The immature reticulocyte fraction: a negative predictor of the harvesting of CD34 cells for autologous peripheral blood stem cell transplantation

The optimal time for the harvesting of peripheral blood stem cells following chemotherapy and growth factors for autologous transplantation is based on the CD34 cell count. In this study, 51 patients having 59 stem cell mobilizations were assessed for the timing of the harvest by a CD34 cell count and an immature reticulocyte fraction (IRF). Results from 272 preharvest tests showed that when the CD34 cells were not harvestable, defined as a CD34 cell count of < 15 cells/microl, the IRF was always < or = 0.2. A low IRF resulted in a negative predictive value of 1 for the harvesting of stem cells. The IRF is therefore a valuable negative predictor of the timing of autologous stem cell harvesting.     

Successful treatment of post-transplant lymphoproliferative disorder in autologous blood stem cell transplant recipients

We report three cases of post-transplant lymphoproliferative disorder (PTLD) in the context of autologous stem cell transplantation (ASCT) for multiple myeloma (MM) and non-Hodgkin's lymphoma. The first two cases received ASCT for MM, one with a CD34-selected autograft and the other with an unmanipulated autograft. Both these cases of PTLD achieved a complete response following treatment with IVIG, gancyclovir, solumedrol and interferon (IFN). The third case received ASCT with an unmanipulated autograft for relapsed angioimmunoblastic lymphoma. He also achieved a complete response but only after rituximab was added to IVIG, gancyclovir, solumedrol and IFN. None of these patients experienced a relapse of their PTLD with follow-up ranging from 1.5 to 5 years. These cases highlight the importance of considering PTLD in the differential diagnosis of lymphadenopathy and fever post ASCT. They also demonstrate the possibility of durable complete remission of post-ASCT PTLD following antiviral and immune modulating therapy.     

Severe sepsis in autologous stem cell transplant recipients: microbiological aetiology, risk factors and outcome

Infectious complications are the main reason for early treatment-related mortality after autologous stem cell transplantation (ASCT). We evaluated retrospectively microbiological aetiology, risk factors and clinical consequences of severe sepsis in this patient cohort. From 1996 to 2006 a total of 319 patients underwent ASCT at our institution. Antibacterial prophylaxis was not used. Neutropenic fever occurred in 83% (n=265) and was complicated by severe sepsis in 5% (n=17) of patients. Severe sepsis tended to be more common in patients with non-Hodgkin's lymphoma (NHL) than in other patients (9% vs 3%, p=0.009). Bacteraemia was observed more commonly in patients with severe sepsis (76% vs 22%, p<0.001); Pseudomonas sp. was found in 30% (n=5) of these patients. Kinetics of C-reactive protein (CRP) more commonly coincided with, rather than predicted, the development of severe sepsis. All other observed risk factors for severe sepsis (length of neutropenia, fever and blood culture findings) were late indicators. Severe sepsis was fatal in 9 patients (53%), and all had NHL (p=0.003 compared to other patients). Severe sepsis is an important cause of early mortality after ASCT, especially in NHL patients. Ways to prevent development of severe sepsis or predict its development might reduce early mortality among ASCT recipients.     

Telomere length predicts neutrophil recovery in the absence of G-CSF after autologous peripheral blood stem cell transplantation

Summary:Haemopoietic regeneration after autologous peripheral blood progenitor cell (PBPC) transplantation can be delayed in some patients despite adequate infusion of CD34(+) cells. This suggests variability in the proliferation potential of the implanted cells, a capacity that may be predicted by their telomere length. To test this theory, telomere length was measured on stored apheresis samples from 36 patients aged 46.6+/-11.1 years, who had undergone successful autologous PBPC transplantation with a median of 5.6 x 10(6)/kg (1.3 x 10(6)-36.1 x 10(6)/kg) CD34(+) cells. The mean PBPC telomere length for the cohort was 9.4+/-2.3 kbp. For patients who did not receive G-CSF post transplantation (n=7), days to absolute neutrophil recovery (ANC), >/=0.1, 0.5 and 1.0 x 10(9) cells/l, were significantly inversely correlated with telomere length of the infused PBPC (r=-0.88, -0.81, -0.77, respectively; P<0.05,). However, no correlation was found for patients who received G-CSF from day 1 post transplantation (n=20). These data suggest that for transplantation with sufficient CD34(+) cells, neutrophil recovery is less efficient in patients receiving infusions of cells with short telomeres, but this deficiency can be corrected with adequate post transplantation administration of G-CSF.Bone Marrow Transplantation (2004) 34, 439-445. doi:10.1038/sj.bmt.1704607 Published online 19 July 2004     

采用未成熟网织红细胞指数监测恶性肿瘤患者放疗前、后骨髓功能恢复的临床价值

目的　探讨采用未成熟网织红细胞指数 (IRF)监测恶性肿瘤患者放疗前、后骨髓功能恢复的临床价值。方法　采用XE 2 10 0型血液细胞分析仪检测未成熟网织红细胞指数 (IRF)、网织红细胞比率 (RET)和嗜中性粒细胞计数 (NEUT )。结果　患者组放疗后第 10天以上 3项指标均显著低于对照组 (P <0 .0 1) ,放疗后第 15天IRF开始增高 ,并显著高于第 10天的水平 (P <0 .0 1) ,而RET、NEUT未发生显著改变 (P >0 .0 5 ) ,患者组放疗后第 2 0天IRF继续升高 ,并显著高于第 15天的水平 (P <0 .0 1) ,RET和NEUT也开始增高 ,但与第 15天比较 ,无显著性差异 (P >0 .0 5 )。患者组放疗后第 2 5天 ,IRF已经基本恢复至放疗前水平 ,RET和NEUT也开始显著升高 ,但仍低于放疗前水平 (P <0 .0 1)。结论　肿瘤患者IRF升高较RET和NEUT要早。未成熟网织红细胞指数是放、化疗时反映骨髓抑制和恢复较敏感的指标     

Insufficient recovery of thymopoiesis predicts for opportunistic infections in allogeneic hematopoietic stem cell transplant recipients

Background

Recovery of thymopoiesis after allogeneic hematopoietic stem cell transplantation is considered pivotal for full immune competence. However, it is still unclear to what extent insufficient recovery of thymopoiesis predicts for subsequent opportunistic infections and non-relapse mortality.

Design and Methods

A detailed survey of all post-engraftment infectious complications, non-relapse mortality and overall survival during long-term follow-up was performed in 83 recipients of allogeneic stem cell grafts after myeloablative conditioning. Recovery of thymopoiesis was assessed using analysis of signal joint T-cell receptor rearrangement excision circles. The impact of recovery of thymopoiesis at 2, 6, 9 and 12 months post-transplantation on clinical outcome beyond those time points was evaluated by univariate and multivariate Cox regression analyses.

Results

The cumulative incidence of severe infections at 12 months after transplantation was 66% with a median number of 1.64 severe infectious episodes per patient. Patients in whom thymopoiesis did not recover were at significantly higher risk of severe infections according to multivariable analysis. Hazard ratios indicated 3- and 9-fold increases in severe infections at 6 and 12 months, respectively. Impaired recovery of thymopoiesis also translated into a higher risk of non-relapse mortality and outweighed pre-transplant risk factors including age, donor type, and disease risk-status.

Conclusions

These results indicate that patients who fail to recover thymopoiesis after allogeneic hematopoietic stem cell transplantation are at very high risk of severe infections and adverse clinical outcome.     

Infectious gastro-enteritis: an uncommon cause of diarrhoea in adult allogeneic and autologous stem cell transplant recipients

The incidence and aetiology of acute diarrhoea in 60 adult allogeneic or autologous stem cell transplant (SCT) recipients was determined in a prospective study. Stool specimens were obtained prior to SCT and on days +20, +40, +60 and +100 post transplant. Microbiological evaluation was performed for pathogenic bacteria, fungi, parasites and viruses. Forty-seven patients were evaluable of whom 31 had a total of 48 acute diarrhoeal episodes. Diarrhoea occurred in 79% of allogeneic and 47% of autologous SCT recipients (P < 0.05). Intestinal infections were found in three of 48 (6%) diarrhoeal episodes. Clostridium difficile with positive toxin was cultured twice and one stool specimen was positive for cryptosporidium. Intestinal pathogens were identified in 13 out of 172 stool specimens from asymptomatic patients and included: rotavirus (4), adenovirus (3), C. difficile, toxin positive (2), and others (4). Graft-versus-host disease was confirmed by biopsy in two of 36 episodes of diarrhoea in allogeneic patients, and in three patients a relationship between reactivation of cytomegalovirus and diarrhoea was suspected. In 40 of 48 (83%) episodes of diarrhoea no clear aetiology could be found.     

Invasive fungal infections in autologous stem cell transplant recipients: a nation-wide study of 1188 transplanted patients

Based on small single-centre series, the risk of invasive fungal infections (IFI) has been considered small in autologous stem cell transplant (ASCT) recipients. PURPOSE: To analyse epidemiological and clinical features of (IFI) among ASCT recipients in Finland 1990-2001. PATIENTS: During the study period, 1188 adult patients received high-dose therapy supported by ASCT in six centres. Altogether, 1112 patients (94%) received blood progenitor cells. The graft was CD34+ selected in 261 patients (22%). The major diagnostic groups were non-Hodgkin's lymphoma (n = 417), multiple myeloma (n = 395), breast cancer (n = 132) and Hodgkin's lymphoma (n = 53). RESULTS: Eighteen patients (1.5%) with IFI were identified. The incidence of proven or probable invasive aspergillosis was 0.8%, followed by candidaemia with an incidence of 0.3%. The median time to the diagnosis of IFI was 35 d (6-162) from the progenitor cell infusion. In fourteen patients (78%) IFI was diagnosed during lifetime and they were treated with antifungal therapy for a median of 50 d. Nine patients (64%) were cured. CONCLUSIONS: IFI appears to be a rare event after ASCT and Aspergillus infections seem to be predominant. These epidemiological features have an impact in planning prophylactic and empirical antifungal strategies in ASCT recipients.     

Early treatment-related mortality in adult autologous stem cell transplant recipients: a nation-wide survey of 1482 transplanted patients

OBJECTIVES: To evaluate early (<100 d) treatment-related mortality (TRM) in autologous stem cell transplant (ASCT) recipients. PATIENTS: Altogether 1482 adult patients received ASCT in six Finnish centres 1990-2003. The most common diagnoses were non-Hodgkin's lymphoma (NHL) (n = 542), multiple myeloma (MM) (n = 528), breast cancer (BC) (n = 132), Hodgkin's lymphoma (n = 86) and chronic lymphocytic leukaemia (CLL) (n = 63). RESULTS: Forty-two patients (2.8%) died from treatment-related reasons <100 d from ASCT. The median time to death was 38 d from ASCT (0-99). The risk of TRM varied according to the diagnoses. The highest risk was observed in patients with AL amyloidosis (24%) followed by NHL (4.4%) and MM (1.9%). No early TRM was observed in patients transplanted for BC or CLL. Infections were the cause of death in 16 patients (fungal 7, bacterial 6, viral 3). Organ toxicity was responsible for early death in 26 patients (heart 9, lungs 7, other 10). CONCLUSIONS: This nation-wide survey indicated a low early TRM in ASCT recipients in general, but higher risks in patients with AL amyloidosis or NHL. In addition to patient selection, also optimization of transplant procedure may be needed in these patient groups to reduce early TRM.     

Invasive fungal infections in allogeneic and autologous stem cell transplant recipients: a single-center study of 166 transplanted patients

OBJECTIVES: Invasive fungal infections (IFIs) remain a major cause of infection-related morbidity and mortality following hematopoietic stem cell transplantation (HSCT). PATIENTS AND METHODS: We retrospectively analyzed the incidence of IFIs in 166 patients undergoing either allogeneic or autologous HSCT at our institution between January 2000 and December 2003. RESULTS: Incidence of invasive aspergillosis (IA) and invasive candidiasis among allogeneic HSCT recipients was 23% (16-32%, 95% confidence interval [CI]) and 3% (1-9%, 95% CI), respectively. Duration of neutropenia and reduced-intensity conditioning were the only risk factors for IA in the multivariate model. Patients with IA had significantly reduced overall survival (8% versus 56%, P=0.01) due to higher transplant-related mortality (63% versus 31%, P=0.03). Following autologous HSCT, incidence of IA and invasive candidiasis was 8% (4-19%, 95% CI) and 2% (0.2-11%, 95% CI), respectively. Duration of neutropenia was the only risk factor for the development of IA following autologous HSCT. Overall survival of autologous HSCT recipients with IA was similar to that of patients without IA. Seventeen percent of autologous HSCT recipients were colonized with Candida species. Compared with non-colonized patients these patients had significantly reduced overall survival (72% versus 23%, P=0.004), due to increased treatment-related mortality (23% versus 9%, P=0.02). CONCLUSION: Diagnosis of IA following allogeneic HSCT and Candida colonization in the setting of autologous HSCT defines patient populations with poor outcome but primarily not as a result of the fungal pathogen. Regarding the incidence of IA, duration of neutropenia is the main risk factor, and dose-reduced conditioning is an additional risk factor for the development of IA following allogeneic HSCT, probably owing to increased recipient age in this patient cohort, requiring further studies in this transplantation setting.     

Adenovirus infection in paediatric stem cell transplant recipients: increased risk in young children with a delayed immune recovery

Adenovirus (HAdV) infections are a frequent cause of morbidity and mortality after allogeneic human stem cell transplantation (HSCT). We report a retrospective single-centre study on 328 consecutive paediatric recipients of an allogeneic HSCT. During the first 6 months after HSCT, HAdV infection occurred in 37 children (cumulative incidence 12%). The highest incidence was found in young children up to 5 years of age, transplanted after 1994, with >2 log T-cell depletion of a graft of another than an HLA-genotypically identical related donor (actuarial frequency at 6 months 84%). Persistence of HAdV and spreading of the virus over multiple sites showed a trend towards the development of HAdV disease or death, but did not reach significance. Recovery of immunity after HSCT, that is, serum concentrations of IgM and peripheral blood counts of T cells and subsets, was delayed in children with an HAdV infection compared with noninfected children. In seven out of seven patients with HAdV DNA in serum and decreasing lymphocyte counts, the infection had a fatal course. Manipulation of cellular immunity either by tapering of immunosuppression, infusion of donor lymphocytes or immunotherapy using HAdV-specific T cells should be considered in graft recipients at risk for a severe HAdV infection.     

Isolation of viruses from stools in stem cell transplant recipients: a prospective surveillance study

We prospectively examined stool specimens for enteric viruses in 75 stem cell transplant recipients (autologous 48, allogeneic 27) to determine the frequency and significance of these infections. Only six patients (8%) had a positive isolate. Five of these were allograft recipients (18%) compared to one autograft recipient (2%) (P = 0.02). Unrelated donor BMT recipients were at the highest risk for a viral isolate (OR = 10.5). Adenovirus was the commonest isolate (four patients). One patient each had an echovirus, enterovirus and small round structured virus identified. No correlation was found between the severity of gastro-intestinal symptoms and detection of a viral pathogen. There was no correlation with GVHD or CMV status. The only risk factor identified for isolation of an enterovirus was allogeneic BMT from an unrelated donor. There was a negative correlation with PBSC grafts. All the patients infected with an enteric virus had concomitant infection with other pathogens, compared to only 18% of uninfected patients (P = 0.001). The non-relapse mortality of the infected patients was 50% and only 7% in the uninfected patients (P = 0.01, OR = 12.5), although the isolated virus was the direct cause of death in one patient only. This study indicates a low rate of enteric virus isolation in recipients of PBSC grafts, both autologous and allogeneic. However, unrelated donor BMT is associated with a higher risk of enteric virus infection and an adverse outcome. Bone Marrow Transplantation (2000) 25, 277-282.     

Antibody responses to vaccinations given within the first two years after transplant are similar between autologous peripheral blood stem cell and bone marrow transplant recipients.

As a consequence of the significantly larger inoculum of lymphoid cells present in peripheral blood stem cell (PBSC) harvests compared to bone marrow (BM), it is possible that autoPBSCT recipients may have an earlier and*or enhanced response to vaccines. Until data to confirm this become available, the European Blood and Marrow Transplantation Association (EBMT) recommend that all transplant recipients be immunized in the same way regardless of stem cell source. We performed a prospective study comparing serological responses to influenza, pneumococcal polysaccharide and tetanus toxoid vaccines between autoPBSCT with autoBMT recipients. Antibody responses in sibling HLA-matched allogeneic BMT (alloBMT) survivors were also evaluated. All vaccines were administered within the first 2 years after stem cell transplantation. Fifty patients were enrolled. The time of vaccination after transplant was similar between autoPBSCT (mean 11 months for each vaccine) and autoBMT recipients (mean 12 months except 13 months for tetanus toxoid) (P = NS). Serological responses were poor and no significant difference in response to any of the vaccines used was seen between the three transplant cohorts. We provide no evidence that current EBMT guidelines be modified. Large prospective vaccine studies are needed to address the issue more fully.