Long-term outcome of myeloablative allogeneic stem cell transplantation for multiple myeloma.

Allogeneic stem cell transplantation (alloSCT) has been used in the hopes of harnessing the curative potential of the graft-versus-myeloma effect. This study examines the long-term outcomes of a large cohort of patients with myeloma who were treated with myeloablative alloSCT at a single center. Comparisons are made with those who were treated with autologous stem cell transplantation (ASCT). Between January 1989 and February 2002, 158 patients age10 years post myeloablative alloSCT, similarly there are long-term survivors post-ASCT. Myeloablative alloSCT should not be considered standard treatment, and should only be considered in the context of a clinical trial.     

CTLA-4 polymorphism and clinical outcome post allogeneic hematopoietic stem cell transplantation

CTLA-4 inhibitory molecule plays an important role in regulating T cell activation. It is considered a crucial element in keeping the immune balance and has been implicated in cancer, autoimmunity and transplantation immunology. Inconsistent observations are reported regarding its association with hematopoietic stem cell transplantation (HSCT). Genotyping of CTLA-4 was performed in recipients and their HLA-matched donors for +49A/G and CT60 polymorphisms (80 and 94 pairs, respectively) using PCR-RFLP. No association was encountered between both polymorphisms in patients and donors and acute or chronic graft versus host disease. Significant association was observed between recipient +49A/G G allele and lower disease-free survival and overall survival compared to AA genotype (HR: 2.17, p = 0.03, 95% CI: 1.05–4.48 and HR: 2.54, p = 0.01, 95% CI: 1.16–5.54), respectively. Our results suggest that CTLA-4 genotyping may predict outcome in patients post HSCT. To validate our results, further studies on a larger cohort are needed.     

Efficacy of CD34+ stem cell dose in patients undergoing allogeneic peripheral blood stem cell transplantation after total body irradiation.

We estimated the effect of CD34(+) stem cell dose during peripheral blood stem cell transplantation (PBSCT) in predicting mortality after total body irradiation (TBI). Between 1997 and 2004, 146 consecutive patients with hematologic malignancies received fractionated TBI (12-13.6 Gy) in 8 fractions over 4 days before undergoing PBSCT; 61 patients received TBI with reduced radiation dose to the lung (6-9 Gy). The number of CD34(+) cells transplanted was recorded for all patients. A cubic spline representation for CD34(+) dose within a Cox proportional hazards model was used to model the relationship between the CD34(+) dose and mortality. Median follow-up was 44 months (range, 12-90 months). The CD34(+) cell dose ranged from 2.45 to 15.90 x 10(6) cells/kg (median, 5.15 x 10(6) cells/kg). Risk of mortality decreased with CD34(+) doses between 4-8 x 10(6) cells/kg and then began to increase. For all patients, CD34(+) doses of 5.1-12.9 x 10(6)/kg resulted in at least a doubling of median survival associated with the lowest CD34(+) value. In patients treated with lung dose reduction, a similar range of CD34(+) dose (4.3-10.2 x 10(6) cells/kg) produced at least a 5-fold improvement from the survival associated with the lowest CD34(+) dose; however, the relationship between CD34(+) dose and mortality was not statistically different when analyzed by lung dose reduction. A method for assessing risk of mortality by CD34(+) dose as a continuous variable is presented. Risk of mortality decreased with CD34(+) doses between 4-8 x 10(6) cells/kg and then began to increase.     

Cytokine adsorption therapy in lymphoma-associated hemophagocytic lymphohistiocytosis and allogeneic stem cell transplantation

Journal of Artificial Organs - Lymphoma-associated Hemophagocytic lymphohistiocytosis (HLH) represents a severe complication of disease progression, mediated through cytokine release from the...     

Improving outcome of allogeneic stem cell transplantation by immunomodulation of the early post-transplant environment

There has been great progress in understanding the alloresponse and the process of immune recovery after stem cell transplantation. Here, we highlight ways in which transplant outcome is determined by unique immunological features of the early post-transplant period that modulate the growth and function of the grafted donor T cells and stem cells. Better understanding of these early events and more detailed knowledge of the phenotype and function of transplanted donor cells facilitate strategies to optimize immune recovery, prevent graft-versus-host disease (GVHD) and boost immunity to viruses and leukemia. Approaches that optimize CD34 cell dose, techniques to remove GVHD-reacting T cells by T cell subset selection, suicide gene insertion or selective allodepletion, and the adoptive transfer of antigen-specific T cells have reached the stage of clinical trials. Furthermore, murine transplant experiments indicate ways to prevent GVHD while preserving immune function by depletion of na?ve cells, T cytotoxic 1 and T helper 1 cells, or by enrichment of regulatory T cells. Many of these approaches appear feasible in clinical transplantation and have yielded promising initial results, but proof that the goal of controlled selective immune reconstitution can be achieved is still awaited.     

Harnessing dendritic cells to improve allogeneic hematopoietic cell transplantation outcome

In clinical practice, hematopoietic cell transplantation (HCT) is now recognized as a powerful means of delivering effective cellular immunotherapy for malignant and non-malignant diseases. In patients with severe hematological malignancies, the success of allogeneic HCT is largely based on immunologic graft-versus-tumor (GVT) effects mediated by allogeneic T lymphocytes present in the graft. Unfortunately, this beneficial effect is counterbalanced by the occurrence of graft versus host reactions directed against normal host tissues resulting in graft versus host disease (GVHD), a potentially life-threatening complication that limits the success of allogeneic HCT. Therefore, while preserving beneficial GVT effects, a major objective in allogeneic HCT is the prevention of GVHD. Studies in the last decade revealed the central role of dendritic cells and macrophages in modulating graft versus host immune reactions after allogeneic HCT. In this review, we summarize recent progress and potential new therapeutic avenues using dendritic cell-based strategies to improve allogeneic HCT outcome.     

Etanercept (Enbrel) administration for idiopathic pneumonia syndrome after allogeneic hematopoietic stem cell transplantation.

Acute pulmonary dysfunction remains a frequent and severe complication of hematopoietic stem cell transplantation (SCT). Almost half of the pulmonary insults that occur in this seating are noninfectious in origin and are referred to as idiopathic pneumonia syndrome (IPS). In this series of 3 patients, etanercept (Enbrel; Immunex, Seattle, WA), a soluble, dimeric tumor necrosis factor alpha-binding protein, was administered to 3 consecutive pediatric allogeneic BMT recipients with IPS. The administration of etanercept, in combination with standard immunosuppressive therapy, was well tolerated and associated with significant improvements in pulmonary dysfunction within the first week of therapy. These data suggest that etanercept may represent a safe, non-cross-reactive, therapeutic option for patients with IPS and that clinical trials studying etanercept for this indication are warranted.     

Reduced-intensity allogeneic stem cell transplantation for patients whose prior autologous stem cell transplantation for hematologic malignancy failed.

Autologous hematopoietic stem cell transplantation (autoSCT) is an effective treatment for patients with various hematologic malignancies. Despite the significant improvement in the overall outcome, disease progression after transplantation remains the major cause of treatment failure. With longer follow-up, therapy-related myelodysplasia/acute myelogenous leukemia is becoming an important cause of treatment failure. The prognosis for these 2 groups of patients is very poor. Allogeneic hematopoietic stem cell transplantation (alloSCT) is a potential curative treatment for these patients. However, the outcome with conventional myeloablative alloSCT after failed autoSCT is typically poor because of high transplant-related mortality. In an attempt to reduce the treatment-related toxicity, we studied a reduced-intensity conditioning regimen followed by alloSCT for patients with progressive disease or therapy-related myelodysplasia/acute myelogenous leukemia after autoSCT. This report describes the outcomes of 28 patients with hematologic malignancies who received a reduced-intensity alloSCT after having treatment failure with a conventional autoSCT. Fourteen patients received a hematopoietic stem cell transplant from a related donor and 14 from an unrelated donor. The conditioning regimen consisted of low-dose (2 Gy) total body irradiation with or without fludarabine in 4 patients and the combination of melphalan (140 mg/m(2)) and fludarabine in 24. Cyclosporine and mycophenolate mofetil were used for posttransplantation immunosuppressive therapy, as well as graft-versus-host disease (GVHD) prophylaxis, in all patients. All patients engrafted and had >90% donor chimerism on day 100 after SCT. Currently, 13 patients (46%) are alive and disease free, 7 patients (25%) developed disease progression after alloSCT, and 8 (32%) died of nonrelapse causes. Day 100 mortality and nonrelapse mortality were 25% and 21%, respectively. With a median follow-up of 24 months for surviving patients, the 2-year probabilities of overall survival, event-free survival, and relapse rates were 56.5%, 41%, and 41.9%, respectively. Six patients (21%) developed grade III to IV acute GVHD. Among 21 evaluable patients, 15 (67%) developed chronic GVHD. We conclude that (1) reduced-intensity alloSCT is feasible and has an acceptable toxicity profile in patients who have previously received autoSCT and that (2) although follow-up was short, a durable remission may be achieved in some patients who would otherwise be expected to have a poor outcome.     

Association of vitamin D receptor polymorphisms with the outcome of allogeneic haematopoietic stem cell transplantation

Recently, vitamin D receptor (VDR) polymorphism has been identified as an additional genetic factor associated with the outcome after allogeneic haematopoietic stem cell transplantation (HSCT) from HLA-matched sibling donors. In the present study, VDR ApaI, TaqI and FokI alleles were typed using single strand conformation polymorphism in 123 Polish recipients and their sibling or alternative donors to test the associations of VDR polymorphisms with HSCT outcome. Four VDR genotypes were identified as risk factors of acute graft-versus-host disease (aGVHD). Donor ApaI AA (OR = 7.245, P = 0.009), source of HSC (OR = 7.001, P = 0.007), transplantation from an alternative donor (OR = 6.630, P = 0.007) and donor FokI FF (OR = 4.473, P = 0.025) significantly contributed to the development of grades II-IV aGVHD, while recipient ApaI aa (OR = 3.233, P = 0.069), recipient FokI FF (OR = 2.558, P = 0.077) and female to male transplants (OR = 2.955, P = 0.099) were found to be less significant factors. In addition, the presence of ApaI aa genotype in the recipient was found to be associated with increased likelihood of death (P = 0.0228). The present study contributes to the studies demonstrating a role of VDR polymorphisms in HSCT outcome. In addition to previously described correlations of ApaI a allele and occurrence of severe grades III-IV aGVHD and (linked with ApaI aa) recipient TaqI TT genotype with aGVHD, the novel associations of recipient and donor FokI FF genotype and the increased aGVHD risk and recipient ApaI aa with survival were identified.     

Sirolimus and thrombotic microangiopathy after allogeneic hematopoietic stem cell transplantation.

Thrombotic microangiopathy (TMA) may occur after allogeneic hematopoietic stem cell transplantation (HSCT) and is related in part to calcineurin inhibitor toxicity. We observed a higher-than-expected rate of TMA when calcineurin inhibitors were combined with sirolimus. To determine the incidence of and risk factors for TMA after HSCT, we performed a retrospective cohort analysis of myeloablative allogeneic HSCT recipients between 1997 and 2003. TMA diagnosis required the simultaneous occurrence of (1) creatinine increase >2 mg/dL or >50% above baseline, (2) schistocytosis, (3) increased lactate dehydrogenase, and (4) no evidence of disseminated intravascular coagulopathy. A total of 111 sirolimus-exposed subjects were compared with 216 nonexposed subjects after HSCT. TMA occurred in 10.8% of the sirolimus group and 4.2% in the nonsirolimus group (odds ratio, 2.79; P=.03). Sirolimus exposure was associated with TMA earlier than in nonsirolimus patients (25 versus 58 days; P=.04). Only the use of sirolimus (exact odds ratio, 3.49; P=.02) and grade II to IV acute graft-versus-host disease (exact odds ratio, 6.60; P=.0002) were associated with TMA in regression analyses. Treatment of TMA varied among affected individuals. Renal recovery was complete in 92% of sirolimus-treated patients. Overall survival after TMA diagnosis was better for sirolimus subjects than for nonsirolimus subjects (58.3% versus 11.1%; P=.02). Sirolimus seems to potentiate the effects of calcineurin inhibitors on TMA after HSCT. TMA associated with sirolimus seems reversible and has a favorable prognosis when compared with TMA associated with calcineurin inhibitors alone. A careful monitoring strategy for TMA should be used with a sirolimus-containing graft-versus-host disease prophylaxis regimen.     

Chronic kidney disease after myeloablative allogeneic hematopoietic stem cell transplantation.

Because survival of recipients of allogeneic hematopoietic stem cell transplantation (HSCT) has improved, long-term complications become more important. We studied the incidence and risk factors of chronic kidney disease in these patients and evaluated associated posttransplant complications and mortality. We performed a retrospective cohort study of 266 adults who received myeloablative allogeneic HSCT and who survived for >6 months in an 11-year period at a Dutch university medical center. Primary outcome was the incidence of chronic kidney disease defined as a glomerular filtration rate (GFR) of <60 mL/min/1.73 m(2). Chronic kidney disease developed in 61 (23%) of 266 patients, with a cumulative incidence rate of 27% at 10 years. Severe kidney disease (GFR of <30 mL/min/1.73 m(2)) developed in 3% of patients. Only 6 patients developed the thrombotic microangiopathic syndrome SCT nephropathy, and 2 of them needed dialysis. Pretransplant risk factors for chronic kidney disease were lower GFR at day 0 (P < .0001, odds ratio [OR] 0.95 95% confidence interval [CI] 0.93-0.97), female gender, and higher age (P = .001 and P < .0001, respectively). The occurrence of hypertension after transplantation was associated with chronic kidney disease (P < .0001, OR 0.34 95% CI 0.18-0.62). Mortality was 39% after a mean follow-up of 5.1 years. There was no significant difference in survival between patients with and without chronic kidney disease. Chronic kidney disease is a common late complication of myeloablative allogeneic HSCT. Because of the natural decline in renal function with time there is a risk of developing end-stage renal disease in the future. SCT nephropathy seems to be a specific cause of chronic kidney disease that is typically associated with severe kidney disease.     

Preemptive cellular immunotherapy after T-cell-depleted allogeneic hematopoietic stem cell transplantation.

GVHD is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT). GVHD is due to donor lymphocytes that are cotransplanted with donor stem cells. These donor lymphocytes are primed by histocompatibility differences between donors and recipients and activated by a cytokine storm caused by the conditioning regimen. The most efficient method for prevention of GVHD consists of T-cell depletion (TCD) of the graft. However, TCD usually leads to an increased risk of leukemia relapse because of the loss of the graft-versus-leukemia (GVL) effect. Several groups have studied the feasibility of preemptive donor lymphocyte infusion (DLI) to lessen the impact of TCD on leukemia relapse. Preemptive DLI is given several weeks to months after the transplantation, ie, after the cytokine storm and after the patient has recovered from conditioning-regimen-related toxicities. After briefly discussing various techniques of TCD of the graft and the efficacy of DLI, this article reviews the first clinical studies evaluating a strategy of TCD of the graft followed by preemptive DLI.     

Strategies to accelerate immune recovery after allogeneic hematopoietic stem cell transplantation

The interplay existing between immune reconstitution and patient outcome has been extensively demonstrated in allogeneic hematopoietic stem cell transplantation. One of the leading causes of infection-related mortality is the slow recovery of T-cell immunity due to the conditioning regimen and/or age-related thymus damage, poor naïve T-cell output, and restricted T-cell receptor (TCR) repertoires. With the aim of improving posttransplantation immune reconstitution, several immunotherapy approaches have been explored. Donor leukocyte infusions are widely used to accelerate immune recovery, but they carry the risk of provoking graft-versus-host disease. This review will focus on sophisticated strategies of thymus function-recovery, adoptive infusion of donor-derived, allodepleted T cells, T-cell lines/clones specific for life-threatening pathogens, regulatory T cells, and of T cells transduced with suicide genes.     

Voriconazole and sirolimus coadministration after allogeneic hematopoietic stem cell transplantation.

Sirolimus is increasingly used in transplantation for prevention and treatment of graft-versus-host disease and organ rejection. Voriconazole is contraindicated when used concomitantly with sirolimus because of a substantial increase in sirolimus drug exposure with unadjusted dosing, but voriconazole is also considered the best initial treatment of invasive aspergillosis and other fungal infections. Patients who received voriconazole and sirolimus concomitantly were identified by a review of the medical records of all allogeneic hematopoietic stem cell recipients at our institution from September 1, 2002, to June 1, 2005. Data including baseline characteristics, indications for both drugs, and potential adverse effects were evaluated. Eleven patients received voriconazole and sirolimus concomitantly for a median of 33 days (range, 3-100 days). In 8 patients whose sirolimus dose was initially reduced by 90%, trough sirolimus levels were similar to those obtained before the administration of voriconazole; no obvious significant toxicity from either drug was observed during coadministration. Serious adverse events were observed in 2 patients in whom sirolimus dosing was not adjusted during voriconazole administration. Sirolimus and voriconazole may be safely coadministered if there is an empiric initial 90% sirolimus dose reduction combined with systematic monitoring of trough levels.     

Prediction and prevention of transplant-related mortality from pulmonary causes after total body irradiation and allogeneic stem cell transplantation.

Between July 1997 and August 2004, 146 consecutive patients with hematologic malignancies received a T cell-depleted peripheral blood stem cell transplant from an HLA-identical sibling by using total body irradiation (TBI) and cyclophosphamide conditioning regimens. Eighty-five patients received 13.6 Gy of TBI with no lung shielding, and 61 received lung shielding (total lung dose, 6-12 Gy). Ninety-four patients (65.5%) had standard-risk disease; the remainder had more advanced disease or unfavorable diagnoses. Of the 21 transplant-related deaths, 14 were from pulmonary causes (10 idiopathic pulmonary syndromes and 4 from infection) that occurred at a median of 90 days (range, 23-238 days) after transplantation. Independent risk factors for pulmonary transplant-related mortality (PTRM) were pretransplantation diffusion capacity for carbon monoxide (relative risk, 5.7 for diffusion capacity for carbon monoxide <85%), smoking (relative risk, 5.0), and CD34 cell dose (relative risk, 9.4 for a CD34 dose of <5 x 10(6) cells per kilogram). Patients receiving lung shielding had significantly lower PTRM (3.3% versus 14.1%; P = .02) and better overall survival (70% +/- 6% versus 52% +/- 5%; P = .04), but lung shielding was not a significant independent factor for determining PTRM. These results suggest that pulmonary mortality after TBI-based preparative regimens is predictable and that higher CD34 cell doses can reduce the risk.     

Assessment of lineage-specific chimerism after allogeneic stem cell transplantation

IntroductionDonor lineage-specific chimerism of hematopoietic cells enables very precise monitoring of engraftment in selected cell lines after allogeneic stem cell transplantation (allo-SCT).Materials and methodsThe study group consisted of 12 acute leukemia patients who underwent allo-SCT in the Department of Hematology and Bone Marrow Transplantation in Katowice, Poland. Lineage-specific chimerism was assessed in B cells (CD19+ CD38−/+), plasma cells (CD19+ CD38++), T cells (CD3+ or CD7+ CD56−), monocytes (CD14+), and immature progenitor cells deriving from myeloid line (CD34+CD19). We also assessed erythrocyte chimerism by flow cytometry.ResultsAll patients engrafted. 8 out of 10 patients presented normal donor hematopoiesis. Lineage specific chimerism in these patients corresponded with chimerism analysis in unsorted material and with undetectable minimal residual disease (MRD). Relapse of the underlying disease was diagnosed in 2 patients. In both cases loss of donor chimerism occurred in leukemia specific cell line and corresponded with detectable MRD. One patient with secondary graft failure presented decreasing lineage specific chimerism in all subpopulations, with negative MRD status. In 10 patients normal hematopoiesis of donor-origin was assessed by flow cytometry. In one case no donor-derived erythrocytes were detected and the diagnosis of pure red cell aplasia was set.ConclusionsLineage specific chimerism as a method of high sensitivity and specificity allows for precise assessment of donor chimerism especially in clinically ambiguous situations. Assessment of erythrocyte chimerism by flow cytometry is a reliable method of monitoring erythroblastic line engraftment. Presented results are preliminary and the study is being continued.     

New directions in the genomics of allogeneic hematopoietic stem cell transplantation.

Despite optimal supportive care and high-resolution HLA matching, complications such as GVHD and infection remain major barriers to the success of allogeneic HCT (allo-HCT). This has led to growing interest in the non-HLA genetic determinants of complications after allo-HCT. Most studies have examined genetic predictors of GVHD, relapse, and mortality and have focused on 3 main areas: minor histocompatibility antigen (miHAs), inflammatory mediators of GVHD, and more recently NK cell-mediated allorecognition. The genetic basis of other outcomes such as infection and drug toxicity are less well studied but are being actively investigated. High-throughput methodologies such as single nucleotide polymorphism arrays are enabling the study of hundreds of thousands of genetic markers throughout the genome and the interrogation of novel genetic variants such as copy number variations. These data offer the opportunity to better predict those at risk of complications and to identify novel targets for therapeutic intervention. This review examines the current data regarding the non-HLA genomics of allo-HCT and appraises the promises and pitfalls for integration of this new genetic information into clinical transplantation practice.