Future health of AYA survivors Burkart, Madelyn; Sanford, Stacy; Dinner, Shira ...
Pediatric blood & cancer,
February 2019, Letnik:
66, Številka:
2
Journal Article
Recenzirano
Adolescent and young adult (AYA) oncology patients (ages 15–39) have been identified as a group with healthcare disparities including gaps and challenges in diagnosis, access to care, research, ...clinical trial participation, and cure rates. Like other patient groups with cancer or other chronic illnesses, disparities can lead to poor future health and outcomes, which is a well‐recognized concern within the AYA population. Cancer is the leading disease‐related cause of death in this age range. Numerous interested groups including the National Cancer Institute have met to address the research and cancer care needs of AYAs. This review highlights how these gaps in care during and after treatment can affect future health of this population of patients. Access to care, models of survivorship care, and lack of provider education are discussed. Survivorship care and use of guidelines, and promotion of psychosocial support and health behaviors during treatment and beyond are essential to optimizing future health of AYA patients.
Mantle cell lymphoma (MCL) is a rare mature B-cell non-Hodgkin lymphoma (B-NHL) with historically poor outcomes. Virtually all patients will eventually experience refractory or relapsed (R/R) ...disease, with a virulent course of resistance and serial relapses, making treatment challenging. The available therapies for R/R MCL are not curative with conventional therapy, their goal being to palliate and prolong survival. A variety of agents approved for R/R MCL, including Bruton's tyrosine kinase inhibitors (BTKi), changed the treatment landscape of R/R MCL. In the pre-BTKi era, the median progression-free survival (PFS) in R/R disease was 4-9 months. With the introduction of ibrutinib, the median PFS improved to 13-14.6 months. Despite these impressive results, the duration of response is limited, and resistance to BTKi inevitably develops in a subset of patients. Outcomes after progression on BTKi are extremely poor, with a median overall survival (OS) of 6 to 10 months. Certain therapies, such as chimeric antigen receptor (CAR) T cells, have shown promising results after BTKi failure. The preferred combination and sequencing of therapies beyond BTKi remain unestablished and are currently being investigated. In this review, we describe the current evidence for the available treatment of R/R MCL after progression on BTKi.
Anti-neutrophil cytoplasmic antibody-associated (ANCA-associated) small vessel necrotizing vasculitis is caused by immune-mediated inflammation of the vessel wall and is diagnosed in some cases by ...the presence of myeloperoxidase-specific antibodies (MPO-ANCA). This multicenter study sought to determine whether differences in ANCA epitope specificity explain why, in some cases, conventional serologic assays do not correlate with disease activity, why naturally occurring anti-MPO autoantibodies can exist in disease-free individuals, and why ANCA are undetected in patients with ANCA-negative disease. Autoantibodies from human and murine samples were epitope mapped using a highly sensitive epitope excision/mass spectrometry approach. Data indicated that MPO autoantibodies from healthy individuals had epitope specificities different from those present in ANCA disease. Importantly, this methodology led to the discovery of MPO-ANCA in ANCA-negative disease that reacted against a sole linear sequence. Autoantibodies against this epitope had pathogenic properties, as demonstrated by their capacity to activate neutrophils in vitro and to induce nephritis in mice. The confounder for serological detection of these autoantibodies was the presence of a fragment of ceruloplasmin in serum, which was eliminated in purified IgG, allowing detection. These findings implicate immunodominant epitopes in the pathology of ANCA-associated vasculitis and suggest that autoantibody diversity may be common to other autoimmune diseases.
B cell significance in ANCA disease pathogenesis is underscored by the finding that ANCA alone can cause disease in mouse models and by the effectiveness of rituximab as therapy in ANCA-small vessel ...vasculitis (ANCA-SVV). To avoid infections and adverse events from therapy, clinicians require improved markers of disease activity and impending relapse to guide immunosuppression strategies after rituximab treatment.
The B cell phenotype was investigated in patients with active ANCA-SVV and in remission. From 2003 to 2009, 54 patients were followed longitudinally for 4-99 months and compared with 68 healthy controls. In a subset of 19 patients, the B cell immunophenotype was examined in samples after rituximab therapy.
Patients with active ANCA-SVV had lower %CD5(+) B cells, whereas %CD5(+) B cells from patients in remission were indistinguishable from healthy controls. After rituximab, median time to relapse was 31 months in patients maintaining normalized %CD5(+) B cells, with or without maintenance immunosuppression. Among patients whose B cells repopulated with low %CD5(+) B cells or had a sharply declining %CD5(+) B cells, those who were on low or no maintenance immunosuppression relapsed sooner (median 17 months) than patients who were maintained on high levels of oral maintenance immunosuppression (29 months; P=0.002).
The %CD5(+) B cells, as a component of the human B regulatory cell phenotype, is a useful indicator of disease activity, remission, and future relapse, and thus may guide remission maintenance therapy after rituximab treatment.
Background
Targeted therapies and checkpoint blockade therapy (CBT) have shown efficacy for patients with Hodgkin lymphoma (HL) in the relapsed and refractory (R/R) setting, but once discontinued ...owing to progression or side effects, it is unclear how successful further therapies will be. Moreover, there are no data on optimal sequencing of these treatments with standard therapies and other novel agents. In a multicenter, retrospective analysis, we investigated whether exposure to CBT could sensitize HL to subsequent therapy.
Materials and Methods
Seventeen centers across the U.S. and Canada retrospectively queried medical records for eligible patients. The primary aim was to evaluate the overall response rate (ORR) to post‐CBT treatment using the Lugano criteria. Secondary aims included progression‐free survival (PFS), duration of response, and overall survival (OS).
Results
Eighty‐one patients were included. Seventy‐two percent had stage III–IV disease, and the population was heavily pretreated with a median of four therapies before CBT. Most patients (65%) discontinued CBT owing to progression. The ORR to post‐CBT therapy was 62%, with a median PFS of 6.3 months and median OS of 21 months. Post‐CBT treatment regimens consisted of chemotherapy (44%), targeted agents (19%), immunotherapy (15%), transplant conditioning (14%), chemotherapy/targeted combination (7%), and clinical trials (1%). No significant difference in OS was found when stratified by post‐CBT regimen.
Conclusion
In a heavily pretreated R/R HL population, CBT may sensitize patients to subsequent treatment, even after progression on CBT. Post‐CBT regimen category did not impact OS. This may be a novel treatment strategy, which warrants further investigation in prospective clinical trials.
Implications for Practice
Novel, life‐prolonging treatment strategies in relapsed and refractory (R/R) Hodgkin lymphoma (HL) are greatly desired. The results of this multicenter analysis concur with a smaller, earlier report that checkpoint blockade therapy (CBT) use in R/R HL may sensitize patients to their subsequent treatment. This approach may potentially enhance therapeutic options or to bridge patients to transplant. Prospective data are warranted prior to practice implementation. As more work is done in this area, we may also be able to optimize sequencing of CBT and novel agents in the treatment paradigm to minimize treatment‐related toxicity and thus improve patient quality of life.
This study investigated the outcome of checkpoint blockade therapy on subsequent treatment for patients with relapsed and refractory Hodgkin lymphoma in a large, multicenter, retrospective analysis.
While there is clear evidence to suggest poorer outcome associated with multi-hit (MH) TP53 mutation compared to single-hit (SH) in lower-risk myelodysplastic syndrome (MDS), data are conflicting in ...both higher-risk MDS and acute myeloid leukemia (AML). We conducted an indepth analysis utilizing data from 10 US academic institutions to study differences in molecular characteristics and outcomes of SH (n= 139) versus MH (n= 243) TP53MTAML. Complex cytogenetics (CG) were more common in MH compared to SH TP53MT AML (p <0.001); whereas ASXL1 (p= <0.001), RAS (p<0.001), splicing factor (p= 0.003), IDH1/2 (p= 0.001), FLT3 ITD (p= <0.001) and NPM1 (p= 0.005) mutations significantly clustered with SH TP53MT AML. Survival after excluding patients who received best supportive care alone was dismal but not significantly different between SH and MH (event free survival EFS: 3.0 vs 2.20 months, p= 0.22/ overall survival OS: 8.50 vs 7.53 months, respectively, p= 0.13). In multivariable analysis, IDH1 mutation and allogeneic hematopoietic stem cell transplantation (allo-HCT) as a time-dependent covariate were associated with superior EFS (HR; 0.44, 95% CI: 0.19-1.01, p= 0.05/ HR; 0.34, 95% CI: 0.18-0.62, p<0.001) and OS (HR; 0.24, 95% CI: 0.08-0.71, p= 0.01/ HR; 0.28, 95% CI: 0.16-0.47, p<0.001). While complex CG (HR; 1.56, 95% CI: 1.01-2.40, p= 0.04) retained unfavorable significance for OS. Our analysis suggests that unlike in MDS, multihit TP53MT is less relevant in independently predicting outcomes in patients with AML.
There have been major paradigm shifts in the treatment of Philadelphia chromosome negative (Ph-) acute lymphoblastic leukemia (ALL) in the last decade with the introduction of new immunotherapies and ...targeted agents, adoption of pediatric-type chemotherapy protocols in younger adults as well as chemotherapy light approaches in older adults and the incorporation of measurable residual disease (MRD) testing to inform clinical decision making. With this, treatment outcomes in adult Ph- ALL have improved across all age groups. However, a subset of patients will still develop relapsed disease, which can be challenging to treat and associated with poor outcomes. Here we review the treatment of Ph- ALL in both younger and older adults, including the latest advancements and future directions.
Mantle cell lymphoma (MCL) is an aggressive, difficult to treat subtype of lymphoma, resulting in relapses and poor outcomes. Novel agents such as Bruton tyrosine kinase (BTK) inhibitors have been ...studied in the treatment of relapsed/refractory (R/R) MCL. BTK inhibitor ibrutinib, in particular, has demonstrated improvement in survival outcomes of R/R MCL. Despite these advancements, many cases of MCL, including the more aggressive blastoid and pleomorphic variants, will undergo disease progression leading to poor survival outcomes. Blastoid variant MCL is associated with an increased risk of central nervous system (CNS) involvement, causing high mortality rates. In this case report, we discuss a patient with a diagnosis of blastoid MCL with CNS relapse who achieved a complete response (CR) after receiving standard rituximab plus ifosfamide-carboplatin-etoposide (R-ICE) salvage chemotherapy with the addition of ibrutinib. The patient subsequently underwent autologous stem cell transplantation (autoSCT) and maintained CR with ibrutinib maintenance.
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