In this review we discuss recent outcomes of hematopoietic cell transplantation (HCT) for patients with severe combined immunodeficiency (SCID), including survival, T- and B-cell reconstitution, and late effects, particularly those related to genotype, use of conditioning regimen, and use of alternative donors. We identify the following issues that require additional data, which can be obtained through cooperative studies: outcomes of patients with SCID who did not receive conditioning before alternative donor HCT; outcomes of patients with SCID who did not receive graft-versus-host disease prophylaxis after T cell-replete HCT; late effects of HCT for patients with SCID, including neurocognitive outcomes, growth, and development; and their relationship to genotype and use of alkylating agents for conditioning. Careful follow-up of outcomes of all newborns receiving diagnoses based on newborn screening programs for SCID is essential because data are scarce on the effects of conditioning regimens in very young patients. A consensus on the definition of T- and B-cell recovery, criteria for additional "boosts," pharmacokinetic data of chemotherapy agents used in young children, and uniformity of the use of various chemotherapy agents are needed to compare results among institutions. Finally, development of new nontoxic conditioning regimens for HCT that can be safely used in very young children is required.

Atypical Teratoid/Rhabdoid tumors (AT/RT) of the central nervous system are rare but aggressive tumors of childhood. Median survival with surgery and standard chemotherapy is less than 12 months. In an attempt to improve outcome, patients were treated with aggressive surgical resection and multi-agent chemotherapy, followed by high dose chemotherapy with autologous stem cell rescue. Nine consecutive children (median age 21 months) were diagnosed with AT/RT at the University of California San Francisco Childrens Hospital from 1997 to 2007 and treated with this aggressive approach. Diagnosis was confirmed using molecular markers. There are two long-term survivors (78 and 98 months from diagnosis). One additional patient is alive with disease. Three patients died of disease during therapy. Three patients died of disease after therapy was complete. There were no toxic deaths. Two of nine patients treated for AT/RT at our institution with high dose chemotherapy and autologous bone marrow transplant are long-term survivors, suggesting that a subset of patients can be cured with this approach.

Atypical Teratoid/Rhabdoid tumors (AT/RT) of the central nervous system are rare but aggressive tumors of childhood. Median survival with surgery and standard chemotherapy is less than 12 months. In an attempt to improve outcome, patients were treated with aggressive surgical resection and multi-agent chemotherapy, followed by high dose chemotherapy with autologous stem cell rescue. Nine consecutive children (median age 21 months) were diagnosed with AT/RT at the University of California San Francisco Childrens Hospital from 1997 to 2007 and treated with this aggressive approach. Diagnosis was confirmed using molecular markers. There are two long-term survivors (78 and 98 months from diagnosis). One additional patient is alive with disease. Three patients died of disease during therapy. Three patients died of disease after therapy was complete. There were no toxic deaths. Two of nine patients treated for AT/RT at our institution with high dose chemotherapy and autologous bone marrow transplant are long-term survivors, suggesting that a subset of patients can be cured with this approach.

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.

For children receiving allogeneic hematopoietic stem cell transplants (HSCTs), the toxicity of the conditioning regimen and graft failure remain challenges. We previously reported that targeted i.v. busulfan, fludarabine, and rabbit anti-thymocyte globulin (rATG) decreased toxicity but had a graft failure rate of 21%. To improve the engraftment rate, we replaced ATG with alemtuzumab, a monoclonal Ab targeting CD52. Thirty-five children with malignant and nonmalignant diseases were enrolled in this phase II prospective study. Twelve children had HLA-matched related donors (MRDs), 16 had 10 of 10, and 7 had 9 of 10 HLA allele-matched unrelated donors (MUDs). Thirty-one of 34 evaluable patients (91%) achieved a durable engraftment. All 3 patients who rejected had a nonmalignant disease and received a MUD transplantation (2 mismatched at 1 antigen). Three patients died of a transplantation-related complication (9% ± 5.2%). Seven patients had disease relapse or progression, 2 of whom died. At a median follow-up of 35 months (range, 15-85 months), the event-free survival (EFS) was 61% ± 9.0% and the overall survival (OS) was 78% ± 7.5%. The median time to neutrophil recovery, B cell, and T cell reconstitution were 16 days, 3 months, and 6 months, respectively. At 1 year, the median donor chimerism in whole blood, CD3, CD14/15, and CD19 subsets were 97%, 87%, 100%, and 99%, respectively. Six patients (17% ± 6.6%) developed acute graft-versus-host disease (aGVHD), only 2 of which were >grade II. Two patients (8% ± 5.4%) progressed to chronic GVHD (cGVHD). These results suggest that replacement of rATG with alemtuzumab may improve engraftment as well as decrease cGVHD rates without resulting in delays in immune reconstitution.

For infants with SCID, the ideal conditioning regimen before allogeneic HCT would omit cytotoxic chemotherapy to minimize short- and long-term complications. We performed a prospective pilot trial with G-CSF plus plerixafor given to the host to mobilize HSC from their niches. We enrolled six patients who received CD34-selected haploidentical cells and one who received T-replete matched unrelated BM. All patients receiving G-CSF and plerixafor had generally poor CD34(+) cell and Lin(-) CD34(+) CD38(-) CD90(+) CD45RA(-) HSC mobilization, and developed donor T cells, but no donor myeloid or B-cell engraftment. Although well tolerated, G-CSF plus plerixafor alone failed to overcome physical barriers to donor engraftment.

For infants with SCID the ideal conditioning regimen before allogeneic HCT would omit cytotoxic chemotherapy to minimize short- and long-term complications. We performed a prospective pilot trial with alemtuzumab monotherapy to overcome NK-cell mediated immunologic barriers to engraftment. We enrolled four patients who received CD34-selected haploidentical cells, two of whom failed to engraft donor T cells. The two patients who engrafted had delayed T-cell reconstitution, despite rapid clearance of circulating alemtuzumab. Although well-tolerated, alemtuzumab failed to overcome immunologic barriers to donor engraftment. Furthermore, alemtuzumab may slow T-cell development in patients with SCID in the setting of a T-cell depleted graft.

Background

Population pharmacokinetic (PK) studies of busulfan in children have shown that individualized model-based algorithms provide improved targeted busulfan therapy when compared with conventional dose guidelines. The adoption of population PK models into routine clinical practice has been hampered by the tendency of pharmacologists to develop complex models too impractical for clinicians to use. The authors aimed to develop a population PK model for busulfan in children that can reliably achieve therapeutic exposure (concentration at steady state) and implement a simple model-based tool for the initial dosing of busulfan in children undergoing hematopoietic cell transplantation.

Patients and methods

Model development was conducted using retrospective data available in 90 pediatric and young adult patients who had undergone hematopoietic cell transplantation with busulfan conditioning. Busulfan drug levels and potential covariates influencing drug exposure were analyzed using the nonlinear mixed effects modeling software, NONMEM. The final population PK model was implemented into a clinician-friendly Microsoft Excel-based tool and used to recommend initial doses of busulfan in a group of 21 pediatric patients prospectively dosed based on the population PK model.

Results

Modeling of busulfan time-concentration data indicates that busulfan clearance displays nonlinearity in children, decreasing up to approximately 20% between the concentrations of 250-2000 ng/mL. Important patient-specific covariates found to significantly impact busulfan clearance were actual body weight and age. The percentage of individuals achieving a therapeutic concentration at steady state was significantly higher in subjects receiving initial doses based on the population PK model (81%) than in historical controls dosed on conventional guidelines (52%) (P = 0.02).

Conclusions

When compared with the conventional dosing guidelines, the model-based algorithm demonstrates significant improvement for providing targeted busulfan therapy in children and young adults.

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.

Background. Pediatric hematopoietic cell transplant (HCT) is a lifesaving treatment that often results in physical and psychological discomfort. An acupressure-massage intervention may improve symptom management in this setting. Methods. This randomized controlled pilot trial compared a combined massage-acupressure intervention to usual care. Children were offered three practitioner-provided sessions per week throughout hospitalization. Parents were trained to provide additional acupressure as needed. Symptoms were assessed using nurses' reports and two questionnaires, the behavioral affective and somatic experiences scale and the Peds quality of life cancer module. Results. We enrolled 23 children, ages 5 to 18. Children receiving the intervention reported fewer days of mucositis (Hedges' g effect size ES = 0.63), lower overall symptom burden (ES = 0.26), feeling less tired and run-down (ES = 0.86), having fewer moderate/severe symptoms of pain, nausea, and fatigue (ES = 0.62), and less pain (ES = 0.42). The intervention group showed trends toward increasing contentness/serenity (ES = +0.50) and decreasing depression (ES = -0.45), but not decreased anxiety (ES = +0.42). Differences were not statistically significant. Discussion. Feasibility of studying massage-acupressure was established in children undergoing HCT. Larger studies are needed to test the efficacy of such interventions in reducing HCT-associated symptoms in children.