Tisagenlecleucel for treatment of children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia.

The treatment landscape for cancer therapy has changed drastically over the past decade. Tisagenlecleucel, the first genetically engineered adoptive cellular therapy approved by the United States Food and Drug Administration, has revolutionized this field by demonstrating impressive clinical success in children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL). Now 3 years since its approval, we have gained a deeper understanding on the basic immunobiology and clinical efficacy of this drug. This review will provide an updated summary of tisagenlecleucel in childhood and young adults with r/r B-ALL, common side effects and their associated management strategies, as well as barriers that remain to be addressed in order to realize the maximum potential of this drug.

Myeloablative Busulfan/Melphalan Consolidation following Induction Chemotherapy for Patients with Newly Diagnosed High-Risk Neuroblastoma: Children's Oncology Group Trial ANBL12P1.

Consolidation using high-dose chemotherapy with autologous stem cell transplantation (ASCT) is an important component of frontline therapy for children with high-risk neuroblastoma. The optimal preparative regimen is uncertain, although recent data support a role for busulfan/melphalan (BuMel). The Children's Oncology Group (COG) conducted a trial (ANBL12P1) to assess the tolerability and feasibility of BuMel ASCT following a COG induction. Patients with newly diagnosed high-risk neuroblastoma who did not progress during induction therapy and met organ function requirements received i.v. busulfan (every 24 hours for 4 doses based on age and weight) and melphalan (140 mg/m2 for 1 dose), followed by ASCT. Busulfan doses were adjusted to achieve to an average daily area under the curve (AUC) <5500 µM × minute. The primary endpoint was the occurrence of severe sinusoidal obstruction syndrome (SOS) or grade ≥4 pulmonary complications within the first 28 days after completion of consolidation therapy. A total of 146 eligible patients were enrolled, of whom 101 underwent BuMel ASCT. The overall incidence of protocol-defined unacceptable toxicity during consolidation was 6.9% (7 of 101). Six patients (5.9%) developed SOS, with 4 (4%) meeting the criteria for severe SOS. An additional 3 patients (3%) experienced grade ≥4 pulmonary complications during consolidation. The median busulfan AUC was 4558 µM × min (range, 3462 to 5189 µM × minute) for patients with SOS and 3512 µM × min (2360 to 5455 µM × minute) (P = .0142). No patients died during consolidation. From the time of study enrollment, the mean 3-year event-free survival for all 146 eligible patients was 55.6 ± 4.2%, and the mean 3-year overall survival was 74.5 ± 3.7%. The BuMel myeloablative regimen following COG induction was well tolerated, with acceptable pulmonary and hepatic toxicity.

Outcomes After Proton Therapy for Treatment of Pediatric High-Risk Neuroblastoma.

PURPOSE: Patients with high-risk neuroblastoma (HR-NBL) require radiation to the primary tumor site and sites of persistent metastatic disease. Proton radiation therapy (PRT) may promote organ sparing, but long-term outcomes have not been studied. METHODS AND MATERIALS: Sequential patients with HR-NBL received PRT: 2160 cGy (relative biological effectiveness) to primary tumor bed and persistent metastatic sites, with 3600 cGy (relative biological effectiveness) to gross residual disease. RESULTS: From September 2010 through September 2015, 45 patients with HR-NBL received PRT after systemic therapy, primary tumor resection, and high-dose chemotherapy with stem cell rescue. Median age was 46 months at the time of PRT (range, 10 months to 12 years); 23 patients (51%) were male. Primary tumors were adrenal in 40 (89%); 11 (24%) received boost. Ten metastatic sites in 8 patients were radiated. Double scattered proton beams were used for 19 (42%) patients, in combination with x-rays for 2 (5%). The remaining 26 (58%) received pencil beam scanning, available since January 2013. We observed 97% freedom from primary site recurrence at 3, 4, and 5 years. Overall survival rates were 89%, 80%, and 80% and disease-free survival rates were 77%, 70%, and 70%, at 3, 4, and 5 years, respectively. With median follow-up of 48.7 months from diagnosis (range, 11-90 months) for all patients (57.4 months for those alive), 37 (82%) patients are alive, and 32 (71%) are without evidence of disease. One patient experienced locoregional recurrence; the remaining 12 (27%) experienced relapse at distant, nonradiated sites. Acute toxicities during treatment were mainly grade 1. No patient has experienced World Health Organization grade 3 or 4 long-term renal or hepatic toxicity. Pencil beam scanning plans required less planning time and resources than double scattered plans. CONCLUSIONS: We observe excellent outcomes in patients treated with PRT for HR-NBL from 2010 through 2015, with 82% of patients alive and 97% free of primary site recurrence. No patient has experienced long-term renal or liver toxicity. This treatment maximizes normal tissue preservation and is appropriate for this patient population.

Cardiac Profile of Chimeric Antigen Receptor T Cell Therapy in Children: A Single-Institution Experience.

Immunotherapy with chimeric antigen receptor (CAR)-modified T cells targeting CD19 for pediatric acute lymphoblastic leukemia (ALL) has demonstrated significant efficacy. The principle toxicity is cytokine release syndrome with resultant hypotension. However, the spectrum of cardiovascular effects associated with CAR T cell therapy has not been systematically evaluated. We reviewed all patients who received CD19-directed CAR T cells at the Children's Hospital of Philadelphia between April 2012 and September 2016. The primary endpoint was hypotension-requiring inotropic support. Secondary endpoints included echocardiographic dysfunction at discharge and 6-month follow-up. Descriptive and univariate analyses were performed, and 98 encounters were included (55% male patients; mean age, 11.8 years [range, 1.7 to 27.1]); 98% had B-ALL. Before infusion 10 had cardiomyopathy and 1 had single-ventricle physiology. Primary endpoint occurred in 24 patients with mean onset 4.6 days (range, 1 to 9) after CAR T cell infusion, including 6 patients receiving milrinone. Worsened systolic function occurred in 10 patients; there were no cardiac-related deaths. Pretreatment factors associated with primary endpoint included higher pretreatment blast percentage on bone marrow biopsy (blast > 25%: odds ratio, 15.5; 95% confidence interval, 5.1 to 47.1; P < .001) and baseline lower ejection fraction (P = .019) or diastolic dysfunction (P = .021); neither pre-existing cardiomyopathy (P = .062), total body irradiation (P = .629), nor anthracycline dose (P = .444) were associated. At discharge, 7 patients had worsened echocardiographic function, but persistent dysfunction by the 6-month follow-up was rare. Pretreatment factors were not associated with persistent dysfunction at discharge. This is the first study to describe the cardiovascular effects of pediatric CAR T cell therapy. Although 10% had new systolic dysfunction after treatment, persistence was rare. Pretreatment blast count > 25% or pre-existing cardiac dysfunction increased the risk for hypotension-requiring inotropic support; these patients may warrant close observation.

Persistence of long-lived plasma cells and humoral immunity in individuals responding to CD19-directed CAR T-cell therapy.

The mechanisms underlying the maintenance of long-lasting humoral immunity are not well understood. Studies in mice indicate that plasma cells (PCs) can survive up to a lifetime, even in the absence of regeneration by B cells, implying the presence of long-lived PCs as a mechanism for long-lasting immunity. Evidence from humans treated with anti-CD20, which depletes circulating B cells, also suggests B-cell-independent long-term survival of some PCs. On the other hand, antibody responses may be sustained solely by short-lived PCs with repopulation from clonally related memory B cells. To explore PC longevity and humoral immunity in humans, we investigated the fate of PCs and their antibodies in adult and pediatric patients who received chimeric antigen receptor-based adoptive T-cell immunotherapy targeting CD19 to treat B-cell lineage malignancies (CTL019). Treatment with CTL019 is frequently associated with B-cell aplasia that can persist for years. Serum antibody titers to vaccine-related antigens were measured, and quantitative assessment of B cells and PCs in blood and bone marrow was performed at various time points before and after CTL019 therapy. While total serum immunoglobulin concentrations decline following CTL019-induced B-cell aplasia, several vaccine/pathogen-specific serum immunoglobulin G and A (IgG and IgA) titers remain relatively stable for at least 6 and 12 months posttreatment, respectively. Analysis of bone marrow biopsies after CTL019 revealed 8 patients with persistence of antibody-secreting PCs at least 25 months post-CTL019 infusion despite absence of CD19(+)CD20(+) B cells. These results provide strong evidence for the existence of memory B-cell-independent, long-lived PCs in humans that contribute to long-lasting humoral immunity.

Proton versus photon radiation therapy for patients with high-risk neuroblastoma: the need for a customized approach.

BACKGROUND: Proton therapy for treatment for high-risk neuroblastoma may offer sparing of organs at risk (OAR) when compared to intensity-modulated X-ray therapy (IMXT). PROCEDURE: Double-scattered proton plans and IMXT plans delivering 2,160 cGy to the primary tumor site and other residual disease were developed for 13 consecutive HR-NBL patients. Radiation doses to target volumes and OAR were calculated to determine the optimal modality for each. RESULTS: All patients received radiation (5/13 ≥ 2 sites). No patient has experienced local recurrence or clinical organ toxicity. Coverage was excellent using both protons and IMXT: median % dose delivered to 95% clinical target volume was 99% and 100%, respectively. For nine patients with lateralized disease, proton therapy offered sparing of the contralateral kidney both with regard to median dose and dose to 20% (median <1 cGy vs. 362 cGy, P = 0.01; median 100 cGy vs. 634 cGy, P = 0.02, respectively). Proton therapy did not reduce ipsilateral kidney dose, and for 2 select patients with lateralized disease IMXT improved overall bilateral renal sparing. Proton therapy improved median bowel (median 33 cGy vs. 590 cGy, P = 0.01), total body (median <1 cGy vs. 30 cGy, P = 0.15), and liver dose (median <1 cGy vs. 529, P < 0.001). When chest RT was required, proton therapy decreased median heart dose and mean lung dose. CONCLUSIONS: For most patients (11/13), proton therapy offered the optimal combination of target coverage and organ sparing, and is a feasible treatment for HR-NBL. We recommend a customized approach with careful evaluation of renal dosimetry; IMXT may be preferred for select patients.

Biomarkers in newly diagnosed pediatric-extensive chronic graft-versus-host disease: a report from the Children's Oncology Group.

Numerous chronic graft-versus-host disease (cGVHD) biomarkers have been identified in limited, single-institution studies without validation. We hypothesized that plasma-derived biomarkers could diagnose, classify, and evaluate response in children with cGVHD. We performed a concomitant analysis of a number of known and predicted peripheral blood cGVHD biomarkers from a Children's Oncology Group (COG) phase 3 cGVHD therapeutic trial. A total of 52 newly diagnosed patients with extensive cGVHD were compared for time of onset after blood and marrow transplantation (BMT) (early, 3-8 months; late, > or = 9 months) with 28 time-matched controls with no cGVHD (early, 6 months after BMT; late, 12 months after BMT). Soluble B-cell activation factor (sBAFF), anti-dsDNA antibody, soluble IL-2 receptor alpha (sIL-2Ralpha), and soluble CD13 (sCD13) were elevated in patients with early-onset cGVHD compared with controls. sBAFF and anti-dsDNA were elevated in patients with late-onset cGVHD. Some of the biomarkers correlated with specific organ involvement and with therapeutic response. These 4 biomarkers had high specificity with higher sensitivity in combination. Changes in biomarker concentrations with immune reconstitution after transplantation significantly affected interpretation of results. The identified biomarkers have the potential for improved classification, early response evaluation, and direction of cGVHD treatment, but require validation in larger studies. This study is registered at www.cancer.gov/clinicaltrials as no. COG-ASCT0031.

Cell division rates of primary human precursor B cells in culture reflect in vivo rates.

Bone marrow stroma-based cultures provide a powerful model for studying cell division and apoptosis of primary human precursor B cells. Studies using this model are elucidating the mechanisms by which stromal cells inhibit apoptosis of cultured normal precursor B cells and have demonstrated that the apoptotic rate of cultured leukemic precursor B cells can predict clinical outcome in acute lymphoblastic leukemia. In contrast to apoptosis, cell division in this model has not been well characterized. In this study, we quantified the rates of cell division in cultured primary human normal and leukemic precursor B cells by labeling precursor B cells with the fluorescent dye carboxyfluorescein diacetate, succinimyl ester. Based on the rate of decreasing fluorescent signal over 3 weeks, normal CD19(+), CD10(+) precursor B cells divided once every 90.5 hours, a number that correlates well with the known in vivo rate of 65.5 hours. The division rates were similar among different cultures and constant throughout the 3 weeks of culture, suggesting that the variable expansions of precursor B cells seen among different samples and culture durations are not secondary to different cell division rates. Unlike normal cells, cultured leukemic B cells had a heterogeneous division rate that ranged from once every 26-240 hours. These rates correlated well with their respective in vivo proliferation index. These findings indicate that the stroma-based cultures faithfully replicate in vivo cell division rates and can be used to elucidate the pathways that regulate cell division of primary human precursor B cells.

Primary tumor control in patients with stage 3/4 unfavorable neuroblastoma treated with tandem double autologous stem cell transplants.

OBJECTIVE: To assess the efficacy and toxicity of local radiotherapy in achieving local control in patients with stage 4 or high-risk stage 3 neuroblastoma treated with induction chemotherapy and tandem stem cell transplants. METHODS: Fifty-two children with stage 4 or high-risk stage 3 neuroblastoma were treated on a standardized protocol that included five cycles of induction chemotherapy, surgical resection of the primary tumor when feasible, local radiotherapy, and then consolidation with tandem myeloablative cycles with autologous peripheral blood stem cell rescue. Local radiotherapy (10.5-18 Gy) was administered to patients with gross or microscopic residual disease prior to the myeloablative cycles. Thirty-seven patients received local radiotherapy to the primary tumor or primary tumor bed. Two patients with unknown primaries each received radiotherapy to single, unresectable, bulky metastatic sites. The second of the myeloablative regimens included 12 Gy of total body irradiation. RESULTS: Of the 52 consecutively treated patients analyzed, 44 underwent both transplants, 6 underwent a single transplant, and 2 progressed during induction. Local radiotherapy did not prolong recovery of hematopoiesis following transplants, did not increase peritransplant morbidity, and did not prolong the hospital stay compared with patients who had not received local radiotherapy. Local control was excellent. Of 11 patients with disease recurrence after completion of therapy, 9 failed in bony metastatic sites 3 to 21 months after the completion of therapy, 1 recurred 67 months following therapy in the previously bulky metastatic site that had been irradiated, and 1 had local recurrence concurrent with distant progression 15 months following the second transplant. The three-year event-free survival was 63%, with a median follow-up of 29.5 months. The actuarial probability of local control was 97%. CONCLUSIONS: The use of induction chemotherapy, aggressive multimodality therapy for the primary tumor, followed by tandem myeloablative cycles with stem cell transplant in patients with stage 4 or high risk stage 3 neuroblastoma has resulted in acceptable toxicity, a very low local recurrence risk, and an improvement in survival.