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Table of Contents


1.1 Importance 2

1.2 Objective 2

1.3 Data Sources 2

1.4 Study Selection 2

1.5 Data Extraction and Synthesis 2

1.6 Main Outcomes and Measures 3

1.7 Results 3

1.8 Conclusions and Relevance 3


2.1 Description of problem 4

2.2 Description of the intervention 5

2.3 Why is it important to do this review? 7



4.1 Study selection and data extraction 9

4.2 Statistical analysis 10

4.3 Criteria for including studies in the review 11


5.1 Mortality and Relapse 13

5.2 Chronic GVHD 15

5.3 Acute GVHD 15



8. References 20


1.1 Importance

The reality of dropping a whole body is more tragic than losing a tail.” “We thought that it would soon die without a heart and other vital organs but were again surprised by the regeneration of the entire body

1.2 Objective 

This analysis’s main objective was to derive and synthesize established studies about stem cell transplants’ effects with associated donor transplants, unrelated donors, or unrelated donors for acute lymphoblastic leukemia in younger adults.

1.3 Data Sources  

While undertaking this task, the primary information sources were Google Scholar, Science Direct, PubMed, and Cochrane Library. These platforms have the necessary articles that were appropriate for the study. The keywords used during my search included haploidentical, acute lymphoblastic leukemia, and cyclophosphamide.

Study Selection 

Literature studies of haploidentical stem cell transplantation are eligible for this meta-analysis for acute lymphoblastic leukaemia

1.5 Data Extraction and Synthesis

Pooled odds ratios were calculated using a random-effects model. Both qualitative and quantitative approaches were utilized in extracting the relevant data from the selected articles.

1.6 Main Outcomes and Measures 

The primary outcomes were all-cause mortality, non-relapse mortality, and relapse.

1.7 Results

The study evaluated a total of 26 reports. In total, 22,974 participants participated in all studies. Increases in all-cause mortality compared with matching associated donors, comparable all-cause mortality compared to matched unrelated donors, and decreases in all-cause life compared to malattained unrelated donors have been combined to treat haploidentical stem cell transplants and post-transplant cyclophosphane. In non-relapse mortality, haploidentical stem cell transplants were linked to worse results than matching related donors in the post-transplant treatment of cyclophosphamide. However, the results were better than matched non-related donors and in approximately associated donors.

1.8 Conclusions and Relevance 

This meta-analysis indicates that the optimum donor conditions for haploidentical stem cell transplant involve matching associated donors with post-transplant cyclophosphamide therapy.


2.1 Description of problem

Acute lymphoblastic leukemia is also known as acute lymphocytic. The disorder primarily occurs when a given tissue produces too many unprocessed lymphocytes in the white blood cell. In the lymph tissue, immature lymphocytes accumulate. The tissues swell, hindering the bone marrow from forming the other blood cells. Consequently, the reduced number of red blood cells in the respective human body resulting from bone marrow malfunctioning leads to anaemia. The bone marrow cannot even produce platelets that induce coagulation, making it easier for the body to bleed and bleed (Esparza & Kathleen, 2005).

Lymphocytes may invade other body parts and organs, thus affecting their proper functioning (Schwab et al., 2007). The bone marrow produces both B and T lymphocytes. However, T lymphocytes shift to the thymus to get mature. The primary difference between B and T lymphocytes is that the latter only detects the antigens from the infected cell’s outer side. In contrast, the former identifies surface antigens of the respective disease-causing germs (Sapi et al., 2019). In either B or T lymphocytes, leukemic cells begin. Around 80% of cases start with premature B cells. Mature B cells are 1 to 2%. T cells are produced from fifteen to 20 percent in all cases. These cases are linked to older men and need a higher dose of chemotherapy. Chromosomes also play a significant role in diagnosing the ALL subtype. The fusion gene TEL-AML1 can specify an early-B leukemia type cell. ALL people who have this gene will be diagnosed with a higher WBC count and a lower prognosis. 80% of child ALL cases require a rearrangement of the MLL gene. While high-intensity chemotherapeutics are being used, the prognosis is low. Only a 20% survival rate is available (Esparza & Kathleen, 2005).

In the cases of children and younger adults, acute lymphoblastic leukemia is quite common. However, the condition is rare among relatively older adults (Hunger & Mullighan, 2015). Studies reveal that acute childhood lymphoblast leukemia also has remission levels above 80%. The rate of recurrence in adult patients has been significantly reduced to between 20 and 40 percent. Moreover, the disorder’s pathophysiology’s unique variations are encountered between childhood and adult acute lymphoblastic leukemia cases (Faderl et al., 2010). These patient populations are only predisposed to chemotherapy resistance by the adverse genetic characteristics present in older adults, thus raising the recurrence risk after the initial complete remission. Besides, the high incidence of comorbidity and side effects caused by the treatment is other factors that may lead to failure in this age group. Although 80 percent of older patients with acute lymphoblastic leukemia have been diagnoses, on average, the first complete remission is above 60 percent recurrent in ten months, the major challenge in achieving long-term survival.

2.2 Description of the intervention

Healthcare professionals and the respective leadership authorities employ unique interventions to combat the situation. During the treatment process, the involved professionals encounter technical many technical challenges. Although allogeneic stem cell transplantation indications and timing are controversial, it is the accepted care recommendation for all patients who experience reciprocity, not just those at high risk (Pavlovsky et al., 2019). However, extensive studies have shown that the most appropriate donor is the siblings or the fully macheted unrelated donor in any transplant operation. This scenario is not only limited to haploidentical stem cell transplantation. A haploidentical or cord blood donor can be used as a possible option if the respective patient lacks a matching relative or a wholly matched unrelated donor.

In addition, the haploidentical stem cell hematopoietic transplantation is among the best treatment approaches for acute lymphoblastic leukaemia. Therefore, the approach is commonly utilized to assist patients in undergoing stem cell transplants. In this case, most patients are normally provided with haploidentical donors such as siblings, infants, parents, and families (Kingebiel, et al., 2010). There is also easy access to other forms of adoptive cell therapy or alternative stem cell donations. Besides, the Unmanipulated T-cell depletion grafts are also commonly utilized. In particular, they were used over the last decade and, more often than not, are also used as the incubators of host diseases in addition to anti-thymocyte globulins and cyclophosphamides after transplantation. Optimization of conditions extends the use of haploidentical stem cell transplants to older patients with significant pre-transplantation.

Several studies have shown significant findings between Haploidic stem cell transplants and unrelated donors and cord blood transplants in patients with acute lymphoblastic leukemia. In short, the operation room positive results in the 2020 study (Nagler, Labopin, & Angeluci, 2021). were seen in conjunction with graft versus host disease in all adults with acute lymph leukemia by haploid stem cell transplantation.

Different health challenges attract unique healthcare interventions to ensure success. For instance, patients with advanced hematologic malignancies require specific interventions to improve their health. In this case, healthcare professionals employ hematopoietic stem cell transplantation as the most preferred treatment choice (Bayraktar et al., 2011). Even though the intervention requires the respective patients to have a matched related donor, many patients do not get such individual. The healthcare professionals involve a matched unrelated donor (MUD) because the respective transplant outcomes are similar. However, the chance of acquiring MUD is significantly low due to biological diversity among individuals. The process of searching for a MUD in the case of non-Caucasian patients is quite challenging and expensive. The process of identifying a matched donor is even more challenging when the respective patient emanates from a mixed-race family lineage (Barker et al., 2019). Due to these challenges, healthcare professionals employ the haploidentical stem cell transplantation approach. This approach requires the patient to identify a close relative who matches in atleast a single human leukocyte antigen (HLA) haplotype (McCurdy & Luznik, 2019).

A haploidentical treatment is an allogeneic transplant type that uses a semi-assembled donor to replace unhealthy blood-forming cells. In this case, the donor is usually a member of the respective family. Your doctor will test your blood to find the human antigen leukocyte (HLA) type in the case of allogeneic transplants. In several of the cells of the body, HLA is a protein — or marker — found. Doctors search for a blood donor or umbilical cord that fits the HLA closely. But a similar HLA match can often not be found. A haploidentical transplant could then be an option. The donor corresponds precisely with the part of your HLA, a form of allogeneic transplant (Santoro & Ruggeri, 2017).

2.3 Why is it important to do this review?

The healthcare industry continually undergoes gradual changes due to various dynamics. Various external factors result in more complicated health conditions that require specialized care (Ben et al., 2019). Through this review, healthcare scholars and professionals would acquire more relevant information in controlling the emerging health problems. Notably, the results obtained through this review could be employed to assess the effectiveness of haploidentical stem cell transplantation compared to the other alternatives. The approach could also be utilized to prevent graft versus host disease in acute lymphoblastic Leukaemia with Cyclophosphamide. Moreover, this analysis can be helpful and in guiding potential researchers.

Researchers employ multiple approaches to gain the necessary data. In particular, primary and secondary research methods are utilized to gain more information and facilitate quality improvement. Secondary research utilizes the existing qualitative and quantitative data to formulate new findings (Sherif, 2018). Therefore, this review’s results could be used as secondary data sources, hence fostering healthcare and treatment systems.


This study focuses on the assessment and effectiveness of acute lymphoblastic leukemia haploidentical stem-cell transport in younger adults. The process entails a well-known therapeutic solution for hematological as well as non-malignant disorders such as abstinence anemia and hemoglobinopathies for hematopoietic stem cell transplantation. Haploidentical donors are an additional and convenient pool of donors for patients without a matching family or unrelated donor. Haploidentical transplantation has traditionally led to high rates of rejection of HDGV. T-cell depletion and treatment of GVHD prophylaxis complications and complete T-transplants are these approaches.


Following the Cochrane handbook, the systematic evaluation and meta-analysis methods were completed. The information was reported under the Systematic Reviews and Meta-Analysis Guideline as per the preferred reporting items. Searched is carried out by Medline, Google Scholar, PubMed, direct science, and the Cochrane library. All these platforms have multiple articles explaining hematopoietic stem cell transplantation and its effects on the respective patients. Moreover, the American Society of Haematology, the American Society for Transplant and Cellular Therapy, the international centre for blood and marrow research, and the ESB are used for recent research. Extensive analysis of the recent study has also been carried out to identify more details concerning the topic.

Various scholarly platforms and organizational websites provide a wide range of healthcare information. However, the researchers should embrace specific strategies to obtain the most relevant information. For instance, some of the approaches embraced include choosing search terms, using specific keywords, utilizing exact phrases, searching with subject headings, and utilizing Boolean logic (Aromataris & Riitano, 2014). The use of a combination of these elements aids in achieving the most critical aspects in a given article. Through this study, all these aspects were utilized to obtain more information on the topic. Specifically, the study maximized the use of specific keywords and exact phrases to search for the content. Acute leukemia, cyclophosphamide, blood and marrow research, and treatment of GVHD have been extensively utilized. However, the study also used additional keywords to get specified details concerning the topic.

4.1 Study selection and data extraction

The majority of the research reviewed for this analysis was retrospective register-based testing conducted between 2000 and 2020 in adult patients diagnosed with acute lymphoblastic leukemia. The selected articles and study materials were published by specific professionals, scholars, or authentic entities. Moreover, the EBMT, a collection of over 500 transplantation centres, was included in every checked paper. These centres need a report and follow-up at least once a year on all successive stem cell transplantations. Routine audits are carried out to assess the quality of the data collected. Based on the fundamental inclusion and exclusion requirements, titles, abstracts, and the full text of related papers were reviewed. A comparable study has been included when the following conditions have been complied with: adult leukemia patients with acute lymphoblastic; retrospective/forward-looking trials with more than ten haploidentical stem cell transplantation participants undergoing post-transplant cyclophosphamide treatment.

Notably, the study included the following information: the names of the authors, the nature of the study, the year of publication, the graft versus the prophylaxis of host disease, the types of transplants, the type of marrow source, the transplantation disease status, the number of participants, the kind of conditioning scheme and the follow-up treatment period. The most popular endpoints for the synthesis were mortality all-cause, non-relapse, relapse, chronic operation room graft vs. host disease, acute graft vs. grade 4 host disease, and retrieval free graft.

The quality of secondary data sources determines the value of the respective research. Therefore, utilizing broad and more informative secondary data sources results in more informative studies. The time and accuracy of a given scholarly resource contribute to the respective study’s quality (Field & Gillett, 2010). This study has maintained a close observation of the sources utilized in achieving the best outcomes. Remarkably, the inclusion criteria eliminated all the possible erroneous and vague resources that could reduce the research quality. The healthcare sector is quite extensive and essential. Therefore, providing misleading information could result in significant negative effects.

4.2 Statistical analysis

Leukaemia-free survival was the main objective of all interventions listed in the articles reviewed (LFS). Operation room survival (OS), refined vs. host free graft, GRFS, acute ((a) GVHD, chronic (c)GVHD (graffiti vs host disease), the occurrence of relapse (RI), and non-relapse mortality were the secondary target to evaluate the operation room survival of the graft against host diseases (NRM). Leukaemia-free survival can be described as the interval elapsed from either relapse or death in remission of the haploidentical stem cell transplant. The operation room survival of all causes can be defined as the time to die. The cumulative incidence (CI) of relapse was calculated from the transplant date to the date of relapse or death in remission. The grade of 3-4 acute graft versus host disease, extreme graft versus host disease degeneration, and death caused by any stem cell transplant can be classified as relapse-free survival. A multivariate analysis was used in all selected studies using Cox proportional hazards model. If the variables were conceptually important, they were included in this model.

4.3 Criteria for including studies in the review

When selecting studies to include in a systemic review, it is necessary to include high-quality research. In order to obtain these studies, the respective researchers embrace specific selection criteria to ensure that all studies selected can be compared and have the same goal. The types of participants included in this study had to comply with a specific age. 18-35 was the younger adult target group that we were specifically interested in analyzing in this review.

<18 was viewed as children. >35 were considered as older adults. Even though we were only interested in the younger adult target group, the other two groups functioned as control groups to ensure this review’s specificity and validity. The participants were also diagnosed with acute lymphoblastic leukemia. To increase our credibility, we further specialized our criteria to include first-time diagnosed participants and not patients relapsing. However, relapsing patients were not entirely excluded based on diversity and ensuring accurate statements. The study embraced all these measures to ensure effective selection of the study participants, enhancing the quality of results. By eradicating ambiguity and other sources of errors through the employment of specific inclusion criteria, the study realized reliable and believable results.


A total of 2315 citation were obtained from the databases that were searched together with the other sources. The researchers used the titles and abstracts of the respective scholarly resource to screen for the citations. The study excluded 2167 citations that did not meet the required criteria. The main reasons for excluding these articles are; using the pediatric population as the target group, lack of comprehensive results, haploidentical group that is not restricted to patients receiving cyclophosphamide as the only post-transplant treatment.

This study included thirty studies in total. The 26 studies that were chosen had a total of 22 974 participants. One of the researches chosen was prospective, while the other twenty-five were retrospective. Match related donors only (9 studies), matched unrelated donors only (6 studies), matched associated donors and matched unrelated donors (7 studies), mismatched unrelated donors only (1 study), matched unrelated donors and mismatched unrelated donors (2 studies), and mismatched unrelated donors and mismatched unrelated donors (2 studies) are the reference groups for haploidentical stem cell transplantation with cyclophosphamide as a post-transplant treatment (1 study). Five studies used peripheral blood as a marrow source type, while three studies looked at bone marrow transplants when it came to haploidentical stem cell transplantation using cyclophosphamide as a post-transplant treatment. Sequence ranged from 1.5 and 4 years

Figure: A systemic review flow diagram

5.1 Mortality and Relapse

The cumulative recurrence was 1.06. The value was 1.17 relatives to matched donors and 1.06 in comparison to matching donors. Cyclophosphamide haploidentical stem cell transplantation was combined to better effects than unrelated donors as a post-transplant therapy, with a recurrence of 0.79 in general. In 24 of the 26 studies chosen, non-relapse mortality was evaluated. The total recurrence was 0.88. Cyclophosphamide haploidentical stem cell transplant was associated with increased non-relapse mortality as a post-transplant treatment, compared with the average 1.20 relapse of the matched relapse donor.


Figure: Pie chart showing Average recurrence

Relapse was assessed in 25 of the 26 selected studies. The overall operation room relapse was 1.09. In the case of the pooled operation room relapse analysis, applying the haploidentical stem cell transplantation with cyclophosphamide as the post-transplant treatment appeared to be associated with similar outcomes seen in relapse when compared with matched related mismatched unrelated donors. Haploidentical stem cell transplantation with cyclophosphamide as a post-transplant treatment was associated with increased degeneration when compared with matched unrelated donors exhibiting a pooled operation room relapse of 1.20 (Raiola et al., 2018).

5.2 Chronic GVHD

Twenty-three studies were consisting of 17,115 patients in total assessed chronic graft versus host disease. After conducting an extensive analysis, it was concluded that haploidentical stem cell transplantation with cyclophosphamide as a post-transplant treatment was associated with better outcomes. The conclusion was based on the significance of patient outcomes obtained upon application of the intervention.

5.3 Acute GVHD

Twenty reports constituted 13,795 gross acute graft-assessed patients relative to grades 3-4 host disease. After a conclusive analysis, it had been concluded that the acute graft reduction versus host disease of degrees 3 to 4 was directly associated with haploidentical cells transplantation with cyclophosphamide as a post-transplant therapy. Consequently, twenty-two studies constituted 16,389 acute graft against host disease grade 2-4 patients in total. Haploidentical stem cell transplants with cyclophosphamide were concluded to include increased acute graft versus host disease grades (2-4). The respective treatments were used. The results were obtained.


This meta-analysis included 26 studies in which the available literature on acute lymphoblastic leukemia was reviewed in 22 974 patients. Results of haploidentical cyclophosphamide stem cell transplantation for post-transplant care with matched or mixed donors were summarized and analyzed for precise findings. As described in the previous results, haploidentical stem cell transplants were associated with reduced chronic graft vs. host disease with cyclophosphamide for post-transparent care. Transplantation of haploidentical stem cells along with cyclophosphamide was correlated with decreased non-relapse mortality. However, there was an increased rebound in comparison with matching unrelated donors. The employment of haploidentical stem cell transplantation using cyclophosphamide is entirely preferred as a post-transplant treatment approach. Therefore, the approach is quite beneficial to the respective patients.

According to the identified articles, it is evident that haploidentical stem cell transplantation and cyclophosphamide are the preferred treatment methods. From 2000 to 2020, 15 of the 26 studies chosen were published in this systemic review. Most of these studies indicate that the most efficient choice for patients who do not have a matched sibling or unrelated donor alternative is the haploidentical stem cell transplant along with after transplant cyclophosphamide care. According to Zhou et al. (2014), it is evident that haploidentical stem cell transplant results in lasting positive patient outcomes. The underlying practices that are involved during this treatment approach contribute to its tremendous positive impacts. Notably, the method utilizes specific blood-forming cells extracted from the identified half-matched donor (Ricci et al., 2014). Using these cells to replacing the unhealthy ones in the respective patient’s body significantly improves their immunity. Therefore, the underlying activities and theories supporting the application of haploidentical stem cell transplant result in its success.

On the other hand, cyclophosphamide can be used after transplant at 50 mg/kg/d 3 to 4 days. It can be used alone or in combination with other graft compared with prophylactic agents for host illness, depending on their characteristics as well as the types of the donor (Luznik et al., 2010). Historically, cyclophosphamide is considered to prevent extreme acute but even chronic graft versus host illness, usually minimizing the need for some other immunosuppressant agent. More recent findings indicate that cyclophosphamide cannot wholly kill T-cells as a post-transplant therapy.

The findings of this systematic analysis will improve the evidence that haploidentical stem cell transplantation with cyclophosphamide can serve as an alternative to paired, unrelated donor transplants as post-transplant therapy. These transplants also include improved donor availability, quicker graft collection, and shorter time between collection and infusion. This practice will make the second transplant process simpler by making donations easier to receive. For the case of relapse, it tends to be correlated with an increased relapse rate in patients when used along with cyclophosphamide in post-transplantation.

Deducing from the findings above, the most common treatment post-remission for younger adult patients with acute lymphoblastic leukaemia is stem cell transplantation. It is also the standard treatment in high-risk patients, particularly those who suffer from recurrence, steroid or chemical resistance, and relapse following initial CR. Several studies have confirmed a 5- years free leukaemia survival in patients who receive a matched sibling or matched non-identified donor allogeneic transplantation (Aints, 2002).

An equivalent donor could only explore options for a substantial proportion of the patients interested in the trials. These methods include either unrelated or haploidentical donor transplantation. Thanks to the advanced technology used to scan unrelated donors, this process could be arranged relatively quickly. A systematic review of the findings to achieve possible benefits and drawbacks related to the increased risk of immune-related complications would confirm the call for haploidentical stem cell transplantation. The results of all study reports indicate that the treatment in question is credible and thriving in this high-risk disease. I found no variations in the results using GVHD prophylaxis used during this analysis, but this did not achieve statistical importance. Therefore, it is clear that both types of GVHD prophylaxis are successful in adults with acute lymphoblastic leukaemia. All the scholarly articles utilized during the study greatly support using the best available approaches in enhancing positive patient outcomes. Primarily, Acute Lymphoblastic leukemia is a unique type of cancer affecting the blood cells’ lymphoid line. One of the disease’s main effects is the massive production of immature lymphocytes (Mullighan et al., 2008).  

This therapy’s effect on the disease’s re-occurrence is still not understood and can differ in diagnosis and disease status from patient to patient. This phenomenon explains why more research on diagnosis and treatment is necessary. The study was conducted with acute lymphoblastic leukaemia on younger adult individuals.

The disease status, as mentioned above, was a significant factor in taking the prognosis of repetition and survival into account. The outcomes of CR1-treated patients can be compared to the HLA-matched stem cell transplantation results, although the results are still very low in acute disease patients. However, with haploidentical stem cell transplantation, there is still inadequate evidence in patients with advanced disease; the likelihood of leukemia-free survival is estimated to be 28 percent.

In a study conducted by Gorin et al. (2020), it is clear that the outcome of patients with the refractory or resistant disease was affected by the type of conditioning and donor/recipient-gender combination. It showed better results for the female donor than the male recipient. On the contrary, in a recently conducted study, neither the type nor the intensity of the conditioning impacted the results. Modern methods such as bi-specific, anti-CD22, or anti-CD22 have been more widely used to bridge a significant number of chronic patients to stem cell transplants (Zhao et al., 2019). The use of Chimeric Antigen Receptor T cells also emerges as a choice of treatment for malignant lymphoid patients with typical chemotherapy resistance

Additionally, more studies showed a substantially reduced risk of relapse from a female donor to a male recipient, without any other substantial effect on results. This scenario indicates that acute lymphoblastic leukaemia is particularly sensitive to graft-versus leukemia’s reaction to the Y chromosome’s slight antigenic mismatches.

Therefore, it can be concluded from this review that the type of stem cell source used for haploidentical stem cell transplant showed no difference when comparing the incidence of graft versus host disease and survival. It also indicates that the stem cells’ source directly impacts the haploidentical stem cell transplant outcome in young adults with acute lymphoblastic leukaemia. Peripheral blood was associated with a considerably higher risk of acute graft versus host disease, which resulted in a decreased survival rate as well as leukemia-free survival.

The effect of the stem cell source on the possible outcome of the treatment requires further research. The topic needs urgent attention due to the rapid increase of haploidentical stem cell transplantation in our modern times. Due to various health dynamics in modern society, more individuals encounter more health problems that require haploidentical stem cell transplantation. Moreover, the approach is utilized in treating both malignant and non-malignant conditions among patients (Copelan, 2006). The outstanding success level of using this method in treating multiple health prompt the respective healthcare professionals to conduct further research to maximize its effectiveness.

In this review, there might be factors that have not been considered, which is regarded as a limitation. Most of the studies reviewed consisted of a homogenous population in terms of the diagnosis, although acute lymphoblastic leukemia is a heterogeneous disease. Tyrosine kinase inhibitors were also widely used in the up-front treatment of acute lymphoblastic leukemia. They are still recommended in post-stem cell transplantation prophylaxis, which may influence the operation room results.


Finally, this systematic analysis shows that haploidentical stem cell transplant is a practical choice for younger adults with acute lymphoblastic leukaemia. It is also beneficial to find a donor simple and fast to avoid the possibility of relapse. The best donor for mortality after stem cell transplantation was found to be the matched linked contributors. The results presented in this review showed that haploidentical stem cell transplantation with cyclophosphamide therapy as a post-transplant treatment is preferred. Further investigation to determine the exact role of haploidentical stem cell transplantation with cyclophosphamide as a post-transplant treatment concerning relapse is needed. This summary could facilitate clinical reasoning and hopefully assist in the design and understanding of future trials. Besides, the study showed a substantially reduced risk of relapse from a female donor to a male recipient, without any other substantial effect on results. Therefore, acute lymphoblastic leukemia is particularly sensitive to graft-versus leukemia reaction related to the Y chromosome’s minor antigenic mismatches.


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