Nonmyeloablative stem cell transplantation is an effective therapy for refractory or relapsed hodgkin lymphoma: results of a spanish prospective cooperative protocol.

We report the results of reduced-intensity conditioning allogeneic stem cell transplantation (allo-RIC) in patients with advanced Hodgkin lymphoma (HL). Forty patients with relapsed or refractory HL were homogeneously treated with an RIC protocol (fludarabine 150 mg/m(2) intravenously plus melphalan 140 mg/m(2) intravenously) and cyclosporin A and methotrexate as graft-versus-host disease (GVHD) prophylaxis. Twenty-one patients (53%) had received >2 lines of chemotherapy, 23 patients (58%) had received radiotherapy, and 29 patients (73%) had experienced treatment failure with a previous autologous stem cell transplantation. Twenty patients (50%) were allografted in resistant relapse, and 38 patients received hematopoietic cells from an HLA-identical sibling. Five patients (12%) died from early transplant-related mortality (before day +100 after allo-RIC). One-year transplant-related mortality was 25%. Acute GVHD developed in 18 patients (45%). Chronic GVHD developed in 17 (45%) of the 31 evaluable patients. The response rate 3 months after the allo-RIC was 67% (21 [52%] complete remissions and 6 [15%] partial remissions). Eleven patients received donor lymphocyte infusions (DLIs) for disease relapse. The response rate after DLI was 54% (3 complete remissions and 3 partial remissions). Overall survival (OS) and progression-free survival (PFS) were 48% +/- 10% and 32% +/- 10% at 2 years, respectively. Refractoriness to chemotherapy was the only adverse prognostic factor for both OS (63% +/- 12% versus 35% +/- 13%; P = .05) and PFS (55% +/- 16% versus 10% +/- 9%; P = .006). For patients with failure of a prior autologous hematopoietic stem cell transplantation, results were especially good for those who experienced late relapses (>/=12 months: 2-year OS and PFS were 75% +/- 16% and 70% +/- 18%, respectively). These data suggest that allo-RIC is feasible in heavily pretreated HL patients and has an acceptable early transplant-related mortality. Results are better in patients allografted in sensitive disease. Both responses observed after the development of GVHD and DLI may suggest a graft-versus-HL effect. Allo-RIC has to be considered an effective therapeutic approach for patients who have had treatment failure with a previous autologous hematopoietic stem cell transplantation.     

Decreased treatment failure in recipients of HLA-identical bone marrow or peripheral blood stem cell transplants with high CD34 cell doses

We studied the association between CD34 cell dose and transplant outcomes in 359 bone marrow (BM) and 511 peripheral blood stem cell (PBSC) transplant recipients from human leucocyte antigen (HLA)-identical siblings, reported to the International Bone Marrow Transplant Registry (IBMTR). Transplants for leukaemia were performed between 1995 and 1998. Patients were divided into those receiving below or above the median CD34+ dose, for BM (3 x 106/kg) and PBSC (6 x 106/kg) grafts respectively. Cox proportional hazards regression was used to adjust for baseline patient-, disease- and transplant-related characteristics. Analysis of the BM recipients showed that high CD34 cell dose was associated with lower transplant-related mortality [relative risk (RR) = 0.60, P = 0.033] and treatment failure (inverse of leukaemia-free survival, RR = 0.69, P = 0.032). Among PBSC recipients, high CD34 dose was associated with faster recovery of neutrophils to > 0.5 x 109/l (RR = 1.38, P < 0.001) and platelets to > 20 x 109/l (RR = 1.34, P = 0.003), lower risk of relapse (RR = 0.62, P = 0.029) and treatment failure (RR = 0.74, P = 0.03). We conclude that higher CD34 cell doses decrease treatment failure in recipients of HLA-identical sibling BM and PBSC transplants.     

Elderly age and prior autologous transplantation have a deleterious effect on survival following allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning: results from the Spanish multicenter prospective trial

Over a 3-year period, 145 patients ineligible for myeloablative conditioning underwent reduced-intensity conditioning (RIC) hematopoietic stem cell transplantation (SCT) from an HLA-identical sibling in a prospective study. The median age was 54 years, 88 patients were male and 61 patients were beyond the early-intermediate phase of their disease. The 100-day probability of developing grade II-IV acute graft-versus-host disease (GVHD) was 34%, and the 1-year probability of developing chronic extensive GVHD was 41%. The 1-year probabilities of transplant-related mortality (TRM), overall (OS) and progression-free survival were 20, 60 and 52%, respectively. Multivariate analyses found a better OS in: (i) patients <60 years; and (ii) recipients of a first SCT; and a higher TRM in: (i) age >60 years, (ii) recipients of a prior autologous SCT, and (iii) an ECOG performance status >1. The 1-year TRM in patients with 0 or 1 and >2 of the above-mentioned adverse prognostic factors were 17 vs 53%, respectively (P<0.001). In summary, our study shows that elderly patients have a higher TRM following an RIC protocol. However, age by itself should not preclude these RIC transplants, since TRM appears to be unacceptably high only in the presence of additional adverse factors.     

Transmission of donor illness by stem cell transplantation: should screening be different in older donors?

With increasing donor age, the potential of transmitting diseases from donor to recipient reaches new dimensions. Potentially transmittable diseases from donors include infections, congenital disorders, and acquired illnesses like autoimmune diseases or malignancies of hematological or nonhematological origin. While established nonmalignant or malignant diseases might be easy to discover, early-stage hematological diseases like CML, light-chain multiple myelomas, aleukemic leukemias, occult myelodysplastic syndromes and other malignant and nonmalignant diseases might not be detectable by routine screening but only by invasive, new and/or expensive diagnostic tests. In the following article, we propose recommendations for donor work-up, taking into consideration the age of the donors. In contrast to blood transfusions, stem cells from donors with abnormal findings might still be acceptable for HCT, when no other options are available and life expectancy is limited. This issue is discussed in detail in relation to the available donor and stem cell source. Finally, the recommendations presented here aim at harmonized worldwide work-up for donors to insure high standard quality.     

Allogeneic transplantation of CD34(+) selected cells from peripheral blood from human leukocyte antigen-identical siblings: detrimental effect of a high number of donor CD34(+) cells?

Clinical results after T-cell-depleted allografts might be improved by modifying the graft content of progenitor and accessory cells. Although the association of the number of donor T cells with the clinical outcome has been studied extensively, the optimum number of progenitor cells that should be administered to patients is unknown. The characteristics of 84 consecutive human leukocyte antigen (HLA)-identical sibling transplants of granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood progenitor cells depleted of T cells by CD34(+) positive selection (allo-PBT/CD34(+)) were analyzed for their effect on clinical outcome. After a median follow-up of 24 months (range, 1-70 months), 50 patients remain alive (59.5%) and 34 have died (21 [25%] as a result of the transplant and 13 [15.5%] due to disease relapse). The median number of CD34(+) cells administered to the patients was 3.9 x 10(6)/kg (range, 1.2-14.3 x 10(6)/kg). A number of CD34(+) cells in the inoculum of 1 x 10(6)/kg to 3 x 10(6)/kg was associated with increased survival: 21 of 28 (75%) patients are alive, as compared with 29 of 56 (52%) patients receiving more than 3 x 10(6)/kg (actuarial probability 75% vs. 42%, respectively; P =.01). In the multivariate analysis, the independent prognostic variables for survival were CD34(+) cell dose 1 x 10(6)/kg to 3 x 10(6)/kg (RR = 4.8; P =.0008), sex-pairing match (RR = 3.2; P =.002), and early stage of disease (RR = 2.8; P =.007). From these results it appears that, in allo-PBT/CD34(+) from HLA-identical siblings, a number of CD34(+) cells in the inoculum between 1 x 10(6)/kg to 3 x 10(6)/kg is an important factor for better survival, and that higher CD34(+) cell doses might be associated with a poorer outcome.     

A constitutional variant in the transcription factor EP300 strongly influences the clinical outcome of patients submitted to allo-SCT

An adequate response of the innate immune system after allo-SCT is crucial for the clinical outcome of patients submitted to this procedure. EP300 is one of the key genes of the innate immune system (IIS). We evaluated the influence of gene variant A>G rs20551 in EP300 in donor and/or recipient on clinical results after HLA-identical sibling allo-SCT. Patients with AA gene variant had a lower relapse incidence (31 vs 48%, P=0.025; odds ratio (OR)=1.6, P=0.05), attained better disease-free survival (AA: 53% vs AG+GG: 24%, P=0.001; OR=1.8, P=0.01), and better OS (AA: 53% vs AG+GG: 34%, P=0.001; OR=1.9, P=0.007). This beneficial association was more evident when AA gene variant was present in both donor and patient. In healthy individuals, AA gene variant was associated with lower IL2 production after a mitogenic stimuli, higher CD4+ cell response after CMV infection, and higher expression of innate immune genes (IRF-3 and MIF), cell cycle genes (AURKB, CCNA2 and CCNB1), lymphocyte survival genes (NFAT5 and SLC38A2), and with a lower expression of P53 compared with recessive GG gene variant. These findings suggest a beneficial effect of the AA gene variant in rs20551 on clinical outcome after allo-SCT.     

Nonmyeloablative transplantation with or without alemtuzumab: comparison between 2 prospective studies in patients with lymphoproliferative disorders

Although nonmyeloablative conditioning regimen transplantations (NMTs) induce engraftment of allogeneic stem cells with a low spectrum of toxicity, graft-versus-host disease (GVHD) remains a significant cause of morbidity and mortality. In vivo T-cell depletion, using alemtuzumab, has been shown to reduce the incidence of GVHD. However, this type of maneuver, although reducing GVHD, may have an adverse impact on disease response, because NMTs exhibit their antitumor activity by relying on a graft-versus-malignancy effect. To explore the efficacy of alemtuzumab compared with methotrexate (MTX) for GVHD prophylaxis, we have compared the results in 129 recipients of a sibling NMT enrolled in 2 prospective studies for chronic lymphoproliferative disorders. Both NMTs were based on the same combination of fludarabine and melphalan, but the United Kingdom regimen (group A) used cyclosporin A plus alemtuzumab, whereas the Spanish regimen (group B) used cyclosporin A plus MTX for GVHD prophylaxis. Patients receiving alemtuzumab had a higher incidence of cytomegalovirus (CMV) reactivation (85% versus 24%, P <.001) and a significantly lower incidence of acute GVHD (21.7% versus 45.1%, P =.006) and chronic GVHD (5% versus 66.7%, P <.001). Twenty-one percent of patients in group A and 67.5% in group B had complete or partial responses 3 months after transplantation (P <.001). Eighteen patients in group A received donor lymphocyte infusions (DLIs) to achieve disease control. At last follow-up there was no difference in disease status between the groups with 71% versus 67.5% (P =.43) of patients showing complete or partial responses in groups A and B, respectively. No significant differences were observed in event-free or overall survival between the 2 groups. In conclusion, alemtuzumab significantly reduced GVHD but its use was associated with a higher incidence of CMV reactivation. Patients receiving alemtuzumab often required DLIs to achieve similar tumor control but the incidence of GVHD was not significantly increased after DLI.     

Haematopoietic stem cell transplantation (HSCT) in Europe 2002. Changes in indication and impact of team density. A report of the EBMT activity survey

This 2002 European Group for Blood and Marrow Transplantation (EBMT) activity survey concentrates on current status, increase and decrease in haematopoietic stem cell transplantation (HSCT) activity in Europe and investigates the association of transplant rates with team density. In 2002, there were 20 207 HSCT, 6915 allogeneic (34%), 13 292 autologous (66%) and 3947 additional re- or multiple transplants collected from 586 centres in 39 European countries. Main indications were leukaemias (6523 (32%; 76% allogeneic)); lymphomas (10 760 (53%; 92% autologous)); solid tumours (1913 (9%; 92% autologous)) and nonmalignant disorders (874 (4%; 92% allogeneic)). Compared to 2001, there were increases (>10%) for AML, ALL 1st CR, CML not 1st cP, MDS, SAA and CLL in allogeneic HSCT and for MDS, Ewing's sarcoma, soft-tissue sarcoma and ovarian cancer in autologous HSCT. Decreases (>10%) were observed in autologous HSCT for acute leukaemias beyond 1st CR, CML cP, glioma, breast cancer and lung cancer. Correlation of transplant rates (number of transplants per 10 million inhabitants) with team density (number of transplant teams per 10 million inhabitants) suggests different diffusion patterns for autologous compared to allogeneic HSCT. These data describe current practice for blood and marrow transplantation in Europe and give some hints about mechanisms involved in HSCT rates.     

Demonstration of surface antigens on bronchoalveolar lavage cells using the immunoalkaline phosphatase method

The immunoalkaline phosphatase procedure is described as a method for labelling bronchoalveolar lavage cellular specimens with monoclonal antibodies. This method has several advantages over conventional immunofluorescent techniques: it can be performed on cytocentrifuge preparations stored for long periods before staining; cell morphology can be observed in detail in positive and negative cells; the staining is permanent and stable, and, the reaction can be evaluated with a light microscope. Normal values for lymphocyte subpopulations in smokers and nonsmokers are also reported.