The role of allogeneic hematopoietic cell transplantation for chronic lymphocytic leukemia: A review

Although the use of allogeneic hematopoietic cell transplantation (HCT) for chronic lymphocytic leukemia (CLL) has declined with the development of novel targeted agents, it continues to play an important role for eligible patients with high-risk or heavily pretreated CLL who lack other treatment options. CLL is susceptible to a potent graft-versus-leukemia (GVL) effect which produces long-lasting remissions in 30-50% of transplanted patients. While allogeneic HCT is associated with significant risks of graft-versus-host disease (GVHD), infection, and non-relapse mortality (NRM), improvements in patient and donor selection, reduced intensity conditioning (RIC), GVHD prophylaxis, and supportive care have rendered this an increasingly safe and effective procedure in the current era. In this review, we discuss recent advances in allogeneic HCT for CLL, with a focus on the optimal evidence-based strategies to maximize benefit and minimize toxicity of this potentially curative cellular therapy

Reconstitution of the immune system after hematopoietic stem cell transplantation in humans

Hematopoietic stem cell transplantation is associated with a severe immune deficiency. As a result, the patient is at high risk of infections. Innate immunity, including epithelial barriers, monocytes, granulocytes, and NK cells recovers within weeks after transplantation. By contrast, adaptive immunity recovers much slower. B- and T-cell counts normalize during the first months after transplantation, but in particular, T-cell immunity may remain impaired for years. During the last decade, much of the underlying mechanisms have been identified. These insights may provide new therapies to accelerate recover

Allergen-specific T cell quantity in blood is higher in allergic compared to nonallergic individuals

Article deposited according to agreement with BMC, December 6, 2010.YesFunding provided by the Open Access Authors Fund

Nasal Epithelial Cells of Donor Origin after Allogeneic Hematopoietic Cell Transplantation are Generated at a Faster Rate in the First 3 Months Compared with Later Posttransplantation

Detection of donor-type epithelial cells (ECs) after allogeneic hematopoietic cell transplantation (allo-HCT) using XY chromosome fluorescein in situ hybridization (FISH) has suggested that hematopoietic stem cells carry a degree of developmental plasticity. This is controversial, given artifacts of XY-based detection and the possibility of hematopoietic–nonhematopoietic cell fusion. Moreover, the kinetics of donor-type ECs (quantity at different time points after transplant) is unknown. Here, we document unequivocally the existence of donor-type ECs using a method obviating the artifacts of XY-FISH and study their kinetics. Nasal scrapings and blood specimens were collected from 60 allo-HCT survivors between 7 days and 22 years posttransplantation. DNA extracted from laser-captured nasal ECs (ie, CK+CD45− cells) and blood leukocytes was polymerase chain reaction–amplified for a panel of 16 short tandem repeat markers. The median percentage of donor-type ECs (among nasal ECs) was 0% on day 7 posttransplantation, 2.8% at 3 months posttransplantation, and 8.5% at 12-22 years posttransplantation. Cell fusion was ruled out by FISH analysis for two autosomes. We conclude that donor-type nasal ECs exist after HCT, and that their percentage rises rapidly in the first 3 months posttransplantation and more slowly thereafter

Cytomegalovirus Viral Load and Virus-Specific Immune Reconstitution after Peripheral Blood Stem Cell versus Bone Marrow Transplantation

Peripheral blood stem cell (PBSC) products contain more T cells and monocytes when compared with bone marrow (BM), leading to fewer bacterial and fungal infections. Cytomegelovirus (CMV) viral load and disease as well as CMV-specific immune reconstitution were compared in patients enrolled in a randomized trial comparing PSBC and BM transplantation. There was a higher rate of CMV infection and disease during the first 100 days after transplantation among PBSC recipients (any antigenemia/DNAemia: PBSC, 63% vs BM, 42%, P = .04; CMV disease: PBSC, 17% vs BM, 4%, P = .03). By 2 years, CMV disease rates were similar. The early increase in CMV events correlated temporarily with lower CMV-specific CD4+ T helper and CD8+ cytotoxic T lymphocyte function at 30 days after transplantation in PBSC recipients. By 3 months after transplantation and thereafter, CMV-specific immune responses were similar between BM and PBSC recipients. In conclusion, higher CMV infection and disease rates occurred in PBSC transplant recipients early after transplantation. These differences may be because of a transient delay in CMV-specific immune reconstitution following PBSC transplantation

Establishing a Target Exposure for Once-Daily Intravenous Busulfan Given with Fludarabine and Thymoglobulin before Allogeneic Transplantation

AbstractA combination of fludarabine (Flu) and daily i.v. busulfan (Bu) is well tolerated and effective in patients undergoing allogeneic hematopoietic stem cell transplantation. Although there is some evidence that Bu exposures exceeding 6000 μM/min may lead to excessive toxicity, there is little information on the effect of exposures below this level on outcomes. We studied Bu exposure, as measured by area under the concentration-time curve (AUC), in 158 patients with various hematologic malignancies in an attempt to identify an optimal range for targeted therapy. The preparative chemotherapy regimen comprised Flu 50 mg/m2 on days -6 to -2 and i.v. Bu 3.2 mg/kg on days -5 to -2 inclusive. Graft-versus-host disease (GVHD) prophylaxis included methotrexate, cyclosporin A, and antithymocyte globulin. Patients with Bu exposures below the median AUC of 4439 μM/min were at increased risk for acute GVHD grade II-IV (hazard ratio [HR], 2.30; 95% confidence interval [CI], 1.19 to 4.49; P = .014). Those in the highest and lowest Bu exposure quartiles (daily AUC <3814 μM/min and >4993 μM/min) had an increased risk of nonrelapse mortality (subdistribution HR, 3.32; 95% CI, 1.46 to 7.54; P = .004), as well as worse disease-free survival (HR, 1.81; 95% CI, 1.09 to 2.99; P = .021) and overall survival (HR, 1.94; 95% CI, 1.12 to 3.37; P = .018). Bu exposures between 4440 and 4993 μM/min were accompanied by the lowest risk of both nonrelapse mortality and acute GVHD

Improved survival after acute graft-

A cute graft- versus -host disease remains a major threat to a successful outcome after allogeneic hematopoietic cell transplantation. While improvements in treatment and supportive care have occurred, it is unknown whether these advances have resulted in improved outcome specifically among those diagnosed with acute graft- versus -host disease. We examined outcome following diagnosis of grade II-IV acute graft- versus -host disease according to time period, and explored effects according to original graft- versus -host disease prophylaxis regimen and maximum overall grade of acute graft- versus -host disease. Between 1999 and 2012, 2,905 patients with acute myeloid leukemia (56%), acute lymphoblastic leukemia (30%) or myelodysplastic syndromes (14%) received a sibling (24%) or unrelated donor (76%) blood (66%) or marrow (34%) transplant and developed grade II-IV acute graft- versus -host disease (n=497 for 1999-2001, n=962 for 2002-2005, n=1,446 for 2006-2010). The median (range) follow-up was 144 (4-174), 97 (4-147) and 60 (8-99) months for 1999-2001, 2002-2005, and 2006-2010, respectively. Among the cohort with grade II-IV acute graft- versus -host disease, there was a decrease in the proportion of grade III-IV disease over time with 56%, 47%, and 37% for 1999-2001, 2002-2005, and 2006-2012, respectively ( P <0.001). Considering the total study population, univariate analysis demonstrated significant improvements in overall survival and treatment-related mortality over time, and deaths from organ failure and infection declined. On multivariate analysis, significant improvements in overall survival ( P =0.003) and treatment-related mortality ( P =0.008) were only noted among those originally treated with tacrolimus-based graft- versus -host disease prophylaxis, and these effects were most apparent among those with overall grade II acute graft- versus -host disease. In conclusion, survival has improved over time for tacrolimus-treated transplant recipients with acute graft- versus -host disease

Rabbit Anti-T Cell Globulin in Allogeneic Hematopoietic Cell Transplantation

Anti-T cell globulin (ATG) is polyclonal IgG from rabbits immunized with human thymocytes or a human T cell line. Prophylaxis using ATG infused with conditioning for adult marrow or blood stem cell transplantation reduces both acute and chronic graft-versus-host disease (GVHD). However, ATG is not or minimally efficacious in steroid refractory GVHD treatment. Regarding preemptive therapy, ATG is promising; however, further work is needed on establishing adequate biomarkers to be used as triggers for preemptive therapy before it can be used routinely. Relapse is not increased by ATG, except possibly in the setting of reduced-intensity conditioning. Infections are probably increased when using high but not low-dose ATG, except for Epstein-Barr virus-driven post-transplantation lymphoproliferative disorder, which may be increased even with low-dose ATG. Survival is not improved with ATG; however, survival free of immunosuppressive therapy is improved. Pharmacokinetics of ATG are highly variable, resulting in highly variable areas under the time-concentration curves. Optimized dosing of ATG might improve transplantation outcomes. In conclusion, ATG reduces GVHD and, thus, may improve quality of life, without compromising survival