Risk assessment of relapse by lineage-specific monitoring of chimerism in children undergoing allogeneic stem cell transplantation for acute lymphoblastic leukemia.

UNLABELLED: Allogeneic hematopoietic stem cell transplantation is required as rescue therapy in about 20% of pediatric patients with acute lymphoblastic leukemia. However, the relapse rates are considerable, and relapse confers a poor outcome. Early assessment of the risk of relapse is therefore of paramount importance for the development of appropriate measures. We used the EuroChimerism approach to investigate the potential impact of lineage-specific chimerism testing for relapse-risk analysis in 162 pediatric patients with acute lymphoblastic leukemia after allogeneic stem cell transplantation in a multicenter study based on standardized transplantation protocols. Within a median observation time of 4.5 years, relapses have occurred in 41/162 patients at a median of 0.6 years after transplantation (range, 0.13-5.7 years). Prospective screening at defined consecutive time points revealed that reappearance of recipient-derived cells within the CD34(+) and CD8(+) cell subsets display the most significant association with the occurrence of relapses with hazard ratios of 5.2 (P=0.003) and 2.8 (P=0.008), respectively. The appearance of recipient cells after a period of pure donor chimerism in the CD34(+) and CD8(+) leukocyte subsets revealed dynamics indicative of a significantly elevated risk of relapse or imminent disease recurrence. Assessment of chimerism within these lineages can therefore provide complementary information for further diagnostic and, potentially, therapeutic purposes aiming at the prevention of overt relapse. This study was registered at clinical. TRIALS: gov with the number NC01423747.

Costs and cost-effectiveness of allogeneic stem cell transplantation in children are predictable.

The overall costs of pediatric stem cell transplantation (SCT), including donor search and costs during the first year post-SCT, were calculated in a cohort of 141 consecutive children undergoing SCT in a single institution. Costs were correlated with patient and transplantation characteristics and with a risk score for transplantation-related mortality. Cost-effectiveness was calculated based on the overall cost per surviving patient. Life-years gained were extrapolated from overall survival, and the costs per expected life-year gained were calculated. The overall median cost was €136,382 (175,815$), with a wide range, of €26,897 (34,679$) to €601,348 (775,343$). Increased costs were significantly associated with age, use of donors other than matched siblings, and advanced disease. There was a strong correlation of costs with a simple transplantation-related mortality risk score; median total costs were €89,550 (115,463$) for a score of 0, €127,349 (164,179$) for a score of 1, €156,578 (201,861$) for a score of 2, and €274,915 (354,499$) for a score of 3 (P < .001). Cost-effectiveness decreased with increasing transplantation-related mortality risk score; costs per survivor increased from €93,209 (120,200$) for a score of 0 to a maximum of €1,216,348 (1,568,579$) for a score of 3. Costs associated with pediatric SCT vary substantially; however, the combination of variables such as age, disease, and donor type is predictive of costs and cost-effectiveness. Costs per life-year gained are within the broadly accepted range in life-threatening hemato-oncologic diseases, even in the most cost-intensive patient cohort.

Standardization of flow cytometric minimal residual disease evaluation in acute lymphoblastic leukemia: Multicentric assessment is feasible.

BACKGROUND: Single-laboratory experience showed that flow cytometric (FCM) assessment of minimal residual disease (MRD) in acute lymphoblastic leukemia (ALL) is feasible in most patients and gives independent prognostic information. It is, however, not known whether FCM analysis can reliably be standardized for multicentric application. METHODS: An extensive standardization program was installed in four collaborating laboratories, which study FCM-MRD in children treated with the AIEOP-BFM-ALL 2000 protocol. This included methodological alignment, continuous quality monitoring, as well as personnel education by exchange and performance feed-back. RESULTS: Blinded inter-laboratory tests of list-mode data interpretation concordance (n = 202 blood and bone marrow samples from follow-up during induction of 31 randomly selected patients of a total series of n = 395) showed a very high degree of inter-rater agreement among the four centers despite differences in cytometers and software usage (intraclass correlation coefficient [ICC] 0.979 based on n= 800 single values). Lower concordance was reached with amounts of MRD below 0.1%. Comparing data from sample exchange experiments (n = 42 samples; ICC 0.98) and from independent patient cohorts from the four centers (regarding positive samples per time-point of follow-up as well as risk estimates) concordance was also good. CONCLUSION: MRD-evaluation by FCM in ALL can be standardized for reliable multicentric assessment in large trials.

Bone marrow assessment in Langerhans cell histiocytosis.

BACKGROUND: Bone marrow changes and their relation to blood cytopenia in patients with Langerhans cell histiocytosis (LCH) have not been extensively studied to date. The aim of the present study was to characterize the bone marrow changes in LCH patients and to ascertain their relation to disease severity. METHODS: Fifty-seven marrow samples of LCH patients were studied by conventional cytology, immunocytochemistry (ICC) and flow cytometry (FCM). RESULTS: On conventional cytology there was no significant difference between LCH cases and controls with respect to cellularity, number of monocytes and progenitor cells, and presence of histiocytes and hemophagocytosis. The numbers of nucleated cells, CD34(pos) cells, and CD14(pos) cells on FCM did not differ, either. The CD1a staining by ICC was positive in 14/41 LCH samples, and was consistently negative in controls. FCM staining for CD1a was positive in 12/54 samples, but also in 5/35 controls. The number of the CD1a(pos) cells in LCH marrows was usually very low (<10-20 cells/slide by ICC, or <0.5% of the leukocytes by FCM). The CD1a staining was more frequently positive and more pronounced in patients with severe disease. CONCLUSIONS: The combination of conventional aspirate cytology with ICC (CD1a staining) appears to be the most reliable tool for bone marrow assessment in LCH.