The review, conducted by researchers at the University of Winchester and published in March 2026, followed the PRISMA 2020 reporting standard and searched seven bibliographic sources for randomised controlled trials published between January 2019 and February 2026. To qualify, trials had to compare structured exercise-based rehabilitation against usual care or a control condition in adult transplant recipients, with outcomes measured at least three months after transplant or after the intervention ended. The screening process whittled 1,212 records down to seven trials comprising 529 participants across seven countries, spanning inpatient, outpatient, home-based and telehealth delivery. Two trials enrolled exclusively allogeneic recipients, who receive donor stem cells and typically remain on immunosuppressive drugs; two enrolled exclusively autologous recipients, who receive their own cells; and three enrolled mixed cohorts. Because the trials differed so much in modality, timing, population and outcome instruments, the authors abandoned meta-analysis and synthesised the findings narratively, rating certainty with the GRADE framework.

The clearest signal concerned walking ability. In the largest trial, an Australian telehealth-delivered programme of exercise and mindfulness reported in the Journal of Clinical Oncology, patients who exercised improved their six-minute walk distance by 51.4 metres more than controls at three months, an effect that persisted at 59.3 metres at twelve months. That is a substantial mechanical difference: a published threshold for clinically meaningful deterioration in the six-minute walk, borrowed from lung cancer research, sits between 22 and 42 metres, so the observed gains meet or exceed it, though the review authors are careful to note that no such threshold has been formally established in transplant survivors. A United States prehabilitation trial reported a non-significant between-group difference of 62.8 metres at day 100 post-transplant, and a Spanish telehealth trial found that the exercise group recovered to its pre-admission walking distance while controls remained 41 metres below baseline.

Lower-body strength told an even more consistent story. Across four trials that measured sit-to-stand or chair-stand performance, exercise groups gained roughly 2.5 to 3.8 extra repetitions in thirty seconds compared with controls, and no trial reported findings contradicting the direction of benefit. In the German whole-body vibration trial, which had patients training on a vibrating platform for about twenty minutes five times a week during their transplant admission, chair-rising power improved significantly in the intervention group. Grip strength, by contrast, showed no consistent between-group advantage anywhere, suggesting that the benefits of exercise after transplant concentrate in the large muscle groups of the legs rather than the hands.

The picture darkens for the outcomes patients often care about most. Effects on cardiorespiratory fitness, measured directly as peak oxygen uptake, were inconsistent: the German trial found a within-group gain in the exercisers, while the large Dutch EXIST trial, which tested an eighteen-week supervised programme in autologous recipients, found no between-group difference immediately after the programme or twelve months later, and the intervention was not cost-effective. Fatigue results were similarly mixed, with benefits reported in trials that began during or close to the transplant period but null findings in late-survivorship cohorts. Global quality of life was largely unchanged across trials, although physical functioning and daily-activity domains did improve in several. The GRADE ratings reflect this patchwork: low certainty for strength and walking benefits, very low certainty for everything else.

Perhaps the most provocative pattern in the review is the split between transplant types. Autologous recipients, whose immune systems typically engraft without long-term immunosuppression and whose main late risk is relapse, showed essentially no durable benefit in the only fully powered trial, EXIST. Allogeneic recipients, by contrast, face chronic graft-versus-host disease, steroid-related bone loss, late infections and years of deconditioning, and it is precisely in these patients that exercise appeared to deliver the most. The Spanish trial’s allogeneic subgroup showed a 77-metre between-group walking difference, and the allogeneic peri-transplant trials preserved strength, fatigue levels and even body cell mass while controls declined. The biology makes sense: patients with more deconditioning have more room to recover. The practical implication is that exercise referrals and future trials should be designed differently for the two populations rather than pooling them, as most mixed-cohort studies have done.

Two trials dipped a toe into immunometabolism, the least-studied domain and arguably the most tantalising. The Australian trial measured 27 serum cytokines and found, in an exploratory analysis of 69 of its 139 participants, a significant between-group reduction in soluble intercellular adhesion molecule-1, a marker of vascular inflammation and endothelial activation, at three months. No other cytokine differed, and samples were collected only at baseline and three months, so the finding is a hypothesis rather than a conclusion. The German trial reported that body cell mass, a proxy for metabolically active lean tissue, fell significantly in controls over the six months after transplant while exercisers regained their baseline values. Strikingly, no trial measured lymphocyte subset reconstitution, T-cell receptor diversity, vaccination responses, lipid profiles or glycaemic control, leaving the question of whether exercise can actually reshape immune recovery after transplant entirely open.

Safety, at least, is settled. No serious exercise-related adverse events were reported in any of the seven trials. Whole-body vibration was performed at platelet counts as low as 10,000 per microlitre without bleeding complications, the American prehabilitation trial reported zero exercise-related adverse events with 92 percent adherence, and the only serious event in any trial, a fall during a baseline walking test that caused a subarachnoid haemorrhage, occurred in a participant who had not been randomised and was unrelated to exercise.

Methodological honesty tempers all of these findings. Using the Cochrane Risk of Bias 2.0 tool, the reviewers judged six of the seven trials at high risk overall, mostly because of large and often health-related losses to follow-up: the Canadian feasibility trial retained roughly a third of its participants by one year, and the German trial analysed 44 of 71 randomised patients. Because exercise cannot be blinded, every trial was open-label, and none used blinded outcome assessment. Trials at higher risk of bias tend to report larger effects, which means the conservative null results from the largest study, EXIST, may in some respects represent the more realistic estimate of what exercise achieves in unselected survivors.

The review’s authors conclude that structured exercise appears safe and may improve objective physical function after transplant, with the greatest benefit in allogeneic and more impaired recipients, but that cardiorespiratory fitness, fatigue and quality-of-life effects remain uncertain and immunometabolic evidence is preliminary. Their prescriptions for the field are specific: future trials should report outcomes separately by transplant type, adopt harmonised core outcome sets, pre-specify immunological endpoints such as lymphocyte subsets and inflammatory panels alongside metabolic measures like fasting lipids and HbA1c, and follow patients well beyond twelve months to test effects on cardiometabolic risk, immune reconstitution and survival. For now, the practical message for the growing population of transplant survivors is measured but real: if you are still rebuilding strength and walking distance months after your transplant, structured exercise, particularly through telehealth models that reach patients at home, is a reasonable and safe bet, and the sooner after treatment it starts, the more deconditioning there may be to reverse.

Subject of Research: Exercise-based rehabilitation outcomes and immunometabolic parameters in adult haematopoietic stem cell transplant recipients

Article Title: Long‐Term Outcomes of Exercise‐Based Rehabilitation and Immunometabolic Parameters in Adult Haematopoietic Stem Cell Transplant Recipients: An Updated Systematic Review of Randomised Controlled Trials

Article References: Bayquen, D. D., & Narasimhan, P. (2026). Long‐Term Outcomes of Exercise‐Based Rehabilitation and Immunometabolic Parameters in Adult Haematopoietic Stem Cell Transplant Recipients: An Updated Systematic Review of Randomised Controlled Trials. eJHaem, 7(5), Article e70420. https://doi.org/10.1002/jha2.70420

Image Credits: AI Generated

DOI: 10.1002/jha2.70420

Keywords: haematopoietic stem cell transplantation, exercise rehabilitation, systematic review, randomised controlled trials, allogeneic transplant, autologous transplant, physical function, six-minute walk distance, fatigue, quality of life, immune reconstitution, sICAM-1

The report, published as an open-access case series in Annals of Hematology by a team from the Department of Paediatric Haematology and Bone Marrow Transplant at Manchester University NHS Foundation Trust, describes three children who developed non-haematological alloimmune disease after transplantation. Led by corresponding author Hilary Cahill, with co-authors including Ramya Hanasoge-Nataraj, Oana Mirci-Danicar, Omima Mustafa, Robert F. Wynn and Srividhya Senthil, the team emphasises that although these manifestations are rare, they contribute significant morbidity and mortality in paediatric transplant recipients. The literature to date consists almost entirely of isolated case reports of individual patients, which makes pattern recognition difficult and leaves clinicians without a clear framework for diagnosis or treatment. By presenting three cases together, the Manchester group demonstrates the remarkable breadth of alloimmunity that can emerge in children after a transplant, ranging from disease confined to a single organ to a systemic illness so severe that it required a second haematopoietic stem cell transplant.

To understand why these complications matter, it helps to consider what happens immunologically after a stem cell transplant. The donor’s stem cells gradually rebuild the recipient’s immune system, a process known as immune reconstitution. In theory, the newly generated donor-derived immune cells should learn tolerance to the recipient’s tissues. In practice, particularly when the donor is unrelated or only partially matched, the developing immune repertoire can include cells that react against recipient antigens. When these self-perpetuating donor cells attack host tissues, the result can look strikingly like an autoimmune disease in a genetically susceptible child: organ-specific inflammation, autoantibody-like phenomena and chronic damage that does not respond to the standard immunosuppressive regimens used for graft-versus-host disease. Because these syndromes are rare and their presentations overlap with infections, drug toxicities and other post-transplant complications, diagnosis is often delayed, sometimes for months, during which time irreversible organ injury can accumulate.

The Manchester cases illustrate this diagnostic challenge vividly. In one of the children, the alloimmune process was confined to a single organ, requiring targeted local and systemic therapy to bring the inflammatory attack under control. In another, the disease manifested in a different organ system entirely, underscoring that there is no single clinical picture that should alert clinicians to alloimmunity; instead, the unifying feature is a new inflammatory syndrome arising after engraftment that behaves like autoimmunity rather than infection or conventional graft-versus-host disease. The third case represents the most dramatic end of the spectrum: a widespread systemic alloimmune disease that proved refractory to multiple lines of therapy and ultimately necessitated a second haematopoietic stem cell transplant as the only way to reset the aberrant immune system. That such an intervention was required highlights both the severity these conditions can reach and the fact that, in the most severe cases, replacing the rogue immune system may be the definitive cure.

The authors stress that diagnosis is frequently the greatest hurdle. Symptoms can be nonspecific, and the differential diagnosis in a post-transplant child is broad, encompassing opportunistic infections, medication side effects, thrombotic microangiopathy, disease relapse and organ toxicity from prior chemotherapy or radiation. Distinguishing alloimmune injury from these mimics often requires tissue biopsies, specialist serology and careful correlation of clinical course with laboratory findings. In the published report, the team acknowledges the contribution of Dr Chinna Thambi Narayanan Sai Shalini from the Department of Pathology at Manchester University NHS Foundation Trust, who provided the renal biopsy images used in the manuscript, an indication of the multi-disciplinary work-up that these cases demand. Verbal informed consent was obtained from the children’s legal guardians, and the authors declare no competing interests.

Treatment, too, is far from standardised. Because the evidence base consists of scattered case reports, clinicians resort to a patchwork of approaches: escalation of corticosteroids, calcineurin inhibitors and other broad immunosuppressants, followed by biological agents targeting specific immune pathways when first-line measures fail. The Manchester series notes that these conditions often require multiple lines of therapy before remission is achieved, and in the systemic case, even aggressive sequential immunosuppression could not substitute for eliminating the dysregulated immune system itself. This therapeutic pessimism is precisely why the authors argue for earlier consideration of non-haematologic alloimmune manifestations. The earlier the diagnosis is made, the earlier targeted therapy can begin, and the greater the chance of preventing permanent organ damage or the need for heroic interventions such as a second transplant.

For the wider transplant community, the significance of this series lies less in its size, three patients, than in its conceptual framing. It consolidates a scattered literature into a coherent message: alloimmunity after transplantation exists on a spectrum, and its non-haematologic manifestations deserve recognition as a distinct clinical entity rather than being dismissed as atypical graft-versus-host disease or unexplained organ dysfunction. Paediatric patients may be particularly vulnerable because their immune systems are still developing at the time of transplant, and because the donor-derived cells that repopulate them will circulate for decades. A child cured of leukaemia at age five who then develops a chronic alloimmune attack on the kidneys, lungs, liver or endocrine organs faces a lifetime of secondary morbidity that families and clinicians may not have anticipated when consenting to the transplant.

The report also carries implications for how transplant centres counsel families and design follow-up. Parents are routinely warned about infection, graft failure and graft-versus-host disease, but alloimmune single-organ and systemic syndromes are rarely part of the conversation. Building awareness among paediatric haematologists, transplant physicians and the allied specialties that manage post-transplant organ complications could shorten the diagnostic odyssey for future patients. The authors suggest that early consideration of these manifestations, supported by a low threshold for specialist referral and tissue diagnosis, is essential to facilitate appropriate diagnosis and initiation of targeted therapies to improve patient outcomes. In an era when biologics can precisely neutralise individual cytokines and immune cell populations, the difference between a late, organ-destroying diagnosis and an early, targeted intervention may be substantial.

Published on 7 September 2026 after being received on 16 December 2025 and accepted on 19 August 2026, the article is available under a Creative Commons Attribution 4.0 licence, reflecting the growing movement toward open access to clinically relevant research. The study received no external funding. As a case series, it cannot establish incidence rates or identify risk factors definitively; those questions will require multi-centre registries and larger cohorts. But as an early contribution to that effort, it provides a valuable anchor: concrete, well-documented examples of the clinical spectrum that non-haematologic alloimmunity can produce in children after stem cell transplantation, documented at a major UK transplant centre with the pathological and laboratory detail that other clinicians can use as a reference point.

For families facing a paediatric stem cell transplant, the message is one of vigilance rather than alarm. These complications remain rare, and most transplants proceed without them. But the Manchester experience demonstrates that when a child develops unexplained organ inflammation or systemic inflammatory disease after engraftment, alloimmunity belongs on the differential diagnosis from the outset. Recognising the possibility early, pursuing the appropriate investigations and escalating to targeted therapy promptly may spare children months of debility and, in the most severe cases, the trauma of a second transplant. In transplant medicine, where the cure for one disease can inadvertently seed another, the cases reported here are a reminder that the new immune system is a powerful ally that must be watched as carefully as it is welcomed.

Subject of Research: Non-haematologic alloimmune manifestations following paediatric haematopoietic stem cell transplantation

Article Title: Non-haematologic alloimmune manifestations following paediatric haematopoietic stem cell transplantation: a case series

Article References: Cahill, H., Hanasoge-Nataraj, R., Mirci-Danicar, O., Mustafa, O., F. Wynn, R., & Senthil, S. (2026). Non-haematologic alloimmune manifestations following paediatric haematopoietic stem cell transplantation: a case series. Annals of Hematology. https://doi.org/10.1007/s00277-026-07252-1

Image Credits: AI Generated

DOI: 10.1007/s00277-026-07252-1

Keywords: haematopoietic stem cell transplantation, alloimmunity, paediatric transplant, graft-versus-host disease, immune reconstitution, autoimmune-like disease, organ inflammation, immunosuppression, second transplant, case series, Manchester, Annals of Hematology