Brandon M. Triplett

High success rate of hematopoietic cell transplantation regardless of donor source in children with very high-risk leukemia

We evaluated 190 children with very high-risk leukemia, who underwent allogeneic hematopoietic cell transplantation in 2 sequential treatment eras, to determine whether those treated with contemporary protocols had a high risk of relapse or toxic death, and whether non-HLA-identical transplantations yielded poor outcomes. For the recent cohorts, the 5-year overall survival rates were 65% for the 37 patients with acute lymphoblastic leukemia and 74% for the 46 with acute myeloid leukemia; these rates compared favorably with those of earlier cohorts (28%, n = 57; and 34%, n = 50, respectively). Improvement in the recent cohorts was observed regardless of donor type (sibling, 70% vs 24%; unrelated, 61% vs 37%; and haploidentical, 88% vs 19%), attributable to less infection (hazard ratio [HR] = 0.12; P = .005), regimen-related toxicity (HR = 0.25; P = .002), and leukemia-related death (HR = 0.40; P = .01). Survival probability was dependent on leukemia status (first remission vs more advanced disease; HR = 0.63; P = .03) or minimal residual disease (positive vs negative; HR = 2.10; P = .01) at the time of transplantation. We concluded that transplantation has improved over time and should be considered for all children with very high-risk leukemia, regardless of matched donor availability.

Detectable minimal residual disease before hematopoietic cell transplantation is prognostic but does not preclude cure for children with very-high-risk leukemia.

In patients with acute leukemia, detection of minimal residual disease (MRD) before allogeneic hematopoietic cell transplantation (HCT) correlates with risk of relapse. However, the level of MRD that is most likely to preclude cure by HCT is unclear, and the benefit of further chemotherapy to reduce MRD before HCT is unknown. In 122 children with very-high-risk acute lymphoblastic leukemia (ALL; n = 64) or acute myeloid leukemia (AML, n = 58), higher MRD levels at the time of HCT predicted a poorer survival after HCT (P = .0019); MRD was an independent prognostic factor in a multivariate analysis (P = .0035). However, the increase in risk of death associated with a similar increment of MRD was greater in ALL than in AML, suggesting that a pretransplantation reduction of leukemia burden would have a higher impact in ALL. At any given MRD level, survival rates were higher for patients treated in recent protocols: the 5-year overall survival for patients with ALL was 49% if MRD was detectable and 88% if it was not and the corresponding rates for patients with AML were 67% and 80%, respectively. Although MRD before HCT is a strong prognostic factor, its impact has diminished and should not be regarded as a contraindication for HCT.

Haploidentical stem cell transplantation augmented by CD45RA negative lymphocytes provides rapid engraftment and excellent tolerability

Haploidentical donors are being increasingly used for allogeneic hematopoietic cell transplantation (HCT). However, the requisite T‐cell depletion results in a profound and often long‐lasting immunocompromised state, and donor lymphocyte infusions bring a risk of graft‐versus‐host disease (GVHD). Naïve T‐cells are believed to be among the most alloreactive T‐cell subset and can be identified by CD45RA expression. Allogeneic HCT using CD45RA depletion has not been previously described for haploidentical donors.

Human memory CD8 T cell effector potential is epigenetically preserved during in vivo homeostasis

Antigen-independent homeostasis of memory CD8 T cells is vital for sustaining long-lived T cell–mediated immunity. In this study, we report that maintenance of human memory CD8 T cell effector potential during in vitro and in vivo homeostatic proliferation is coupled to preservation of acquired DNA methylation programs. Whole-genome bisulfite sequencing of primary human naive, short-lived effector memory (TEM), and longer-lived central memory (TCM) and stem cell memory (TSCM) CD8 T cells identified effector molecules with demethylated promoters and poised for expression. Effector-loci demethylation was heritably preserved during IL-7– and IL-15–mediated in vitro cell proliferation. Conversely, cytokine-driven proliferation of TCM and TSCM memory cells resulted in phenotypic conversion into TEM cells and was coupled to increased methylation of the CCR7 and Tcf7 loci. Furthermore, haploidentical donor memory CD8 T cells undergoing in vivo proliferation in lymphodepleted recipients also maintained their effector-associated demethylated status but acquired TEM-associated programs. These data demonstrate that effector-associated epigenetic programs are preserved during cytokine-driven subset interconversion of human memory CD8 T cells.

Earlier defibrotide initiation post-diagnosis of veno-occlusive disease/sinusoidal obstruction syndrome improves Day +100 survival following haematopoietic stem cell transplantation

Hepatic veno‐occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a progressive, potentially fatal complication of conditioning for haematopoietic stem cell transplant (HSCT). The VOD/SOS pathophysiological cascade involves endothelial‐cell activation and damage, and a prothrombotic‐hypofibrinolytic state. Severe VOD/SOS (typically characterized by multi‐organ dysfunction) may be associated with >80% mortality. Defibrotide is approved for treating severe hepatic VOD/SOS post‐HSCT in the European Union, and for hepatic VOD/SOS with renal or pulmonary dysfunction post‐HSCT in the United States. Previously, defibrotide (25 mg/kg/day in 4 divided doses for a recommended ≥21 days) was available through an expanded‐access treatment protocol for patients with VOD/SOS. Data from this study were examined post‐hoc to determine if the timing of defibrotide initiation post‐VOD/SOS diagnosis affected Day +100 survival post‐HSCT. Among 573 patients, defibrotide was started on the day of VOD/SOS diagnosis in approximately 30%, and within 7 days in >90%. The relationship between Day +100 survival and treatment initiation before/after specific days post‐diagnosis showed superior survival when treatment was initiated closer to VOD/SOS diagnosis with a statistically significant trend over time for better outcomes with earlier treatment initiation (P < 0·001). These results suggest that initiation of defibrotide should not be delayed after diagnosis of VOD/SOS.

Defibrotide for Patients with Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome: Interim Results from a Treatment IND Study

Hepatic veno-occlusive disease, or sinusoidal obstruction syndrome (VOD/SOS), is a serious and potentially fatal complication of conditioning for hematopoietic stem cell transplantation (HSCT) or of chemotherapy regimens alone. Defibrotide is a complex mixture of single-stranded polydeoxyribonucleotides that is approved in the United States for treating hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT and in the European Union, Israel, and South Korea for treating severe hepatic VOD/SOS post-HSCT. Defibrotide was previously available in the United States as an investigational drug through a treatment protocol (treatment IND) study. Interim results of that large, treatment IND study of patients with VOD/SOS and with or without multiorgan dysfunction (MOD; also known as multiorgan failure) are presented here. Defibrotide was administered i.v. at 6.25 mg/kg every 6 hours (25 mg/kg/day), with a recommended treatment duration of at least 21 days. Enrolled patients (n = 681) were diagnosed with VOD/SOS based on Baltimore or modified Seattle criteria or liver biopsy analysis. Among the 573 HSCT recipients, 288 (50.3%; 95% confidence interval [CI], 46.2% to 54.4%) were alive at day +100 post-HSCT. Day +100 survival for the pediatric (≤16 years) and adult (>16 years) subgroups was 54.5% (95% CI, 49.1% to 60.0%; n = 174 of 319) and 44.9% (95% CI, 38.8% to 51.0%; n = 114 of 254), respectively. In the MOD subgroup, 159 of 351 patients (45.3%; 95% CI, 40.1% to 50.5%) of patients were alive at day +100 post-HSCT. Treatment with defibrotide was generally well tolerated, and drug-related toxicities were consistent with previous studies. Adverse events were reported in 69.6% of safety-evaluable patients (399 of 573). Other than VOD/SOS and associated MOD symptoms, the most commonly reported treatment-emergent adverse event was hypotension (13.8%). Day +100 survival results observed in this trial were consistent with results seen in previous trials of defibrotide for VOD/SOS in adult and pediatric patients. These data support the potential benefit of defibrotide in treating a VOD/SOS patient population that includes those with and without MOD.

Natural killer cell therapy in children with relapsed leukemia.

Novel therapies are needed for children with relapsed or refractory leukemia. We therefore tested the safety and feasibility of haploidentical natural killer cell therapy in this patient population.

Successful Allogeneic Hematopoietic Cell Engraftment after a Minimal Conditioning Regimen in Children with Relapsed or Refractory Solid Tumors

Children with relapsed or refractory solid tumors face dismal prognoses, and novel therapies are desperately needed. Allogeneic hematopoietic cell transplantation (HCT) offers potential for cell-based therapy, but the toxicity of myeloablation limits this approach in heavily pretreated patients. We sought to determine the feasibility of HCT in a cohort of 24 children with incurable solid tumors using human leukocyte antigen-matched sibling or unrelated donors and a minimal conditioning regimen. Before stem cell infusion, all patients received 3 daily doses of 30 mg/m(2) fludarabine followed by 2 Gy of total body irradiation. Hematopoietic cell recovery was rapid and reliable. Median time to neutrophil engraftment was 13.5 days for sibling donors and 12 days for unrelated donors. Donor lymphocyte infusions were used safely in 4 patients, all of whom had either improved chimerism or apparent tumor response. Graft-versus-host disease was comparable across donor sources and did not affect survival. Relapse remains a substantial barrier, although objective graft-versus-tumor effect was observed in several patients. Four patients with detectable disease before HCT achieved a complete response for at least 30 days after HCT, and two remain long-term survivors. Three patients were in complete response before HCT and remained in remission for 3, 6, and 74 months after HCT. Early disease response was associated with improved survival. Allogeneic HCT using this conditioning regimen offers a potential platform for novel immunotherapies.

Effects of conditioning regimens and T cell depletion in hematopoietic cell transplantation for primary immune deficiency.

This study analyzes the hematopoietic cell transplantation experience in patients with immune deficiency at a single institution. The objective is to comprehensively evaluate the short-term and long-term outcomes with various preparative regimens, donor grafts, and ex vivo manipulations to identify transplantation approaches that most likely favor early donor immune competency without generating excessive toxicity. Clinical outcomes were evaluated in 52 consecutive patients with immune deficiencies. Thirty-seven of the 52 patients (71%) survived with attenuation of their underlying disease. The use of a melphalan-based reduced-intensity conditioning preparative regimen and immunomagnetic CD3(+) T cell depletion techniques (when T cell depletion was indicated) were associated with improved event-free survival. Survivors who received a preparative regimen other than a melphalan-based reduced-intensity regimen suffered from therapy-related morbidities or chronic/recurrent infections. Our findings indicate that melphalan-based reduced-intensity conditioning regimens and immunomagnetic CD3(+) T cell depletion limit therapy-related toxicity, and demonstrate promising results for the early establishment of donor immune competency.

Favorable preliminary results using TLI/ATG‐based immunomodulatory conditioning for matched unrelated donor allogeneic hematopoietic stem cell transplantation in pediatric severe aplastic anemia

Pillai A, Hartford C, Wang C, Pei D, Yang J, Srinivasan A, Triplett B, Dallas M, Leung W. Favorable preliminary results using TLI/ATG‐based immunomodulatory conditioning for matched unrelated donor allogeneic hematopoietic stem cell transplantation in pediatric severe aplastic anemia.
Pediatr Transplantation 2011: 15: 628–634.