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Haematopoietic Stem Cell Transplantation in Adolescents and Young Adults With Acute Lymphoblastic Leukaemia: Special Considerations and Challenges.

ABSTRACT: Adolescents and young adults (AYAs) represent a challenging group of acute lymphoblastic leukaemia (ALL) patients with specific needs. While there is growing evidence from comparative studies that this age group profits from intensified paediatric-based chemotherapy, the impact and optimal implementation of haematopoietic stem cell transplantation (HSCT) in the overall treatment strategy is less clear. Over recent years, improved survival rates after myeloablative allogeneic HSCT for ALL have been reported similarly for AYAs and children despite differences in transplantation practise. Still, AYAs appear to have inferior outcomes and an increased risk of treatment-related morbidity and mortality in comparison with children. To further improve HSCT outcomes and reduce toxicities in AYAs, accurate stratification and evaluation of additional or alternative targeted treatment options are crucial, based on specific molecular and immunological characterisation of ALL and minimal residual disease (MRD) assessment during therapy. Age-specific factors such as increased acute toxicities and poorer adherence to treatment as well as late sequelae might influence treatment decisions. In addition, educational, social, work, emotional, and sexual aspects during this very crucial period of life need to be considered. In this review, we summarise the key findings of recent studies on treatment approach and outcomes in this vulnerable patient group after HSCT, turning our attention to the different approaches applied in paediatric and adult centres. We focus on the specific needs of AYAs with ALL regarding social aspects and supportive care to handle complications as well as fertility issues. Finally, we comment on potential areas of future research and concisely debate the capacity of currently available immunotherapies to reduce toxicity and further improve survival in this challenging patient group.

SUBMITTER: Calvo C

PROVIDER: S-EPMC8787274 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Minimal residual disease (MRD) assessment plays a central role in risk stratification and treatment guidance in paediatric patients with acute lymphoblastic leukaemia (ALL). As such, MRD prior to haematopoietic stem cell transplantation (HSCT) is a major factor that is independently correlated with outcome. High burden of MRD is negatively correlated with post-transplant survival, as both the risk of leukaemia recurrence and non-relapse mortality increase with greater levels of MRD. Despite growing evidence supporting these findings, controversies still exist. In particular, it is still not clear whether multiparameter flow cytometry and real-time quantitative polymerase chain reaction, which is used to recognise immunoglobulin and T-cell receptor gene rearrangements, can be employed interchangeably. Moreover, the higher sensitivity in MRD quantification offered by next-generation sequencing techniques may further refine the ability to stratify transplant-associated risks. While MRD quantification from bone marrow prior to HSCT remains the state of the art, heavily pre-treated patients may benefit from additional staging, such as using 18F-fluorodeoxyglucose positron emission tomography/computed tomography to detect focal residues of disease. Additionally, the timing of MRD detection (i.e., immediately before administration of the conditioning regimen or weeks before) is a matter of debate. Pre-transplant MRD negativity has previously been associated with superior outcomes; however, in the recent For Omitting Radiation Under Majority age (FORUM) study, pre-HSCT MRD positivity was associated with neither relapse risk nor survival. In this review, we discuss the level of MRD that may require pre-transplant therapy intensification, risking time delay and complications (as well as losing the window for HSCT if disease progression occurs), as opposed to an adapted post-transplant strategy to achieve long-term remission. Indeed, MRD monitoring may be a valuable tool to guide individualised treatment decisions, including tapering of immunosuppression, cellular therapies (such as donor lymphocyte infusions) or additional immunotherapy (such as bispecific T-cell engagers or chimeric antigen receptor T-cell therapy).

Project description:Total body irradiation (TBI) has been a pivotal component of the conditioning regimen for allogeneic myeloablative haematopoietic stem cell transplantation (HSCT) in very-high-risk acute lymphoblastic leukaemia (ALL) for decades, especially in children and young adults. The myeloablative conditioning regimen has two aims: (1) to eradicate leukaemic cells, and (2) to prevent rejection of the graft through suppression of the recipient's immune system. Radiotherapy has the advantage of achieving an adequate dose effect in sanctuary sites and in areas with poor blood supply. However, radiotherapy is subject to radiobiological trade-offs between ALL cell destruction, immune and haematopoietic stem cell survival, and various adverse effects in normal tissue. To diminish toxicity, a shift from single-fraction to fractionated TBI has taken place. However, HSCT and TBI are still associated with multiple late sequelae, leaving room for improvement. This review discusses the past developments of TBI and considerations for dose, fractionation and dose-rate, as well as issues regarding TBI setup performance, limitations and possibilities for improvement. TBI is typically delivered using conventional irradiation techniques and centres have locally developed heterogeneous treatment methods and ways to achieve reduced doses in several organs. There are, however, limitations in options to shield organs at risk without compromising the anti-leukaemic and immunosuppressive effects of conventional TBI. Technological improvements in radiotherapy planning and delivery with highly conformal TBI or total marrow irradiation (TMI), and total marrow and lymphoid irradiation (TMLI) have opened the way to investigate the potential reduction of radiotherapy-related toxicities without jeopardising efficacy. The demonstration of the superiority of TBI compared with chemotherapy-only conditioning regimens for event-free and overall survival in the randomised For Omitting Radiation Under Majority age (FORUM) trial in children with high-risk ALL makes exploration of the optimal use of TBI delivery mandatory. Standardisation and comprehensive reporting of conventional TBI techniques as well as cooperation between radiotherapy centres may help to increase the ratio between treatment outcomes and toxicity, and future studies must determine potential added benefit of innovative conformal techniques to ultimately improve quality of life for paediatric ALL patients receiving TBI-conditioned HSCT.

Project description:Background/aimsMedication non-adherence is a leading cause of transplant rejection, organ loss, and death; yet no rigorous controlled study to date has shown compelling clinical benefits from an adherence-improving intervention. Non-adherent patients are less likely to participate in trials, and therefore, most studies enroll a majority of adherent patients who do not stand to benefit from the intervention, as they do not have the condition (non-adherence) under investigation. The improving Medication Adherence in adolescent Liver Transplant recipients trial specifically targets non-adherent patients to investigate whether a remote intervention to improve adherence results in reduced incidence of biopsy-confirmed rejection.MethodsImproving Medication Adherence in adolescent Liver Transplant is a randomized single-blind controlled multisite, multinational National Institutes of Health-funded trial involving 13 pediatric transplant centers in the United States and Canada. An innovative, objective adherence biomarker-the Medication Level Variability Index, which is the standard deviation of a series of medication blood levels for each patient, is used to identify non-adherent patients at risk for rejection. The index is computed using electronic health record information for all potentially eligible patients based on repeated reviews of the entire clinic's roster. Identified patients, after consent, are randomized to intervention versus control (treatment as usual) arms. The remote intervention is delivered for 2 years by trained interventionists who reside in various locations in the United States. The primary outcome is the incidence of biopsy-confirmed acute cellular rejection, as confirmed by a majority vote of three pathologists who are masked to the study allocation and clinical information.DiscussionImproving Medication Adherence in adolescent Liver Transplant includes several innovative design elements. The use of a validated, objective adherence index to survey a large cohort of transplant recipients allows the teams to avoid bias inherent in both convenience sampling and referral-based recruitment and enroll only patients whose computed index indicates substantially increased risk of rejection. The remote intervention paradigm helps to engage patients who are by definition hard to engage. The use of an objective, masked medical (rather than behavioral) outcome measure reduces the likelihood of biases related to clinical information and ensures broad acceptance by the field. Finally, monitoring for potential adverse events related to increased medication exposure due to the adherence intervention acknowledges that a successful intervention (increasing adherence) could have detrimental side effects via increased exposure to and potential toxicity of the medication. Such monitoring is almost never attempted in clinical trials evaluating adherence interventions.

Project description:BackgroundThe role of conditioning intensity and stem cell source on modifying pre-transplantation risk in allogeneic haematopoietic stem cell transplantation (HSCT) is a matter of debate, but crucial when benchmarking centres.MethodsThis Retrospective, multicenter exploratory-validation analysis of 9103 patients, (55.5% male, median age 50 years; 1-75 years range) with an allogeneic HSCT between 2010 and 2016 from a matched sibling (N = 8641; 95%) or matched unrelated donor (N = 462; 5%) for acute myeloid (N = 6432; 71%) or acute lymphoblastic (N = 2671; 29%) leukaemia in first complete remission, and reported by 240 centres in 30 countries to the benchmark database of the European Society for Blood and Marrow Transplantation (EBMT) searched for factors associated with use of transplant techniques (standard N = 6375;70% or reduced intensity conditioning N = 2728;30%, respectively bone marrow N = 1945;21% or peripheral blood N = 7158;79% as stem cell source), and their impact on outcome.FindingsTreatment groups differed significantly from baseline population (p < 0.001), and within groups regarding patient-, disease-, donor-, and centre-related pre-transplantation risk factors (p < 0.001); choice of technique did depend on pre-transplantation risk factors and centre (p < 0.001). Probability of overall survival at 5 years decreased systematically and significantly with increasing pre-transplantation risk score (score 2 vs 0/1 HR: 1·2, 95% c.i. [1·1-1·.3], p = 0.002; score 3 vs 0/1 HR: 1·5, 95% c.i. [1·3-1·7], p < 0.001; score 4/5/6 vs 0/1 HR: 1·9, 95% c.i. [1·6-2·2], p < 0.001) with no significant differences between treatment groups (likelihood ratio test on interaction: p = 0.40). Overall survival was significantly associated with selection steps and completeness of information (p < 0.001).InterpretationPatients' pre-transplantation risk factors determine survival, independent of transplant techniques. Transplant techniques should be regarded as centre policy, not stratification factor in benchmarking. Selection criteria and completeness of data bias outcome. Outcomes may be improved more effectively through better identifying pre-transplantation factors as opposed to refinement of transplant techniques.FundingThe study was funded by EBMT.

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Haematopoietic Stem Cell Transplantation in Adolescents and Young Adults With Acute Lymphoblastic Leukaemia: Special Considerations and Challenges.

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