Treatment of MDS, AML and CMML Relapse after Allogeneic Blood Stem Cell Transplantation with Azacitidine, Lenalidomide and Donor Lymphocyte Infusions - Final Results of the Prospective Azalena-Trial (NCT02472691)

Background Azacitidine (Aza) in combination with donor lymphocyte infusions (DLI) is an established treatment option for pts with relapse of myeloid malignancies after allo-SCT. Accounting for its immunomodulatory and anti-leukemic properties, we considered Lenalidomide (Len) to be a synergistic partner for Aza and DLI that may further improve response rate and outcome. To investigate the tolerability and efficacy of the combination of Aza, Len and DLI as first salvage therapy for relapsed MDS, AML and CMML after allo-SCT we performed a prospective, multicenter, single-arm phase-II trial. Results from two safety interim analyses have previously been reported. Here, we report the final results from this investigator-initiated trial. Design/Methods: Patients with relapse of MDS, AML and CMML after first allo-SCT were eligible. Envisaged treatment according to the protocol consisted of up to 8 cycles Aza (75 mg/m 2/d d1-7, every 28 days) and up to 3 DLI with increasing T cell dosages (0.5×10 6 - 1.5×10 7 cells/kg). Len was administered concomitantly for 21 days of a 28-day cycle. Following a positive first interim safety analysis in 10 patients the daily dose of Len was increased from 2.5 to 5mg. The primary endpoint of the study was safety, while secondary efficacy endpoints included response type and rates, time to and duration of response and overall survival. Results: Overall, 50 pts with molecular (n=29, 58%) or hematological (n=21, 42%) relapse of MDS (n=24, 48%), AML (n=23, 46%) or CMML (n=3, 6%) detected after median of 233 days (range, 98 to 2659) after allo-SCT were included. Fourteen patients (28%) received Len at a daily dosage of 2.5 mg and 36 patients (72%) at a daily dosage of 5 mg with no DLTs observed in the interim analyses. Median number of Len cycles per patient was 7 (range, 1 to 8) with no differences between the two dose levels. Concomitantly, 34 pts (68%) received at least one DLI (median: 3, range: 1-11). Overall response rate (ORR) during treatment was 56% (CR n=25, 50%, PR n=3, 6%). ORR and CR rates did not differ between Len dose levels. Of interest, CR rate did not differ between pts treated at the stage of molecular relapse and those initiated at hematological relapse (52% vs. 48%). Median time to CR was 112 days (range 1-286) corresponding to 4 cycles (range 1 to 8). At the time of data lock, 20 patients (80%) were still in CR without additional therapy for a median of 15 months, while 5 patients (20%) had relapsed again after a median of 8 months. With a median follow-up of 20 months median OS was 21 months and 1-year OS rate 65%. While therapy-related CTC grade III/IV neutropenia (92%), thrombopenia (80%) or anemia (36%) occurred frequently, drug-related non-hematological adverse events (AE) >grade II were rare and mainly consisted of gastrointestinal toxicity (6%), laboratory findings (28%) and infections (22%). Twenty-three pts (46%) developed acute GvHD including 5 patients (10%) with grade III/IV aGvHD, and 26 pts (52%) chronic GvHD (mild n=10; moderate n=11; severe n=5). During the study period, 3 secondary malignancies (squamous cell, basal cell and vulvar carcinoma) occurred. There were no therapy related deaths. Conclusion: Len up to a dosage to 5 mg/day can be safely added to the combination of AZA and DLI without excess of GvHD and toxicity. Furthermore, these data suggest that the combination of Aza, Len and DLI has promising clinical activity for relapse of myeloid malignancies after allo-SCT and is able to induce durable responses and survival in a substantial proportion of pts. Disclosures Schroeder: Celgene: Honoraria, Other: Travel support, Research Funding. Stelljes: Kite/Gilead: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Celgene/BMS: Consultancy, Speakers Bureau; Medac: Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau. Holtick: Celgene: Honoraria; Sanofi: Honoraria. Germing: Janssen: Honoraria; Bristol-Myers Squibb: Honoraria, Other: advisory activity, Research Funding; Jazz Pharmaceuticals: Honoraria; Celgene: Honoraria; Novartis: Honoraria, Research Funding. Kröger: AOP Pharma: Honoraria; Celgene: Honoraria, Research Funding; Gilead/Kite: Honoraria; Jazz: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; Novartis: Honoraria; Riemser: Honoraria, Research Funding; Sanofi: Honoraria. Kobbe: Celgene: Research Funding. OffLabel Disclosure: Lenalidomide is not licensed for AML, CMML and advanced MDS except for MDS with isolated del5q

Comparison of infected and vaccinated transplant recipients highlights the role of Tfh and neutralizing IgG in COVID-19 protection

Transplant recipients, which receive therapeutic immunosuppression to prevent graft rejection, are characterized by high COVID-19-related mortality and defective response to vaccines. Having observed that previous infection by SARS-CoV-2 but not the standard 2 doses scheme of vaccination, provided complete protection against COVID-19 to transplant recipients, we undertook this translational study to compare the cellular and humoral immune responses of these 2 groups of patients. Neutralizing anti-Receptor Binding Domain (RBD) IgG were identified as the critical immune effectors associated with protection. Generation of anti-RBD IgG was dependent upon spike-specific T follicular helper (Tfh) CD4+ T cells, which acted as limiting checkpoint. Tfh generation was impeded by high dose mycophenolate mofetil in non-responders to vaccine but not in infected patients, suggesting that increasing immunogenicity of vaccine could improve response rate to mRNA vaccine. This theory was validated in two independent prospective cohorts, in which administration of a 3rd dose of vaccine resulted in the generation of anti-RBD IgG in half of non-responders to 2 doses.

AUREA study: Atezolizumab (Atezo) combined with split-dose gemcitabine plus cisplatin (s-GC) in locally advanced or metastatic urothelial cancer (LA/mUC): A SOGUG study.

TPS4589 Background: First-line cisplatin-based chemotherapy (70 mg/m2) is the standard of care for LA/mUC patients (pts). However, about 50% will be ineligible for Cisplatin according to Galsky´s criteria. Moreover, a significant proportion of cisplatin-fit pts will receive carboplatin based on physician criteria. s-GC represents a feasible alternative in such situations, and could improve response rate compared to carboplatin regimens. Atezo is a programmed death-ligand 1 (PD-L1) inhibitor that is approved as first line treatment for cisplatin-ineligible LA/mUC pts with PD-L1 expression ≥5% (Ventana SP142). We present the study design of a phase II single arm trial of Atezo +s-GC in previously untreated pts with LA/mUC (NCT04602078). Methods: This single arm, open-label, multicenter study evaluates the efficacy and safety of Atezo +s-GC in previously untreated pts with LA/mUC. 66 pts will be enrolled and receive s-GC x 6 cycles (Cisplatin 35mg/m2 + Gemcitabine 1000mg/m2 on days 1 and 8 Q3W) and Atezo (1200 mg IV Q3W), followed by Atezo (1200 mg IV Q3W) until disease progression, toxicity or absence of clinical benefit. Eligibility criteria include histologically confirmed unresectable LA/mUC, measurable disease per RECIST 1.1 and adequate organ and marrow. Pts must be unfit for full cisplatin dose based on: age > 70 years, PS ECOG 0-2, creatinine Clearance >30 and <60 mL/min per Cockroft-Gault formula or by 24-hour urine collection. Other reasons for cisplatin ineligibility as considered by investigator, including those uncovered by Galsky´s criteria, will be allowed, prior discussion with PI. Exclusion criteria include prior systemic therapy for LA/mUC (adjuvant/neoadjuvant allowed if finished > 12 months prior to inclusion), prior autoimmune disease and uncontrolled significant illnesses. The primary endpoint is ORR per RECIST 1.1 assessed by investigator; the secondary endpoints are DoR, OS, PFS and safety. Biomarker analysis, including PD-L1 expression and microbiome relationship, will be an exploratory objective. The first two patients were enrolled in February 2021. Clinical trial information: NCT04602078.

The pharmacogenetics of opioid treatment for pain management

Background: Opioids are widely used as an analgesic for the treatment of moderate to severe pain. However, there are interindividual variabilities in opioid response. Current evidence suggests that these variabilities can be attributed to single nucleotide polymorphisms in genes involved in opioid pharmacodynamics and pharmacokinetics. Knowledge of these genetic factors through pharamacogenetic (PGx) testing can help clinicians to more consistently prescribe opioids that can provide patients with maximal clinical benefit and minimal risk of adverse effects. Aim: The research outlined in this literature review identifies variants involved in opioid PGx, which may be an important tool to achieving the goal of personalized pain management. Results: Cytochrome P450 ( CYP) 2D6, CYP3A4, CYP3A5, catechol-o-methyltransferase ( COMT), adenosine triphosphate binding cassette transporter B1 ( ABCB1), opioid receptor mu 1 ( OPRM1), and opioid receptor delta 1 ( OPRD1) are all important genes involved in opioid drug response, side effect profile and risk of dependence; these are important genetic factors that should be included in potential opioid PGx tests for pain management. Conclusions: Employing a PGx-guided strategy for prescribing opioids can improve response rate, reduce side effects and increase adherence to treatment plans for pain; more research is needed to explore opioid-related PGx factors for the development and validation of an opioid genetic panel. Optimal prescriptions could also provide healthcare payers with beneficial savings, while reducing the risk of propagating the current opioid crisis.

Evolving Role of Immunotherapy in Recurrent Metastatic Head and Neck Cancer

Immunotherapy has revolutionized cancer treatment in the past 2 decades, mostly with immune checkpoint blockade approaches. In squamous cell carcinoma of the head and neck (SCCHN), the initial efficacy of immunotherapy was observed in patients with recurrent or metastatic (R/M) disease who received other prior systemic treatment. As monotherapy, anti–PD-1 therapies induce responses in 13% to 18% of patients. More recently, immunotherapy in combination with cytotoxic chemotherapy demonstrated greater safety and efficacy as first-line systemic treatment compared with chemotherapy alone. In R/M SCCHN, the most important benefit of immunotherapy is the significantly improved overall survival, especially in patients with PD-L1–positive tumors. As of 2019, immunotherapy can be used as first-line or subsequent treatment of R/M SCCHN. Many ongoing trials are evaluating immunotherapy combinations or novel immunotherapy strategies, aiming to improve response rate and overall survival. As new targets are identified and new approaches are leveraged, the role of immunotherapy in R/M SCCHN continues to evolve.

Enclosing a pen to improve response rate to postal questionnaire: an embedded randomised controlled trial

Background: Poor response to questionnaires collecting outcome data in randomised controlled trials (RCTs) can affect the validity of trial results. The aim of this study within a trial (SWAT) was to evaluate the effectiveness of including a pen with a follow-up postal questionnaire on response rate. Methods: A two-armed RCT was embedded within SSHeW (Stopping Slips among Healthcare Workers), a trial of slip-resistant footwear to reduce slips in NHS staff. Participants were randomised 1:1 to receive a pen or no pen with their follow-up questionnaire. The primary outcome was the proportion of participants who returned the questionnaire. Secondary outcomes were: time to response, completeness of response, and whether a postal reminder notice was required. Data were analysed using logistic regression, linear regression and Cox proportional hazards regression. Results: Overall, 1466 SSHEW trial participants were randomised into the SWAT. In total, 13 withdrew from the host trial before they were due to be sent their follow-up questionnaire, 728 participants received a pen with their questionnaire, and 725 did not receive a pen. A questionnaire was returned from 67.7% of the pen group and 64.7% of the group who did not receive a pen. There was no significant difference in return rates between the two groups (OR 1.15, 95% CI 0.92 to 1.43, p=0.22), nor level of completeness of the questionnaires (AMD -0.01, 95% CI 0.06 to 0.05, p=0.77). There was weak evidence of a reduction in the proportion of participants requiring a reminder and in time to response in the pen group. Conclusion: Inclusion of a pen with the follow-up postal questionnaire sent to participants in the SSHeW trial did not statistically significantly increase the response rate. These results add to the body of evidence around improving response rates in trials. Trial registration: ISRCTN 33051393 (for SSHEW). Registered on 14/03/2017.

Two sequential dose-dense regimens of CGP, followed by MVAC in patients with metastatic urothelial carcinoma (mUC): A single institution, explorative trial.

e16023 Background: Currently, cisplatin, gemcitabine, paclitaxel (CGP) and MVAC are the most active chemotherapy regimens in mUC. We tested the hypothesis that two sequential non-cross-resistant, dose-dense (DD) regimens may target different cancer cells, avoid drug resistance, and improve response rate. Methods: This is a single institution, explorative trial. The aim is to evaluate the incremental benefit of the two regimens in terms of complete response and long term survival. We treat all consecutive, chemo-naïve mUC patients with 4 cycles of CGP dose-dense every 14 days followed by 4 cycles of MVAC every 14 days. In all cycles we used Pegfilgrastim 6 mg on day 3. Pts were evaluated with CT scan at the baseline, after 4 cycles, at the end of chemotherapy and then every 3 months for 2 years and 6 months thereafter. Results: From 2007 to 2018, 67 consecutive pts were included. Male were 82%; median age 66 years (33-83); Bajorin risk factors was 0 in 31%, 1 in 52%, 2 in 16%. The majority of pts were hospitalized for three days during chemotherapy and received hydration and supportive therapy. After the first 4 cycles of CGP, we observed 7% CR, 46% PR, 31% SD, and 12% PD. After the 4 sequential cycles of MVAC DD we observed a global 25% of CR, 33% PR, 10% SD, and 24% PD. Median TTP was 8.2 months (95% CI, 7.3-10.1) and median OS was 18 months (95% CI, 10.8-26.1). 5 pts are still alive after more than 30 months and maintaining complete response. Main grade 3–4 toxicity included anemia 27%, asthenia 23%, neutropenia 19% (febrile 7%), thrombocytopenia 13%. Conclusions: The sequential use of these two DD regimens is active and leads to an increased number of complete response and possible longer survival. A randomized trial is needed to confirm our results.

Strategies to Improve Cancer Immune Checkpoint Inhibitors Efficacy, other than Abscopal Effect: A Systematic Review

Despite the impact of immune checkpoint inhibitors on malignancies treatment is unprecedented, a lack of response to these molecules is observed in several cases. Differently from melanoma and non-small cell lung cancer, where the use of immune checkpoint inhibitors results in a high efficacy, the response rate in other tumors, such as gastrointestinal cancers, breast cancer, sarcomas, and part of genitor-urinary cancers remains low. The first strategy evaluated to improve the response rate to immune checkpoint inhibitors is the use of predictive factors for the response as PD-L1 expression, tumor mutational burden, and clinical features. In addition to the identification of the patients with a high sensibility to immune checkpoint inhibitors, another approach currently under intensive investigation is the use of therapeutics in a combinatory manner with immune checkpoint inhibitors to obtain an enhancement of efficacy through the modification of the tumor immune microenvironment. In addition to the abscopal effect induced by radiotherapy, a lot of studies are evaluating several drugs able to improve response rate to immune checkpoint inhibitors, including microbiota modifiers, drugs targeting co-inhibitors receptors, anti-angiogenic therapeutics, small molecules, and oncolytic viruses. In view of the rapid and extensive development of this research field, we conducted a systematic review of the literature identifying which of these drugs are closer to achieving validation in the clinical practice.

Teaching evaluation and student response rate

Purpose The purpose of this paper is to share the author’s viewpoint on how to increase student response rate in course evaluation surveys. Design/methodology/approach The approach is to highlight measures which increased student response rate in online surveys of the author’s teaching evaluation at The University of the West Indies, Jamaica. Findings This viewpoint suggests that student response rate to course evaluation can be improved by the lecturer’s effective communication. The examples of effective communication are given in this paper. Originality/value This work will encourage the lecturers to initiate more student engagement to improve response rate of their teaching evaluation.