Vu H. Nguyen

Reduced-intensity conditioning with combined haploidentical and cord blood transplantation results in rapid engraftment, low GVHD, and durable remissions.

We conducted a 45 patient prospective study of reduced-intensity conditioning (RIC) and transplantation of unrelated umbilical cord blood (UCB) and CD34(+) stem cells from a haploidentical family member. Median age was 50 years; weight was 80 kg. Fifty-eight percent had active disease. Neutrophil engraftment occurred at 11 days (interquartile range [IQR], 9-15) and platelet engraftment at 19 days (IQR, 15-33). In the majority of patients, early haploidentical engraftment was replaced by durable engraftment of UCB by 100 days, with regular persistence of minor host and/or haplo-hematopoiesis. Percentage of haplochimerism at day 100 correlated with the haplo-CD34 dose (P = .003). Cumulative incidence of acute GVHD (aGVHD) was 25% and chronic GVHD (cGVHD) was 5%. Actuarial survival at 1 year was 55%, progression-free survival (PFS) was 42%, nonrelapse mortality (NRM) was 28%, and relapse was 30%. RIC and haplo-cord transplantation results in fast engraftment of neutrophils and platelets, low incidences of aGVHD and cGVHD, low frequency of delayed opportunistic infections, reduced transfusion requirements, shortened length of hospital stay, and promising long-term outcomes. UCB cell dose had no impact on time to hematopoietic recovery. Therefore, UCB selection can prioritize matching, and better matched donors can be identified rapidly for most patients. This study is registered at http://clinicaltrials.gov as NCI clinical trial no. NCT00943800.

Role of gut microbiota in graft-versus-host disease

Our understanding of graft-versus-host disease (GVHD) has mostly focused on the role of adaptive immunity in mediating host–recipient genetic disparity in the proinflammatory milieu. These experimental models rarely address the unique biology of GVHD whereby it targets mainly epithelial compartments of the intestine, skin, and liver. Recent discoveries of the role of the microbiota in health and disease have reinvigorated questions about how the innate immunity contributes to the pathogenesis of GVHD and perhaps explains its tissue tropism. In this review, we discuss findings indicating the potential role of pattern-recognition receptors of the innate immune system in mediating GVHD and present evidence that shows how the microbiota interact with the host to shape health and disease. These findings support a reevaluation of our current clinical practice and encourage further studies of the potential critical role of the gut microbiota in hematopoietic stem cell transplant which may lead to novel preventive and therapeutic targets against GVHD.

Phase I-II Study of Clofarabine-Melphalan-Alemtuzumab Conditioning for Allogeneic Hematopoietic Cell Transplantation

We conducted a phase I-II study of transplantation conditioning with clofarabine-melphalan-alemtuzumab for patients with advanced hematologic malignancies. Ten patients were accrued to the phase I portion, which utilized an accelerated titration design. No dose-limiting toxicity was observed, and clofarabine 40 mg/m(2) × 5, melphalan 140 mg/m(2) × 1, and alemtuzumab 20 mg × 5 was adopted for the phase II study, which accrued 72 patients. Median age was 54 years. There were 44 patients with acute myelogenous leukemia or myelodysplastic syndromes, 27 with non-Hodgkin lymphoma, and nine patients with other hematologic malignancies. The largest subgroup of 35 patients had American Society for Blood and Marrow Transplantation high-risk, active disease. All evaluable patients engrafted with a median time to neutrophil and platelet recovery of 10 and 18 days, respectively. The cumulative incidence of treatment-related mortality was 26% at 1 year. Cumulative incidence of relapse was 29% at 1 year. Overall survival was 80% (95% confidence interval [CI], 71-89) at 100 days and 59% (95% CI, 47-71) at 1 year. Progression-free-survival was 45% (95% CI, 33-67) at 1 year. Rapid-onset renal failure was the main toxicity in the phase II study and more frequent in older patients and those with baseline decrease in glomerular filtration rate. Grade 3-5 renal toxicity was observed in 16 of 74 patients (21%) treated at the phase II doses. Clofarabine-melphalan-alemtuzumab conditioning yields promising response and duration of response, but renal toxicity poses a considerable risk particularly in older patients.

Immune reconstitution after combined haploidentical and umbilical cord blood transplant

Abstract Umbilical cord blood (UCB) stem cells are frequently employed for allogeneic stem cell transplant, but delayed myeloid and lymphoid immune reconstitution leads to increased risk of infections. We recently reported the clinical results of 45 patients enrolled on a pilot study combining UCB with a human leukocyte antigen (HLA)-haploidentical donor with reduced-intensity conditioning who showed rapid neutrophil and platelet recovery. We report here preliminary immune reconstitution data of these patients. Patients were assessed for lymphocyte subsets, T-cell diversity, Cylex ImmuKnow assay and serological response to pneumococcal vaccination. Natural killer (NK)-cell and B-cell reconstitution were rapid at 1 month and 3 months, respectively. T-cell recovery was delayed, with a gradual increase in the number of T-cells starting around 6 months post-transplant, and was characterized by a diverse polyclonal T-cell repertoire. Overall, immune reconstitution after haplo-cord transplant is similar to that seen after cord blood transplant, despite infusion of much lower cord blood cell dose.

Influence of related donor age on outcomes after peripheral blood stem cell transplantation

BACKGROUND AIMS The rising use of allogeneic transplantation in older recipients necessitates considering older related donors. The effect of related donor age for peripheral blood stem cell allografts (PBSC) on graft maintenance and outcomes, independent of CD34(+)cell dose, has not been well-characterized. METHODS HLA-related donors (98% siblings) underwent a uniform filgrastim-based mobilization regimen aiming to collect and infuse 5 × 10(6) CD34(+) cells/recipient kg. Donor and recipient age were modeled in multiple ways to account for the correlation, and outcomes reported by decade of donor age. RESULTS The median donor and recipient ages were 52 years and 54 years, respectively. The mean CD34(+) cell dose infused was 5.6 × 10(6) CD34(+)/kg and 75% of patients received a narrow range between 4.4 and 6.6 × 10(6) CD34(+) cells/kg. Neither better PBSC mobilization nor higher CD34(+) content of allografts was significantly associated with engraftment or transplant outcomes. After adjusting for recipient age and other prognostic factors, older donor age by decade conferred a lower risk of non-relapse mortality (NRM) [hazard ratio (HR) = 0.64, 95% confidence interval (CI) 0.45-0.91, P = 0.013] and borderline improvement in overall survival (OS) (HR = 0.76, 95% CI 0.58-0.99, P = 0.045) without altering progression-free survival (PFS) (HR = 0.85, 95% CI 0.66-1.07, P = 0.18). CONCLUSIONS Older donor age does not worsen outcome after matched related donor PBSC transplantation in patients receiving a narrow range CD34(+) cells. The relatively small sample size mandates that the finding of similar to improved outcomes for older related donor age must be confirmed in larger studies.

Associations between acute gastrointestinal GvHD and the baseline gut microbiota of allogeneic hematopoietic stem cell transplant recipients and donors

Growing evidence suggests that host-microbiota interactions influence GvHD risk following allogeneic hematopoietic stem cell transplant. However, little is known about the influence of the transplant recipient’s pre-conditioning microbiota nor the influence of the transplant donor’s microbiota. Our study examines associations between acute gastrointestinal GvHD (agGvHD) and 16S rRNA fecal bacterial profiles in a prospective cohort of N=57 recipients before preparative conditioning, as well as N=22 of their paired HLA-matched sibling donors. On average, recipients had lower fecal bacterial diversity (P=0.0002) and different phylogenetic membership (UniFrac P=0.001) than the healthy transplant donors. Recipients with lower phylogenetic diversity had higher overall mortality rates (hazard ratio=0.37, P=0.008), but no statistically significant difference in agGvHD risk. In contrast, high bacterial donor diversity was associated with decreased agGvHD risk (odds ratio=0.12, P=0.038). Further investigation is warranted as to whether selection of hematopoietic stem cell transplant donors with high gut microbiota diversity and/or other specific compositional attributes may reduce agGvHD incidence, and by what mechanisms.

Balancing act for Treg immunotherapy

In this issue of Blood , Gaidot and colleagues demonstrate effective suppression of graft-versus-host disease (GVHD) by recipient-specific regulatory T cells without compromising immunity after hematopoietic stem cell transplantation (HCT).[1][1] Should these findings push the transplant community

Late relapse following allogeneic transplant for chronic lymphocytic leukemia: How good are graft versus leukemia effects?

Chronic lymphocytic leukemia (CLL) remains incurable with conventional therapies and is frequently a fatal disorder. For patients with relapsed or refractory CLL, the median survival remains less than 1 year [1]. Allogeneic hematopoietic cell transplantation (AHCT) leads to high complete response (CR) and has been reported to result in durable event-free survival [2,3]. But the follow-up of most clinical trials is short and updated studies report continued relapse following AHCT, thus challenging the conclusion that allogeneic transplantation can cure CLL [3]. In this issue of Leukemia & Lymphoma, Malhotra et al. report a cohort of patients with prolonged follow-up and find that relapse can occur up to 10 years following transplantation [4]. This observation raises further questions regarding the role of AHCT in patients with CLL, the identification of patient groups appropriate for AHCT, the definition of CR and cure following AHCT, and the biological underpinnings of late treatment failure. The toxicity of AHCT requires careful selection of patients. In practice, AHCT are offered to younger patients who have aggressive CLL and are considered ‘‘poor risk’’ [5]. These patients may include those with 17p deletion and/or fludarabine resistance. Other biological markers of aggressive disease include the presence of the unmutated IgH VH gene and high expression of ZAP-70 and CD38. To date, the impact of these biological characteristics on the outcome of transplantation has not been studied in a prospective fashion, and it is conceivable that different CLL subsets will have different long-term results. One study suggests that allogeneic transplant is particularly useful for those with unmutated VH genes [6]. The therapeutic potential of AHCT has been attributed mainly to the graft-versus-leukemia (GVL) effect. Evidence of this effect is shown in patients who were allografted with non-myeloablative conditioning and achieved durable minimal residual disease (MRD) negativity after the development of chronic graft-versus-host disease or after donor lymphocyte infusion (DLI) [7,8]. But the biology of the GVL effect is not fully understood. Kinetic studies of MRD demonstrate that the GVL effect may take up to two years to achieve CR. However, in most studies, CR is assessed at dþ100 and is defined by clinical and blood and marrow examination for clearance of clonal B-CLL cells, the latter by standard flow cytometry [9]. The current approach leads to several questions. First, does the current measure of CR exclude patients who achieve CR at a much later time point given the prolonged GVL effect? These latter patients may instead be defined prematurely as having achieved a PR or as treatment failures. Second, new techniques such as allelespecific oligonucleotide PCR and 4-color flow cytometry (MRD flow) have led to determinations that many patients who achieved CR by the 1996 NCI-WG guidelines in fact had MRD [9]. Could this MRD partially explain the steady and late relapses observed in studies with long-term follow-up, such as reported by Malhotra et al.? Thus, would re-defining CR by MRD negativity over a longer period provide a more accurate assessment of response to AHCT? A very recent study from the German CLL study group provides fascinating insights in this issue. Using a combination of PCR and sensitive flow cytometry, they find various response patterns to reduced intensity allogeneic stem cell transplantation: (a)