Justin T. Wahlstrom

Chimerism-based pre-emptive immunotherapy with fast withdrawal of immunosuppression and donor lymphocyte infusions after allogeneic stem cell transplantation for pediatric hematologic malignancies.

The presence of increasing host chimerism or persistent mixed chimerism (MC) after hematopoietic stem cell transplantation for leukemia in children is a predictor of relapse. To reduce the risk of relapse, we prospectively studied post-transplantation chimerism-based immunotherapy (IT) using fast withdrawal of immunosuppression (FWI) and donor lymphocyte infusions (DLI) in children with early post-transplantation MC. Forty-three children with hematologic malignancies at 2 institutions were enrolled prospectively in this study from 2009 until 2012 and were followed for a mean of 42 (SD, 10) months. Twelve patients (28%) were assigned to the observation arm based on the presence of graft-versus-host disease (GVHD) or full donor chimerism (FDC), and 5 (12%) sustained early events and could not undergo intervention. Twenty-six (60%) patients with MC were assigned to IT with FWI, which started at a median of 49 days (range, 35 to 85 days) after transplantation. Fourteen patients proceeded to DLI after FWI. Toxicities of treatment included GVHD, which developed in 19% of patients undergoing intervention, with 1 of 26 (4%) dying from GVHD and 1 (4%) still requiring therapy for chronic GVHD 21 months after DLI. Patients with MC undergoing IT had similar 2-year event-free survival (EFS) (73%; 95% confidence interval (CI), 55% to 91%) compared with patients who achieved FDC spontaneously (83%; 95% CI, 62% to 100%); however, because 50% of all relapses in the IT occurred later than 2 years after transplantation, the EFS declined to 55% (95% CI, 34% to 76%) at 42 (SD, 11) months. There were no late relapses in the observation group. EFS in the entire cohort was 58% (95% CI, 42% to 73%) at 42 (SD, 11) months after transplantation. Evidence of disease before transplantation remained a significant predictor of relapse, whereas development of chronic GVHD was protective against relapse.

Hematopoietic Stem Cell Transplantation for Severe Combined Immunodeficiency

Hematopoietic stem cell transplantation is an effective approach for the treatment of severe combined immunodeficiency (SCID). However, SCID is not a homogeneous disease, and the treatment required for successful transplantation varies significantly between SCID subtypes and the degree of HLA mismatch between the best available donor and the patient. Recent studies are beginning to more clearly define this heterogeneity and how outcomes may vary. With a more detailed understanding of SCID, new approaches can be developed to maximize immune reconstitution, while minimizing acute and long-term toxicities associated with chemotherapy conditioning.

Transplacental maternal engraftment and posttransplantation graft-versus-host disease in children with severe combined immunodeficiency

Background: Graft‐versus‐host disease (GVHD) is a complication of allogeneic hematopoietic stem cell transplantation (HSCT). Transplacental maternal engraftment (TME), the presence of maternal T cells in peripheral blood before transplantation, is detectable in a significant proportion of patients with severe combined immunodeficiency (SCID). Although the presence of TME is associated with a decreased risk of rejecting a maternal graft, it is unknown whether TME plays a role in development of GVHD after HSCT. Objective: The purpose of this study was to determine whether the presence of pretransplantation TME is associated with posttransplantation GVHD in patients with SCID. Methods: This was an institutional retrospective review of 74 patients with SCID undergoing transplantation between 1988 and 2014. The incidence of acute graft‐versus‐host disease (aGVHD) was compared in patients with versus those without TME. Confounding variables, such as donor type and conditioning regimen, were included in a multivariate regression model. Results: TME was identified in 35 of 74 children. Post‐HSCT aGVHD developed with an incidence of 57.1% versus 17.9% in those without TME (P < .001). In univariate analysis donor type (mother) and GVHD prophylaxis (T‐cell depletion) were also significant predictors of aGVHD. In multivariate analysis TME and chemotherapy conditioning were independent risk factors for the development of aGVHD (relative risk, 2.75, P = .006 and relative risk, 1.42, P = .02, respectively). Conclusion: TME independently predicts the development of posttransplantation aGVHD, even when controlling for donor type and conditioning used. The presence of TME should be considered when assessing the risk of aGVHD in patients with SCID and designing the approach for GVHD prophylaxis.

Safety of pre-emptive donor lymphocyte infusions (DLI) based on mixed chimerism (MC) in peripheral blood or bone marrow subsets in children undergoing hematopoietic stem cell transplant (HSCT) for hematologic malignancies

Safety of pre-emptive donor lymphocyte infusions (DLI) based on mixed chimerism (MC) in peripheral blood or bone marrow subsets in children undergoing hematopoietic stem cell transplant (HSCT) for hematologic malignancies

Neurologic event–free survival demonstrates a benefit for SCID patients diagnosed by newborn screening

TO THE EDITOR: Severe combined immunodeficiency (SCID) may be diagnosed via newborn screening (NBS) by measuring T-cell receptor excision circles.[1][1],[2][2] The incidence of SCID has risen, and this is rise attributed to the identification of patients who would have previously died of infections

Pharmacokinetics and Model-Based Dosing to Optimize Fludarabine Therapy in Pediatric Hematopoietic Cell Transplant Recipients

A prospective multicenter study was conducted to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of fludarabine plasma (f-ara-a) and intracellular triphosphate (f-ara-ATP) in children undergoing hematopoietic cell transplantation (HCT) and receiving fludarabine with conditioning. Plasma and peripheral blood mononuclear cells (PBMCs) were collected over the course of therapy for quantitation of f-ara-a and f-ara-ATP. Nonlinear mixed-effects modeling was used to develop the PK model, including identification of covariates impacting drug disposition. Data from a total of 133 children (median age, 5 years; range, .2 to 17.9) undergoing HCT for a variety of malignant and nonmalignant disorders were available for PK-PD modeling. The implementation of allometric scaling of PK parameters alone was insufficient to describe drug clearance, particularly in very young children. Renal impairment was predicted to increase drug exposure across all ages. The rate of f-ara-a entry into PBMCs (expressed in pmoles per million cells) decreased over the course of therapy, resulting in 78% lower f-ara-ATP after the fourth dose (1.7 pmoles/million cells [range, .2 to 7.2]) compared with first dose (7.9 pmoles/million cells [range, .7 to 18.2]). The overall incidence of treatment-related mortality (TRM) was low at 3% and 8% at days 60 and 360, respectively, and no association with f-ara-a exposure and TRM was found. In the setting of malignancy, disease-free survival was highest at 1 year after HCT in subjects achieving a systemic f-ara-a cumulative area under the curve (cAUC) greater than 15 mg*hour/L compared to patients with a cAUC less than 15 mg*hour/L (82.6% versus 52.8% P = .04). These results suggest that individualized model-based dosing of fludarabine in infants and young children may reduce morbidity and mortality through improved rates of disease-free survival and limiting drug-related toxicity. ClinicalTrials.gov Identifier: NCT01316549.

Severe, persistent, and fatal T-cell immunodeficiency following therapy for infantile leukemia

We describe five cases of children who completed chemotherapy for infantile acute lymphoblastic leukemia (ALL) and soon after were diagnosed with severe T‐cell, non‐HIV immunodeficiency, with varying B‐cell and NK‐cell depletion. There was near absence of CD3+, CD4+, and CD8+ cells. All patients developed multiple, primarily opportunistic infections. Unfortunately, four patients died, although one was successfully treated by hematopoietic stem cell transplantation. These immunodeficiencies appeared to be secondary to intensive infant ALL chemotherapy. Our report highlights the importance of the early consideration of this life‐threatening immune complication in patients who received chemotherapy for infantile ALL.

Early mixed chimerism-based preemptive immunotherapy in children undergoing allogeneic hematopoietic stem cell transplantation for acute leukemia: Horn et al.

This retrospective analysis comprises 10‐year experience with early posttransplant mixed chimerism‐based preemptive intervention. Out of 104 patients, 51 received preemptive immunotherapy. Their outcomes were similar to patients achieving full donor chimerism spontaneously. Among patients receiving intervention, 5‐year event‐free survival was identical in patients with and without pretransplant residual disease, respectively (68% [95% confidence interval (CI) 38–98%] vs. 69% [95% CI 54–85%] log–rank = 0.4). In patients who received preemptive immunotherapy, chimerism status and residual disease prior to transplant were no longer predictors of poor outcome; however, 41% of the patients with residual disease prior to transplant relapsed early and did not benefit from this strategy.

Unconditioned unrelated donor bone marrow transplantation for IL7Rα- and Artemis-deficient SCID

Unconditioned unrelated donor bone marrow transplantation for IL7Rα- and Artemis-deficient SCID

Evaluation of Pre–Hematopoietic Cell Transplantation (HCT) Brain MRI and Neurologic Complications of Pediatric Patients Undergoing HCT for Hematologic Malignancies

Adverse neurologic complications (NC) occur commonly in pediatric patients with hematologic malignancies both pre- and post–allogeneic hematopoietic cell transplant (HCT). Given this known risk, we previously obtained pre-HCT brain magnetic resonance imaging (MRI) to document baseline abnormalities but utility of this and findings are not well described. This study aimed to (a) determine the prevalence and risk factors for abnormal brain MRI and (b) determine prevalence and risk factors for development of new NC during and 2 years post-HCT. Retrospective chart review included 102 patients with hematologic malignancies who underwent allogeneic HCT between 2000 and 2009 at University of California San Francisco (UCSF) Children’s Hospital and included standard HCT data, brain MRI reports, and NC and symptoms pre- and post-HCT. Forty-three percent of patients had abnormal findings on pre-MRI, most commonly nonspecific white matter changes. Neurologic symptoms pre-HCT was the only significant risk factor for abnormal MRI. Eleven patients (11%) developed post-HCT NC. Non-Caucasian race was the only significant risk factor for new NC. Although abnormal pre-HCT brain MRI is common, these findings are not predictive of subsequent NC post-HCT. Therefore routine surveillance may not be informative for that purpose, particularly when general anesthesia is required, which can have detrimental neurocognitive effects. Etiology of NC in pediatric HCT is likely multifactorial and may include genetic and ethnic predispositions.