Katanguri 1

The factors associated with bone marrow donors:

A chance for a cure
Neha Katanguri
Independent Research G/T
May 1, 2018

Advisor: Dr. Clifford Takemoto

https://www.behance.net/gallery/20869467/Bone-Marrow-Donation-Infographic
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Abstract:
For patients with blood cancers like Leukemia, there are only a few options for treatment. One of the most common treatments
include a bone marrow transplant. The donor sources available are HLA- matching related/unrelated, HLA-mismatching,
haploidentical, and cord blood units with a donor source. The main factors that interfere with the success of the transplant are the
relapse and survival rate. An HLA-matching donor is more preferred than mismatching donors, haploidentical donors, or cord blood
units. According to Dr. Morishima, ​HLA-C and HLA-DPB1 alleles, when mismatched are the best alleles to use when this donor type
is the only option available. Haploidentical and cord blood units are also an option, but since there is a likeliness for the donor cells to
not be 100% matching, these options can cause relapse in future years. Other factors such as age, gender, and ethnic background can
play a huge role in the availability of HLA-matching donors in bone marrow registries. Lastly, the main objective of the research is to
raise awareness and convince more people to donate their stem cells. If more people donate their cells, then over the next decade the
rate of survival for leukemia will be higher. This is mainly because there will be a higher variety of stem cells in national registries,
which will help patients that need to undergo a bone marrow transplant. The benefits of having a variety of stem cells in national
registries include that the doctor can find a donor for a transplant in a short period of time, and the patient will have a better outcome
with having various donor types available.
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Table of Contents:
Abstract-------------------------------------------------------------------------------------------------------------------------------------------------- 2
Introduction----------------------------------------------------------------------------------------------------------------------------------------------- 4
Literature Review---------------------------------------------------------------------------------------------------------------------------------------- 4
HLA-matching related vs unrelated donor-------------------------------------------------------------------------------------------------- 4
Difference between related and unrelated donor---------------------------------------------------------------------------------- 4
Effect on survival rate---------------------------------------------------------------------------------------------------------------- 6
Effect on relapse rate----------------------------------------------------------------------------------------------------------------- 7
Mismatching unrelated donor---------------------------------------------------------------------------------------------------------------- 9
Different types of mismatching donor types and their effects------------------------------------------------------------------ 9
Effect on survival rate---------------------------------------------------------------------------------------------------------------- 10
Effect on relapse rate----------------------------------------------------------------------------------------------------------------- 12
Haploidentical donors/cord blood sources------------------------------------------------------------------------------------------------- 13
Usage of a haploidentical donor/cord blood sources------------------------------------------------------------------------------ 13
Effect on survival rate----------------------------------------------------------------------------------------------------------------- 14
Effect on relapse rate------------------------------------------------------------------------------------------------------------------ 15
Other factors affecting the process to find a matching donor----------------------------------------------------------------------------- 16
Factor 1: Age and gender effect on survival and relapse rates------------------------------------------------------------------- 17
Factor 2: Ethnicity--------------------------------------------------------------------------------------------------------------------- 18
Data collection------------------------------------------------------------------------------------------------------------------------------------------- 19
Data-------------------------------------------------------------------------------------------------------------------------------------- 19
Rationale-------------------------------------------------------------------------------------------------------------------------------- 24
Analysis--------------------------------------------------------------------------------------------------------------------------------- 25
Data Collection conclusion----------------------------------------------------------------------------------------------------------- 27
Conclusion------------------------------------------------------------------------------------------------------------------------------------------------ 28

References------------------------------------------------------------------------------------------------------------------------------------------------ 30
 Katanguri 4

I: Introduction:
Do you know anyone that has been diagnosed with leukemia or has had leukemia multiple times in their life? Thousands of

patients across the world are diagnosed with multiple blood cancers, and one of the options for survival is a bone marrow transplant.

Other options include chemotherapy but it depends on the severity of the condition. However, these hematologic transplants require a

donor, and there are multiple donor types the patient’s doctor could consider. The main donor types include: HLA-matching related,

HLA-matching unrelated, HLA-mismatching unrelated donor, and haploidentical. One of the common donor sources include using

cord blood units. Within these donor types, there are a variety of low and high expression alleles. The factors that affect the process of

obtaining a donor are the severity of the patient’s condition, the number of matching donors they have from their family, age of donor

and patient, and ethnicity. Relapse, the probability of cancer to reoccur, is the main cause of death in some leukemic patients.

Although some patients may have a successful transplantation, they may be in risk of a relapse in the future. If no cancerous cells

capable of causing a relapse are present in the patient, then the blood cancer can be considered as cured. This scientific paper will

discuss and analyze how the presence of an HLA-matching donor type during a blood transplant will lead to a higher survival rate and

a lower relapse rate.

II: HLA-matching related vs unrelated donor:

Difference between related and unrelated donor

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HLA-matching markers are generally used to examine similarities and differences between the donor and patient’s

cells. There are ​HLA-A, -B, - C, -DRB1, -DQB1, and DPB1 alleles in which the doctor must compare with the donor.​ As Dr.

Saber mentions in his article, “Impact of donor source on hematopoietic cell transplantation outcomes for patients with

myelodysplastic syndromes (MDS),” relapses are one of the most common causes of death in patients with myelodysplastic

syndromes. HLA-matched related donor stem cells are typically obtained from the patient’s family, while HLA- matched

unrelated donor stem cells are from a non-sibling and are obtained from national bone marrow registries. There is higher

possibility of finding a matching donor in a registry than in the patient’s family. The problem is that patients may not find a

perfect matching HLA- typed donor. Having a significant difference in the number of matching HLA markers may lead to

further complications affecting the patient’s health condition.

Generally, using a related donor for the transplant is a more viable option as regards to the severity of the cancer. But,

Dr. Tiercy discusses that,“​HLA genotypically identical sibling donors are, therefore, the gold standard for transplantation

purposes, but only 30% patients have such a donor” (Tiercy, 2016). There is a low possibility that there is a matching donor in

the patient’s family, thus doctors find other unrelated donor types through organizations and registries. In some cases, a

matching unrelated donor is a better option if there are more matching alleles between the patient and the donor. As the

number of siblings in a family increase, there is a higher probability of finding an HLA-matching donor in the patient’s family.
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As shown in Tiercy’s article, there is a 90% chance of finding an HLA-matching donor in their family if they have eight

siblings.

However, for older patients that need a bone marrow transplant, finding a sibling or related donor may be difficult. Dr.

Brissot mentions in his article that, “​A patient with PRF-AML may not have a matching related donor as an option, so they can

go with the unrelated donor option” (Brissot, 2017). Additionally, an unrelated donor may be associated with a higher survival

rate depending on how severe the cancer in the patient is. More matching HLA alleles results in a lower risk of relapse, and a

higher survival rate. This is because if the cells are matching between the patient and the donor, the immune system will not try

to attack the donor cells.

Effect on survival rate

A low percentage of leukemic patients survive after their blood transplant due to the recurrence of cancer and other

factors. As a result of those factors, a cure for leukemia and other blood cancers is only determined once the patient has

survived without the possibility for a relapse to occur in future years. Dr. Yam concludes, “​In conclusion, patients with MDS

who received allografts from unrelated donors had a lower risk of relapse and improved relapse-free survival when compared

to patients who received allografts from related donors” (Yam, 2016). This proves the claim that in some types of blood

disorders like Myelodysplastic syndrome, patients that had unrelated donor cells had a higher survival rate without the
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reoccurrence of that condition. However, the rate of survival also depends on the condition the patient has acquired and the

population represented in the experiment. The population size in Dr. Yam’s study was 53 patients.

In a different study by the Center For International Blood & Marrow Transplant Research (CIBMTR), centers all across

the world were used so there was a larger population examined. Additionally, CIBMTR slides by D'Souza from 2017 show

that, HLA-matched sibling donor had a higher probability of survival in the following conditions: AML, MDS, ALL, and

CML. The HLA-matching sibling donor was not that clearly better and the results between that and the HLA-matching

unrelated donor had not varied as much. Analyzing the graphs, the lines for the related and unrelated donor were not very far

apart on the scale of probability of survival. Therefore, in this case study, the survival rate was higher with HLA-matching

sibling donors and the explanation for this could be provided with the fact that it used a larger population than the previous

study. Additionally, the likeliness for a transplant to lead to a higher survival rate could be that some patients had siblings that

were closely matched-but this is random.

The population size in a study and the severity of the condition helps determine whether a related or unrelated donor is

the best choice for the patient. Dr. Kröger explains, “​Also young unrelated donors (<30 years) had improved survival in

comparison with sibling transplantation” (Kr​öger, 2012). Overall, since the results for an unrelated and related donor are very

similar, an HLA-matching donor must be used for the best chance of a successful blood transplant. The author concludes that

due to the condition of the patient, usually if they need an urgent transplant, a related donor is used. This can decrease the
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survival rate, therefore Dr. Kroger convinces the audience that more younger people should donate to help contribute to the

donor pool so it does not take as long for doctors to find an HLA-matched unrelated donor.

Effect on relapse rate

If a patient shows signs of cancer recurrence, then the survival rate will not be as high the second time the patient

acquires cancer. This is the main reason to why cancer is so hard to cure, because there is a higher chance of relapse following

the patient’s recovery. According to Dr. Yam’s study, a one- year relapse rate for unrelated donors was 38%, and for related

donors it was 58%. The two- year relapse incidence for unrelated donors was 41%, and in related donors it was 63% (Yam,

2016). As shown above, the relapse rate in unrelated donors was lower by about 20%, as compared to the related donors. This

is because if there is a broader donor pool, the doctor can easily find an HLA-matched unrelated donor that has more HLA

markers in common with the patient. When time is constrained, the doctor ends up choosing a related donor, but the donor

cells may be mismatched which leads to further problems.

The fact that HLA-matching unrelated donors are associated with a lower occurrence of relapse than a HLA-matching

related donor is usually the case in most blood cancers. For example, “​The main cause of death of MRD≥60y recipients was

relapse and relapse incidence was higher for these patients compared with MUD recipients” (Servais, 2014). If the unrelated

donor cells match the patient’s cells with almost no mismatches or multiple allele differences, then the patient’s immune

system will respond suitably to the donor cells. If the donor cells are responding well in the patient, then the treatment had
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been successful, and there is a low chance of getting a relapse if the donor cells can attack the cancer and support the immune

system.

As mentioned above, the condition of the patient is a huge factor in determining which donor type to use. In this case

study, the performance level of the patient is a strong determinant of which donor is more suitable. The article explains, “For

patients with performance scores of 90 or 100, NRM and relapse risks were higher after MUD compared with MSD

transplants. Consequently, DFS and OS were significantly lower after MUD transplants” (Alousi, 2013). For patients that have

90-100 as their performance level, it is significantly high, meaning that they are not severely affected by their condition. Thus,

they did not require a donor as perfectly HLA-matched, so their doctor went with the related donor option. As a result of this,

the outcomes were positive and the relapse rate was low. The article also includes that the overall survival rate and disease-

free survival rate for related donors were higher than unrelated donors. With this evidence, it could be predicted that patients

with more severe conditions require an HLA-matched unrelated donor but with the time constraint, may obtain an

HLA-matched/mismatched related donor. This is the reason for why the relapse rate is lower in unrelated donors in some

cases. Likewise, patients with less severe conditions can still have a higher survival rate and a lower relapse rate with an

HLA-matched related donor because their immune system is still responsive. Therefore, the relapse rate in related and

unrelated donors are affected by the patient’s health state. Overall, the patient that obtains an HLA-matching donor regardless

of whether it is related or unrelated will have better outcomes.

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III: Mismatching unrelated donor

Different types of mismatching donor types and their effect

Mismatching unrelated donors are typically used when the patient has no other option, or finds a few matching alleles

between the donor and the patient. Multiple mismatching alleles can have a vast impact on the patient and may cause future

relapses. However, there are some types of single mismatches that can be beneficial for the patient, rather than worsen their

condition. An article that discusses the outcomes after a blood transplant describes that, “A single mismatch in highly

expressed HLA-A, -B, -C, and -DRB1 loci (HEL) is associated with worse outcomes in hematopoietic stem cell

transplantation, while less is known about the cumulative impact of mismatches in the lesser expressed HLA loci DRB3/4/5,

DQ, and DP (LEL)” (​Fernández-Viña, 2013). The author concludes that mismatches at high expressed alleles can lead to a

longer recovery rate, but not as much scientific proof is found about lower expressed alleles.

Additionally, there has been comparisons between HLA-matching unrelated donors and mismatching unrelated donors.

Dr. Yam explains, “The improved outcomes in unrelated donors appeared to be driven by HLA matched unrelated donors

while HLA mismatched unrelated donors and related donors were associated with similarly poor outcomes” (Yam, 2016). This

shows that HLA-matching unrelated donors are involved with better outcomes because there are more alleles in common with

the donor and the patient. In mismatching unrelated donors, the donor and patient may have some different alleles, which

explains why this is not always the first option to choose as a donor.
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Although there are a variety of alleles used to determine similarities between the patient and the donor, there are some

that are most frequently used. In a case study discussing unrelated donors, the authors mention that, “​HLA-A, -B, -C, -DRB1,

-DQB1, and -DPB1 alleles were obtained by retyping” (Morishima, 2015). If patients and donors have these alleles in

common, then it is HLA-matched. But, if there are single, double, etc. mismatches in the alleles, then it is considered

mismatched.

Effect on survival rate

Usually, HLA-A, -B, and -C are compared together, and HLA-DRB1, -DQB1, and -DPB1 are as well. When

examining mismatches between the donor and patient’s cells, single and double mismatches are considered. An article

examining mismatching alleles concludes, “... single HLA-A, -B or -C allele mismatches and double HLA-DRB1/DQB1

mismatches are associated with increased mortality in non-T-cell-depleted bone marrow transplantation. Interestingly single

HLA-DRB1, -DQB1 or -DPB1 mismatches did not significantly affect overall survival rate” (Tiercy, 2016). To simplify, the

article discusses that if there are single mismatches in HLA-A, -B, or -C, or double mismatches in HLA-DRB1 or DQB1, it

could lead to a lower survival rate. However, single mismatches in HLA-DRB1, -DQB1, and -DPB1 did not determine

whether the patient is going to have a low or high survival rate. This shows that some single mismatches can be harmful,

whereas others in different alleles can be useful or have no effect on the patient.
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Mismatching unrelated donors, as compared to HLA-matching unrelated donors is commonly discussed. It is clear

from scientific research that matching donors are associated with better survival rates than mismatching donors. As evidence to

prove that claim, Dr. Eapen includes, “Clearly, survival after adult unrelated donor transplantation mismatched at a single

HLA-locus is lower than that after matched unrelated donor transplantation” (Eapen, 2014). Even though during the transplant

the donors were unrelated, the similarities/differences between the alleles had a huge impact on the survival rate. This shows

that a few mismatching alleles can control whether the patient is going to recover faster or not. There are some cases where

mismatching donor cells can lead to a lower relapse rate, but have high mortality rates associated with it.

As mentioned above, some mismatched alleles can benefit the patient. A meta-analysis study conveys that,

“Mismatched HLA-DPB1 was significantly associated with a reduced risk of disease relapse (HR, 0.74; ​P​ < .001) but not with

increased risks of transplant-related mortality (TRM) and overall mortality” (Tie, 2017). Therefore, mismatching HLA-DPB1

alleles will lead to a higher survival rate, and a lower mortality rate. This is an accommodating option for patients to use if they

have no HLA-matching donors.

Effect on relapse rate

The number of mismatches (single or double) and the HLA-alleles can be a strong determinant on the relapse rate and

survival rate of the patient. An article describes that, “Of note, only HLA-C and HLA-DPB1 mismatch reduced leukemia

relapse, and this graft-versus-leukemia effect of HLA-DPB1 was independent of chronic GVHD. HLA-DRB1 and HLA-DQB1
 Katanguri 13

double (DRB1_DQB1) mismatch was revealed to be a significant RR for acute GVHD and mortality, whereas single mismatch

was not” (Morishima, 2015). Overall, mismatches in the HLA-C and HLA-DPB1 alleles were associated with a lower relapse

rate. It is a critical decision for doctors to choose because mismatching alleles in HLA-C and HLA-DPB1 may be a better

option for the donor if they are worried about cancer recurrence in future years.

In some cases, a single allele mismatch can lead to a faster recovery rate than double mismatches. However, it all

depends on the specific HLA-alleles that are mismatching since some are associated with a lower relapse rate, and other alleles

may increase mortality. Dr. Tiercy’s article provides that, “... more than one mismatch among the HLA-A, -B, -C, -DRB1, and

-DQB1 loci should be avoided;” (Tiercy, 2016). If there are double mismatches, the doctor should be cautious in selecting the

best alleles. The article explains that if other allele mismatches are a necessity, mismatches in the alleles, HLA-DQB1 and

-DRB3/4/5 should be used. An increase in the number of mismatches can lead to further complications like higher rate for

relapse and mortality.

Scientists warn that even though some allele mismatches are better to be used than others, it all depends on the patient’s

condition and how urgent they need the donor. Dr. Morishima and his colleagues include that, “In cases where the transplant

team is particularly concerned about the prevention of severe acute GVHD, leukemia relapse or early mortality, the specific

HLA locus mismatches and number of mismatched locus should be considered with regard to the patient’s disease, disease

status, and clinical condition” (Morishima, 2015). As described above, there are certain alleles better fit to use if the doctor
 Katanguri 14

does not want the patient to relapse. Overall, an HLA-matching donor is a better option when considering relapse and survival

rates because of all the complications associated with single and double mismatches at different alleles.

IV: Haploidentical donors/cord blood sources

Usage of a Haploidentical donor/cord blood sources

Haploidentical donors are generally siblings or parents that have ½ of their HLA markers common to the patient. This

donor type is used if HLA-matching related or unrelated donors are not available. Dr. Tiercy explains that, “Haploidentical

donors are increasingly used as an alternative source of stem cells for those patients lacking a matched unrelated donor”

(Tiercy, 2016). Even though there are many different donor types a patient could obtain, a haploidentical donor is used because

it is easier to find a donor in the patient’s family since the parents have common HLA markers to the patient.

Haploidentical means that the matching between the donor and the recipient is about ½. Thus, the donor cells will have

some mismatching alleles compared to the patient. But Dr. Tiercy includes that, “In selecting the best haploidentical donor, the

number of mismatched HLA antigens on the non-shared haplotype does not seem to play a role” (Tiercy, 2016). Although

having a haploidentical donor may lead to further complications depending on the patient’s condition, the doctor will not need

to focus on the number of mismatches.

Using cord blood units are another donor option. When a mother gives birth to their baby, they may choose to donate

blood from the baby’s umbilical cord. Dr. Eapen states that, “UCB units are readily available and generally HLA-match
 Katanguri 15

requirements are less stringent than that for the adult grafts (BM or PBPC) making this an attractive alternative option in the

absence of a suitably HLA-matched related or unrelated adult donor” (Eapen, 2014). The umbilical cord blood cells do not

have to be perfectly matching with the patient’s cells for the transplant to be successful. Usually a HLA-matching

related/unrelated donor is preferred for the patient, but using cord blood units is another highly accessible option.

Effect on survival rate

Since the the number of matching alleles in a haploidentical donor transplant differ, it could lead to a longer recovery.

In this type of donor choice, only ½ of the donor cells are in common with the patient’s, meaning that the donor cells are likely

to reject in the patient’s body. Dr. Eapen discusses that, “Early studies of HLA-haploidentical stem cell transplantation clearly

showed worsening outcomes with increasing HLA disparity between donor and recipient” (Eapen, 2014). This shows that as

the differences in HLA increase, the outcomes of the patient after transplant becomes substandard. This can not only decrease

the survival rate, but can also lead to other diseases in the body like graft-versus-host disease.

Cord blood units lead to a higher survival rate when compared with the haploidentical donor option. But, it depends on

how matching the cord blood unit cells are to the patient’s. The same author from the previous article explains that, “However,

two recent publications suggest considering allele-level HLA-matching including matching at the HLA-C when selecting UCB

units leads to better hematopoietic recovery and lower non-relapse mortality” (Eapen, 2014). This shows that if the cord blood
 Katanguri 16

unit cells are HLA-matching as opposed to mismatching, it will lead to a better outcome and survival rate. Thus,

HLA-matching donor cells (even if it is umbilical cord blood) are associated with lower mortality rates.

However, sometimes cord blood units can lead to worse outcomes, especially the alleles are mismatching between the

patient and donor. An article discussing mismatching donors states, “​In contrast, increased rates of death without GVHD or

relapse have been described with UCB grafts, which is likely related to delayed engraftment compared with other graft

sources” (Holtan, 2015). In some cases where the HLA markers are mismatching, cord blood units can be harmful rather than

helpful. Overall, there are higher survival rates associated with matching donor cells, as compared to mismatching.

Effect on relapse rate

In some types of blood malignancies, a bone marrow transplant can be a better option than using peripheral or cord

blood cells. Dr. Holton shares that, “HLA-matched sibling donor marrow resulted in the best GRFS (51%, 95% CI 46-66),

whereas HLA-matched sibling donor peripheral blood stem cells were significantly worse (25%, 95% CI 20-30, ​P​ = .01).

GRFS after umbilical cord blood transplants and marrow from matched unrelated donors were similar (31%, 95% CI 27-35

and 32%, 95% CI 22-42, respectively)” (Holtan, 2015). GRFS is GVHD-free/relapse-free survival, and is a main factor in

determining how successful the transplant was. As shown by the data, umbilical cord blood and matching unrelated donors had

similar results and are associated with a higher relapse rate. Other data in this article has shown that cord blood donors are

linked to a higher relapse rate than HLA-matching related donors with the bone marrow transplant.
 Katanguri 17

In some cases, haploidentical donor types can have lower relapse rates than HLA-matching donors. In an article

analyzing the outcomes of a blood transplant, it states that, “Before re-relapse, patients had a median CR duration of 3 months

(range, 1–15 months). MRD transplant recipients had a higher re-relapse rate than HID transplant recipients, 92.3 vs 66.7%,

respectively (​P​=0.195)” (Ma, 2016). Even though the relapse rate in both the haploidentical and HLA-matched related donor

option are extremely high, the results are in favor of the haploidentical donor cells. In comparison, the haploidentical option

and cord blood units have some benefits and may be used depending on the patient’s condition, type of transplant, and

prognosis. But weighing the factors considering the survival rate, HLA-matching donors are a more viable option.

V: Other factors affecting the process to find a matching donor.

Factor 1: Age and gender effect on survival and relapse rates

Along with the different donor types, there are other factors that influence a patient’s ability to find a matching donor.

Generally, younger donors have been proved scientifically to be a better option than older donors. This is why communities try

to raise awareness to have people that are young adults donate more of their blood cells. An article describing the prognostic

factors related with matching donors explain that, “By further exploring for a donor age cut off among MRD, they observed

that patients who received grafts from MRD aged ≥67 years experienced higher relapse and mortality risks compared to those

transplanted from younger MRD” (Servais, 2014). An increase in the donor age can lead to higher relapse rates and lower

survival rates, as opposed to younger donors.

 Katanguri 18

More evidence supports the claim that younger donors will have better outcomes than older donors. This is mainly

because younger donors have more newly formed cells that can be beneficial for a patient with blood cancers. Additionally, an

article discussing donor age influence states, “There was a trend for lower risk of relapse (3 years) and lower non-relapse (at 1

year) mortality for patients transplanted from younger HLA-MUDs in comparison with HLA-identical sibling

transplantation...” (Kröger, 2012). Since this article talks about matching donors, donor age can affect the process of choosing

a donor for the patient.

Additionally, gender also be a factor in choosing a matching donor. Dr. Kollman discovered that, “​The only donor

characteristic associated with lower relapse risk was transplantation of grafts from parous females compared with male donors”

(Kollman, 2016). This shows that female donors had better outcomes associated with it, which may help doctors find the

perfect matching donor for their patient.

Factor 2: Ethnicity

People that are minority groups generally have a difficult time finding an HLA-matching donor. Whites and Europeans

donor cells are more frequently found in registries and donor cell organizations, than any other ethnicity. This can be a

problem for patients that are minorities and are in need of an HLA-matching donor. Dr. Kollman announces that, “We

acknowledge the likelihood of identifying a fully HLA-matched donor for nonwhites is substantially lower than for whites, and

incorporating donor age to the selection algorithm may mitigate some of the excess mortality associated with
 Katanguri 19

HLA-mismatched transplantations” (Kollman, 2016). If more people that are minorities donate their bone marrow cells,

patients battling blood cancers will not have to worry about using mismatching donors.

As mentioned above, Western Europeans are the most common donor type in registries, and Africans are the least

common donor types. This evidence is proved by Dr. Tiercy as she compares that,​ ​“As shown in ​Table 2​, the ​average

probability of identifying a matched unrelated donor differs greatly depending on the ethnic origin of the patients and on the

matching grade required by the transplant center” (Tiercy, 2016). Generally, patients will find more matching alleles/HLA

markers in common with people that have the same ethnicity as them. Lastly, raising awareness to communities, organizations,

and other people will help gather attention to donate more bone marrow cells to help patients with blood cancers. With more

bone marrow cells available in registries, a patient will have better outcomes following a transplant with an HLA-matching

donor.

VI: Data Collection

The criteria examined was evidence that proved that matching or any types of donors would help increase the rate of survival, and
decrease the rate of relapse.
Articles used: Results of the study: Comparison:

Runzhe Chen, Jos L Campbell, and Baoan 1. “Protection against relapse can be ● All articles were related to
Chen. ​Prophylaxis and treatment of increased using unrelated donors, hematopoietic stem cell
acute lymphoblastic leukemia relapse cord blood donors, or transplantation.
after allogeneic hematopoietic stem cell HLA-matched donors.​17​,​37​,​40​,​51 ● All had evidence or were inferring

transplantation. ​Published: 10 February To improve outcomes and
2015. decrease the risk of relapse,
younger donors should also be
sought ​52​” (Chen, 2015).
2. “The occurrence of acute GVHD
is affected by the degree of HLA
matching and the type of donor.
The development of chronic
GVHD after DLIs is associated
with the highest rate of response to
DLI and higher survival rates ​68​”
(Chen, 2015).
3. “The GVL effect in ALL is
probably one of the most potent
strategies with curative potential,
and DLI is an attractive option for
prophylaxis against relapse of
ALL after transplantation ​14​”
(Chen, 2015).
Nelli Bejanyan, Daniel J. Weisdorf, Brent
R. Logan, Hai-Lin Wang, Steven M.
Devine, Marcos de Lima, Donald W.
Bunjes, and Mei-Jie Zhang. ​Survival of
AML patients relapsing after allogeneic
hematopoietic cell transplantation: a
Katanguri 20
that HLA-matching related was
the best donor option.
● All came to the conclusion that
various types of donors are
needed.
● All compared different donor
types on a population in the data.
● Bejanyan and Solh’s articles had
evidence based on the same case
study (CIBMTR).
● All discussed the survival rates
and impacts of a relapse on the
patient.
● Articles mentioned Donor
Lymphocyte Infusions as a method
to prevent future relapses.
● Discussed both common cases of
Leukemia (ALL and AML).
Relapses are associated with
GVHD within the patient.

CIBMTR study. ​Published: March 2015.
M Solh, X Zhang, K Connor, S Brown, S
R Solomon, L E Morris, H K Holland, and
A Bashey.​ ​Post-relapse survival after
haploidentical transplantation vs
matched-related or matched-unrelated
hematopoietic cell transplantation.
Published online: 21 March 2016.
Katanguri 21
The above data was provided by “Survival
of AML patients relapsing after allogeneic
hematopoietic cell transplantation: a
CIBMTR study” by Nelli Bejanyan, et al.
5. “​...patients with relapsed acute
myelogeneous leukemia after
mismatched-unrelated or double cord
transplantation had a worse PRS than
recipients of a matched sibling or
matched-unrelated HCT ​8​” (Solh, 2016).
Katanguri 22
 Katanguri 23

The above graphs were provided by

“​Post-relapse survival after haploidentical
transplantation vs matched-related or
matched-unrelated hematopoietic cell
transplantation” by Melhem M. Solh, et
al.

6. “...immune recovery remains delayed,

and infections remain a leading cause of
mortality in this group of patients [​31​-​33​].
This is further evidence that expanding
 Katanguri 24

the donor pool with alternative bone

Orly R. Klein, Allen R. Chen, Christopher
Gamper, David Loeb, Elias Zambidis,
Nicolas Llosa, Jeffrey Huo, Amy E.
Dezern, Diana Steppan, Nancy Robey,
Mary Jo Holuba, Kenneth R. Cooke,
Heather J. Symons. ​Alternative donor
hematopoietic stem cell transplantation
with post-transplantation
cyclophosphamide for nonmalignant
disorders. ​Published: May 2016.
marrow donors, including both
mismatched unrelated and related
HLA-haploidentical donors, is greatly
needed” (Klein, 2016).
7. “Given that HLA-matched donors can
only be found for 50% of patients (and for
less than 20% of African American
patients), there is tremendous need to
develop novel strategies for all patients,
especially racial minorities [​3​]” (Klein,
2016).
8. “There is great success using
HLA-matched related donors for these
patients; however, the use of alternative
donors has been associated with increased
graft failure, graft versus host disease
(GVHD), and transplant-related mortality
(TRM)” (Klein, 2016).

Rationale:

Meta-analysis was used to collect the data because the valid data could not be obtained from any of the other options. Since the data

collected was based on various donor types and their effect on the rate of relapses, there was nothing available on that through

surveys, interviews, or observations. There had to be accurate data on experiments that were conducted on patients with Leukemia
 Katanguri 25

that had a relapse and the donor type that contributed to their transplant. Through articles, there was information obtained to support

the claims on how the type of donor during a transplant affects the rate of relapse. Initially, the data collection method for this topic

was a survey by comparing the outcomes of why people may not want to become a bone marrow donor. It has come to conclusion

that to have the most accurate results on evidence concerning relapses, Meta-Analysis had to be used to gather the data. After

examining the four sources picked, the data supported the hypothesis and research. These specific four sources were picked mainly

because the data was current and it explained the evidence discovered thoroughly. Through the data collection, and analyzing the

main donor options, it was discovered which ones were associated with the highest survival rate and lowest relapse rate.

Analysis:

As shown in the results gathered, it is important for leukemic patients to have numerous options of donor cells to insure that the

patient does not relapse. The main donor types in these studies include: HLA matching related, HLA-matching unrelated, and

mismatching. Dr. Runzhe Chen’s article concludes that for best results in childhood Leukemia, a patient needs a young donor that

has a matching HLA-type. Mismatching donor types may lead to further complications and increase the mortality rate. It states in

Nelli Bejanyan’s article that patients that had a related or HLA identical sibling, had a survival rate of over 50% one or more years

after a relapse. For DLI±2nd HCT, the survival rate after a relapse was 68% with an HLA-identical sibling. But the survival rate is
 Katanguri 26

lower for patients that had a unrelated donor. For patients that had a second Hematopoietic cell transplantation (HCT) after their

relapse, 52% of patients had survived post relapse with a related donor, but less than 50% of patients with an unrelated donor

survived. Patients with Acute myeloid leukemia (AML) that had mismatching unrelated donor cells had lower survival rates after

relapse as opposed to patients that had an HLA-matching related or HLA-matching unrelated (Solh, 2016). It can be concluded that

for the best success after a transplant, the donor needs to have the criteria of having a HLA-identical/unrelated or matching donor,

because it has higher survival rates associated with it than a mismatching donor.

Also, in Solh’s article, the data provided had graphs comparing the survival rate to the time since transplant and years since relapse.

The Figure 1 graph showed that patients with a Matching-related donor (MRD) had a higher survival rate and less frequent

incidence of Graft versus host disease (GVHD), as opposed to patients with a Matching-unrelated donor (MUD). In Figure 2, the

results were similar. A MRD or MRD/MUD/with the Donor lymphocyte infusioN (DLI) had a high survival rate linked to it. This

provides evidence for the fact that a MRD can be one of the factors leading to a decrease in GVHD and relapses.

Therefore, both articles show that a patient with an HLA-matching related donor will have the best survival rate after a relapse.

Although in some cases, the patient can not obtain HLA-matching related cells. So as proven by the data, an HLA-matching

unrelated donor would be the next viable option. Even though the statistics show that the probability of survival is lower for the
 Katanguri 27

MUD than the MRD, the MUD option still shows higher rates of survival after relapse, as opposed to the mismatching donor cell

options. Dr. Runzhe Chen and the authors contributing to her article mentioned that acute GVHD occurs as a result of the

connections between the donor and patient’s stem cells (whether its matching).

As explained in the article written by Klein, the authors state that patients that are racial minorities may have difficulty finding a

matching HLA type in a donor registry. It shows statistics that only about 50% of patients can find an HLA- matching donor,

leaving the rest of the patients without an HLA-matching donor to proceed in their transplant (Klein, 2016). The authors persuade

the audience to promote awareness to enlarge the variety of bone marrow donors in the registries to help increase the survival rate of

patients undergoing a transplant, and lower the rate of relapses in Leukemia. The only limitations are that some experiments may

include only part of the data and not correlations between all the donor types. Overall, an HLA-matched donor is the best option,

according to the evidence provided by all the articles. All this data supports the claim that with more donor cells in the registry,

more leukemic patients can have HLA-matching cells during their transplant to prevent a relapse, and propose a cure.

Conclusion:

The results explain that scientists can help the leukemic patient obtain an HLA-matching related donor for a successful transplant.
 Katanguri 28

When patients do not have an HLA-matching related donor in their family, the second best option would be an HLA-matched

unrelated donor to use. Since this type of donor can save a leukemic patient and lower the risk of relapse, more people and

communities will donate to a bone marrow registry. The results show evidence for the claims that relapses can be prevented and that

a transplant with an HLA- matching donor can have a successful outcome. Through this data collection process, new knowledge has

been gained on the correlations between these three main donor sources (matched related, matched unrelated, and mismatched), and

how one can lead to a better outcome for a patient than another. After analysing the results and making the comparisons between all

four articles, a new conclusion was made about how raising awareness for bone marrow donors can lead to more donors in the gene

pool. With more donors in the gene pool, there will be a variety of donor options for the patient undergoing the transplant, lowering

the relapse rate and increasing the survival rate. The relapse rate will never be 0%, but finding the perfect donor can help decrease

the probability of a patient obtaining cancer again.

VII: Overall Conclusion

Scientists and other researchers have proved correlations and comparisons between multiple donor types during a bone marrow

transplant. A bone marrow transplant is used for specific blood cancers depending on the various curative options. As hundreds of

patients each year are diagnosed with a variety of blood cancers, relapse and survival have been some of the most important factors to

focus on. An HLA-matching donor is the best option because it is associated with higher positive outcomes as compared to the other
 Katanguri 29

donor sources. Also, since an HLA-matched donor is difficult to find in most of the population, other donor sources can be used as

well. Rather than comparing one or two donor types, this article has synthesized: HLA-matching related, HLA-matching unrelated,

mismatching, haploidentical, and cord blood donor source; and analyzed which will result in the best outcome. The main problems a

doctor may experience when finding a donor is how close the patient’s alleles are in comparison to the donor. Advancements in

research and analyzing the patient’s condition, will allow the doctor to choose the most efficient donor. In conclusion, as there are

various other factors that influence the outcome of a patient’s condition, obtaining an HLA-matching donor is a more reliant source.

Additionally, bringing attention to this matter and contributing to the advancement in donating more bone marrow cells around the

world will help simplify the process doctors and patients have to take to find the perfect, matching donor. With more support from the

world, leukemic and blood cancer patients can have a faster recovery and a chance for a cure.
 Katanguri 30

References from Data Collection

Bejanyan, N., Weisdorf, D. J., Logan, B. R., Wang, H., Devine, S. M., Lima, M. D., . . . Zhang, M. (2015, March). Survival of AML

patients relapsing after allogeneic hematopoietic cell transplantation: A CIBMTR study. Retrieved April 30, 2018, from

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4329076/

Chen, R., Campbell, J. L., & Chen, B. (2015, February 10). Prophylaxis and treatment of acute lymphoblastic leukemia relapse after

allogeneic hematopoietic stem cell transplantation. Retrieved April 30, 2018, from

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334331/

Klein, O. R., Chen, A. R., Gamper, C., Loeb, D., Zambidis, E., Llosa, N., . . . Symons, H. J. (2016, May). Alternative donor

hematopoietic stem cell transplantation with post-transplantation cyclophosphamide for nonmalignant disorders. Retrieved

April 30, 2018, from ​https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4898048/

Solh, M., Zhang, X., Connor, K., Brown, S., Solomon, S. R., Morris, L. E., . . . Bashey, A. (2016, March 21). Post-relapse survival

after haploidentical transplantation vs matched-related or matched-unrelated hematopoietic cell transplantation. Retrieved

April 30, 2018, from ​https://www.nature.com/articles/bmt201662

 Katanguri 31

Literature Review References

Alousi, A. M., Le-Rademacher, J., Saliba, R. M., Appelbaum, F. R., Artz, A., Benjamin, J., . . . Champlin, R. E. (2013, March 28).

Who is the better donor for older hematopoietic transplant recipients: An older-aged sibling or a young, matched unrelated

volunteer? Retrieved March 19, 2018, from ​https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3612864/

Brissot, E., Labopin, M., Stelljes, M., Ehninger, G., Schwerdtfeger, R., Finke, J., . . . Nagler, A. (2017). Comparison of matched

sibling donors versus unrelated donors in allogeneic stem cell transplantation for primary refractory acute myeloid leukemia: A

study on behalf of the Acute Leukemia Working Party of the EBMT. Retrieved March 19, 2018, from

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5483262/

D'Souza A, Fretham C. Current Uses and Outcomes of Hematopoietic Cell Transplantation (HCT): CIBMTR Summary Slides, 2017.

Available at: ​http://www.cibmtr.org

Eapen, M., O’Donnell, P., Brunstein, C. G., Wu, J., Barowski, K., Mendazibal, A., & Fuchs, E. J. (2014, October). Mismatched

related and unrelated donors for allogeneic hematopoietic cell transplantation for adults with hematologic malignancies.

Retrieved March 19, 2018, from ​https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4163123/

 Katanguri 32

Fernández-Viña, M. A., Klein, J. P., Haagenson, M., Spellman, S. R., Anasetti, C., Noreen, H., . . . Lima, M. D. (2013, May 30).

Multiple mismatches at the low expression HLA loci DP, DQ, and DRB3/4/5 associate with adverse outcomes in

hematopoietic stem cell transplantation. Retrieved March 19, 2018, from

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3668493/

Holtan, S. G., DeFor, T. E., Lazaryan, A., Bejanyan, N., Arora, M., Brunstein, C. G., . . . Weisdorf, D. J. (2015, February 19).

Composite end point of graft-versus-host disease-free, relapse-free survival after allogeneic hematopoietic cell transplantation.

Retrieved March 19, 2018, from ​https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4335084/

Kollman, C., Spellman, S. R., Zhang, M., Hassebroek, A., Anasetti, C., Antin, J. H., . . . Eapen, M. (2016, January 14). The effect of

donor characteristics on survival after unrelated donor transplantation for hematologic malignancy. Retrieved March 19, 2018,

from ​https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4713163/

Kröger, N., Zabelina, T., Wreede, L. D., Berger, J., Alchalby, H., Biezen, A. V., . . . Witte, T. D. (2012, July 23). Allogeneic stem cell

transplantation for older advanced MDS patients: Improved survival with young unrelated donor in comparison with

HLA-identical siblings. Retrieved March 19, 2018, from ​https://www.nature.com/articles/leu2012210

 Katanguri 33

Ma, Y., Xu, L., Zhang, X., Yan, C., Wang, Y., Wang, F., . . . Huang, X. (2016, October 31). Comparable post-relapse outcomes

between haploidentical and matched related donor allogeneic stem cell transplantation. Retrieved March 19, 2018, from

https://www.nature.com/articles/bmt2016283

Morishima, Y., Kashiwase, K., Matsuo, K., Azuma, F., Morishima, S., Onizuka, M., . . . Sasazuki, T. (2015, February 12). Biological

significance of HLA locus matching in unrelated donor bone marrow transplantation. Retrieved March 19, 2018, from

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326776/

Saber, W., Cutler, C. S., Nakamura, R., Zhang, M., Atallah, E., Rizzo, J. D., . . . Horowitz, M. M. (2013, September 12). Impact of

donor source on hematopoietic cell transplantation outcomes for patients with myelodysplastic syndromes (MDS). Retrieved

March 19, 2018, from ​https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772501/

Servais, S., Porcher, R., Xhaard, A., Robin, M., Masson, E., Larghero, J., . . . Latour, R. P. (2014, March). Pre-transplant prognostic

factors of long-term survival after allogeneic peripheral blood stem cell transplantation with matched related/unrelated donors.

Retrieved March 19, 2018, from ​https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943316/

 Katanguri 34

Tie, R., Zhang, T., Yang, B., Fu, H., Han, B., Yu, J., . . . Huang, H. (2017, April 18). Clinical implications of HLA locus mismatching

in unrelated donor hematopoietic cell transplantation: A meta-analysis. Retrieved March 19, 2018, from

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5432365/

Tiercy, J. (2016, June). How to select the best available related or unrelated donor of hematopoietic stem cells? Retrieved March 19,

2018, from ​https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5013969/

Yam, C., Crisalli, L., Luger, S. M., Loren, A. W., Hexner, E. O., Frey, N. V., . . . Reshef, R. (2016, September). Unrelated Donors are

Associated with Improved Relapse Free Survival Compared to Related Donors in Patients with Myelodysplastic Syndrome

Undergoing Reduced Intensity Allogeneic Stem-Cell Transplantation. Retrieved March 19, 2018, from

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5066393/

Additional references

Haploidentical transplant. (n.d.). Retrieved March 25, 2018, from

https://bethematch.org/patients-and-families/about-transplant/what-is-a-bone-marrow-transplant/haploidentical-transplant/

Cord blood and transplants. (n.d.). ​Retrieved March 25, 2018, from

https://bethematch.org/transplant-basics/cord-blood-and-transplants/