Joerg Krueger

Immune Checkpoint Inhibition for Hypermutant Glioblastoma Multiforme Resulting From Germline Biallelic Mismatch Repair Deficiency

PURPOSE Recurrent glioblastoma multiforme (GBM) is incurable with current therapies. Biallelic mismatch repair deficiency (bMMRD) is a highly penetrant childhood cancer syndrome often resulting in GBM characterized by a high mutational burden. Evidence suggests that high mutation and neoantigen loads are associated with response to immune checkpoint inhibition. PATIENTS AND METHODS We performed exome sequencing and neoantigen prediction on 37 bMMRD cancers and compared them with childhood and adult brain neoplasms. Neoantigen prediction bMMRD GBM was compared with responsive adult cancers from multiple tissues. Two siblings with recurrent multifocal bMMRD GBM were treated with the immune checkpoint inhibitor nivolumab. RESULTS All malignant tumors (n = 32) were hypermutant. Although bMMRD brain tumors had the highest mutational load because of secondary polymerase mutations (mean, 17,740 ± standard deviation, 7,703), all other high-grade tumors were hypermutant (mean, 1,589 ± standard deviation, 1,043), similar to other cancers that responded favorably to immune checkpoint inhibitors. bMMRD GBM had a significantly higher mutational load than sporadic pediatric and adult gliomas and all other brain tumors (P < .001). bMMRD GBM harbored mean neoantigen loads seven to 16 times higher than those in immunoresponsive melanomas, lung cancers, or microsatellite-unstable GI cancers (P < .001). On the basis of these preclinical data, we treated two bMMRD siblings with recurrent multifocal GBM with the anti-programmed death-1 inhibitor nivolumab, which resulted in clinically significant responses and a profound radiologic response. CONCLUSION This report of initial and durable responses of recurrent GBM to immune checkpoint inhibition may have implications for GBM in general and other hypermutant cancers arising from primary (genetic predisposition) or secondary MMRD.

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.)

Hematopoietic stem cell transplantation in infants

It is rare for infants, who are less than 365 days old, to receive hematopoietic stem cell transplantation (HSCT). Our objective was to review the indications, survival, and late effects of infants who received HSCT.

Comparison of two apheresis systems for autologous stem cell collections in pediatric oncology patients

Peripheral stem cell collections can be challenging in the pediatric population and respective experience is limited. Since February 2015 our institution is utilizing the new Spectra Optia (Optia) apheresis device, which has replaced the former COBE Spectra (COBE) device. As a quality initiative we collected and compared collection efficiency (CE2) and other collection variables between the two devices.

Successful Allogeneic Hematopoietic Stem Cell Transplantation in XIAP Deficiency Using Reduced-Intensity Conditioning.

Hematopoietic stem cell transplantation (HSCT) is currently the only available curative therapy for X‐linked inhibitor of apoptosis (XIAP) deficiency. Myeloablative conditioning regimens are associated with high mortality rates. Reduced‐intensity conditioning (RIC) is recommended in order to decrease treatment‐related toxicities, but RIC regimens increase the risk for mixed donor‐recipient chimerism that may progress to graft loss. We report our experience with a patient with XIAP deficiency who was successfully treated with allogeneic HSCT using a RIC protocol. Post‐transplant chimerism was vigilantly monitored and maintained with donor lymphocyte infusions and a stem cell boost to a level that prevented hemophagocytic lymphohistiocytosis recurrence. Pediatr Blood Cancer

Successful Myeloablative Matched Unrelated Donor Hematopoietic Stem Cell Transplantation in a Young Girl With GATA2 Deficiency and Emberger Syndrome

Patients with GATA2 (Emberger syndrome) deficiency needs early hematopoietic stem cell transplant (HSCT) before evolving in to myelodysplastic syndrome or acute myeloid leukemia and with time given compromised organ dysfunction leads to increase regimen-related toxicities. Most published cases have used nonmyeloablative conditioning regimens, show higher incidences of rejection and relapse rates and umbilical cord blood transplant has been reported to be suboptimal in patients with GATA2 deficiency because of longer period of engraftment leads to more infections and mortality. We report a 4.5-year-old girl with GATA2 deficiency who underwent matched unrelated donor HSCT utilizing a myeloablative conditioning regimen including intravenous busulfan (total dose of 12.8 mg/kg) and fludarabine (total dose of 160 mg/m) She tolerated the conditioning regimen and bone marrow infusion well. Her initial chimerism was mixed (90% donor), cyclosporine was gradually weaned and discontinued at day+85 and this resulted in conversion to full-donor chimerism. Bone marrow assessment 3 months post-HSCT revealed normal hematopoiesis and absence of monosomy 7. At 20 months of follow-up she had full-donor chimerism with complete reconstitution of the all hematopoietic stem cells. Myeloablative matched unrelated donor HSCT represents an effective option for cure in patients with GATA2 deficiency and Emberger syndrome.

The yield of monitoring for HSV and VZV viremia in pediatric hematopoietic stem cell transplant patients

Reactivation of HSV and VZV is common following HSCT. Consensus guidelines do not support the use of routine screening for viremia following HSCT in adults, but no such clear guidelines exist in pediatrics. In our center, routine practice was to screen patients weekly for HSV and VZV viremia until engraftment in autologous transplant patients and up to day +100 in allogeneic transplant patients. We conducted a retrospective study of over 500 patients to establish whether this screening identified any patients with HSV or VZV viremia who would not have been identified by clinical signs or symptoms. Over a 4.5‐yr period, routine screening identified three cases of HSV viremia and one case of VZV viremia. Two patients had persistent, unexplained fever and two patients had skin or mucosal lesions suggestive of HSV/VZV. We conclude that routine screening for HSV and VZV viremia in pediatric HSCT patients has a very low yield and that viremia can be reliably identified by targeted testing in patients with vesicular skin lesions, oral or genital ulceration, unexplained fever, neurological symptoms, or unexplained abnormal liver transaminases.

Eltrombopag for secondary failure of platelet recovery post-allogeneic hematopoietic stem cell transplant in children.

Secondary failure of platelet engraftment occurs in 20% of patients undergoing allogeneic HSCT and is associated with poor outcome. Currently, there are no guidelines for treatment of late thrombocytopenia and platelet transfusion is the mainstay of treatment. Here, we describe the use of Eltrombopag to treat secondary failure of platelet recovery following HSCT in a child with severe aplastic anemia. Eltrombopag resulted in recovery of platelet count with no need for platelet transfusion support with no reported side effects. Eltrombopag may be used successfully in children with secondary failure of platelet recovery post‐HSCT for SAA.

Diagnosis of central nervous system relapse of pediatric acute lymphoblastic leukemia: Impact of routine cytological CSF analysis at the time of intrathecal chemotherapy.

Despite the success of central nervous system (CNS) directed therapy in pediatric acute lymphoblastic leukemia (ALL), relapse involving the CNS continues to be observed in 5–10% of children when utilizing standard intrathecal prophylactic chemotherapy. While most pediatric ALL treatment protocols mandate regular lumbar punctures (LP) for the intrathecal injection of chemotherapy, the value of routine cytological analysis of cerebrospinal fluid (CSF) during therapy is unknown. Our objective was to assess the diagnostic value of routine CSF analysis during ALL therapy.

Optimizing autologous nonmobilized mononuclear cell collections for cellular therapy in pediatric patients with high‐risk leukemia

The manufacturing of cellular products for immunotherapy, such as chimeric antigen receptor T cells, requires successful collection of mononuclear cells. Collections from children with high‐risk leukemia present a challenge, especially because the established COBE Spectra apheresis device is being replaced by the novel Spectra Optia device (Optia) in many institutions. Published experience for mononuclear cell collections in children with Optia is lacking. Our aim was to compare the two collection devices and describe modified settings on the Optia to optimize mononuclear cell collections.