Muna Qayed

Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia

Background In a single‐center phase 1–2a study, the anti‐CD19 chimeric antigen receptor (CAR) T‐cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B‐cell acute lymphoblastic leukemia (ALL). Methods We conducted a phase 2, single‐cohort, 25‐center, global study of tisagenlecleucel in pediatric and young adult patients with CD19+ relapsed or refractory B‐cell ALL. The primary end point was the overall remission rate (the rate of complete remission or complete remission with incomplete hematologic recovery) within 3 months. Results For this planned analysis, 75 patients received an infusion of tisagenlecleucel and could be evaluated for efficacy. The overall remission rate within 3 months was 81%, with all patients who had a response to treatment found to be negative for minimal residual disease, as assessed by means of flow cytometry. The rates of event‐free survival and overall survival were 73% (95% confidence interval [CI], 60 to 82) and 90% (95% CI, 81 to 95), respectively, at 6 months and 50% (95% CI, 35 to 64) and 76% (95% CI, 63 to 86) at 12 months. The median duration of remission was not reached. Persistence of tisagenlecleucel in the blood was observed for as long as 20 months. Grade 3 or 4 adverse events that were suspected to be related to tisagenlecleucel occurred in 73% of patients. The cytokine release syndrome occurred in 77% of patients, 48% of whom received tocilizumab. Neurologic events occurred in 40% of patients and were managed with supportive care, and no cerebral edema was reported. Conclusions In this global study of CAR T‐cell therapy, a single infusion of tisagenlecleucel provided durable remission with long‐term persistence in pediatric and young adult patients with relapsed or refractory B‐cell ALL, with transient high‐grade toxic effects. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02435849.)

CMV reactivation drives posttransplant T-cell reconstitution and results in defects in the underlying TCRβ repertoire

Although cytomegalovirus (CMV) reactivation has long been implicated in posttransplant immune dysfunction, the molecular mechanisms that drive this phenomenon remain undetermined. To address this, we combined multiparameter flow cytometric analysis and T-cell subpopulation sorting with high-throughput sequencing of the T-cell repertoire, to produce a thorough evaluation of the impact of CMV reactivation on T-cell reconstitution after unrelated-donor hematopoietic stem cell transplant. We observed that CMV reactivation drove a >50-fold specific expansion of Granzyme B(high)/CD28(low)/CD57(high)/CD8(+) effector memory T cells (Tem) and resulted in a linked contraction of all naive T cells, including CD31(+)/CD4(+) putative thymic emigrants. T-cell receptor β (TCRβ) deep sequencing revealed a striking contraction of CD8(+) Tem diversity due to CMV-specific clonal expansions in reactivating patients. In addition to querying the topography of the expanding CMV-specific T-cell clones, deep sequencing allowed us, for the first time, to exhaustively evaluate the underlying TCR repertoire. Our results reveal new evidence for significant defects in the underlying CD8 Tem TCR repertoire in patients who reactivate CMV, providing the first molecular evidence that, in addition to driving expansion of virus-specific cells, CMV reactivation has a detrimental impact on the integrity and heterogeneity of the rest of the T-cell repertoire. This trial was registered at www.clinicaltrials.gov as #NCT01012492.

An early-biomarker algorithm predicts lethal graft-versus-host disease and survival

BACKGROUND. No laboratory test can predict the risk of nonrelapse mortality (NRM) or severe graft-versus-host disease (GVHD) after hematopoietic cellular transplantation (HCT) prior to the onset of GVHD symptoms. METHODS. Patient blood samples on day 7 after HCT were obtained from a multicenter set of 1,287 patients, and 620 samples were assigned to a training set. We measured the concentrations of 4 GVHD biomarkers (ST2, REG3α, TNFR1, and IL-2Rα) and used them to model 6-month NRM using rigorous cross-validation strategies to identify the best algorithm that defined 2 distinct risk groups. We then applied the final algorithm in an independent test set (n = 309) and validation set (n = 358). RESULTS. A 2-biomarker model using ST2 and REG3α concentrations identified patients with a cumulative incidence of 6-month NRM of 28% in the high-risk group and 7% in the low-risk group (P < 0.001). The algorithm performed equally well in the test set (33% vs. 7%, P < 0.001) and the multicenter validation set (26% vs. 10%, P < 0.001). Sixteen percent, 17%, and 20% of patients were at high risk in the training, test, and validation sets, respectively. GVHD-related mortality was greater in high-risk patients (18% vs. 4%, P < 0.001), as was severe gastrointestinal GVHD (17% vs. 8%, P < 0.001). The same algorithm can be successfully adapted to define 3 distinct risk groups at GVHD onset. CONCLUSION. A biomarker algorithm based on a blood sample taken 7 days after HCT can consistently identify a group of patients at high risk for lethal GVHD and NRM. FUNDING. The National Cancer Institute, American Cancer Society, and the Doris Duke Charitable Foundation.

Gemcitabine and docetaxel (GEMDOX) for the treatment of relapsed and refractory pediatric sarcomas

Patients with relapsed pediatric sarcomas have a poor outcome and are in need of novel effective therapies.

International, Multicenter Standardization of Acute Graft-versus-Host Disease Clinical Data Collection: A Report from the Mount Sinai Acute GVHD International Consortium.

Acute graft-versus-host disease (GVHD) remains a leading cause of morbidity and nonrelapse mortality after allogeneic hematopoietic cell transplantation. The clinical staging of GVHD varies greatly between transplant centers and is frequently not agreed on by independent reviewers. The lack of standardized approaches to handle common sources of discrepancy in GVHD grading likely contributes to why promising GVHD treatments reported from single centers have failed to show benefit in randomized multicenter clinical trials. We developed guidelines through international expert consensus opinion to standardize the diagnosis and clinical staging of GVHD for use in a large international GVHD research consortium. During the first year of use, the guidance followed discussion of complex clinical phenotypes by experienced transplant physicians and data managers. These guidelines increase the uniformity of GVHD symptom capture, which may improve the reproducibility of GVHD clinical trials after further prospective validation.

Irinotecan as maintenance therapy in high-risk hepatoblastoma.

Children with high‐risk hepatoblastoma (metastatic disease or a low alpha‐fetoprotein at presentation) and those with recurrent disease have an extremely poor prognosis and are in need of novel therapeutic agents and strategies. We describe three patients who were treated with irinotecan (two in combination with vincristine). In two patients, this contributed to a clinical remission. All three patients received a 1‐ to 2‐year course of irinotecan as maintenance therapy and all remain disease free. Treatment was well tolerated with minimal toxicity. Further evaluation of the use of irinotecan as maintenance therapy in high‐risk and recurrent HB patients is warranted. Pediatr Blood Cancer 2010;54:761–763.

Tandem stem cell rescue as consolidation therapy for high-risk neuroblastoma.

Despite aggressive treatment for high‐risk neuroblastoma (NB), event‐free survival (EFS) remains <40%. In single arm studies, intensifying therapy with high‐dose chemotherapy and tandem autologous stem cell rescue (HDC/SCR) improved outcome. We retrospectively describe our institutional experience in using HDC/SCR for patients with high‐risk NB, focusing on outcome and acute toxicities.

Bone Marrow Mesenchymal Stromal Cells from Patients with Acute and Chronic Graft-versus-Host Disease Deploy Normal Phenotype, Differentiation Plasticity, and Immune-Suppressive Activity

The success of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is often limited by the development of acute and/or chronic graft-versus-host disease (GVHD). The lack of effective therapies to treat steroid-refractory GVHD patients has bolstered clinical evaluation of mesenchymal stromal cell (MSC) therapy for GVHD. Currently, testing of MSCs for the treatment of GVHD has exclusively used allogeneic MSCs despite emerging evidence that MSCs lose their immunoprivileged status in vivo. We hypothesized that autologous MSCs could be a viable alternative MSC source for treating active GVHD. MSCs were isolated and successfully expanded from the bone marrow of 12 volunteers (ages 2 to 55 years) who had allo-HSCT transplants and subsequently developed GVHD. MSCs from subjects with GVHD demonstrated an initial lag in growth compared with healthy control subjects; however, this lag disappeared with continued ex vivo expansion. Immunophenotype and mesodermal differentiation capacity of MSCs from GVHD patients were indistinguishable from that of healthy control MSCs. In vitro immunomodulatory functional analyses also demonstrated that GVHD MSCs were equivalent to healthy control MSCs with regards to dose dependently suppressing T cell proliferation and up-regulating indoleamine 2,3-dioxygenase expression when primed with IFN-γ. Single tandem repeat chimerism analyses further demonstrated that MSCs expanded from GVHD patients were exclusively recipient derived. Based on these data, we conclude that recipient-derived MSCs from patients with GVHD are analogous to MSCs from healthy volunteers and represent a viable option for clinical testing as an immunomodulatory option for symptomatic GVHD.

Allogeneic hematopoietic cell transplantation for neuroblastoma: the CIBMTR experience

Although the role of autologous hematopoietic cell transplantation (auto-HCT) is well established in neuroblastoma (NBL), the role of allogeneic HCT (allo-HCT) is controversial. The Center for International Blood and Marrow Transplant Research conducted a retrospective review of 143 allo-HCT for NBL reported in 1990–2007. Patients were categorized into two different groups: those who had not (Group 1) and had (Group 2) undergone a prior auto-HCT (n=46 and 97, respectively). One-year and five-year OS were 59% and 29% for Group 1 and 50% and 7% for Group 2, respectively. Among donor types, disease-free survival (DFS) and OS were significantly lower for unrelated transplants at 1 and 3 years but not at 5 years post HCT. Patients in CR or very good partial response (VGPR) at transplant had lower relapse rates and better DFS and OS, compared with those not in CR or VGPR. Our analysis indicates that allo-HCT can cure some neuroblastoma patients, with lower relapse rates and improved survival in patients without a history of prior auto-HCT as compared with those patients who had previously undergone auto-HCT. Although the data do not address why either strategy was chosen for patients, allo-HCT after a prior auto-HCT appears to offer minimal benefit. Disease recurrence remains the most common cause of treatment failure.

Building blocks for institutional preparation of CTL019 delivery

Chimeric antigen receptor (CAR) T-cell therapy is an investigational immunocellular therapy that reprograms a patients cytotoxic T cells to engage and eliminate malignant cells. CAR T-cell therapies targeting the CD19 antigen have demonstrated high efficacy in clinical trials for patients with B-cell malignancies and may potentially be available on a broader scale in the future. CAR T-cell therapy begins with the collection of a sufficient number of T cells from a patients peripheral blood through leukapheresis. Several factors must be considered when patients undergo leukapheresis for CAR T-cell therapy, including age and prior therapies. The leukapheresis material is shipped to a manufacturing facility, followed by return of the CAR T cells to the treatment center. Careful coordination of a multidisciplinary team composed of physicians, nurses, pharmacists and other hospital personnel is critical for the proper care of the patient before, during and after CAR T-cell therapy. CAR T-cell therapy has been associated with adverse events (AEs) such as cytokine release syndrome, which requires rapid attention by the emergency department, intensive care unit and hospital pharmacy. In this review, we discuss several aspects of institutional preparation for leukapheresis, CAR T-cell infusion and AE management based on our experience with clinical trials of the CD19 CAR T-cell therapy CTL019.