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.     

Invasive zygomycosis in patients with graft‐versus‐host disease after allogeneic stem cell transplantation

M. Leithauser, C. Kahl, C. Aepinus, F. Prall, M. Maruschke, H. Riemer, D. Wolff, K. Jost, I. Hilgendorf, M. Freund, C. Junghanss. Invasive zygomycosis in patients with graft‐versus‐host disease after allogeneic stem cell transplantation
Transpl Infect Dis 2010: 12: 251–257. All rights reserved Abstract: Invasive mold infections are a threat to immunosuppressed patients such as patients with graft‐versus‐host disease (GVHD) after allogeneic stem cell transplantation (SCT). Up to 10% of SCT recipients develop invasive aspergillosis (IA). Invasive zygomycosis (IZ) may occur during treatment against IA. Here we report 4 SCT patients with GVHD diagnosed with IZ. All patients had received myeloablative hematopoietic SCT and developed chronic GVHD requiring systemic immunosuppression. Underlying diseases were acute lymphocytic leukemia (2), osteomyelofibrosis, and multiple myeloma. All patients had developed pulmonary infiltration that led to initiation of antifungal therapy. Treatment for IA was voriconazole, caspofungin, or itraconazole. Organs involved with zygomycosis were lung, nasal sinus, skin, and kidney. Treatment with liposomal amphotericin and posaconazole was initiated in all patients, and 2 patients also had surgical debridement as well. Despite intensive treatment, no patient survived. IZ is becoming more common in patients with GVHD on successful treatment for IA. Even non‐specific symptoms are suspicious in this group of patients and need to be evaluated by vigorous diagnostics. Despite effective antifungals and surgical intervention, the prognosis is grim in patients with active GVHD, as immunoreconstitution is mandatory for successful management.     

Nephrotic syndrome as a complication of chronic graft‐versus‐host disease after allogeneic haemopoietic stem cell transplantation

Nephrotic syndrome (NS) is a rare complication following allogeneic haemopoietic stem cell transplantation (allo‐HSCT), with limited current understanding of its pathogenesis. Here, we describe four cases of NS following allo‐HSCT diagnosed at our institutions to identify key clinical and pathological features. In addition, a PubMed search was performed to identify existing reports that were pooled together with our cases for analysis. NS occurred as a late complication following allo‐HSCT, with median onset 19.5 months after transplant (range: 3.9–84 months). The most common histopathology observed was membranous nephropathy; however, cases of minimal change disease have also been reported. There is a high incidence of prior extra‐renal graft‐versus‐host disease (GvHD), with all four of our cases and 82% of published cases having prior GvHD. Glucocorticosteroids are the most common treatment, with variable degrees of response. Responses to immunosuppression with calcineurin inhibitors and rituximab have been described in steroid‐refractory cases.     

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.     

High incidence of engraftment syndrome after haploidentical allogeneic stem cell transplantation

We determined the incidence, clinical manifestations, and outcomes of engraftment syndrome (ES) in haploidentical stem cell transplantation (SCT) recipients. We compared the incidence of ES between the patient group that received haploidentical SCT (n = 516) and the patient group that received HLA‐identical sibling SCT (n = 393). The transplantations were performed in the Peking University People's Hospital in the period between October 2001 and October 2012. The ES incidence data were collected retrospectively. Patients that presented non‐infectious fever or skin rash within the 24‐h window before or after the beginning of neutrophil recovery were diagnosed with ES in accordance with the Maiolino criteria. ES incidence in haploidentical SCT recipients (21.9%) was significantly higher than that in HLA‐identical sibling SCT recipients (2.0%; P < 0.001). Major symptoms included fever (119/121, 98.3%), skin rash (98/121, 81.0%), and diarrhea (51/121, 42.1%), with the median time of +10 d (range: 6–20 d). The median C‐reactive protein level of the ES group (99.0 mg/L; n = 13) was significantly higher than that of the non‐ES group (13.9 mg/L; n = 38; P < 0.001). Similarly, the results showed that the median C3 plasma concentration of the ES group (1.30 g/L) was higher than that of the non‐ES group (1.16 g/L, P = 0.003). ES was not associated with non‐relapse mortality or overall survival. High incidence of ES was observed in haploidentical SCT recipients; however, ES did not predict poor clinical outcomes.     

Activating killer immunoglobulin‐like receptor incompatibilities enhance graft‐versus‐host disease and affect survival after allogeneic hematopoietic stem cell transplantation

Objectives: Killer immunoglobulin‐like receptors (KIRs) regulate function of natural killer (NK) cells and a subset of T cells. In this study, we prospectively evaluated the impact of donor and recipient activating KIR genes on outcome of allogeneic hematopoietic stem cell transplantation (alloHSCT) for patients with hematological malignancies. Methods: One‐hundred consecutive recipients of myeloablative transplantation and their donors were tested for KIR genotype as well as for immune reconstitution, including activating KIR expression on NK cells and T cells. Results: In a multivariate analysis, mismatches of particular activating KIRs such that the patient was negative and the donor was positive (P^?D⁺) resulted in increased risk of acute (KIR2DS1) and chronic (KIR2DS3) graft‐versus‐host disease (GVHD) as well as relapse (KIR2DS5). KIR2DS1 incompatibility in the same direction in the presence of HLA‐C‐group 2 ligand in recipient was associated with reduced overall (risk ratio, RR = 3.01; P = 0.01) and disease‐free survival (RR = 2.92, P = 0.03). Activating mismatches in P^?D⁺ direction resulted in decreased CD4⁺ : CD8⁺ T‐cell ratio up to 1 yr after alloHSCT, as a consequence of decreased CD3⁺CD4⁺ number within the first 100 d and increased CD3⁺CD8⁺ number in later time‐points. Among six evaluated patients, expression of activating KIRs on NK cells and T cells was particularly prominent for those developing intestinal GVHD. Conclusion: Our findings indicate that the presence of particular activating KIRs in donor with their absence in recipient enhances GVHD, which is not accompanied by graft‐versus‐leukemia effect. Evaluation of activating KIR genotype may allow optimization of both donor selection and transplantation procedure in order to avoid GVHD.     

Rescue haploidentical peripheral blood stem cell transplantation for engraftment failure: a single‐centre case series

Graft failure affects approximately 5% of allogeneic stem cell transplants, with a poor prognosis. Salvage second allogeneic stem cell transplantation (alloSCT2) is limited by high rates of transplant‐related mortality from infection and graft‐versus‐host disease. We report on five adult patients receiving rescue alloSCT2 using haploidentical peripheral blood stem cells. All patients achieved neutrophil engraftment, two subsequently died from sepsis and disease relapse, respectively. Three patients remain alive up to 2 years post‐transplant. We suggest consideration of haploidentical alloSCT2 for patients with graft failure.     

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.     

Effect of blood cyclosporine concentration on the outcome of hematopoietic stem cell transplantation from an HLA-matched sibling donor

We retrospectively evaluated the effect of the blood cyclosporine (CsA) concentration on the outcome of allogeneic hematopoietic stem cell transplantation from an HLA-matched sibling donor in 171 patients who received a continuous infusion of CsA and short-course methotrexate to prevent graft-versus-host disease (GVHD). CsA was started at 3.0 mg/kg/day and the dose was adjusted to maintain the blood CsA concentration between 250 and 350 ng/ml. The actual dose of CsA averaged 1.9 mg/kg/day at the 3rd week after transplantation. The incidence of grade II-IV acute GVHD was 29.9%. Patient age and sex were identified as independent significant risk factors for acute GVHD. The CsA concentration during the 3rd week after transplantation most strongly affected the incidence of grade II-IV acute GVHD (RR 0.995 for an increase in CsA concentration by 1 ng/ml, P = 0.037) adjusted for other risk factors. The incidence of acute GVHD was significantly lower in patients with a 3rd-week CsA concentration higher than 300 ng/ml than in those with values between 200 and 300 ng/ml (20% vs. 35%, P = 0.036). We concluded that the blood CsA concentration at peri-engraftment period may be important in preventing acute GVHD.