Our case series suggests that sorafenib administration is feasible and tolerable in pediatric FLT3/ITD+ AML patients early post HSCT. Ongoing prospective controlled studies are needed to further define the dosing of sorafenib in the post-HSCT period and to determine the optimal context for this treatment approach.
Key Points Priming of CMV-specific CD4+ and CD8+ T cells occurs as early as day 42 in patients undergoing UCBT. Lack of CMV control in UCBT patients could be related to low absolute frequency of T cells and lack of in vivo expansion of T cells.
Background Perceptions of high cost and resource intensity remain political barriers to the prioritization of childhood cancer treatment programs in many low‐ and middle‐income countries (LMICs). Little knowledge exists of the actual cost and cost‐effectiveness of such programs. To improve outcomes for children with Burkitt lymphoma (BL), the most common childhood cancer in Africa, the Uganda Cancer Institute implemented a comprehensive BL treatment program in 2012. We undertook an economic evaluation of the program to ascertain the cost‐effectiveness of BL therapy in a specific LIC setting. Methods We compared the treatment of BL to usual care in a cohort of 122 patients treated between 2012 and 2014. Costs included variable, fixed, and family costs. Our primary measure of effectiveness was overall survival (OS). Patient outcomes were determined through prospective capture and retrospective chart abstraction. The cost per disability‐adjusted life‐year (DALY) averted was calculated using the World Health Organization’s Choosing Interventions That Are Cost‐Effective (WHO‐CHOICE) methodology. Results The 2‐year OS with treatment was 55% (95% CI, 45% to 64%). The cost per DALY averted in the treatment group was US$97 (Int$301). Cumulative estimate of national DALYs averted through treatment was 8607 years, and the total national annual cost of treatment was US$834,879 (Int$2,590,845). The cost of BL treatment fell well within WHO‐CHOICE cost‐effectiveness thresholds. The ratio of cost per DALY averted to per capita gross domestic product was 0.14, reflecting a very cost‐effective intervention. Conclusion This study demonstrates that treating BL with locally tailored protocols is very cost‐effective by international standards. Studies of this kind will furnish crucial evidence to help policymakers prioritize the allocation of LMIC health system resources among noncommunicable diseases, including childhood cancer.
Purpose “Endemic” Burkitt lymphoma (BL) is a common childhood cancer in Africa. Social and treatment factors may contribute to poor survival. With the aim of improving BL outcomes in Uganda, we undertook a comprehensive project (BL Project) that provided diagnostic support, access to standard chemotherapy, nutritional evaluations, and case management. We evaluated survival of children with BL in the context of the project. Patients and methods Patients followed by the BL Project who consented to research were enrolled in this study. Children with a pathology diagnosis consistent with BL were eligible. Data were collected prospectively. First‐line chemotherapy generally consisted of six cycles of cyclophosphamide, vincristine, low‐dose methotrexate (COM). We used Kaplan–Meier and Cox regression analyses to evaluate factors associated with overall survival (OS). Results Between July 2012 and June 2017, 341 patients with suspected BL presented to the BL Project. One hundred eighty patients with a pathology‐based diagnosis were included in this study. The median age was seven years (interquartile range, 5–9), 74% lived ≥100 km from the Uganda Cancer Institute, 61% had late‐stage disease, 84% had ECOG performance status < 3, 63% reported B‐symptoms, and 22% showed neurologic symptoms. Fewer than 10% abandoned therapy. The four‐year OS rate was 44% (95% CI, 36%–53%). In a multivariate model, ECOG status was significantly associated with mortality. Conclusion The BL Project reduced effects of lacking supportive care and oncology resources, and allowed patients from Uganda to receive curative intent therapy with minimal loss to follow‐up. Nonetheless, OS remains unacceptably low. Improved therapeutic approaches to endemic BL are urgently needed in Africa.
Delayed T-cell recovery is an important complication of allogeneic bone marrow transplantation (BMT). We demonstrate in murine models that donor BM-derived T cells display increased apoptosis in recipients of allogeneic BMT with or without GVHD. Although this apoptosis was associated with a loss of Bcl-2 and Bcl-X L expression, allogeneic recipients of donor BM deficient in Fas-, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-or Bax-, or BM-overexpressing Bcl-2 or Akt showed no decrease in apoptosis of peripheral donor-derived T cells. CD44 expression was associated with an increased percentage of BM-derived apoptotic CD4 ؉ and CD8 ؉ T cells. Transplantation of RAG-2-eGFP-transgenic BM revealed that proliferating eGFP lo CD44 hi donor BM-derived mature T cells were more likely to undergo to apoptosis than nondivided eGFP hi CD44 lo recent thymic emigrants in the periphery. Finally, experiments using carboxyfluorescein succinimidyl ester-labeled T cells adoptively transferred into irradiated syngeneic hosts revealed that rapid spontaneous proliferation (as opposed to slow homeostatic proliferation) and acquisition of a CD44 hi phenotype was associated with increased apoptosis in T cells. We conclude that apoptosis of newly generated donor-derived peripheral T cells after an allogeneic BMT contributes to delayed T-cell reconstitution and is associated with CD44 expression and rapid spontaneous proliferation by donor BM-derived T cells. IntroductionImmune deficiency after allogeneic bone marrow transplantation (BMT) is a major cause of posttransplantation morbidity and mortality. In contrast to the early recovery of innate immunity (myeloid and NK cells), all recipients of allogeneic BMT experience various degrees of posttransplantation deficiency in B-and T-cell reconstitution. 1,2 In particular, T-cell deficiency in adult recipients of a T cell-depleted (TCD) or unrelated BMT can negatively affect the clinical outcome of transplantation by increasing the risk of infection or malignant relapse. 1,3 Posttransplantation T-cell recovery is slower in adult BMT recipients than in pediatric BMT recipients, most probably because of a decreased capacity for thymic regeneration after puberty. 3,4 Naive T cells can expand in lymphopenic recipients, and this homeostatic T-cell proliferation contributes to the regulation of the size of the T-cell pool. 5,6 Homeostatic proliferation is controlled by cytokines (including interleukin 7 and IL-15) and interactions of the T-cell receptor with self-major histocompatibility complex (MHC) molecules. [7][8][9] Studies in experimental BMT models have shown that homeostatic proliferation of T cells contributes to peripheral T-cell reconstitution after allogeneic BMT in addition to de novo T-cell generation in the thymus of the recipient. 10 However, in addition to potential defects in posttransplantation thymopoiesis and impaired homeostatic proliferation, 2 clinical studies have suggested that peripheral apoptosis may also retard peripheral T-cell reconstitution afte...
1005 Background: Tucatinib (TUC) is an investigational, highly selective HER2 kinase inhibitor. HER2CLIMB (NCT02614794) showed clinically meaningful and statistically significant improvements in overall survival (OS) and progression free survival (PFS) in all pts, prolongation of PFS in pts with brain metastases (BM), and objective response rate (ORR) when TUC was added to trastuzumab (T) and capecitabine (C). Primary methods and outcomes have been reported previously (Murthy NEJM 2019). We report the results of exploratory efficacy analyses in pts with BM. Methods: All pts with HER2+ metastatic breast cancer (MBC) enrolled in HER2CLIMB had a baseline brain MRI. Pts with BM were eligible and classified as untreated, treated stable, or treated and progressing. Pts were randomized 2:1 to receive TUC or placebo, in combination with T and C. Efficacy analyses in pts with BM at baseline were performed by applying RECIST 1.1 to the brain based on investigator evaluation. CNS-PFS (progression in the brain or death) and OS were evaluated in BM pts overall. Intracranial (IC) confirmed ORR (ORR-IC) and IC duration of response (DOR-IC) were evaluated in BM pts with measurable IC disease. After isolated brain progression, pts could continue study therapy after local treatment until second progression, and time from randomization to second progression or death was evaluated. Results: Overall, 291 pts (48%) had BM at baseline: 198 (48%) in the TUC arm and 93 (46%) in the control arm. There was a 68% reduction in risk of CNS-PFS in the TUC arm (HR: 0.32; 95% CI: 0.22, 0.48; P < 0.0001). Median CNS-PFS was 9.9 mo in the TUC arm vs 4.2 mo in the control arm. Risk of death overall was reduced by 42% in the TUC arm (OS HR: 0.58; 95% CI: 0.40, 0.85; P = 0.005). Median OS was 18.1 mo vs 12.0 mo. ORR-IC was higher in the TUC arm (47.3%; 95% CI: 33.7, 61.2) vs the control arm (20.0%; 95% CI: 5.7, 43.7). Median DOR-IC was 6.8 mo (95% CI: 5.5, 16.4) vs 3.0 mo (95% CI: 3.0, 10.3). In pts with isolated brain progression who continued study therapy after local treatment (n = 30), risk of second progression or death was reduced by 67% (HR: 0.33; 95% CI: 0.11, 1.02), and median PFS from randomization was 15.9 mo vs 9.7 mo, favoring the TUC arm. Conclusions: In pts with heavily previously treated HER2+ MBC with BM, TUC in combination with T and C doubled the ORR-IC, reduced risk of IC progression or death by two thirds and reduced risk of death by nearly half. If approved, TUC in combination with T and C has the potential to become a new standard of care in pts with HER2+ MBC with and without BM. Clinical trial information: NCT02614794 .
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