Real-World Analysis of Off-Label Use of Molecularly Targeted Therapy in a Large Academic Medical Center Cohort.

PURPOSE: The primary objective of this study is to quantify the use of off-label molecularly targeted therapy and describe the clinical situations in which off-label targeted therapy are used. A key secondary objective is to report the outcomes of patients treated with off-label use of targeted therapy. PATIENTS AND METHODS: We searched the electronic health record between 2000 and 2020 at our center to characterize the volume, clinical settings, and outcomes associated with off-label use of targeted therapies in different types of solid tumors. RESULTS: Among 46,712 patients who received targeted therapies, we identified 119 instances of off-label use of targeted therapy. Colon cancer was the most common cancer type to receive off-label targeted therapy in 18 patients (15.1%), followed by 13 with non-small-cell lung cancer (10.9%), eight with cholangiocarcinoma (6.7%), and seven with glioblastoma (5.9%). The most frequent molecular rationale for off-label therapy came from a comprehensive next-generation sequencing test (53.7%). The most frequently mutated gene that provided the rationale for targeted therapy was BRAF (20.1%), with BRAFV600E being the most common molecular alteration overall (15.1%). The median duration of off-label targeted therapy was 3.58 months, and the overall survival of treated patients was 7.59 months. There were 37 patients (31.1%) treated for longer than 6 months, 23 patients (19.3%) who survived ≥ 2 years, and 13 patients who were still on therapy as of June 2020. CONCLUSION: In this large cohort study of patients with solid tumors, off-label use of targeted therapy was uncommon. With that said, a notable proportion of patients had treatment durations ≥ 6 months and survivals of ≥ 2 years.

Genomic Profiling of Combined Hepatocellular Cholangiocarcinoma Reveals Genomics Similar to Either Hepatocellular Carcinoma or Cholangiocarcinoma.

PURPOSE: Combined hepatocellular cholangiocarcinoma (cHCC-CCA) is a rare, aggressive primary liver carcinoma, with morphologic features of both hepatocellular carcinomas (HCC) and liver cholangiocarcinomas (CCA). METHODS: The genomic profiles of 4,975 CCA, 1,470 HCC, and 73 cHCC-CCA cases arising from comprehensive genomic profiling in the course of clinical care were reviewed for genomic alterations (GA), tumor mutational burden, microsatellite instability status, genomic loss of heterozygosity, chromosomal aneuploidy, genomic ancestry, and hepatitis B virus status. RESULTS: In cHCC-CCA, GA were most common in TP53 (65.8%), TERT (49.3%), and PTEN (9.6%), and 24.6% cHCC-CCA harbored potentially targetable GA. Other GA were predominantly associated with either HCC or CCA, including, but not limited to, TERT, FGFR2, IDH1, and presence of hepatitis B virus. On the basis of these features, a machine learning (ML) model was trained to classify a cHCC-CCA case as CCA-like or HCC-like. Of cHCC-CCA cases, 16% (12/73) were ML-classified as CCA-like and 58% (42/73) cHCC-CCA were ML-classified as HCC-like. The ML model classified more than 70% of cHCC-CCA as CCA-like or HCC-like on the basis of genomic profiles, without additional clinico-pathologic input. CONCLUSION: These findings demonstrate the use of ML for classification as based on a targeted exome panel used during routine clinical care. Classification of cHCC-CCA by genomic features alone creates insights into the biology of the disease and warrants further investigation for relevance to clinical care.

Landscape Analysis of Oncology Mobile Health Applications.

PURPOSE: More than 325,000 mobile health (mhealth) applications (apps) have been developed. We sought to describe the state of oncology-specific apps and to highlight areas of strength and opportunities for future development. METHODS: We searched for oncology apps in the Apple iOS and Google Play app stores in January 2020. Apps were classified by English language support, date of last update, downloads, intended audience, intended purpose, and developer type. RESULTS: We identified 794 oncology-specific, English language applications; only 257 (32%) met basic recency standards and were considered evaluable. Of evaluable apps, almost half (47%) were found in the Medical Store Category and the majority were free (88%). The most common intended audience was health care professionals (45%), with 28% being geared toward the general public and 27% being intended for patients. The intended function was education for 36%, clinical decision support for 19.5%, and patient support for 18%. Only 23% of education apps and 40% of clinical decision support apps reported any formal app content review process. Web developers created 61.5% of apps, scientific societies created 10%, and hospitals or health care organizations created just 6%. Of 54 studies that used mobile apps in oncology identified by a recent meta-analysis, only two could be matched to commercially available apps from our study, suggesting a substantial divide between investigation and product dissemination. CONCLUSION: Relatively few oncology-related apps exist in the commercial marketplace, up-to-date apps are uncommon, and there is a notable absence of key oncology stakeholders in app development. Meaningful development opportunities exist.

Multicenter analysis of outcomes in blastic plasmacytoid dendritic cell neoplasm offers a pretargeted therapy benchmark.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an uncommon hematologic malignancy with poor outcomes. Existing data on the clinical behavior of BPDCN are limited because reported outcomes are from small retrospective series, and standardized treatment guidelines are lacking. The interleukin-3 cytotoxin conjugate tagraxofusp was recently tested in phase 1/2 trials that led to US Food and Drug Administration approval, the first ever for BPDCN. However, because there was no matched internal comparator in this or any clinical study to date, results of BPDCN trials testing new drugs are difficult to compare with alternative therapies. We therefore sought to define the clinical characteristics and outcomes of a group of patients with BPDCN treated at 3 US cancer centers in the modern era but before tagraxofusp was available. In 59 studied patients with BPDCN, the median overall survival from diagnosis was 24 months, and outcomes were similar in patients with "skin only" or with systemic disease at presentation. Intensive first-line therapy and "lymphoid-type" chemotherapy regimens were associated with better outcomes. Only 55% of patients received intensive chemotherapy, and 42% of patients underwent stem cell transplantation. Clinical characteristics at diagnosis associated with poorer outcomes included age >60 years, abnormal karyotype, and terminal deoxynucleotidyltransferase (TdT) negativity in the BPDCN cells. We also identified disease responses to pralatrexate and enasidenib in some patients. This study highlights poor outcomes for patients with BPDCN in the modern era and the need for new treatments. Outcomes from ongoing clinical trials for BPDCN can be evaluated relative to this contemporary cohort.

Utilizing a PLASMIC score-based approach in the management of suspected immune thrombotic thrombocytopenic purpura: a cost minimization analysis within the Harvard TMA Research Collaborative.

The PLASMIC score is a recently described clinical scoring algorithm that rapidly assesses the probability of severe ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) deficiency among patients presenting with microangiopathic haemolytic anaemia. Using a large multi-institutional cohort, we explored whether an approach utilizing the PLASMIC score to risk-stratify patients with suspected immune thrombotic thrombocytopenic purpura (iTTP) could lead to significant cost savings. Our consortium consists of institutions with an unrestricted approach to ADAMTS13 testing (Group A) and those that require pre-approval by the transfusion medicine service (Group B). Institutions in Group A tested more patients than those in Group B (P < 0·001) but did not identify more cases of iTTP (P = 0·29) or have lower iTTP-related mortality (P = 0·84). Decision tree cost analysis showed that applying a PLASMIC score-based strategy to screen patients for ADAMTS13 testing in Group A would have reduced costs by approximately 27% over the 12-year period of our study compared to the current approach. Savings were primarily driven by a reduction in unnecessary therapeutic plasma exchanges, but lower utilization of ADAMTS13 testing and subspecialty consultations also contributed. Our data indicate that using the PLASMIC score to guide ADAMTS13 testing and the management of patients with suspected iTTP could be associated with significant cost savings.

Predictors of relapse and efficacy of rituximab in immune thrombotic thrombocytopenic purpura.

Patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP) often experience life-threatening relapses of the disease, and rituximab (RTX) can be used to mitigate relapse risk. However, the predictors of relapse in iTTP and the magnitude and duration of effect of RTX remain key unanswered questions. Using a multi-institutional cohort of consecutive adult patients with iTTP, we used survival analysis to compare relapse rates between patients who received RTX during the index presentation with acute iTTP and those who did not. Of 124 patients, 60 (48%) received RTX and 34 (27%) experienced relapse. Median time to relapse was 3.71 (interquartile range, 1.75-4.9) and 1.33 (interquartile range, 0.43-2.35) years for RTX-treated and untreated patients, respectively. RTX conferred protection from relapse at 1 year of follow-up (P = .01) but not at 5 years of follow-up. Extended Cox regression was then used to identify predictors of relapse and to estimate the protective effect of RTX. The following parameters were independently associated with increased risk for subsequent relapse: presenting in iTTP relapse (hazard ratio [HR], 2.97; 95% confidence interval [CI], 1.4-6.4), age younger than 25 years (HR, 2.94; 95% CI, 1.2-7.2), and non-O blood group (HR, 2.15; 95% CI, 1.06-4.39). RTX initially provided protection from relapse (HR, 0.16; 95% CI, 0.04-0.70), but this effect gradually diminished, returning to the baseline risk for untreated patients at approximately 2.6 years. Patients who are young, have non-O blood group, or present with relapsed iTTP are at increased risk for subsequent relapse. RTX appears to confer short-term protection from relapse.

Induction chemotherapy in acute myeloid leukaemia: origins and emerging directions.

PURPOSE OF REVIEW: This review summarizes the hallmark developments in induction chemotherapy for acute myeloid leukaemia and further describes future directions in its evolution. RECENT FINDINGS: We describe the origin of induction chemotherapy. We also describe notable modifications and adjustments to 7+3 induction chemotherapy since its development. Finally, we describe new efforts to modify and add new agents to induction therapy, including '7+3 Plus' combinations. SUMMARY: Induction chemotherapy remains the standard of care for the majority of patients with acute myeloid leukaemia. However, its success is limited in a subset of patients by toxicity, failure to achieve remission and potential for subsequent relapse. Novel agents such as mutant fms like tyrosine kinase 3 inhibitors, mutant isocitrate dehydrogenase inhibitors, CD33-antibody drug conjugates and liposomal formulations have demonstrated significant potential as modifications to traditional induction chemotherapy.

Isocitrate dehydrogenase (IDH) inhibition as treatment of myeloid malignancies: Progress and future directions.

Isocitrate dehydrogenase (IDH) is an essential metabolic enzyme. Over the last two decades, there has been a growing focus on the metabolic derangements that occur with IDH1 and IDH2 mutations. The altered IDH protein leads to accumulation of 2-hydroxyglutarate (2-HG), a metabolite with oncogenic activity via epigenetic mechanisms. The advent of IDH inhibitors has engendered hope in novel and targeted therapies in IDH1/2 mutant myeloid malignancies. We here summarize the basic physiology of IDH, the metabolic and oncogenic consequences of mutant IDH1/2, and the clinical significance of IDH inhibition in hematologic malignancies. We also discuss completed and ongoing clinical trials focusing on the inhibition of IDH proteins, which have demonstrated preliminary indications of efficacy. The promise of IDH inhibition is now being further investigated as a novel therapeutic approach for AML and other myeloid malignancies.

The Approach to Acute Lymphoblastic Leukemia in Older Patients: Conventional Treatments and Emerging Therapies.

Acute lymphoblastic leukemia (ALL) among older adult patients presents significant clinical challenges. As opposed to pediatric populations, in whom long-term outcomes are markedly superior, those for adults remain grim. Nevertheless, younger adults with ALL have experienced a steady improvement in long-term survival in the last few decades. This is significantly different for older ALL patients, for whom long-term outcomes remain poor. Conventional chemotherapies are associated with sub-optimal outcomes and increased toxicity in this population. However, several emerging therapies, including antibody-drug conjugates, bi-specific engagers, and chimeric antigen receptor (CAR) T cells, have demonstrated much promise and are either incorporated into the existing therapeutic paradigms or being actively investigated to improve outcomes.