Checkpoint Blockade Treatment May Sensitize Hodgkin Lymphoma to Subsequent Therapy.

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.

Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia.

Drug sensitivity and resistance testing on diagnostic leukemia samples should provide important functional information to guide actionable target and biomarker discovery. We provide proof of concept data by profiling 60 drugs on 68 acute lymphoblastic leukemia (ALL) samples mostly from resistant disease in cocultures of bone marrow stromal cells. Patient-derived xenografts retained the original pattern of mutations found in the matched patient material. Stromal coculture did not prevent leukemia cell cycle activity, but a specific sensitivity profile to cell cycle-related drugs identified samples with higher cell proliferation both in vitro and in vivo as leukemia xenografts. In patients with refractory relapses, individual patterns of marked drug resistance and exceptional responses to new agents of immediate clinical relevance were detected. The BCL2-inhibitor venetoclax was highly active below 10 nM in B-cell precursor ALL (BCP-ALL) subsets, including MLL-AF4 and TCF3-HLF ALL, and in some T-cell ALLs (T-ALLs), predicting in vivo activity as a single agent and in combination with dexamethasone and vincristine. Unexpected sensitivity to dasatinib with half maximal inhibitory concentration values below 20 nM was detected in 2 independent T-ALL cohorts, which correlated with similar cytotoxic activity of the SRC inhibitor KX2-391 and inhibition of SRC phosphorylation. A patient with refractory T-ALL was treated with dasatinib on the basis of drug profiling information and achieved a 5-month remission. Thus, drug profiling captures disease-relevant features and unexpected sensitivity to relevant drugs, which warrants further exploration of this functional assay in the context of clinical trials to develop drug repurposing strategies for patients with urgent medical needs.

Financial toxicity in patients with leukemia undergoing hematopoietic stem cell transplantation: A systematic review.

Financial toxicity (FT) is a term used to describe the objective financial burden of cancer care including the associated coping behaviors used by patients and their caregivers. FT has been shown to result in both direct financial burdens and in clinically relevant outcomes, such as non-adherence with care, diminished quality of life, and even decreased overall survival. Much of the data has been described in solid tumors, with limited investigations in the malignant hematology population. Patients with hematologic malignancies undergoing hematopoietic stem cell transplantation (HSCT) face a unique financial burden driven by lengthy hospitalizations and acute and chronic morbidity that have downstream implications on their income and costs. In this review, we discuss the prevalence of FT in patients with leukemia who are eligible for HSCT. We review the impact of FT on financial and clinical outcomes and the role of various interventions that have been studied within this population.

Do Prostate Cancer Patients With Markedly Elevated PSA Benefit From Radiation Therapy?: A Population-based Study.

OBJECTIVES: Patients with clinically localized prostate cancer but markedly elevated prostate-specific antigen (PSA) are often treated with systemic agents alone. We hypothesized that they would benefit from radiation therapy. METHODS: We utilized the Survival, Epidemiology and End Results (SEER) Database for patients diagnosed with nonmetastatic prostate cancer from 2004 to 2008. Patients treated surgically or with brachytherapy were excluded. Survival was analyzed using the Kaplan-Meier method and Cox proportional hazard models. Propensity score was used to adjust for the nonrandomized assignment of local therapies. RESULTS: A total of 75,539 nonmetastatic prostate cancer patients were identified who received either radiotherapy or no local treatment. Median age was 70 years. Median follow-up of alive subjects was 60 months, with an interquartile range of 47 to 77 months. Estimated 4-year overall survival of entire population was 88%. Significant prognostic variables for overall survival on multivariate analysis included age, grade, PSA level, T stage, and use of radiation therapy. Use of radiation therapy was the most powerful predictor of both cause-specific and overall survival (HR=0.41 and 0.46, respectively, P<0.001). The benefit conferred by local treatment was seen even in subjects with PSA≥75 ng/mL. Four-year cancer-specific survival was 93.8% in those receiving radiation treatments versus 76.5% in those who did not receive any local treatment. CONCLUSIONS: Survival was significantly improved by radiotherapy for localized prostate cancer. Extremely high PSA levels (≥25 ng/mL) should not be considered a contraindication to local treatment.

Prostate-specific membrane antigen-based therapeutics.

Prostate cancer (PC) is the most common noncutaneous malignancy affecting men in the US, leading to significant morbidity and mortality. While significant therapeutic advances have been made, available systemic therapeutic options are lacking. Prostate-specific membrane antigen (PSMA) is a highly-restricted prostate cell-surface antigen that may be targeted. While initial anti-PSMA monoclonal antibodies were suboptimal, the development of monoclonal antibodies such as J591 which are highly specific for the external domain of PSMA has allowed targeting of viable, intact prostate cancer cells. Radiolabeled J591 has demonstrated accurate and selective tumor targeting, safety, and efficacy. Ongoing studies using anti-PSMA radioimmunotherapy with (177)Lu-J591 seek to improve the therapeutic profile, select optimal candidates with biomarkers, combine with chemotherapy, and prevent or delay the onset of metastatic disease for men with biochemical relapse. Anti-PSMA monoclonal antibody-drug conjugates have also been developed with completed and ongoing early-phase clinical trials. As PSMA is a selective antigen that is highly overexpressed in prostate cancer, anti-PSMA-based immunotherapy has also been studied and utilized in clinical trials.