Viral‐specific T‐cell response in hemorrhagic cystitis after haploidentical donor stem cell transplantation

Viral hemorrhagic cystitis (HC) after hematopoietic stem cell transplantation (HSCT) can be devastating. Standard treatment modalities have not been well established, but immune reconstitution may be necessary for sustained viral clearance. We studied five pediatric patients who developed viral HC after haplo‐identical HSCT. All patients developed virus‐specific CD4‐ and CD8‐positive T cells, and the emergence of these viral‐specific T cells was temporally associated with successful viral clearance.     

Experts’ considerations on HLA‐haploidentical stem cell transplantation

Recently, novel strategies to control graft‐versus‐host disease and facilitate engraftment have allowed an increasing number of human leukocyte antigen (HLA)‐haploidentical hematopoietic stem cell transplantation (haploHSCT) to be performed. A meeting was convened to review the biological rationale and the clinical results of various T‐cell‐depleted (TCD) and T‐cell‐replete (TCR) HLA‐haploidentical ‘transplant platforms’. The objective of the meeting was to promote discussion and consent among leading researchers in the field on three main crucial issues for haploHSCT: (i) eligibility criteria, (ii) choice of the most suitable donor, and (iii) choice of the most appropriate transplant platform. The experts in attendance agreed that a patient who is eligible for an allogeneic transplant and lacks an HLA‐identical sibling or an HLA‐matched unrelated donor should be considered for an alternative donor transplant. Together with the experience of the individual center, the most important decision criteria in choosing an alternative donor source should be the rapidity of transplantation so as to avoid disease relapse/progression. The choice of the mismatched donor should be driven by younger age, ABO blood group compatibility, and Cytomegalovirus status. If a TCD transplant is planned, NK‐alloreactive donors and/or the mother should be preferred. Prospective comparative studies are needed to establish the relative efficacy of different transplant platforms. However, expertise in stem cell manipulation and in adoptive immunotherapy is essential if a TCD transplant platform is chosen.     

Transfer of Hexon‐ and Penton‐selected adenovirus‐specific T cells for refractory adenovirus infection after haploidentical stem cell transplantation

Adenovirus (HAdV) infections confer a high risk of morbidity and mortality for immunocompromised patients after stem cell transplantation (SCT). Treatment with standard antiviral drugs is of limited efficacy and associated with a high rate of adverse effects. HAdV‐specific T cells are crucial for sustained viral elimination and the efficacy of adoptive T‐cell therapy with donor‐derived HAdV‐specific T cells has been reported by several investigators. Here, we report our experience with the transfer of HAdV‐specific T cells specific for penton, which was recently identified as an immunodominant target of T cells, and hexon in a 14‐year‐old boy after T‐cell‐depleted haploidentical SCT for myelodysplastic syndrome (MDS). He developed severe HAdV‐associated enteritis complicated by acute graft‐versus‐host disease (GvHD). The patient received ten infusions of allogeneic HAdV‐specific T cells manufactured from the haploidentical stem cell donor using the CliniMacs Interferon‐γ (IFN‐γ) cytokine capture and immunomagnetic selection. Initially, T cells were generated against the immunodominant target hexon and in subsequent transfers dual antigen‐specific T cells against hexon and penton were applied. T‐cell transfers were scheduled individually tailored to current immunosuppressive treatment. Each transfer was followed by reduction of HAdV load in peripheral blood and clinical improvement. Importantly, T‐cell responses to both penton and hexon pools emerged in patient blood after repetitive transfers. Unfortunately, the patient experienced bacterial sepsis, and in this context, severe GvHD requiring intensive immunosuppression followed by secondary progression of HAdV infection. The patient succumbed to multiorgan failure 283 days after SCT. This case demonstrates the feasibility of HAdV‐specific T‐cell transfer even in the presence of immunosuppressive treatment. Targeting of multiple immunodominant viral proteins may prove valuable in patients with complicated HAdV infections.     

Successful hyperbaric oxygen therapy for refractory BK virus‐associated hemorrhagic cystitis after cord blood transplantation

BK virus‐associated hemorrhagic cystitis (BKV‐HC) is a common and major cause of morbidity in recipients of allogeneic hematopoietic stem cell transplantation. A 32‐year‐old woman developed severe BKV‐HC on day 24 after cord blood transplantation (CBT). Despite supportive therapies – such as hyperhydration, forced diuresis, and urinary catheterization – macroscopic hematuria and bladder irritation persisted for over a month. Hyperbaric oxygen (HBO) therapy at 2.1 atmospheres for 90 min per day was started on day 64 after CBT. Macroscopic hematuria resolved within a week, and microscopic hematuria was no longer detectable within 2 weeks. Hematuria did not recur after 11 sessions of HBO therapy, and no significant side effects were observed during or after treatment. HBO therapy could thus be useful in controlling refractory BKV‐HC after CBT.     

Donor‐derived CD19‐targeted T cell infusion induces minimal residual disease‐negative remission in relapsed B‐cell acute lymphoblastic leukaemia with no response to donor lymphocyte infusions after haploidentical haematopoietic stem cell transplantation

Relapse is a common cause of failure in patients with B‐cell acute lymphoblastic leukaemia (B‐ALL) after haploidentical haematopoietic stem cell transplantation (haplo‐HSCT), and non‐responders to donor lymphoblastic infusion after HSCT have a very poor prognosis. Although donor‐derived CD19‐directed chimeric antigen receptor‐modified (CAR) T cells can potentially cure leukaemia, their effectiveness and safety have not been confirmed in relapsed B‐ALL cases after haplo‐HSCT. Between January 2015 and January 2017, two and four patients each received one and two infusions of CAR T cells from haplo‐HSCT donors. Five (83·33%) achieved minimal residual disease (MRD)‐negative remission; one patient was discharged automatically without evaluation after developing severe thrombotic microangiopathies. Four of five responsive patients relapsed after 2–7 months, and one died of sepsis following MRD‐negative remission after a second infusion. None of the other second infusion recipients achieved a second complete remission. Five patients (83·33%) experienced eight courses of grade 1–3 cytokine release syndrome; two were treated with tocilizumab. Two (33·3%) and one patient developed grade 2 and 3 acute graft‐versus‐host disease (aGVHD), respectively; the former was controlled with glucocorticoids. Donor‐derived CAR T‐cell infusion seems be effective and safe for relapsed B‐ALL after haplo‐HSCT, although larger clinical studies are needed.     

HLA‐haploidentical nonmyeloablative stem cell transplantation: induction to tolerance without passing through mixed chimaerism

There are few reports of unmanipulated HLA‐haploidentical nonmyeloablative stem cell transplantation (NST) using only pharmacological acute graft‐vs.‐host disease (GVHD) prophylaxis. We present here a successful case of unmanipulated HLA‐haploidentical NST for mediastinal large B cell lymphoma that was resistant to autologous peripheral blood stem cell transplantation (PBSCT). The conditioning regimen consisted of fludarabine, busulfan and rabbit anti‐T‐lymphocyte globulin (ATG) in addition to rituximab. GVHD prophylaxis was performed using tacrolimus and methylprednisolone 1 mg/kg. The patient had rapid engraftment, with 100% donor chimaerism in the lineages of both T cells and granulocytes on day +12, but developed no GVHD clinically. The patient is still in complete remission past day +1020, with no sign of chronic GVHD without receiving immunosuppressive agents. HLA‐haploidentical NST may be performed without utilizing mixed chimaerism.     

Progressive multifocal leukoencephalopathy after T‐cell replete HLA‐haploidentical transplantation with post‐transplantation cyclophosphamide graft‐versus‐host disease prophylaxis

A 52‐year‐old man suffered from progressive multifocal leukoencephalopathy (PML) after human leukocyte antigen (HLA)‐haploidentical transplantation with post‐transplantation cyclophosphamide (PTCY). Mirtazapine, mefloquine, and cytarabine failed to improve his symptoms, and he finally died 4.5 months after PML onset. This is the first case report of a patient with PML after HLA‐haploidentical transplantation with PTCY. Although T‐cell replete HLA‐haploidentical transplantation with PTCY has enabled early immune reconstitution, PML should be considered if a patient's mental condition deteriorates.     

Inhibitory killer cell immunoglobulin‐like receptor (iKIR) mismatches improve survival after T‐cell‐repleted haploidentical transplantation

Alloreactivity triggered by interaction between killer cell immunoglobulin‐like receptors (KIRs) and natural killer (NK) cells plays a role in the graft‐versus‐tumor effect after hematopoietic stem cell transplantation (SCT). Our aim in this study was to evaluate this role in the setting of T‐cell‐repleted haploidentical SCT with postinfusion high‐dose cyclophosphamide (PT‐Cy). We included 33 patients. Among patient–donor pairs with at least 1 inhibitory KIR (iKIR) gene mismatch, event‐free survival (EFS) and cumulative incidence of relapse 1 year after transplant were significantly better (85% vs. 37% [P = 0.008] and 18% vs. 46% [P = 0.041], respectively). A subanalysis in 12 patients with Hodgkin's lymphoma (HL) showed an improvement in EFS 1 year after transplant in those patients with KIR ligand mismatch (100% vs. 25%, P = 0.012), although overall survival (OS) was not affected (85% vs. 80%, P = 0.2). Eight of 12 patient–donors pairs presented iKIR mismatches. Of note, this outcome was better in the small subgroup, both for EFS (100% vs. 25%, P = 0.012) and for OS (100% vs. 37%, P = 0.004). Our data suggest that in the setting of T‐cell‐repleted haploidentical SCT with PT‐Cy, iKIR mismatch is associated with improved survival, with particularly good results for both iKIR and KIR ligand mismatches in patients with HL.     

Post‐transplantation cyclophosphamide versus conventional graft‐versus‐host disease prophylaxis in mismatched unrelated donor haematopoietic cell transplantation

Post‐transplantation cyclophosphamide (PTCy) is an effective strategy to prevent graft‐versus‐host disease (GVHD) after haploidentical haematopoietic cell transplantation (HCT). We determined the efficacy of PTCy‐based GVHD prophylaxis in human leucocyte antigen (HLA)‐mismatched unrelated donor (MMUD) HCT. We analysed 113 adult patients with high‐risk haematological malignancies who underwent one‐antigen MMUD transplantation between 2009 and 2013. Of these, 41 patients received PTCy, tacrolimus and mycophenolate mofetil (MMF) for GVHD prophylaxis; 72 patients received conventional prophylaxis with anti‐thymocyte globulin, tacrolimus and methotrexate. Graft source was primarily bone marrow (83% PTCy vs. 63% conventional group). Incidence of grade II–IV (37% vs. 36%, P = 0·8) and grade III–IV (17% vs. 12%, P = 0·5) acute GVHD was similar at day 100. However, the incidence of grade II‐IV acute GVHD by day 30 was significantly lower in the PTCy group (0% vs. 15%, P = 0·01). Median time to neutrophil (18 days vs. 12 days, P < 0·001) and platelet (25·5 days vs. 18 days, P = 0·05) engraftment was prolonged in PTCy group. Rates of graft failure, chronic GVHD, 2‐year non‐relapse mortality, relapse, progression‐free survival or overall survival were similar. Our results demonstrate that PTCy, tacrolimus and MMF for GVHD prophylaxis is safe and produced similar results as conventional prophylaxis in patients with one antigen HLA‐MMUD HCT.     

Donor‐derived myelodysplastic syndrome and acute leukaemia after allogeneic haematopoietic stem cell transplantation: incidence,natural history and treatment response

Donor‐derived myelodysplastic syndrome/acute leukaemia (DD‐MDS/AL) is a rare life‐threatening complication of allogeneic haematopoietic stem cell (HSC) transplantation. However, it is unknown whether the risk differs by HSC source. Therefore, we evaluated the incidence of DD‐MDS/AL in 2390 engrafted patients. With a median follow‐up of 7·1 years (1–20·8), the incidence of DD‐MDS/AL was 0·53% (95% confidence interval (CI), 0·01–1·41%], 0·56% (95%CI, 0·01–1·36%) and 0·56% (95%CI, 0·01–1·10%) in recipients of bone marrow (n = 1117), peripheral blood (n = 489) and umbilical cord blood (UCB, n = 784), respectively. While follow‐up is shorter in recipients of UCB and peripheral blood, incidence of DD‐MDS/AL is, thus far, similar between HSC sources.     

T memory stem cells after allogeneic haematopoietic cell transplantation: unique long-term kinetics and influence of chronic graft-versus-host disease

T memory stem cells (TSCMs) are a subset of primitive T cells capable of both self-renewal and differentiation into all subsets of memory and effector T cells. Therefore, TSCMs may play a role in immune reconstitution and graft-versus-host disease (GVHD) in patients receiving allogeneic haematopoietic cell transplantation (HCT). We conducted a cross-sectional study to evaluate the proportions, absolute counts, phenotypes and functions of TSCMs in 152 adult patients without disease recurrence at least 12 months after undergoing HCT. CD4⁺ TSCMs were negatively correlated with number of months after transplantation in HCT patients that received cord blood transplantation, but not in patients that received bone marrow transplantation or peripheral blood stem cell transplantation. The proportions and absolute counts of CD4⁺ TSCMs and expression levels of inducible co-stimulator (ICOS) in CD8⁺ TSCMs were significantly higher in patients with mild and moderate/severe cGVHD compared to patients without cGVHD. These data suggested that, more than 12 months after allogeneic HCT, the kinetics of CD4⁺ TSCMs were dependent on the type of donor source, and further that CD4⁺ TSCMs and ICOS levels in CD8⁺ TSCMs were associated with cGVHD.     

Monitoring of adenovirus (ADV)‐specific T cells in a boy with ADV pneumonia and disseminated disease after lung transplantation

Human adenovirus (ADV) infections are the cause of severe morbidity and mortality in transplant recipients. Cidofovir (CDV) is the current standard antiviral treatment. We report the case of a 3‐year‐old boy after lung transplantation with severe ADV sepsis, who was monitored for ADV‐specific T cells during his disease and recovery. A strong increase in ADV‐specific T cells was accompanied by resolution of ADV in blood and bronchoalveolar lavage fluid. Antiviral treatment with CDV was individually adapted according to anti‐ADV immune responses, which provides a new method for tailoring antiviral treatment in lung transplant recipients.     

巨细胞病毒特异性细胞毒性T淋巴细胞治疗造血干细胞移植后难治复发性巨细胞病毒感染的临床分析

目的 探讨体外扩增的巨细胞病毒(CMV)特异性细胞毒性T淋巴细胞(CMV-CTL)在难治复发性巨细胞病毒感染患者中的疗效及安全性.方法 给予28例难治复发性CMV感染患者输注CMV-CTL,其中19例患者CMV-CTL来自造血干细胞移植原供者,9例来自第三方供者.第1疗程输注1～2次,观察疗效和副作用;第1疗程完全缓解(CR)后复发的患者给予第2疗程治疗,输注1～2次.结果 21例CMV血症患者和7例CMV病患者接受CMV-CTL治疗,首次输注CTL中位治疗时间为移植后76(39 ～321)d,CTL输注中位细胞数为1.0(0.5～10.0)×10 7.第1疗程后,21例CMV血症患者和4例CMV病患者获得CR,CMV血症CR率为100％,CMV病CR率为4/7;获得CR的中位时间分别为首次CTL输注后9(3～23)d和7(4～18)d.6例CMV血症患者和1例CMV病患者CR后复发而给予第2疗程治疗,其中4例CMV血症患者和1例CMV病患者获得CR.5例次患者输注后出现移植物抗宿主病,均为轻中度皮肤受累.随访中6例死于CMV感染,2例死于其他移植后并发症.结论 初步结果显示,体外扩增的CMV-CTL输注治疗难治复发性CMV感染安全有效,但输注方案有待进一步完善.     

Prevention and management of BK-virus associated haemorrhagic cystitis in children following haematopoietic stem cell transplantation--a systematic review and evidence-based guidance for clinical management

Haemorrhagic cystitis (HC) is a common and, in its severe form, potentially life-threatening complication of Haematopoietic stem cell transplantation (HSCT) in children. Recent data indicate an important role of BK virus reactivation during the time of maximal post-transplant immune suppression in the pathogenesis of late-onset HC. Treatment of HC is mainly symptomatic and often frustrating. To give clinicians guidance on prevention and treatment options and their backing by scientific evidence, we have systematically assessed the available literature and devised evidence-based guidelines. Our comprehensive review demonstrates that evidence for the most commonly used interventions (such as cidofovir, oestrogen, hyperbaric oxygen, bladder instillation with formalin, alum salts or prostaglandin) is very limited. Some of these interventions also carry significant risks. Higher level evidence exists only for 2-mercaptoethane sodium (MESNA) and hyperhydration as a preventative intervention, and for systemic recombinant Factor VII as a treatment to stop acute haemorrhage. Further high-quality studies are required to establish effective and safe prevention and treatment options for HC.