1. 1
Pittala, Keerthana, Elly Ranum, Keighley Reisenauer
Lab 503, 407, 314
5/3/2013
A META-ANALYSIS OF TREATMENTS FOR MYELODYSPLATIC SYNDROME
EVALUATING EFFECTIVENESS OF EPIGENETIC THERAPY, CHEMOTHERAPY,
AND BONE MARROW TRANSPLANT
PRELIMINARY ABSTRACT
Myelodysplastic syndrome (MDS) is a “pre-cancer” of the bone marrow that usually results in
Acute Myelogenous Leukemia (AML). These syndromes involve the degeneration of stem cells
in the bone marrow inducing irregular production of red blood cells. There are several possible
treatments, but the most successful target the genome or the location of cancer. We produced a
meta-analysis of thirty journals, 10 on each type of treatment, and focused on remission rates.
Several databases were used in accumulating data. We addressed the question: of epigenetic
therapy, chemotherapy, and bone marrow transplant, which treatment of MDS is the most
effective in terms of suppression? We concluded that bone marrow transplant was the most
effective treatment (as defined by the highest average score achieved by our index analysis).
INTRODUCTION
“Myelodysplastic syndromes (MDS) include a heterogeneous group of clonal myeloid
stem cell disorders characterized by peripheral cytopenias and dysplasia of bone marrow
progenitor cells” (Candelaria, 2010). Myelodysplastic syndrome is a highly complex disease that
has no known cure. Several treatments are available; among the most commonly used and
researched are epigenetic therapy, chemotherapy, and bone marrow transplant. However, no

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study has been found that evaluates the effectiveness of each type of these treatments as
compared to each other.
Epigenetic Therapy (Reisenauer)
“Epigenetic mechanisms that can dysregulate gene expression have become increasingly
attractive as potential targets in the therapy of human cancer” (Maslak, 2006). To determine the
best treatment and regimen, a multitude of drugs and treatment regimens have been assayed. An
overall assessment has been achieved that a combination therapy of low dosages and high
intensities will result in the most remissions. “Strategies of combining different drugs aim at
increasing the efficacy of the single agents, therefore improving response rates, prolonging
response duration, and decreasing the toxicities associated with the treatment” (Follo, 2011)
Epigenetic therapy trials define the outcomes of their study in terms of complete remission (CR),
partial remission (PR), and other defined levels of symptom suppression.
Chemotherapy (Ranum)
Lenalidomide has proven to be a promising drug for the treatment of patients with
Myelodysplastic Syndrome. This drug was chosen for this analysis as it is the most widely used
and researched, when compared to other chemotherapy drug regimens. The drug is especially
effective in patients exhibiting a genetic abnormality called 5q syndrome and leads to transfusion
independence in over two thirds of these patients (Ades, 2008). The drug is given in different
amounts and phases depending on the patient. The exact function of Lenalidomide is unknown,
however, as an immunomodulatory agent, it is believed to have several broad biological effects.
The drug can stimulate the immune system by enhancing the response of Cytotoxic T Cells and
Helper T Cells. It is also believed that the drug can slow the growth of blood vessels to prevent
rapid tumor growth (Rami 2011).

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Bone Marrow/Stem Cell Transplant (Pittala)
Clinical trials show that the effects of Bone Marrow transplants depend on the source,
relatives or an outside source, and the progression of the disease (Anderson, 1993). MDS that has
progressed to serious levels should not respond as actively to Bone Marrow/ Stem Cell
transplants; this progression also depends on the age of patients as the age of contraction and
years with disease influence the treatment type and overall effectiveness (Chunkang, 2007).
The effectiveness of Bone Marrow Transplants, Chemotherapy, and Epigenetic Therapy
is variable. There is no one treatment that has been labeled as the best or most effective method,
as based on our initial literature review; however, by comparing data from additional studies we
can hope to deduce the most effective treatment for patients with MDS. More formally, our
hypothesis is that there is no strong difference between epigenetic therapy, chemotherapy, and
bone marrow transplant in the treatment of MDS. The remainder of this paper will explore this
hypothesis by first describing the methods we used in gathering and analyzing our data. The
results section will highlight our findings; the discussion section will develop the implications of
this data and also explain any shortcomings of the study. The conclusion will recap the findings
and overall process of this study.
METHODS
In completing this meta-analysis, databases were searched using key terms and filtering
techniques. The relevant articles were compared within each treatment type and then cross-
analyzed to determine overall effectiveness. A scale and index (Appendix, Table 2) were
established to analyze success.

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Epigenetic Therapy
Using PubMed and Web of Knowledge databases to search for information, the key
terms “epigen*”, “MDS”, “Myelodysplastic syndrome”, and “therapy” were searched. Articles
written in English or translated into English were used. Subjects must have a median age over 55
years, no interfering health problems, and be classified with MDS or acute myelogenous
leukemia (AML). The studies must be clinical trials and published after 2000. They must also
report their results in terms of remission or symptom suppression. MDS is most common in older
patients and other interfering health problems could be inadequately accounted in the study, so
these studies were ruled out. Clinical trials were chosen because the focus was on recent work
being applied in a realistic setting to accurately trace the effectiveness of each treatment in “real
time.” No common drug was chosen because the variance between each study was too high.
Studies were excluded if the average age of subjects was below the selected age or if the study
was not conducted on humans. Also, the full article must be available (See Figure 1.3). The type
of trial, subject information, method controls and measurements, and results were recorded in a
table using headers to organize data (see Table 1). Overall, in these studies, CR is defined as
disease stabilization with successful methylation of the targeted gene. PR is considered no
regression or advancement of MDS or AML but without achieving complete stabilization or
remission. Null patients were unable to complete the full treatment regimen due to early death or
alternative complications.
Chemotherapy
Using Medline, Google Scholar, and Web of Knowledge as resources, several articles
were identified relating to the treatment of Myelodysplastic Syndrome using a chemotherapy
regimen of Lenalidomide. The databases were searched using the keywords “Myelodysplastic
Syndrome,” “MDS,” “Lenalidomide,” “chemotherapy,” and “treatment.” Studies that were

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written in English or translated into English were considered. Because MDS is most commonly
diagnosed in older patients, studies were only considered if they had a median age of at least 60
years old. Studies also needed to have been published in the last 20 years to ensure that the
findings and experimental methods are recent. The studies must involve the use of Lenalidomide
for the treatment of transfusion dependent adults with MDS, and report their results in terms of
treatment independence and/or erythroid response in patients. Studies were excluded if patients
were treated with more than one drug or therapy during their chemotherapy regimen. If the full
article was not available, the study was not considered. The selected articles’ authors’ names,
date of publication, age, sex, and health status of the patients, as well as results of the trials
including erythroid and cytogenic response, were recorded. The citing articles and citations of
related articles were also considered (See Figure 2.3). The information from all the articles was
then organized into an Excel spreadsheet (Table 1).
Bone Marrow/Stem Cell Transplant
Using Pubmed and Google Scholar, articles were found that related to MDS treatment
with Bone Marrow transplants. Data from clinical trials was preferred for the best analysis of a
treatment but retrospective studies provided greater insight into the long-term effects of a
treatment. Retrospective studies took patients from a single location that had undergone Stem
Cell or Bone Marrow transplants and compared their current state to their state during treatment
within a set time span. These studies consisted of patients who had previously received treatment
for MDS but did not benefit from it. Subjects of the studies aged from 3 years to 70+ years, no
age groups were specifically excluded so that the impact of age on treatment could be analyzed.
Articles were compiled using the keywords: “MDS”, “Bone Marrow transplants”, “Acute
Myelogenous Leukemia”, and “suppression”. The articles were then limited to studies done
within the past five years, except for one article which proved to be a basic study done on the

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subject and was cited by many current studies (Anderson, 1993 ). The data from the articles
collected was then compiled on Excel (Table 1). Data that was recorded included: author, year of
publication, duration of treatment, number of subjects and characteristics, methods and control of
the studies, method of measurement whether statistical or numerical, and the final results. Even
though the fields used for finding articles and studies was very broad this allows for a
consideration of a select few characteristics in patients that are addressed and therefore allow for
a better analysis of the effectiveness of this treatment on certain groups of people. Studies
involving Bone Marrow transplants, including allogeneic bone marrow transplants, and
Hematopoietic cell transplantation were selected. Age of the subjects of the studies was not used
to separate studies (See Figure 3.3). Chance and rate of relapse and overall success of
suppression were used to compare the different treatments.
To compare all these studies between treatments, both an independent scale and an
overarching index analysis were introduced. In the scale, complete remission (CR) consists of
patients who did not relapse within the timeframe of the study and became independent of
regular treatment; partial remission (PR) achieves similar results as CR, but still requires a
degree of treatment continuation and these patients do not fully achieve “success” as defined by
the study; failure to complete the study in full, early death, or placebo treatment is defined as
null. For epigenetic treatment, CR is defined as disease stabilization with successful methylation
of the targeted gene; PR is defined as no regression or advancement of MDS or AML, but
without achieving complete stabilization or remission; null is defined as patients who were
unable to complete the full treatment regimen due to early death or alternative complications. For
chemotherapy, CR is defined as transfusion independence , PR is defined as a reduction in the
number of transfusions needed monthly by at least half , and null is defined as patients who did

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not complete the treatment regimen or were taking a placebo. For bone marrow transplant, CR is
defined as being disease-free and without relapse within the time frame of the study, PR is
defined as relapse, and null is defined as death directly caused by treatment (not due to relapse)
and includes subjects that could not be used for analysis of partial remissions.
The index was established as a means to compare several variables across each study and
reach numeric conclusions of effectiveness of treatment. Each study was analyzed on length of
trial, number of participants, the percentage of participants showing any positive effects out of
total number of participants, and the percentage of participants showing CR, PR, and Null, again,
out of the total number of participants. A numeric value range was set up for each category
mentioned. A particular study received a number score for each of these variables. The first three
columns give a baseline numeric value to each individual study. From there, studies were given
three separate scores based on the three outcome categories’ (CR, PR, and Null) percentage of
patients that fell within each type of category, respectively. To stratify this data and put more
emphasis on effectiveness, the scale was re-introduced and a value 10 (CR), 5 (PR), or 0 (Null)
was added to each respective group. The total score for each study was, thus, comprised of a
series of three numbers that numerically evaluated the effectiveness of the trial (See Table 2).
The average score for each treatment type was then calculated and used as a comparison between
the studies.
RESULTS
In a cross-study of all the articles between treatment types, no consistent measurement of
treatment success existed. To diminish this, an encompassing definition of symptom suppression
was defined. For our purposes, treatment success was defined as independence from continual
treatment for a length of time and a reduction in cancerous symptoms.

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Epigenetic Therapy
10 journals were identified as viable epigenetic treatment clinical trial studies of MDS.
Between these ten, 345 patients were identified, all with diagnosed MDS or AML, the secondary
disease to MDS. In these studies, CR is defined as disease stabilization with successful
methylation of the targeted gene. PR is considered no regression or advancement of MDS or
acute myelogenous leukemia (AML), but without achieving complete stabilization or remission.
Null patients were unable to complete the full treatment regimen due to early death or alternative
complications.
Overall, of the 345 patients analyzed, 24% of patients were CR, 47% were PR, and 29%
were null for epigenetic therapy (see Figure 1.1). The average index score for epigenetic
treatment was calculated to be 40.8 (Table 2).
Chemotherapy
10 studies were identified studying the use of Lenalidomide to treat MDS involving a
total of 867 human participants. Transfusion independence is considered to be complete
remission (CR) and a decrease in the number of transfusion needed monthly by at least half is
considered partial remissions(PR). Participants who were taking a placebo or who did not
complete the drug regimen are considered null.
Overall, 336(39%) participants achieved CR, 106(12%) achieved PR and 425(49%) were
considered null(see figure 2.1). The average index score for chemotherapy was 47.9 (see figure
2.2).

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Bone Marrow/Stem Cell Transplant
The result of allogeneic bone marrow transplants must be observed over the course of
months or years; therefore, most studies were retrospective studies. These studies took patients
who had received bone marrow or stem cell transplants within a certain time frame from a
specific hospital or clinic and followed their progress. The cause of death, rate of relapse, and
disease-free survival are the main topics of interest. The results vary and patients relapsed
depending on the initial severity of MDS. Clinical trials show that the effects of Bone Marrow
transplants depend on the source, relatives or an outside source, and the progression of the
disease (Zimmerman, 2011). MDS that has progressed to serious levels should not respond as
actively to Bone Marrow/ Stem Cell transplants; this progression also depends on the age of
patients as the age of contraction and years with disease influence the treatment type and overall
effectiveness. The levels of red blood cells, neutrophils, and platelets are monitored to measure
the effects of transplants. It was found that allogeneic bone marrow transplants were successful
for individuals with MDS who were under the age of 40; however, the severity of MDS was a
significant determining factor of the effectiveness of treatment (Anderson, 1993). Some younger
patients benefited from treatment but those suffering from MDS, which was a result of
chemotherapy or radiotherapy for cancer, usually resulted in long-term freedom from disease
(Kröger, 2007). This fact was said to be related to the amount of proliferation of MDS before the
time of treatment. Younger patients who received treatment sooner limited the amount of
proliferation making the effects of the treatment more significant. Older patients who had
received treatment were studied, red blood cell count and neutrophil counts were taken, and
various treatments were used to determine the effectiveness of treatment. Many older patients
died because of relapse (Khabori, 2011). Older patients who participated in studies tended to

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have received previous treatment for MDS including chemotherapy or radiotherapy (Spina,
2012). These patients usually did not respond positively to bone marrow/stem cell transplants
because their condition was worse off compared to younger patients. This showed that bone
marrow transplants and stem cell transplants were helpful in the short term but could not
guarantee the complete prevention of relapse or disease-free survival (Lukenbill, 2013). A
significant portion of patients who underwent treatment relapsed and died about 3-10 years after
treatment due to causes directly related to treatment or because of other adverse causes.
Final Conclusion of Results
For epigenetic therapy 83 (24%) were CR, 162 (47%) PR, and 100 (29%) null. For
chemotherapy, 336(39%) were CR, 106(12%) PR, and 425(49%) null. For bone marrow 572
(34.31%) were CR, 477 (28.61%) PR, and 618 (37.07%) null. Based on these results alone
chemotherapy had the highest percentage of CR patients from score-only analysis. Bone
Marrow/Stem cell transplants had the highest average index score at 56, compared to the other
two treatments, and thusly was deemed the most effective treatment of myelodysplastic
syndrome.
DISCUSSION
In comparing these three treatments, chemotherapy, bone marrow transplant, and
epigenetic treatment, it was concluded that chemotherapy has the highest percentage of patients
who reach CR, but bone marrow transplant has the highest average index score. However, this
comparison is not without error. Each type of treatment focuses on a distinct symptom and
attacks a highly specific cause of MDS. Also, the methods used to study effectiveness and the
metric used to measure progress varied between treatments. For this reason, an overarching scale
and analytical index had to be defined and some of the specific variants of each study were lost.
Also, in order to truly understand which treatment is the most effective, other factors must be

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taken into account. More research and analysis must be done on the relative safety of the
treatments including what, if any, adverse effects occur during and after treatment. How often
adverse events occur and their severity should also be taken into account. Another important
factor that should be considered is the length of time that a patient remains in remission. MDS
does not have a known cure at this time. As a result, all patients will eventually
relapse. However, the length of time that they remain healthy or treatment independent is also a
factor that changes the effectiveness of a treatment.
Epigenetic Therapy
It is important to note that the indexical analysis of the epigenetic therapy trials is
imperfect. Although this is an efficient and partially reliable means of assessment, this index
does not completely account for all the nuances of each trial. The largest concern is with trials
that do not produce results for a certain scale value, especially CR values. Because the scale is
designed to stratify data, large gaps are used to create distinct separations between the most and
least effective outcomes: CR and null, respectively. If a study does not achieve any CR patients,
a large-scale value is still added to this score and the indexical CR score for that particular study
is deceivingly high. Furthermore, the Follo 2011 Study mentioned “10 healthy, normal
volunteers” that were included in the patient group. However, because these patients’ exact
involvement was not described, only the 20 MDS patients whose treatments were outlined in the
article were included.
Chemotherapy
The comparison of each chemotherapy study to other chemotherapy studies is
unsatisfactory. Though the studies all involve the use of the same drug, Lenalidomide, they vary
in their dosage and treatment schedule. Furthermore, the comparison of chemotherapy to bone
marrow transplant and epigenetic studies is flawed. All the studies use a different metric to

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measure success. Though the creation of the index helps to compare the studies, it cannot
account for all of the differences between studies.
Bone Marrow/Stem Cell Transplants
Comparing studies that vary in methods, drug concentrations and length of treatment
does not yield perfectly accurate results. There are many discrepancies that must be taken into
account when compiling data and comparing results of studies. The results of some studies
contradicted each other when stating that bone marrow or stem cells were beneficial to the
recipient while other studies stated that treatment was not significant. Statistical measures also
varied from study to study so comparing result was not as accurate.
CONCLUSION
In conclusion, our hypothesis is that there is no significant difference between epigenetic
therapy, chemotherapy, and bone marrow transplant in the treatment of MDS. This paper
explored this hypothesis by first describing the methods we used in gathering and analyzing our
data. The results section highlighted our findings; the discussion section developed the
implications of this data and also any shortcomings of the study. Based on percentages of CR
and the results of our index, Bone Marrow Transplant appears to be the most promising
treatment for MDS among the three treatments studied.

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REFERENCES
Excel sheet attached in Appendix (Table 1)
Abouyahya et al. 2011, Treatment with Lenalidomide in Myelodysplastic Syndromes with 5q
Deletion; Results From the Patient Named Program (PNP) in the Netherlands.
Ades, et al. 2008, Efficacy and safety of lenalidomide in intermediate-2 or high-risk
myelodysplastic syndromes with 5q deletion: results of a phase 2 study.
Anderson, et al. 1993, Allogeneic bone marrow transplantation for 93 patients with
myelodysplastic syndrome.
Candelaria, Myrna et. al. 2010, Hydralazine and magnesium valproate as epigenetic treatment for
myelodysplastic syndrome. Preliminary results of a phase-II trial.
Chunkang, et al. 2007, Hematopoietic cell transplantation in patients with myelodysplastic
syndrome or acute myeloid leukemia arising from myelodysplastic syndrome: similar
outcomes in patients with de novo disease and disease following prior therapy or
antecedent hematologic disorders.
Claus, Rainer et. al, 2013, Decitabine induces very early in vivo DNA methylation changes in
blasts from patients with acute myeloid leukemia.
Fandy, Tamer E. et, al, 2009, Early epigenetic changes and DNA damage do not predict clinical
response in an overlapping schedule of 5-azacytidine and entinostat in patients with
myeloid malignancies.
Fenaux, et al. 2011, A randomized phase 3 study of lenalidomide versus placebo in RBC
transfusion-dependent patients with Low-/Intermediate-1-risk myelodysplastic
syndromes with del5q.
Follo, M Y, et. al, 2011, Myelodysplasias: Synergistic induction of PI-PLCβ1 signaling by
azacitidine and valproic acid in high-risk myelodysplastic syndromes.
Ho, et al. 2004, Reduced-intensity allogeneic hematopoietic stem cell transplantation for
myelodysplastic syndrome and acute myeloid leukemia with multilineage dysplasia using
fludarabine, busulphan, and alemtuzumab (FBC) conditioning.
Kantarjian, Hagop et. al. 2007, Results of a randomized study of 3 schedules of low-dose
decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic
leukemia.
Khabori, et al, 2011, Impact of intensity of conditioning therapy in patients aged 40-60 years
with AML/myelodysplastic syndrome undergoing allogeneic transplantation.
Klimek, Virginia M. et. al. 2008, Tolerability, Pharmacodynamics, and Pharmacokinetics Studies
of Depsipeptide (Romidepsin) in Patients with Acute Myelogenous Leukemia or
Advanced Myelodysplastic Syndromes.

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Klisovic, Rebecca B. et. al. 2008, A Phase I Biological Study of MG98, an
Oligodeoxynucleotide Antisense to DNA Methyltransferase 1, in Patients with High-
Risk Myelodysplasia and Acute Myeloid Leukemia.
Kröger, et al. 2007, Autologous stem cell transplantation for therapy-related acute myeloid
leukemia and myelodysplastic syndrome.
Le Bras, et al. 2011, Treatment by Lenalidomide in lower risk myelodysplastic syndrome with
5q deletion—The GFM experience.
List, et al. 2005, Efficacy of Lenalidomide in Myelodysplastic Syndromes.
List, et al. 2006, Lenalidomide in the Myelodysplastic Syndrome with Chromosome 5q Deletion.
Litzow, et al. 2010, Allogeneic transplantation for therapy-related myelodysplastic syndrome and
acute myeloid leukemia.
Lukenbill, et al. 2013, Defining Incidence, Risk Factors, and Impact on Survival of Central Line-
Associated Blood Stream Infections Following Hematopoietic Cell Transplantation in
Acute Myeloid Leukemia and Myelodysplastic Syndrome.
Majhail, et al. 2012, Reduced-intensity hematopoietic cell transplantation in older patients with
AML/MDS: umbilical cord blood is a feasible option for patients without HLA-matched
sibling donors.
Maslak, P, et. all, 2006, Pilot study of combination transcriptional modulation therapy with
sodium phenylbutyrate and 5-azacytidine in patients with acute myeloid leukemia or
myelodysplastic syndrome.
Olivia et al. 2009 Lenalidomide for the Treatment of Low- and Int-1-Risk MDS with Del(5q):
Efficacy and Quality of Life Study.
Olivia et al. 2013 Lenalidomide in Low-and Intermediate-1 IPSS risk myelodysplastic
syndromes with del(5q): an Italian phase II trial of health-related quality of life, safety,
and efficacy.
Potapova, Anna et. al. 2009, Epigenetic inactivation of tumour suppressor gene KLF11 in
myelodysplastic syndromes.
Raza, et al. 2007, Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and
intermediate-1–risk myelodysplastic syndromes with karyotypes other than deletion 5q.
Sibon, et al. 2011, Lenalidomide in lower-risk myelodysplastic syndromes with karyotypes
other than deletion 5q and refractory to erythropoiesis-stimulating agents.
Spina, et al. 2012, Allogeneic stem cell transplantation in therapy-related acute myeloid
leukemia and myelodysplastic syndromes: impact of patient characteristics and timing of
transplant.
Stresemann, Carlo et. al. 2008, Azacytidine causes complex DNA methylation responses in
myeloid leukemia.
Zimmerman, et al. 2011, Allogeneic hematopoietic cell transplantation in patients with
myelodysplastic syndrome and concurrent lymphoid malignancy.

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FIGURES AND TABLES

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Figure3.1:Thisgraphshowsthepercentageofpatientsfromeachstudythat
achievedCR,PR,andNull.
Figure3.2:ThisgraphshowstheindexscoresofCR,PRandNullforeach
trial.

17. 17
Figure 1.3: This flowchart depicts the online search process for eliminating and selecting various
articles specific to epigenetic treatment.
Search Results (219)
PubMed (123)
Web of Knowledge (96)
Unduplicated Results
n = 219
Duplicates Removed
n = 0
Restriction 1 : English,
Published before 2000
Restriction 2 : Clinical Trials,
Article
Refined Search Results
n = 68
Refined Search Results
n = 210
Excluded Articles:
(n = 9) Restriction 1
(n = 142) Restriction 2
Articles Used:
n = 10
Articles rejected for relevance
after review of Abstract

18. 18
Figure 2.3: This flowchart depicts the online search process for eliminating and selecting various
articles specific to chemotherapy.
Search Results (116)
Medline (41)
Google Scholar (39)
Web of Knowledge (36)
Unduplicated Results
91
Duplicates Removed
25
Restriction 1: Non-primary
sources were excluded
Chemotherapy
Irrelevant Articles
45
Relevant Articles
25
Refined Search Results
70
Refined Search Results
10
2
Articles found through
citations
Excluded Articles:
2 were not available in full
text
Articles Used:
10
Restriction 2 : Report results
in terms of erythroid
response

19. 19
Figure 3.3: This flowchart depicts the online search process for eliminating and selecting various
articles specific to bone marrow transplant.
Search Results (3210)
Pubmed (3201)
Web of Knowledge (9)
Unduplicated Results
n = 3204
Duplicates Removed
n = 6
Restriction 1:
Articles published in past 5
years, Clinical trials, Human
subjects
Bone Marrow/Stem Cell Transplant
Irrelevant Articles
n = 20
Relevant Articles
n = 17
Refined Search Results
n = 37
Refined Search Results
n = 14n = 2
Articles found through
citations
Excluded Articles:
(n = 6) Drug-based treatment
Articles Used:
n = 10
Restriction 2:
Full text available, relevant
bone marrow-based
transplants

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APPENDIX