches a patient's tissue type, specifically their human leukocyte antigen (HLA) tissue type. HLAs are proteins — or markers — found on most cells in the body. The immune system uses these markers to recognize cells that belong in the body versus those that do not. The closer the match between a patient's HLA markers and the donor’s, the better for the patient. In most cases of sickle cell disease, for example, doctors looked for a nearly full match prior to bone marrow transplantation. This was extremely difficult because in many cases, the person with the closest match, such as a sibling, may also have carried the sickle cell gene. The Hopkins procedure requires just a half-match, meaning that a patient’s parents or children could be suitable donors. With this option, doctors estimate that more than half of sickle cell patients, and nearly all patients with other blood cancers or autoimmune disorders, have potential matches.

14. ADVANTAGES OF HAPLO-SCT
Near universal availability of highly motivated donors
Patients have an average of 2.7 potential HLA-haploidentical donors among first degree relatives
Rapid availability
Ability to collect adequate doses of stem cells compared to cord blood
Advantages and limitations of haploidentical donors — Sources of stem cells for allogeneic HCT include HLA-matched siblings, suitably HLA-matched unrelated donors, HLA-haploidentical donors, and unrelated umbilical cord blood. When compared with the other stem cell sources, the major advantages of the HLA-haploidentical donor option include:
●Near universal availability of highly motivated donors – Patients have an average of 2.7 potential HLA-haploidentical donors among first degree relatives. In comparison, only approximately 30 percent of patients will have a HLA-matched sibling, and availability of an unrelated donor genotypically matched at eight of eight alleles (HLA-A, -B, -C, and -DRB1) ranges from 16 to 75 percent depending upon the recipient’s ethnic background [4].
●Rapid availability – The time to identify and mobilize an adult unrelated donor can be longer than three months for up to 25 percent of patients. An HLA-haploidentical donor can be identified and mobilized in two weeks to one month.
●Adequate doses of hematopoietic stem cells (HSCs) – HLA-haploidentical grafts have sufficient doses of HSCs for transplantation and of memory T cells for immune reconstitution. In contrast, the total dose of nucleated cells in a single umbilical cord blood unit may be suboptimal for engraftment in larger adults and immune reconstitution is delayed. (See "Selection of an umbilical cord blood graft for hematopoietic cell transplantation", section on 'Importance of cell dose' and "Strategies for immune reconstitution following allogeneic hematopoietic cell transplantation", section on 'Source of hematopoietic stem cells'.)
●Low cost of graft acquisition – The costs of acquiring grafts from adult unrelated donors and especially from umbilical cord blood banks can be substantially higher than that of related donors.
●Availability of the donor for repeated donations of HSCs or lymphocytes to treat relapse – In contrast, umbilical cord blood is a non-recurring source of cells. If a patient suffers relapse of the underlying hematologic malignancy after umbilical cord blood transplantation, donor lymphocytes to treat the relapse are not available. (See "Immunotherapy for the prevention and treatment of relapse following hematopoietic cell transplantation".)
●Graft-versus-leukemia effect – For patients with high risk acute leukemia, HLA-haploidentical HCT may be associated with a stronger graft-versus-leukemia effect compared with HLA-matched sibling HCT, resulting in a lower cumulative incidence of relapse [5] and an improved overall survival [6].
The major challenge of HLA-haploidentical HCT is the high frequency of host and donor T cells reactive to HLA alloantigens resulting in intense bi-directional alloreactivity and, in the absence of effective prophylactic measures, high incidences of fatal graft rejection or severe or fatal GVHD.
The high incidence of bi-directional alloreactivity was illustrated in an analysis of over 2000 allogeneic HCTs performed between 1985 and 1991 and reported to the International Bone Marrow Transplant Registry [7]. When compared with HLA-matched sibling HCT, two HLA antigen-mismatched related donor transplants resulted in higher rates of the following adverse transplant outcomes:
●Transplant-related mortality (55 versus 21 percent at three years among patients with leukemia)
●Graft failure (16 versus 1 percent)
●Grade II to IV acute GVHD (56 versus 29 percent)
●Severe (grade III/IV) acute GVHD (36 versus 13 percent)
●Chronic GVHD (60 versus 42 percent)

15. ADVANTAGES OF HAPLO-SCT
Availability of the donor for repeated donations
Needed to treat relapse or if the patient needs a stem cell boost
Potentially lower chances of disease relapse
With a higher level of mismatch between the donor and recipient, the immune system reacts more strongly against the cancer cells and lowers the chance of relapse- Graft-vs-Tumor Effect
Advantages and limitations of haploidentical donors — Sources of stem cells for allogeneic HCT include HLA-matched siblings, suitably HLA-matched unrelated donors, HLA-haploidentical donors, and unrelated umbilical cord blood. When compared with the other stem cell sources, the major advantages of the HLA-haploidentical donor option include:
●Near universal availability of highly motivated donors – Patients have an average of 2.7 potential HLA-haploidentical donors among first degree relatives. In comparison, only approximately 30 percent of patients will have a HLA-matched sibling, and availability of an unrelated donor genotypically matched at eight of eight alleles (HLA-A, -B, -C, and -DRB1) ranges from 16 to 75 percent depending upon the recipient’s ethnic background [4].
●Rapid availability – The time to identify and mobilize an adult unrelated donor can be longer than three months for up to 25 percent of patients. An HLA-haploidentical donor can be identified and mobilized in two weeks to one month.
●Adequate doses of hematopoietic stem cells (HSCs) – HLA-haploidentical grafts have sufficient doses of HSCs for transplantation and of memory T cells for immune reconstitution. In contrast, the total dose of nucleated cells in a single umbilical cord blood unit may be suboptimal for engraftment in larger adults and immune reconstitution is delayed. (See "Selection of an umbilical cord blood graft for hematopoietic cell transplantation", section on 'Importance of cell dose' and "Strategies for immune reconstitution following allogeneic hematopoietic cell transplantation", section on 'Source of hematopoietic stem cells'.)
●Low cost of graft acquisition – The costs of acquiring grafts from adult unrelated donors and especially from umbilical cord blood banks can be substantially higher than that of related donors.
●Availability of the donor for repeated donations of HSCs or lymphocytes to treat relapse – In contrast, umbilical cord blood is a non-recurring source of cells. If a patient suffers relapse of the underlying hematologic malignancy after umbilical cord blood transplantation, donor lymphocytes to treat the relapse are not available. (See "Immunotherapy for the prevention and treatment of relapse following hematopoietic cell transplantation".)
●Graft-versus-leukemia effect – For patients with high risk acute leukemia, HLA-haploidentical HCT may be associated with a stronger graft-versus-leukemia effect compared with HLA-matched sibling HCT, resulting in a lower cumulative incidence of relapse [5] and an improved overall survival [6].
The major challenge of HLA-haploidentical HCT is the high frequency of host and donor T cells reactive to HLA alloantigens resulting in intense bi-directional alloreactivity and, in the absence of effective prophylactic measures, high incidences of fatal graft rejection or severe or fatal GVHD.
The high incidence of bi-directional alloreactivity was illustrated in an analysis of over 2000 allogeneic HCTs performed between 1985 and 1991 and reported to the International Bone Marrow Transplant Registry [7].

16. OUTCOMES 6-months survival 85% 1-year cancer-free survival 50%
1-year overall survival 62%
After Haplo-marrow transplantation, the median follow-up of surviving patients was 357 days (range ). The 1-year cumulative incidence of NRM was 7% (95% CI, 0%-15%) and relapse/progression was 45% (95% CI, 30%-61%; Figure 4C). The most frequent cause of death was also relapse (Table 4). Six-month survival, which was the primary end point, was 84% (95% CI, 70%-92%). The 1-year probability of PFS was 48% (95% CI, 32%-62%) and OS 62% (95% CI, 44%-76%; Figure 4D).
When compared with HLA-matched sibling HCT, two HLA antigen-mismatched related donor transplants resulted in higher rates of the following adverse transplant outcomes:
●Transplant-related mortality (55 versus 21 percent at three years among patients with leukemia)
●Graft failure (16 versus 1 percent)
●Grade II to IV acute GVHD (56 versus 29 percent)
●Severe (grade III/IV) acute GVHD (36 versus 13 percent)
●Chronic GVHD (60 versus 42 percent)
Brunstein C, et al. Blood. 2011

17. OUTCOMES The rate of grade II-IV acute GVHD at day 100 is 32%
After Haplo-marrow transplantation, the cumulative incidence of grade II-IV acute GVHD at day 100 was 32% (95% CI, 19%-45%; Figure 3C). There were no reported cases of grade III-IV acute GVHD. The cumulative incidence of chronic GVHD at 1 year was 13% (95% CI, 3%-23%; Figure 3D).
When compared with HLA-matched sibling HCT, two HLA antigen-mismatched related donor transplants resulted in higher rates of the following adverse transplant outcomes:
●Transplant-related mortality (55 versus 21 percent at three years among patients with leukemia)
●Graft failure (16 versus 1 percent)
●Grade II to IV acute GVHD (56 versus 29 percent)
●Severe (grade III/IV) acute GVHD (36 versus 13 percent)
●Chronic GVHD (60 versus 42 percent)
Brunstein C, et al. Blood. 2011

18. OUTCOMES The rate of chronic GVHD at 1 year is 13%
After Haplo-marrow transplantation, the cumulative incidence of grade II-IV acute GVHD at day 100 was 32% (95% CI, 19%-45%; Figure 3C). There were no reported cases of grade III-IV acute GVHD. The cumulative incidence of chronic GVHD at 1 year was 13% (95% CI, 3%-23%; Figure 3D).
Brunstein C, et al. Blood. 2011

19. OUTCOMES 1-year non-relapse mortality 7% 1-year risk of relapse 45%
The most frequent cause of death is relapse
After Haplo-marrow transplantation, the median follow-up of surviving patients was 357 days (range ). The 1-year cumulative incidence of NRM was 7% (95% CI, 0%-15%) and relapse/progression was 45% (95% CI, 30%-61%; Figure 4C). The most frequent cause of death was also relapse (Table 4). Six-month survival, which was the primary end point, was 84% (95% CI, 70%-92%). The 1-year probability of PFS was 48% (95% CI, 32%-62%) and OS 62% (95% CI, 44%-76%; Figure 4D).
When compared with HLA-matched sibling HCT, two HLA antigen-mismatched related donor transplants resulted in higher rates of the following adverse transplant outcomes:
●Transplant-related mortality (55 versus 21 percent at three years among patients with leukemia)
●Graft failure (16 versus 1 percent)
●Grade II to IV acute GVHD (56 versus 29 percent)
●Severe (grade III/IV) acute GVHD (36 versus 13 percent)
●Chronic GVHD (60 versus 42 percent)
Brunstein C, et al. Blood. 2011

20. WHO SHOULD CONSIDER HAPLO-SCT
Patient with a type of blood cancer that needs allo-SCT
No available HLA-matched sibling to donate
Suitably matched unrelated donor CANNOT be found in the donor registry
OR if donor cannot have stem cell collection in a reasonable time frame.

21. SUMMARY Haploidentical donor is a half-matched donor
Potential donors are biological parents, biological children and full and half siblings
Most patients have >1 first degree relative willing & able to donate
Advantages: rapid & universal availability, adequate doses of stem cells and availability of donor for repeated donations
The major challenge is the risk of GVHD
Outcomes are very encouraging with the use of post-transplant cyclophosphamide as part of the immune suppression regimen.
SUMMARY AND RECOMMENDATIONS
●●Potential haploidentical donors include biological parents, biological children, and full or half siblings. Most patients will have more than one HLA-haploidentical first degree relative willing and able to donate. (table 1). (See 'Our approach' above.)

22. THANK YOU