Non-bacterial infections in allogeneic non-myeloablative stem cell transplant recipients

Data on non-bacterial infections during allogeneic non-myeloablative hematopoietic stem cell transplantation (HSCT) are widely different. We evaluated data on 48 consecutive patients who received a conditioning regimen with fludarabine and cyclophosphamide (73%) or fludarabine and total body irradiation (27%) and then underwent allogeneic non-myeloablative HSCT. Cytomegalovirus (CMV) infection was common and occurred in 48% of patients; 3 patients developed CMV disease, and all survived. CMV reactivation was found to be common with both conditioning regimens in our patient population. Invasive aspergillosis occurred in 4 patients (8%) and 3 died. Other serious non-bacterial infections were uncommon. Review of the available literature on non-myeloablative HSCT suggests that the frequency and type of opportunistic infections vary considerably.     

High levels of antiphospholipid antibodies are associated with cytomegalovirus infection in unrelated bone marrow and cord blood allogeneic stem cell transplantation

Antiphospholipid antibodies (APA) are a family of autoimmune and alloimmune immunoglobulins recognizing protein-phospholipid complexes in in vitro laboratory test systems. These antibodies have been associated with several conditions (malignancies, autoimmune diseases, infections, use of drugs); moreover, a syndrome capable of inducing thromboembolic disease has recently been associated with the presence of these antibodies. The aim of this prospective study was to investigate the levels of APA in subjects affected by haematological malignancies undergoing allogeneic haematopoietic stem cell transplantation (ASCT). Between March 1996 and December 1997, 32 patients undergoing ASCT were studied prospectively until day +180 from transplant. The mean values of IgG and IgM anticardiolipin antibodies (ACA) increased in recipients of stem cells from anunrelated donor, and a statistically significant difference inACA IgG mean value between unrelated and related transplanted patients was demonstrated between days +95 and +180. All of the subjects who received stem cells from an unrelated donor had APA levels higher than the mean normal value +3 SD vs. 35% of those receiving stem cells from a related donor (P < 0.01). The reason for such a difference may be a result of the different incidence in documented cytomegalovirus (CMV) infection in the two groups (83% vs. 23%; P < 0.01), as indicated by the significant correlation between APA positivity and CMV infection (P < 0.05). No relationship was found between APA, conditioning regimen and acute or chronic graft vs. host disease (GVHD). Moreover, we did not observe any thromboembolic disorder or veno occlusive disease (VOD).     

Ganciclovir预防异基因造血干细胞移植后巨细胞病毒感染

目的 :评价Ganciclovir在异基因造血干细胞移植 (allo HSCT)后预防巨细胞病毒 (CMV)感染的效果。方法 :观察allo HSCT患者 46例 ,全部病例均系移植前受者和 (或 )供者的CMV IgG阳性 ,分为预防组 2 4例 ,对照组 2 2例。allo HSCT后当患者血中性粒细胞 >1.0× 10 9/L时 ,预防组开始用GCV 10mg·kg-1·d-1,分两次静滴 ,连续 5d ;然后改为 5mg·kg-1·d-1,每周用 5d ,直至 +10 0d。对照组未预防性使用GCV。结果 :在 +10 0d内 ,预防组和对照组的CMV感染率分别为 8% (2 / 2 4)、32 % (7/ 2 2 ) ,P <0 .0 5 ;CMV病发病率分别为 0 %、18% (4 / 2 2 ) ,P <0 .0 5。两组患者在 +10 0d和 +180d内的死亡率分别为 4% (1/ 2 4)和 5 % (1/ 2 2 ) ,P >0 .0 5 ;12 .5 % (3/ 2 4)和 9% (2 / 2 2 ) ,P >0 .0 5。预防组的死因分别为并发细菌和真菌感染、CMV间质性肺炎或原发病复发 ;对照组的死因均是CMV间质性肺炎。结论 :allo HSCT后预防性使用GCV能明显抑制CMV感染 ,减少CMV病发病率。GCV的主要毒副作用是导致中性粒细胞减少 ,使患者继发感染甚至死亡的机率增加。GCV预防性使用的最佳剂量、用药方案及持续时间均有待进一步探讨     

Nephrotic syndrome: an under-recognised immune-mediated complication of non-myeloablative allogeneic haematopoietic cell transplantation

Nephrotic syndrome (NS) is an extremely rare complication of myeloablative allogeneic haematopoietic cell transplantation (HCT) that usually occurs in association with chronic graft-versus-host disease (C-GVHD). We observed an unexpectedly high incidence of NS in a cohort of 163 consecutive patients undergoing non-myeloablative HCT from a related human leucocyte antigen-compatible donor. Seven patients developed NS at a median 318 d post-transplant (range 119-1203 d; cumulative incidence 6.1%). The median age at onset of NS was 46 years (range 33-59 years); three of the seven patients had no evidence of C-GVHD while four had accompanying limited C-GVHD. At diagnosis, median proteinuria was 16.5 g/24 h (range 3-24 g/24 h). Renal biopsy was performed in four cases and revealed membranous nephropathy. NS was not always associated with other symptoms of C-GVHD, and in contrast to previous reports, usually did not improve with the re-initiation of aggressive immunosuppression, resulting in progressive renal failure necessitating dialysis in three of seven cases. Membranous nephropathy resulting in NS is a previously unrecognised and clinically significant complication of non-myeloablative HCT.     

异基因造血干细胞移植后巨细胞病毒感染的发病情况及疗效分析

目的：探讨异基因造血干细胞移植（allo-HSCT）后,巨细胞病毒（CMV）感染的发病情况及抗病毒治疗的疗效。方法：对在我所接受allo-HSCT的患者23例进行回顾性分析,均应用荧光定量PCR法（FQ-PCR法）检测外周血CMV-DNA含量。CMV感染应用更昔洛韦（GCV）10mg.kg-1.d-1进行治疗。结果：23例患者中7例移植后发生CMV感染,占30.43%。GCV治疗的总有效率约为85.71%。6例在GCV治疗过程中出现白细胞和血小板减少。结论：FQ-PCR法可以应用于allo-HSCT后早期准确诊断CMV感染。GCV对allo-HSCT后CMV感染的预防及治疗效果可靠。     

Guillain–Barré syndrome associated with cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation

The association between cytomegalovirus (CMV) infection and the development of Guillain-Barré syndrome (GBS) in the setting of allogeneic hematopoietic stem cell transplantation (alloSCT) has been reported only occasionally. We describe here a 23-year-old patient diagnosed with acute myelogenous leukemia who underwent a partially HLA-mismatched alloSCT and soon after developed GBS along with a CMV infection. Serum autoantibodies to several ganglioside antigens were concomitantly detected. Despite therapy with ganciclovir and plasma exchanges, the patient's clinical condition rapidly deteriorated, and he died 3 weeks later with persisting CMV antigenemia. Although a coincidental association cannot be excluded, it could be speculated that a pathogenetic link exists between the 2 disorders. In this sense, molecular mimicry between viral antigens and neural host tissues could be postulated as the hypothetical mechanism underlying the triggering of the autoimmune disease in the present case.     

The outcome of unrelated donor stem cell transplantation for patients with multiple myeloma

We performed a retrospective analysis of outcome in 45 patients with multiple myeloma receiving unrelated donor stem cell transplants (UD-SCT) in the UK between 1993 and 2002; 17 received myeloablative conditioning regimens and 28 received reduced intensity conditioning (RIC) protocols. Forty patients received pretransplant CAMPATH serotherapy. Forty-two of 45 patients had detectable disease at transplant, but 33 of 45 were chemoresponsive. Sixty per cent of patients had received a previous autograft. Myeloid engraftment was seen in 95% of recipients and was significantly faster in recipients receiving peripheral blood stem cells (P = 0.07) and RIC (P = 0.001). The incidence of severe (grade 3/4) acute graft versus host disease (aGvHD) was 5% (2/40). The 100-d non-relapse mortality was 18% (5/38) following RIC and 53% (9/17) following myeloablative regimens. Twenty-nine per cent of patients achieved a complete remission, 61% a partial remission, giving a 90% overall response rate. At median follow-up (513 d), overall survival was 40%: 54% in the RIC group (median follow-up: 489 d) and 18% in the myeloablative group (median follow-up: 560 d). In recipients of UD-SCT, RIC protocols that incorporated CAMPATH were associated with faster myeloid engraftment, less severe aGvHD and lower 100-d non-relapse mortality than myeloablative regimens, without a corresponding rise in relapse rate during the period of observation.     

Anti-tumour response despite loss of donor chimaerism in patients treated with non-myeloablative conditioning and allogeneic stem cell transplantation

Based on a murine model, we conducted a series of trials of m-myeloablative human leucocyte antigen (HLA)-matched or mismatched related donor stem cell transplantation (SCT) with the intention of inducing mixed chimaerism (MC), then administering prophylactic donor lymphocyte infusions (DLIs), for the treatment of advanced haematologic malignancies. Preparative therapy consisted of cyclophosphamide, equine anti-thymocyte globulin (ATG) or MEDI-507 (an anti-CD2 monoclonal antibody) for in-vivo T-cell depletion, thymic irradiation on day -1 and cyclosporine alone for graft-versus-host disease (GVHD) prophylaxis. DLIs were given as early as 5 weeks post-SCT in patients with MC without evidence of GVHD. Twenty-two patients ultimately lost their graft (<1% donor cells) that could no be rescued by DLIs. Nine of 22 (41%) patients who lost donor chimaerism achieved an objective response, including three patients who showed evidence of disease regression following DLI, despite continued absence of macrochimaerism. Six patients were alive at 2.5-5.5 years following SCT, including four in continuous complete remission. In summary, it is possible to achieve sustained remission in patients with chemorefractory malignancies following non-myeloablative allogeneic SCT, even in the absence of sustained donor macrochimaerism; DLI may contribute to an ongoing anti-tumour effect in these patients. Immunological mechanisms that correlated with rejection of the graft may have a role in anti-tumour responses via a cell or cytokine-mediated pathway.     

Surveillance of cytomegalovirus (CMV) DNAemia in pediatric allogeneic stem cell transplantation: incidence and outcome of CMV infection and disease.

Cytomegalovirus (CMV) remains a serious problem after hematopoietic stem cell transplantation (HSCT). To investigate the incidence of CMV infection and outcome we retrospectively analyzed 70 consecutive pediatric allogeneic HSCTs monitored by CMV polymerase chain reaction (PCR), with at least 1-year follow-up or until death. All patients at risk for CMV infection (CMV-seropositive patients and CMV-seronegative recipients transplanted from CMV-seropositive donors) received hyperimmune anti-CMV globulins whereas in the group of HSCT patients with both donor and recipient CMV negativity, polyvalent immunoglobulins were given, both at a dose of 400 mg/kg. All patients received acyclovir at prophylactic doses for at least 6 months. Patients were monitored twice a week by CMV PCR. Patients with 2 positive results for CMV DNAemia received ganciclovir for 14 days and continued until 2 consecutive negative results were obtained. The incidence of CMV DNAemia was 12.8% (9/70) in the whole group, with significant higher risk for patients with CMV-seropositive recipient status, 8 out of 22 (36%), vs. patients with seronegative status, 1 out of 48 (2%) (P=0.0002). Three out of 9 patients with DNAemia developed CMV disease despite adequate preemptive treatment. The transplant-related mortality was higher in the CMV-seropositive recipient group (P=0.05). Age, use of hyperimmune anti-CMV globulins at a high dose, and the low incidence of graft-versus-host disease might be contributing factors to this low incidence.     

Infectious complications after allogeneic stem cell transplantation: incidence in matched-related and matched-unrelated transplant settings

Abstract: Background. Bacterial, viral, and fungal pathogens frequently cause severe, life‐threatening infections in immunocompromised patients after allogeneic hematopoietic stem cell transplantation (SCT). Objective. To compare the frequency of infections in patients with matched‐related (Group A) or with human leukocyte antigen (HLA)‐matched‐unrelated donors (Group B). Patients and methods. Patients treated at our transplantation unit between April 2004 and April 2005 were enrolled into this analysis. Documentation comprised demographic data, conditioning treatment, stem cell source, clinical course, as well as microbiological and clinical data and mortality. Results. We analyzed 59 patients, 22 in Group A and 37 in Group B. Both groups were well balanced regarding demographic data. Diagnoses were acute myeloid leukemia (30 of 59 patients, 50.8%), multiple myeloma (15.2%), acute lymphoblastic leukemia (11.9%), and chronic myeloid leukemia (10.2%). Patients in Group A developed infections in 95.5% of the cases compared with 97.3% in patients in Group B. Most frequently detected pathogens were Staphylococcus species, human herpesvirus‐6, and Epstein–Barr virus. Three proven fungal infections were detected in Group A compared with 9 proven fungal infections in Group B. Lung infiltrations were observed in equivalent incidence in both groups. Two years after transplantation, 55.9% of patients were alive (Group A: 68.2%; Group B: 48.6%, not significant). Conclusion. Allogeneic SCT from HLA‐matched‐unrelated donors does not have a higher infection risk than patients transplanted from matched‐related donors.     

The impact of transfusion of leucodepleted platelet concentrates on cytomegalovirus disease after allogeneic stem cell transplantation

The impact of transfusion of leucodepleted platelet concentrates (PCs) on cytomegalovirus (CMV) disease was assessed in 215 allogeneic (145 unrelated and 70 related donor) transplants over 3 years. In 43%, both donor and patient were CMV seronegative (CMV-/-). All received CMV-seronegative red cells and random leucodepleted PCs. No CMV disease occurred in any CMV-/- (low risk) transplant. CMV infection occurred in 31 seropositive patients (26%); 13 died and five deaths were attributable to CMV disease. When compared with historical controls, who received CMV-seronegative PCs, we found no difference in transfusion-acquired CMV in the current cohort.     

Unrelated donor haematopoietic cell transplantation after non-myeloablative conditioning for patients with high-risk multiple myeloma

BACKGROUND: Allografting induces long-term molecular remissions and possibly cure in myeloma patients. The development of non-myeloablative conditionings has reduced the transplant-related mortality (TRM) associated with myeloablation and extended the eligible age for transplantation. Moreover, high response rates are reported especially when allografting is preceded by cytoreductive high-dose chemotherapy. We investigated the feasibility of unrelated donor non-myeloablative transplantation as either part of the initial treatment plan or as salvage treatment in heavily pretreated patients. METHODS: Twenty-two patients underwent non-myeloablative allografting, 10 as part of their initial treatment and 12 at relapse. Donors were matched for HLA-A, B, C, DRB1 and DQB1 by high-resolution typing. Only one single class I allele disparity was allowed. Conditioning consisted of fludarabine 90 mg/m(2) and 2 Gy total body irradiation. Graft-vs.-host disease (GVHD) prophylaxis included cyclosporin and mycophenolate mofetil. RESULTS: All patients except two (91%) readily engrafted. After a median follow-up of 20 (10-30) months, incidences of grade II-IV acute and extensive chronic GVHD were 50% and 61%. Overall response (OR) was 55%, with four (20%) complete and seven (35%) partial remissions. However, in patients allografted up-front OR was 89% whereas in the heavily pretreated group OR was 27% (P = 0.01). Two-year overall and event-free survivals were both 79% in the group transplanted up-front and 27% and 25% among relapsed patients (P = 0.025 and P = 0.006, respectively). Overall, six patients died of TRM and three of disease progression. CONCLUSIONS: Unrelated donor non-myeloablative allografting is feasible in myeloma. Disease control appears more pronounced when patients are treated soon after diagnosis.     

Relatively favorable outcomes of post-transplant pulmonary function in patients with chronic myeloid leukemia receiving non-myeloablative allogeneic hematopoietic stem cell transplantation

Abstract:  Pulmonary function tests were performed in 20 patients with chronic myeloid leukemia before and after human leukocyte antigen-matched allogeneic sibling hematopoietic stem cell transplantation (HSCT) to identify any conditioning treatment effects on post-transplant function from January 1995 to December 2002. Of 20 patients, eight received non-myeloablative conditioning treatment and 12 received conventional myeloablative conditioning treatment. Pulmonary function tests including forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), and diffusion capacity for carbon monoxide (DLCO) were performed pretransplant, 6 and 12 months post-transplant. Possible pre-HSCT and post-HSCT risk factors were evaluated for association with pulmonary function. The results showed that myeloablative conditioning treatment had greater negative impact on FEV1, FVC, and DLCO than non-myeloablative conditioning therapy. We conclude that non-myeloablative allogeneic HSCT may apply a better transplant choice in patients who need special concern with post-transplant pulmonary function changes.     

Mixed chimaerism is common at the time of acute graft-versus-host disease and disease response in patients receiving non-myeloablative conditioning and allogeneic stem cell transplantation

We report the clinical outcome and results of chimaerism analysis in various cell lineages of 30 patients given non-myeloablative conditioning, followed by allogeneic stem cell transplantation (SCT). The commonest diagnoses were chronic myelogenous leukaemia (n = 11) and solid tumours (n = 11). Twenty-one patients received SCT from human leucocyte antigen (HLA)-identical siblings and nine from matched unrelated donors. Median patient age was 53 (28-77) years. Four non-myeloablative protocols were used, including fludarabine (30 mg/m2 x 3-6), busulphan (4 mg/kg x 2), cyclophosphamide (Cy) (30 mg/kg/day x 2) or total body irradiation (2 Gy), and anti-thymocyte globulin. The patients were analysed by polymerase chain reaction (PCR) analysis of minisatellites on days 14, 21 and 28, then every other week up to 3 months and monthly thereafter. All samples were cell separated for T, B and myeloid cells using immunomagnetic beads. Eighteen patients were alive at a median follow-up of 11 (6-20) months. Acute graft-versus-host disease (GVHD) occurred in 22 patients. Eighteen of the 22 patients with acute GVHD showed mixed chimaerism (MC) in the T-cell fraction at the time of acute GVHD. However, all patients with acute GVHD showed donor chimaerism (DC) in the T-cell fraction median 76 (7-414) days after onset versus three out of eight patients without acute GVHD, P < 0.001]. Disease response was diagnosed in 15 patients, median 100 (37-531) days after SCT. At the time of disease response, six out of 15 patients showed MC in the T-cell fraction. In conclusion, mixed chimaerism in the T-cell fraction is common at the time of acute GVHD and disease response in patients conditioned with non-myeloablative therapy.     

Impact of stem cell source and conditioning regimen on erythrocyte recovery kinetics after allogeneic haematopoietic stem cell transplantation from an ABO-incompatible donor

We evaluated erythrocyte recovery in 121 allogeneic haematopoietic stem cell transplantation (HSCT) recipients. There were 35 major and minor ABO-incompatible transplants, respectively, including 10 bi-directionally ABO-incompatible transplants. The use of peripheral blood stem cells facilitated erythrocyte recovery, regardless of the presence or absence of major ABO-incompatibility, and was associated with a frequent detection of anti-host isohaemagglutin early after minor ABO-incompatible transplantation, which was not associated with clinically relevant haemolysis. The use of a reduced-intensity regimen combining a purine analogue and busulphan did not delay erythrocyte recovery after major ABO-incompatible transplantation, suggesting this regimen had a strong activity against host plasma cell.