Table of Contents
Allogenic hematopoietic stem cell transplantation has been concluded to be one of the most efficient treatments for acute lymphoblastic leukaemia. The use of use of cyclophosphamide after a transplant is also rapidly increasing in younger adults with acute lymphoblastic leukaemia, however, the specific role has not been determined yet.
The main objective of this review was to extract and synthesize the existing research regarding outcomes of stem cell transplantations for acute lymphoblastic leukaemia in younger adults with transplantations from matched related donors, matched unrelated donors or mismatched unrelated donors.
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
Studies consisting of literature about haploidentical stem cell transplantation for the treatment of acute lymphoblastic leukaemia were eligible for this meta-analysis.
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.
A total of 26 studies were analysed in this review. All the studies combined included 22 974 participants. Haploidentical stem cell transplantation and the post-transplant treatment with cyclophosphamide was linked with an increased all-cause mortality compared with matched related donors, similar all-cause mortality compared with matched unrelated donors, and reduced all-cause mortality compared with mismatched unrelated donors. With regards to non-relapse mortality, haploidentical stem cell transplantation with the post-transplant treatment of cyclophosphamide was associated with worse outcomes when compared to match related donors although it showed better outcomes compared with matched unrelated donors and mismatched unrelated donors.
1.8 Conclusions and Relevance
Results of this meta-analysis suggest that matched related donors are the optimal donors with regards to haploidentical stem cell transplantation together with the post-transplant cyclophosphamide treatment.
2.1 Description of problem
Acute lymphoblastic leukaemia is seen frequency in children and younger adults. It has been reported to be rare in older adults. Childhood acute lymphoblastic leukaemia is often associated with remission rates higher than 80%. This decreases dramatically in adult patients’ to between 20% and 40% with a very high incidence of relapse. The most striking differences between childhood and adult acute lymphoblastic leukaemia is related to the pathophysiology of the disease as well as the treatment, and patient-related factors.
Adverse genetic features only found in older adults predisposes these group of patients to chemotherapy resistance and therefore increases the risk of relapse after the an initial achievement of complete remission. Other factors that may cause failure to be more likely in this age group is the high incidence of comorbidities and side effects caused by the treatment.
Although it has been concluded that an average of 80% of older patients with acute lymphoblastic leukaemia, achieve first complete remission it has been established that the major challenge to obtain long-term survival is the disease recurrence which is over 60% within 10 months.
2.2 Description of the intervention
Even though some controversy exists on the indication and timing, allogenic hematopoietic stem cell transplantation is the standard recommendation of treatment for not only high-risk patients but also all patients who experience relapse.
Multiple studies has shown that in any transplant surgery not only limited to haploidentical stem cell transplantation the most suitable donor is siblings or a fully matched unrelated donor as an alternative. If a patient lacks a matched sibling or a fully matched unrelated donor, a haploidentical or cord blood donor can also be considered as a possible option.
Haploidentical hematopoietic stem cell transplantation as treatment for acute lymphoblastic leukaemia is frequently used as it increasingly used as it allows most patients in need to undergo stem cell transplantation. Haploidentical donors such as siblings, children, parents, and extended relatives family are usually available to most patients. Also, access to alternative stem cell donations or other types of adoptive cellular therapies is easily available.
Unmanipulated grafts without any T cell depletion have been used for the last decade and is also used more frequently in adjunct with anti-thymocyte globulins or post-transplant cyclophosphamide as a prophylaxis for graft versus host disease with optimistic results. The optimization of conditioning regimens, have extended the use of haploidentical stem cell transplantation to older patients with significant pre-transplant comorbidities.
Several studies showed relatable outcomes between haploidentical stem cell transplantations and mismatched unrelated donors as well as cord blood transplants in patients with acute lymphoblastic leukaemia’s. However, there is very limited available studies that has analysed the success rate of haploidentical stem cell transplantations in older adults.
In summary of a 2020 study by Srour et al. stated that the overall showed positive outcomes in all adults with acute lymphatic leukaemia receiving haploidentical stem cell transplantation when used in adjunct to graft versus host disease prophylaxis.
2.3 Why it is important to do this review?
A possible outcome of this review could determine the efficiency of haploidentical stem cell transplantation for acute lymphoblastic leukaemia with cyclophosphamide as prophylaxis for graft versus host disease. This review may prove to be important to future researchers and serve as an efficient helping tool. It may also serve as a basis for future research or secondary analysis regarding this topic.
The main objective of this study is to review the efficiency of haploidentical stem cell transplantation in younger adults with acute lymphoblastic leukaemia.
The systemic review and meta-analysis methods used was done according to the Cochrane handbook. Reporting the obtained information was done according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis guideline. Medline, Google scholar, PubMed, Science direct as well as the Cochrane Library were searched. In addition, the American Society of Haematology, American Society for Transplantation and Cellular Therapy, Centre for International Blood and Marrow Transplant Research, and European Society for Blood and Marrow Transplantation were also used to obtain the most recent research. The search strategy included key words such as acute lymphoblastic leukaemia, and cyclophosphamide.
4.1 Study selection and data extraction
Majority of the studies analysed for this review consisted of retrospective registry-based analysis done in adult patients diagnosed with acute lymphoblastic leukaemia, performed between 2000 and 2020.
All reviewed articles made use of the EBMT which is a voluntary working group of more than 500 transplant centres. These centres requires a report on all consecutive stem cell transplantations and follow-ups at least once a year. Audits are routinely performed to determine the accuracy of the collected data.
Titles, abstracts, and the full text of relevant articles were reviewed based on a specific inclusion and exclusion criteria. Relative studies were included if they complied to the following criteria: adult patients with acute lymphoblastic leukaemia, retrospective/ prospective studies that included more than 10 participants receiving haploidentical stem cell transplantation with cyclophosphamide therapy post-transplant.
While reviewing the following information was obtained from the chosen studies: the names of the authors, the study design, the year of publication, graft versus host disease prophylaxis, type of transplantation, type of marrow source, disease status at transplantation, number of participants, type of conditioning regime and length of the follow-up treatment. The main end points used for data synthesis were all-cause mortality, non-relapse mortality, relapse, overall chronic graft versus host disease, acute graft versus host disease grades 2 to grade 4 and graft relapse-free survival.
4.2 Statistical analysis
The primary goal of all interventions mentioned in reviewed articles was leukaemia-free survival (LFS). The secondary goals were to determine the overall survival (OS), refined graft-versus-host-free, relapse-free survival (GRFS), neutrophil engraftment, acute (a)GVHD and chronic (c)GVHD (graft versus host disease), relapse incidence (RI), and non-relapse mortality (NRM).
Leukaemia free survival can be defined as the interval elapsed from haploidentical stem cell transplant to either relapse or death in remission. Overall survival can be defined as the time to death from all causes. Relapse free survival can be defined as grade 3–4 acute graft versus host disease, severe chronic graft versus host disease, relapse, or death from any cause after stem cell transplantation.
The cumulative incidence (CI) of relapse was calculated from the date of the transplant to the date of relapse or death in remission.
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. To obtain statistical significance by univariate analysis.
4.3 Criteria for including studies in the review
When selecting studies to include in a systemic review it is of utmost importance 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 also had to be 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.
4.4 Search methods for identification of studies
Electronic searches was the main method of finding and reviewing favourable studies. I performed searches in the following databases and resources: Google Scholar, Pubmed, Science Direct, British Medical Journal and An International Journal of Medicine.
These databases cover a wide range of journals from low- to middle- income countries that may be overlooked in larger reviews which increases the validity and accuracy of this review. Initial searches were based on keywords derived from our research questions as mentioned above.
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.
Overall, thirty studies were included in this analyses. A total of 22 974 participants were included in the selected 26 studies. One of the selected studies was prospective while the remaining 25 studies were retrospective. The reference groups for haploidentical stem cell transplantation with cyclophosphamide as a post-transplant treatment is as follows: 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 (1 study). Regarding haploidentical stem cell transplantation with cyclophosphamide as a post-transplant treatment, 5 studies used peripheral blood as a marrow source type while 3 studies evaluated bone marrow transplants. Follow-up ranged from 1.5 to 4 years.
5.1 Mortality and Relapse
The overall OR was 1.06. The respective ORs were 1.17 compared with matched related donors and 1.06 compared with matched unrelated donors. haploidentical stem cell transplantation with cyclophosphamide as a post-transplant treatment were associated with better outcomes compared with mismatched unrelated donors, with a OR of 0.79.
The non-relapse mortality was assessed in 24 of the 26 selected studies. The OR was 0.88. Haploidentical stem cell transplantation with cyclophosphamide as a post-transplant treatment was associated with an increased non-relapse mortality when compared to matched related donors with an OR of 1.20.
Relapse was assessed in 25 of the 26 selected studies. The overall OR was 1.09. Regarding the pooled OR 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 OR 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 studies consisting of 13 795 patients in total assessed acute graft versus host disease grades 3-4. It was concluded that haploidentical stem cell transplantation with cyclophosphamide as a post-transplant treatment was associated with reduced acute graft versus host disease grades 3-4.
Twenty-two studies consisting of 16 389 patients in total assessed acute graft versus host disease grades 2-4. It was concluded that haploidentical stem cell transplantation with cyclophosphamide as a post-transplant treatment was associated with increased acute graft versus host disease grades 2-4.
This meta-analysis that included 26 studies consisting of 22 974 patients analysed the available literature concerning acute lymphoblastic leukaemia. Outcomes of haploidentical stem cell transplantation with cyclophosphamide as a post-transplant treatment with matched or mismatched donors for adult patients were summarised and analysed to report accurate conclusions. As mentioned in the results above, haploidentical stem cell transplantation with cyclophosphamide as a post-transplant treatment were associated with reduced chronic graft versus host disease. Haploidentical stem cell transplantation in conjunction with cyclophosphamide were associated with reduced non-relapse mortality, however it exhibited increased relapse when compared with matched unrelated donors. When this was compared to mismatched unrelated donors, haploidentical stem cell transplantation with cyclophosphamide as a post-transplant treatment is proven to be the preferred treatment option when considering mortality, relapse, and graft versus host disease.
The results obtained from the above mentioned included articles reflects the statement that the use of haploidentical stem cell transplantation in conjunction with post-transplant cyclophosphamide over the past years is the chosen treatment method. 15 of the chosen 26 studies included in this systemic review were published between 2000 and 2020. Most of these studies suggests that haploidentical stem cell transplantation in conjunction with post-transplant cyclophosphamide treatment may be the most effective option for patients who does not have a matched sibling or unrelated donor as an option.
As a standard, cyclophosphamide as a post-transplant treatment is given at 50 mg/kg/d 3 to 4 days after transplant and can be used alone or in combination with other graft versus host disease prophylactic agents depending on its characteristics as well as the donor type.
Cyclophosphamide is historically known to prevent not only severe acute but also chronic graft versus host disease which usually minimizes the need for any other immunosuppressive agents. More recent studies suggest that cyclophosphamide as a post-transplant treatment may not fully eliminate alloreactive T-cells.
The results of this systemic review may strengthen the evidence that haploidentical stem cell transplantation in association with cyclophosphamide as a post-transplant treatment can be used as a potential alternative to matched unrelated donor transplants. Furthermore, these transplants provides a higher donor availability, faster graft obtainment, and a shorter time between collection and infusion. This may ease the procedure of a second transplantation due easier obtainable donations. With regards to relapse, haploidentical stem cell transplantation when used in conjunction with cyclophosphamide as a post-transplant treatment appeared to be associated with an increased relapse rate in patients suffering from acute lymphoblastic leukaemia.
As supported by the results above, stem cell transplantation remains the most effective post-remission treatment for younger adults with acute lymphoblastic leukaemia. It is also the standard care in high-risk patients particularly those prone to relapsing, steroid or chemotherapy-resistant, and experiencing relapse after initial CR. Several studies reported a 5-year leukaemia free survival in patients receiving allogenic transplantation from matched sibling or a matched unidentified donor.
For a significant proportion of patients who participated in the studies, a identical donor could not be located leaving no choice but to explore alternative approaches. These approaches include transplantations from either mismatched unrelated or haploidentical donors. This procedure could be arranged relatively fast due to innovative technologies used to search for unrelated donors. The appeal of haploidentical stem cell transplantation should be confirmed by a detailed analysis of results, to produce potential advantages and disadvantages that may be related to increased risk of immune-related complications.
The impact of this treatment on the incidence of relapse remains unknown and may vary from patient to patient considering their diagnosis and disease status. This explains why there is a need for further research to be done in terms of the diagnosis and treatment. In this review the analysis was performed on younger adults with acute lymphoblastic leukaemia.
The results in all reviewed studies confirms the credibility and efficacy of the procedure in question in this high-risk disease. During this review I did not find any differences regarding the outcome according to the type of GVHD prophylaxis used, however, this did not reach statistical significance. Therefore it is safe to conclude that for adults with acute lymphoblastic leukaemia both types of GVHD prophylaxis may be successful.
As mentioned before, the disease status was one of the most important factors when considering the prognosis regarding relapse and survival. The outcome of patients treated in CR1 can be compared to the results from HLA matched stem cell transplantation, however, in those with active disease the results remain very poor. The probability of leukaemia free survival at 2 years is estimated at 28%, however, with haploidentical stem cell transplantation the results for patients with advanced disease status remain poor. Modern approaches such as bi-specific T-cell engaging antibodies or anti-CD22 immunoconjugates have been more frequently used allowing a large amount of relapsed patients being bridged to receive stem cell transplantations. The use of chimeric antigen receptor T-cells is also emerging as an treatment option for patients with lymphoid malignancies presenting with a resistance to conventional chemotherapy.
In a study conducted by Pavlu et al., the outcome of patients with refractory or resistant disease was affected by the type of conditioning and donor/recipient-gender combination. It showed better results for female donor to male recipient. On the contrary, in a recently conducted study, neither the type nor the intensity of the conditioning had any impact on the results.
In this review, transplants from a female donor to a male recipient showed a significantly reduced risk of relapse, without any other major impact on outcomes. This suggests that acute lymphoblastic leukaemia is particularly susceptible to graft-versus-leukaemia reaction associated with mismatches of minor histocompatibility antigen on the Y chromosome.
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 source of the stem cells have a strong impact on the outcome of the haploidentical stem cell transplant 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 leukaemia-free survival.
The effect of the stem cell source on the possible outcome of the treatment requires further research. This is a topic that needs urgent attention due to the rapid increase of haploidentical stem cell transplantation in our modern times.
In this review there might be factors that have not been considered, and this is considered to be a limitation. Most of the studies reviewed consisted of a homogenous population in terms of the diagnosis although acute lymphoblastic leukaemia is a heterogeneous disease. Tyrosine kinase inhibitors were also widely used in up-front treatment acute lymphoblastic leukaemia, but they are also recommended in post stem cell transplantation prophylaxis, which may influence the overall results.
In conclusion, the results obtained from this systemic review suggests that haploidentical stem cell transplant is an efficient treatment option for younger adults with acute lymphoblastic leukaemia. It also has the great advantage of finding a donor reliably easy and quickly to avoid the relapse risk.
Matched related donors was shown to be the optimal donor when referring to mortality after stem cell transplantation.
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 with respect to relapse is needed. This summary could facilitate clinical reasoning and hopefully assist in the design and understanding of future trials.
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