Leukaemogenic effects of Ptpn11 activating mutations in the stem cell microenvironment

Germline activating mutations of the protein tyrosine phosphatase SHP2 (encoded by PTPN11), a positive regulator of the RAS signalling pathway, are found in 50% of patients with Noonan syndrome. These patients have an increased risk of developing leukaemia, especially juvenile myelomonocytic leukaemia (JMML), a childhood myeloproliferative neoplasm (MPN). Previous studies have demonstrated that mutations in Ptpn11 induce a JMML-like MPN through cell-autonomous mechanisms that are dependent on Shp2 catalytic activity. However, the effect of these mutations in the bone marrow microenvironment remains unclear. Here we report that Ptpn11 activating mutations in the mouse bone marrow microenvironment promote the development and progression of MPN through profound detrimental effects on haematopoietic stem cells (HSCs). Ptpn11 mutations in mesenchymal stem/progenitor cells and osteoprogenitors, but not in differentiated osteoblasts or endothelial cells, cause excessive production of the CC chemokine CCL3 (also known as MIP-1α), which recruits monocytes to the area in which HSCs also reside. Consequently, HSCs are hyperactivated by interleukin-1β and possibly other proinflammatory cytokines produced by monocytes, leading to exacerbated MPN and to donor-cell-derived MPN following stem cell transplantation. Remarkably, administration of CCL3 receptor antagonists effectively reverses MPN development induced by the Ptpn11-mutated bone marrow microenvironment. This study reveals the critical contribution of Ptpn11 mutations in the bone marrow microenvironment to leukaemogenesis and identifies CCL3 as a potential therapeutic target for controlling leukaemic progression in Noonan syndrome and for improving stem cell transplantation therapy in Noonan-syndrome-associated leukaemias

Producer Nutritional Quality Controls Ecosystem Trophic Structure

Trophic structure, or the distribution of biomass among producers and consumers, determines key ecosystem values, such as the abundance of infectious, harvestable or conservation target species, and the storage and cycling of carbon and nutrients. There has been much debate on what controls ecosystem trophic structure, yet the answer is still elusive. Here we show that the nutritional quality of primary producers controls the trophic structure of ecosystems. By increasing the efficiency of trophic transfer, higher producer nutritional quality results in steeper ecosystem trophic structure, and those changes are more pronounced in terrestrial than in aquatic ecosystems probably due to the more stringent nutritional limitation of terrestrial herbivores. These results explain why ecosystems composed of highly nutritional primary producers feature high consumer productivity, fast energy recycling, and reduced carbon accumulation. Anthropogenic changes in producer nutritional quality, via changes in trophic structure, may alter the values and functions of ecosystems, and those alterations may be more important in terrestrial ecosystems

The Effect of Medicare Eligibility on Spousal Insurance Coverage

A majority of married couples in the United States take advantage of the fact that employers often provide health insurance coverage to spouses. When the older spouses become eligible for Medicare, however, many of them can no longer provide their younger spouses with coverage. In this paper, we study how spousal eligibility for Medicare affects the health insurance and health care access of the younger spouse. We find spousal eligibility for Medicare results in the younger spouse having worse insurance coverage and reduced access to health care services

Connectivity within and among a Network of Temperate Marine Reserves

Networks of marine reserves are increasingly being promoted as a means of conserving marine biodiversity. One consideration in designing systems of marine reserves is the maintenance of connectivity to ensure the long-term persistence and resilience of populations. Knowledge of connectivity, however, is frequently lacking during marine reserve design and establishment. We characterise patterns of genetic connectivity of 3 key species of habitat-forming macroalgae across an established network of temperate marine reserves on the east coast of Australia and the implications for adaptive management and marine reserve design. Connectivity varied greatly among species. Connectivity was high for the subtidal macroalgae Ecklonia radiata and Phyllospora comosa and neither species showed any clear patterns of genetic structuring with geographic distance within or among marine parks. In contrast, connectivity was low for the intertidal, Hormosira banksii, and there was a strong pattern of isolation by distance. Coastal topography and latitude influenced small scale patterns of genetic structure. These results suggest that some species are well served by the current system of marine reserves in place along this temperate coast but it may be warranted to revisit protection of intertidal habitats to ensure the long-term persistence of important habitat-forming macroalgae. Adaptively managing marine reserve design to maintain connectivity may ensure the long-term persistence and resilience of marine habitats and the biodiversity they support

Nivolumab Plus 5-Azacitidine in Pediatric Relapsed/Refractory Acute Myeloid Leukemia (AML): Phase I/II Trial Results from the Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) Consortium.

Improvements in survival have been made over the past two decades for childhood acute myeloid leukemia (AML), but the approximately 40% of patients who relapse continue to have poor outcomes. A combination of checkpoint-inhibitor nivolumab and azacitidine has demonstrated improvements in median survival in adults with AML. This phase I/II study with nivolumab and azacitidine in children with relapsed/refractory AML (NCT03825367) was conducted through the Therapeutic Advances in Childhood Leukemia & Lymphoma consortium. Thirteen patients, median age 13.7 years, were enrolled. Patients had refractory disease with multiple reinduction attempts. Twelve evaluable patients were treated at the recommended phase II dose (established at dose level 1, 3 mg/kg/dose). Four patients (33%) maintained stable disease. This combination was well tolerated, with no dose-limiting toxicities observed. Grade 3-4 adverse events (AEs) were primarily hematological. Febrile neutropenia was the most common AE ≥ grade 3. A trend to improved quality of life was noted. Increases in CD8+ T cells and reductions in CD4+/CD8+ T cells and demethylation were observed. The combination was well tolerated and had an acceptable safety profile in pediatric patients with relapsed/refractory AML. Future studies might explore this combination for the maintenance of remission in children with AML at high risk of relapse

Results from the Phase 1 Portion of a Trial of Oral Ixazomib Combined with Chemotherapy in Relapsed/Refractory Acute Lymphoblastic Leukemia or Lymphoma in Children, Adolescents and Young Adults: A Report from the Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) Consortium

ACKNOWLEDGEMENT Proteasome inhibitors potentiate anti-tumor effects of standard cytotoxic chemotherapy in childhood leukemia. Ixazomib is an oral proteasome inhibitor that has a shorter proteasome dissociation half-life than bortezomib, which leads to a higher tumor-to-blood ratio inhibition. We performed a phase 1 trial to determine the dose limiting toxicities (DLT), Recommended Phase 2 Dose (RP2D) of ixazomib in pediatric patients with relapsed/refractory acute lymphoblastic leukemia (ALL) or lymphoma (LL). Patients ≤ 21 years of age with relapsed or refractory ALL (with ≥ 5% detectable disease in the marrow) or LL were eligible. Ixazomib was combined with 28-day blocks of well-established, relapsed ALL backbone chemotherapy. Block 1 contained vincristine (1.5 mg/m 2/dose IV Days 1, 8, 15, 22), dexamethasone (5 mg/m 2/dose IV or oral twice daily Days 1-14), PEG-asparaginase (2500 IU/m 2/dose IV Days 2, 15) and daunorubicin (60 mg/m 2/dose IV Day 1) (VXLD). An optional Block 2 contained vincristine (1.5 mg/m 2/dose IV Day 1), dexamethasone (3 mg/m 2/dose oral twice daily Days 1-5), methotrexate (1000 mg/m 2/dose IV over 36 hours Day 8), PEG-asparaginase (2500 IU/m 2/dose IV Day 9), cyclophosphamide (440 mg/m 2/dose IV Days 15-19) and etoposide (100 mg/m 2/dose IV Days 15-19). An additional optional Maintenance Block contained vincristine (1.5 mg/m 2/dose IV Day 1), prednisone (20 mg/m 2/dose oral twice daily Days 1-5), mercaptopurine (75 mg/m 2/dose oral daily) and methotrexate (20 mg/m 2/dose oral weekly). Intrathecal therapy was given throughout with agents and dosing based on the patient's CNS disease status upon study entry. Ixazomib was given orally and tested at two dose levels (DL) (DL1: 1.6 mg/m 2/dose; DL2: 2 mg/m 2/dose) using a 3+3 design and was given during Block 1 on Days 1, 4, 8 and 11; during Block 2 on Days 1, 4, 8, 15 and 18 and during Maintenance on Days 1, 8 and 15. DLTs during Block 1 only were utilized to make DL escalation decisions and determine the RP2D. Patients without Down Syndrome (DS) entered Cohort A, used to determine the P2RD. Patients with DS were eligible for a 1 DL lagging descriptive-only Cohort B. Ten patients were treated; nine in Cohort A (n = 3 at DL1 and n = 6 at DL2) and one in Cohort B (DL1). Median age (range) at study entry was 10.5 years (5 - 20 years). Nine patients had B-ALL and one had T-ALL. Most were heavily pretreated with a median (range) of 3.4 (1 - 7) previous remission attempts with six having had prior immunotherapy and three patients having had at least one prior hematopoietic stem cell transplant. After Block 1, two patients received Block 2 and one received Maintenance. In Block 1 of Cohort A, non-hematological Grade 3/4 adverse events (AE) possibly, probably or definitely related to ixazomib or the backbone chemotherapy were limited and included neutropenic fever (n = 7), increased AST (n = 3), increased ALT (n = 2) and hypokalemia (n = 2). Two septic events occurred (n = 1 in Cohort A (Grade 3) and n = 1 in Cohort B (Grade 4)). Block 2 and Maintenance AEs were not significantly different than those seen in Block 1. No deaths or DLTs occurred. Response assessment showed that at DL1 two of three patients had a Complete Remission (CR) both of whom were Minimal Residual Disease (MRD) negative (-) and at DL2 three of six patients had a CR, two of whom were MRD- and two patients had a CR with incomplete count recovery (CRi). The overall response rate (CR + CRi) was 78% (7 of 9 patients). With a minimum of 20 months of follow-up six of nine patients in Cohort A and the single patient in Cohort B are still alive. All three deceased patients died of disease progression. Ixazomib can be combined with standard chemotherapy with an acceptable safety profile and an encouraging early efficacy signal in pediatric relapsed ALL including those with DS. The RP2D of Ixazomib combined with chemotherapy is 2 mg/m 2/dose, which is being used in the ongoing phase 2/expansion cohort of the study. We acknowledge the TACL Consortium's scientific contribution to and participation in this study, including participating member institutions, investigators, research teams, and the TACL Operations Center. Takeda Pharmaceuticals Company provided the investigative drug and funding in support of this trial

Phase I trial of the mTOR inhibitor everolimus in combination with multi-agent chemotherapy in relapsed childhood acute lymphoblastic leukemia

Background: We sought to determine the feasibility of co-administering everolimus with a four-drug reinduction in children and adolescents with acute lymphoblastic leukemia (ALL) experiencing a first marrow relapse. Procedure: This phase I study tested everolimus with vincristine, prednisone, pegaspargase and doxorubicin in patients with marrow relapse occurring >18 months after first complete remission (CR). The primary aim was to identify the maximum tolerated dose of everolimus. Three dose levels (DLs) were tested during dose escalation (2, 3, and 5 mg/m2/day). Additional patients were enrolled at the 3- and 5 mg/m2/day DLs to further evaluate toxicity (dose expansion). Results: Thirteen patients enrolled during dose escalation and nine during dose expansion. During dose escalation, one dose-limiting toxicity occurred (grade 4 hyperbilirubinemia) in six evaluable patients at DL3 (5 mg/m2/day). The most common grade ≥3 adverse events were febrile neutropenia, infections, transaminitis, hyperbilirubinemia, and hypophosphatemia. Two of the 12 patients treated at DL3 developed Rothia mucilaginosa meningitis. Nineteen patients (86%) achieved a second CR (CR2). Of those, 13 (68%) had a low end-reinduction minimal residual disease (MRD) level (≤10−3by polymerase chain reaction–based assay). The CR2 rate for patients with B-cell ALL treated at DL3 (n = 12) was 92%; 82% of these patients had low MRD. Conclusions: Everolimus combined with four-drug reinduction chemotherapy was generally well tolerated and associated with favorable rates of CR2 and low end-reinduction MRD. The recommended phase 2 dose of everolimus given in combination with a four-drug reinduction is 5 mg/m2/day. This promising combination should be further evaluated in a larger patient cohort

BCMA CAR-T induces complete and durable remission in refractory plasmablastic lymphoma

Plasmablastic lymphoma (PBL) is a rare subtype of aggressive large B-cell lymphoma, with a dismal prognosis despite aggressive therapies. New approaches are needed for those with refractory disease. PBL expresses antigens similar to multiple myeloma (MM), including B-cell maturation antigen (BCMA). Chimeric antigen receptor T-cell (CAR-T) therapy directed against BCMA has shown efficacy for the treatment of heavily pretreated MM with low rates of grades 3 and 4 cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) in a phase Ib/II trial (A Study of JNJ-68284528, a CAR-T Directed Against BCMA in Participants With Relapsed or Refractory Multiple Myeloma (CARTITUDE-1), NCT03548207). However, data for the use of BCMA CAR-T for treating PBL are lacking.We report a challenging case of multiple refractory PBL that emerged from B-cell acute lymphoblastic leukemia in an adolescent who failed to respond to an allogeneic hematopoietic cell transplant. The patient developed rapidly advancing disease despite withdrawal of immunosuppression, treatment with etoposide, ibrutinib, and daratumumab, prompting consideration of BCMA CAR-T (under emergency investigational new drug (eIND)). The patient achieved a complete remission (CR), without recurrent acute graft versus host disease (GVHD), CRS or ICANS after BCMA CAR-T therapy. BCMA CAR-T expansion was detected in vivo, peaking on day 15. The patient remains in CR for more than a year post CAR-T therapy, supporting consideration of immunotherapy for future patients with refractory PBL, a disease with few treatment options