Phase I / II trial of metformin as a chemo-radiosensitizer in a head and neck cancer patient population.

OBJECTIVES: Retrospective studies have shown that head and neck squamous cell carcinoma (HNSCC) patients taking metformin demonstrate superior survival compared to their counterparts. We sought to determine whether metformin combined with chemoradiation would improve HNSCC patient survival compared to historical controls. MATERIALS AND METHODS: We conducted a Phase I/II prospective, single arm clinical trial in patients with newly diagnosed HNSCC (NCT02949700). Patients received platinum-based chemoradiation in combination with orally dosed metformin at one of 2 doses- 850 mg BID or 1500 mg BID administered during radiation, with a 2-week lead-in phase. Toxicity, disease response and survival metrics were ascertained throughout the study period. RESULTS: A total of 25 patients were evaluable for toxicity and survival; 9 failed to reach the predetermined 70% compliance with the study drug. No dose limiting toxicities were identified in the Phase I component and there were no grade 4 adverse events likely related to metformin throughout the study. The primary outcome for the Phase II component was met with a response rate of 96%. Three-year overall survival was ∼70% in the per protocol p16 + cohort and 0% in the per protocol p16- cohort. Survival among participants with a ≥70% metformin compliance to <70% metformin compliance demonstrated a trend towards improvement in the ≥70% compliance cohort, though this did not reach significance. CONCLUSION: Metformin is well tolerated during concurrent chemoradiation for HNSCC. Its effectiveness as a chemo-radiosensitizer remains unclear and will require further study with randomized controlled clinical trials in this patient population.

Persistent ethnicity-associated disparity in anti-tumor effectiveness of immune checkpoint inhibitors despite equal access.

We reviewed response to immune checkpoint inhibitors (ICI) of 207 patients with diagnoses of lung or head and neck cancer treated with chemotherapy/ICI combination therapy and ICI monotherapy between 2015 and 2020 at one of three clinical pavilions associated with the Dan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine. Two of these pavilions (Harris Health System and the Michael E. DeBakey Veterans Affairs Medical Center) serve large minority populations and provide equal access to care regardless of means. 174 patients had a diagnosis of lung cancer (non-small cell or small cell) and 33 had a diagnosis of head and neck squamous cell carcinoma (HNSCC). 38% self-identified as Black, 45% as non-Hispanic White, and 18% as Hispanic. The objective response rate (ORR) was similar for lung cancer (35.057%) and HNSCC patients (30.3%) (p=0.894). The ORR for Hispanic and Black patients was lower compared to non-Hispanic White patients (H 27.0%, B 32.5%, W 38.7%; H vs. W p=0.209; B vs. W p=0.398). When considering only patients treated with ICI monotherapy, the ORR for Hispanic patients dropped further to 20.7% while the ORR of Black and non-Hispanic White patients remained about the same (B 29.3% and W 35.9%, H vs. W p=0.133; B vs. W p=0.419). Immune related adverse events were the lowest in the Hispanic population occurring in only 30% of patients compared to 40% of patients in the Black cohort and 50% of the non-Hispanic White cohorts.

Clinical Outcomes of Patients With Newly Diagnosed Acute Lymphoblastic Leukemia in a County Hospital System.

BACKGROUND: Major advances in the treatment of acute lymphoblastic leukemia (ALL) over the past decade have resulted in 5-year overall survival (OS) rates of 80% in mature B cell ALL, 50% in precursor B cell ALL, 50% to 60% in T cell ALL, and 60% to 70% in Philadelphia chromosome-positive (Ph+) ALL, as reported in studies from large, specialized centers. However, many patients treated in the community have limited access to novel therapies and stem cell transplantation (HSCT). PATIENTS AND METHODS: The purpose of this retrospective cohort analysis was to evaluate the clinical outcomes of patients ≥ 16 years with newly diagnosed ALL treated from October 2007 to June 2019 in the Harris County Health System, Houston, TX. RESULTS: One hundred forty-six patients were included, with newly diagnosed pre-B-ALL (n = 127), T-ALL (n = 18), and chronic myeloid leukemia and/or lymphoid blast crisis (n = 1). Median age was 35 years (16-82) at diagnosis, and 81(55%) were male. The majority of patients with pre-B ALL identified as Hispanic (n = 118, or 92%). Ninety-eight (67%) of patients were uninsured or indigent, receiving care under the county's financial assistance programs. Hyper-CVAD-based induction chemotherapy was administered in 134 (92%) of patients, while 9 (6%) were treated on different protocols, and 3 (2%) were not treated due to early death, or patient refusal. Imatinib was the most common TKI used in 17 of 30 or 57% of patients with Ph+ disease. Out of 137 evaluable for response patients, 117 (85%) achieved complete remission (CR + CRi), 19 (14%) had refractory disease, and 1 (1%) died within 4 weeks of diagnosis. Median follow-up time was 50 months (1.5-135). For the entire study cohort, the median duration of CR/CRi was 15.4 months. Out of 62 patients who were eligible for consolidative HSCT at first CR, 52 (89%) did not receive it, with lack of insurance being the most common reason (n = 29, or 56%). Barriers to utilization of novel therapies such as blinatumomab or CAR-T were also observed. Patient-caused delays in administration of chemotherapy and treatment interruptions of at least 30 days were seen in 31(23%) patients. At 1, 2, and 5 years, relapse rates were 37%, 56%, and 70%. Recurrent and/or refractory disease was the cause of death in most patients (n = 69 [85%]). Five-year EFS and OS rates were 22% and 38% for patients with pre-B ALL, 24% and 44% for patients with T ALL, and 13% and 27% for patients with Ph+ ALL. Median OS was significantly increased (not reached [NR] vs. 24 months; P = .00088) in patients with an indication for HSCT in first CR due to high-risk features who underwent HSCT, versus those who did not. CONCLUSION: Addressing barriers raised by socioeconomic disparities, increasing access to effective therapies, and including patients with ALL treated in the community in clinical trials may improve survival for underserved populations.

Safety Analysis of Five Randomized Controlled Studies of Daratumumab in Patients With Multiple Myeloma.

BACKGROUND: Multiple studies have demonstrated the efficacy and safety of daratumumab for relapsed/refractory multiple myeloma (MM) and primary treatment for transplant-eligible and -ineligible patients. MATERIALS AND METHODS: We conducted an integrated safety analysis to characterize the frequency, severity, natural history, and outcomes of adverse events (AEs) with daratumumab versus comparators. Data were pooled from 5 completed phase III randomized controlled studies that had included 1798 daratumumab-treated and 1797 comparator-treated patients with MM as a first line in both transplant-eligible and transplant-ineligible patients and for relapsed/refractory disease. Safety analyses included reporting of AEs using crude and exposure-adjusted incidence rates. RESULTS: The median follow-up duration was 16.84 months (range, 7.4-28 months) for both daratumumab-treated and comparator-treated patients. Discontinuation for any reason occurred less often with daratumumab (22% vs. 33.9%), although discontinuation because of AEs occurred at similar rates (25% vs. 26%) as did deaths owing to AEs (2.25% vs. 1.84%). When adjusted for exposure, neutropenia, lymphopenia, diarrhea, fatigue, dyspnea, pneumonia, and hypertension were the only common grade 3/4 AEs reported more often with daratumumab than with the comparators. The prevalence of common grade 3/4 AEs with daratumumab were < 7% apart from neutropenia, lymphopenia, and pneumonia (45.9% vs. 32.3%, 13% vs. 7.5%, and 10.6% vs. 7.2%, respectively). Grade 3/4 daratumumab infusion-related reactions happened in 3.8% of patients. The majority of infusion-related reactions occurred after the first infusion. CONCLUSIONS: These results from an integrated analysis support a favorable benefit/risk profile of daratumumab in patients with MM.

Acute Lymphoblastic Leukemia Presenting Initially as Spinal Cord Compression: When Chemotherapy Alone Is Enough.

Spinal cord compression (SCC) is a rare initial presentation and complication of acute lymphoblastic leukemia (ALL) with nearly all reported cases occurring in the pediatric population. We report a 38-year-old previously healthy man who presented with acute on chronic lower back pain, gait instability, urinary retention, and severe thrombocytopenia. Radiologic examination revealed two soft tissue masses of the thoracic spine associated with compression fractures causing spinal canal narrowing and cord compression. Bone marrow biopsy confirmed the diagnosis of ALL. Immediate initiation of high-dose corticosteroids and systemic chemotherapy resolved the patient's symptoms without radiation therapy or surgical intervention. After two courses of chemotherapy, the patient achieved complete remission in the bone marrow. Rapid administration of chemotherapy alone in this case resulted in a complete resolution of SCC. Given the rarity of this complication in adults, no standardized treatment has been established. The success of this case recommends chemotherapy as the initial management of SCC in chemotherapy-naïve ALL.