Acute lymphoblastic leukaemia

HAPLOIDENTICAL STEM CELL TRANSPLANTATION IN YOUNGER ADULTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA A SYSTEMIC REVIEW AUTHOR Sergei Zharkov STUDENT NUMBER w1712872 Table of Contents 1. ABSTRACT …………………………………………………………………………………………………………………… 2 1.1 Importance ………………………………………………………………………………………………………………….. 2 1.2 Objective …………………………………………………………………………………………………………………….. 2 1.3 Data Sources ………………………………………………………………………………………………………………. 2 1.4 Study Selection …………………………………………………………………………………………………………… 2 1.5 Data Extraction and Synthesis ……………………………………………………………………………………… 3 1.6 Main Outcomes and Measures ……………………………………………………………………………………… 3 1.7 Results ……………………………………………………………………………………………………………………….. 3 1.8 Conclusions and Relevance …………………………………………………………………………………………. 3 2. INTRODUCTION ……………………………………………………………………………………………………………. 3 2.1 Description of problem ………………………………………………………………………………………………… 3 2.2 Description of the intervention …………………………………………………………………………………….. 4 2.3 Why it is important to do this review? …………………………………………………………………………… 5 3. OBJECTIVES ………………………………………………………………………………………………………………… 6 4. METHODS …………………………………………………………………………………………………………………….. 6 4.1 Study selection and data extraction ……………………………………………………………………………… 6 4.2 Statistical analysis ………………………………………………………………………………………………………. 7 4.3 Criteria for including studies in the review ……………………………………………………………………. 7 4.4 Search methods for identification of studies ………………………….. Error! Bookmark not defined. 5. RESULTS ……………………………………………………………………………………………………………………… 8 5.1 Mortality and Relapse ………………………………………………………………………………………………….. 9 5.2 Chronic GVHD …………………………………………………………………………………………………………… 11 5.3 Acute GVHD ………………………………………………………………………………………………………………. 11 5.4 Engraftment and graft-versus-host-disease …………………………… Error! Bookmark not defined. 6. DISCUSSION……………………………………………………………………………………………………………….. 11 7. CONCLUSION ……………………………………………………………………………………………………………… 14 8. REFERENCES ……………………………………………………………………….. Error! Bookmark not defined. 1. ABSTRACT 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 The main objective of this analysis was to derive and synthesize established studies about the effects of stem cell transplants with associated donor transplants, unrelated donors or unrelated donors for acute lymphoblastic leukaemia in younger adults.

1.3 Data Sources Google scholar, Science direct, PubMed and Cochrane Library was the main platforms used to obtain appropriate articles. The key words used during my search included haploidentical, acute lymphoblastic leukaemia, and cyclophosphamide. 1.4 Study Selection Literature studies of haploidentical stem cell transplantation is 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. 1.6 Main Outcomes and Measures The main 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 as 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 in comparison with matching related donors in the post-transplant treatment of cyclophosphamide, although the results were better than matched non-related donors and in approximate associated donors. 1.8 Conclusions and Relevance The results of this meta-analysis indicate that matching associated donors, along with post-transplant cyclophosphamide therapy, are the optimum donor for haploidentical stem cell transplant. Acute lymphoblastic leukaemia

2. INTRODUCTION 2.1 Description of problem Acute lymphoblastic leukaemia is also known as acute lymphocytic. The disorder is mostly when tissue produces too many unprocessed lymphocytes in the white blood cell. In the lymph tissue, immature lymphocytes accumulate. The tissues swell and other blood cells are made more difficult for the bone marrow to develop. RBC reduces the number of blood cells that cause anaemia if bone marrow does not function properly. The bone marrow cannot even produce platelets that induce coagulation, which makes it easier for the body to bleed and bleed (Esparza & Kathleen, 2005). Lymphocytes may invade other bodies as well, thus affecting their proper functioning. In either B or T lymphocytes leukemic cells begin. Around 80% of cases begin 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 leukaemia 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). Acute lymphoblastic leukaemia

In children and younger adults, acute lymphoblastic leukaemia is seen often. In older adults it was confirmed to be uncommon. Acute childhood lymphoblast leukaemia also has remission levels above 80%. The rate of recurrence in adult patients has been significantly reduced to between 20 and 40 percent. The most striking variations in the pathophysiology of the disorder, as well as care and patientrelated factors are between childhood and adult acute lymphoblastic leukaemia. These patient populations are only predisposed to chemotherapy resistance by the adverse genetic characteristics present in older adults and thus raise the risk of recurrence after the initial full remission. 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 leukaemia have been concluded on average, first full remission has been shown to be over 60 percent recurrent in ten months, the major challenge in achieving long-term survival. 2.2 Description of the intervention Although the indications and timing of allogenic stem cell transplantation are controversial, it is the accepted care recommendation for all patients who experience reciprocity, and not just those at high risk. Multiple studies have shown that the most appropriate donor is the siblings or the fully macheted unrelated donor, in any transplant operation not only limited to haploidentical stem cell transplantation. A haploidentical or cord blood donor can be used as a potential choice if a patient lacks a matching relative or a completely matched unrelated donor. As a treatment for acute lymphoblastic leukaemia, haploidentical stem cell hematopoietic transplantation is used more frequent as it helps most patients in need to undergo stem cell transplants.

The majority of 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. Unmanipulated T-cell depletion grafts were used over the last decade and, more often than not, are also used as the pregnancy 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 leukaemia. 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 leukaemia by haploid stem cell transplantation. Acute lymphoblastic leukaemia

Define haploidentical Tx A haploidentical treatment is an allogeneic transplant type. It uses a semi-assembled donor to replace unhealthy blood-forming cells. The donor is normally a member of the 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 exactly with the half of your HLA, this is a form of allogeneic transplant (Santoro & Ruggeri, 2017). 2.3 Why it is important to do this review? Possible results from this analysis could assess haploidentical stem cell transplantation efficiency as a prophylaxis of graft versus host disease in acute lymphoblastic Leukaemia with Cyclophosphamide. This analysis can be useful and an effective guide for potential researchers. It can also provide a basis for future research or secondary study on this subject. 3. Acute lymphoblastic leukaemia

OBJECTIVES Study focuses on the assessment and effectiveness of acute lymphoblastic leukemia haploidentical stem-cell transport in younger adults. A well-known therapeutic solution for hematological as well as non-malignant disorders such as abstinence anemia and haemoglobinopathies is 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. METHODS In accordance with the Cochrane handbook, the systematic evaluation and meta-analysis methods were completed. The information was reported under the Systematic Reviews and Meta-Analysis Guideline in accordance with the preferred reporting items. Searched is carried out by Medline, Google scholar, PubMed, direct science and the Cochrane library. Moreover, the American Society of Haematology, the American Society for Transplant and Cellular Therapy, the international centre for blood and marrow research as well as the ESB is used for recent research. Recent research has also been carried out. Key concepts such as acute leukaemia and cyclophosphamide have been included in the research strategy. 4.1 Study selection and data extraction Most of the research reviewed for this analysis were retrospective register-based testing conducted between 2000 and 2020 in adult patients, who were diagnosed with acute lymphoblastic leukemia. The EBMT, a collective 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 basic 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 leukaemia patients with acute lymphoblastic; retrospective/forward-looking trials with more than 10 haploidentical stem cell transplantation participants on the post-transplant cyclophosphamide treatment. 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 type of conditioning scheme and the follow-up treatment period. The most popular end points for the synthesis were mortality all-cause, non-relapse, relapse, chronic operation room graft vs. host disease, acute graft vs. Acute lymphoblastic leukaemia

grade 4 host disease, and retrieval free graft. 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), 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). Free Leukaemia survival can be described as the interval elapsed from either a relapse or death in remission of the haploidentical stem cell transplant. The operation room survival of all causes can be described as the time to die. The cumulative incidence (CI) of relapse was calculated from the date of the transplant to the date of relapse or death in remission. The grade of 3-4 acute graft versus host disease, extreme graft versus host disease, relapse 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. To obtain these studies a specific selection criterion is often needed to make sure that all studies selected can be compared and have the same goal in mind. The types of participants included in this study had to comply to 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 was viewed 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 the specificity and validity of this review. The participants were also diagnosed with acute lymphoblastic leukemia. To increase our credibility, we further specialized our criteria to only include first time diagnosed participants and not patients relapsing. Although relapsing patients was not totally excluded on the basis of diversity and ensuring accurate statements. 4. RESULTS A total of 2315 citations were obtained from the databases that were searched together with the other sources. Using the title and abstract as a main screening strategy, 2197 citations were excluded. The main reasons for these articles to be excluded were the use of a paediatric 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. Acute lymphoblastic leukaemia

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 related 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 posttransplant 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 cumulative recurrence 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 an increased non-relapse mortality as a post-transplant treatment, compared with the average 1,20 relapse of the matched relapse donor. AVERAGE RECURENCE Overal recurrent , 1.06 Martched recurrence , 1.2 Total recurrence , 0.88 Matched donor recurrence , 1.17 Martched donor no rcurrence, 1.06 Figure: Pie chart showing Average recurrence Relapse was assessed in 25 of the 26 selected studies.

The overall operation room relapse was 1.09. Acute lymphoblastic leukaemia

Regarding the pooled operation room relapse analysis, haploidentical stem cell transplantation with cyclophosphamide as the post-transplant treatment appeared to be associated with similar outcomes as seen in relapse when compared with matched related donors and mismatched unrelated donors. Haploidentical stem cell transplantation with cyclophosphamide as a post-transplant treatment was associated with increased relapse when compared with matched unrelated donors exhibiting a pooled operation room relapse of 1.20. 5.2 Chronic GVHD Twenty-three studies consisting of 17 115 patients in total assessed chronic graft versus host disease. It was concluded that haploidentical stem cell transplantation with cyclophosphamide as a post-transplant treatment was associated with better outcomes. 5.3 Acute GVHD Twenty reports of 13 795 gross acute graft-assessed patients relative to grades 3-4 host disease. It had been concluded that the acute graft reduction versus host disease of degrees 3 to 4 was asso .. Acute lymphoblastic leukaemia