ABSTRACT
Background - The WINDOW-1 regimen introduced first-line ibrutinib with rituximab (IR) followed by 4 cycles of R-HCVAD for younger mantle cell lymphoma (MCL) patients (pts) demonstrating 90% CR on IR alone and we aimed to improve the CR rate with the addition of venetoclax. We therefore investigated the efficacy and safety of IR and venetoclax (IRV) followed by risk-stratified observation or short course R-HCVAD/MTX-ARA-C as consolidation in previously untreated young patients with mantle cell lymphoma (MCL). Our aim was to use a triplet chemotherapy-free induction to reduce the toxicity, complications and minimize chemotherapy exposure in MCL pts. Methods - We enrolled 50 previously untreated pts in this single institution, single arm, phase II clinical trial - NCT03710772. Pts received IR induction (Part-1) for initial 4 cycles. Pts were restaged at cycle 4 and received IRV for up to eight cycles (Cycle 5 to Cycle 12) starting with ramp up venetoclax dosing in Cycle 5. All pts who achieved CR prior to cycle 12 continued to receive IRV for 4 cycles (maximum 12 cycles) and then moved to part 2. Pts were stratified into three disease risk groups: high, moderate and low risk categories from the baseline data for assignment to R-HCVAD/MTX-ARA-C as consolidation in part 2 (4 cycles, 2 cycles, or no chemotherapy for high, medium and low risk pts respectively). Briefly, low risk pts were those with Ki-67 ≤30%, largest tumor mass <3 cm, low MIPI score and no features of high risk disease (Ki-67 ≥50%, mutations in the TP53, NSD2 or in NOTCH genes, complex karyotype or del17p, MYC positive, or largest tumor diameter >5 cm or blastoid/pleomorphic histology or if they remain in PR after 12 cycles of part 1. Medium risk are pts which did not belong to low or high-risk category. Those who experienced progression on part 1 went to part 2 and get 4 cycles of part 2. Patient were taken off protocol but not off study, if they remained in PR after 4 cycles of chemotherapy, these patients were followed up for time to next treatment and progression free survival on subsequent therapies. After part 2 consolidation, all pts received 2 years of IRV maintenance. The primary objective was to assess CR rates after IRV induction. Adverse events were coded as per CTCAE version 4. Molecular studies are being performed. Results - Among the 50 pts, the median age was 57 years (range - 35-65). There were 20 pts in high-risk group, 20 pts in intermediate-risk group and 10 pts in low-risk group. High Ki-67 (≥30%) in 18/50 (36%) pts. Eighteen (36%) had high and intermediate risk simplified MIPI scores. Six (12%) pts had aggressive MCL (blastoid/pleomorphic). Among the 24 TP53 evaluable pts, eight pts (33%) had TP53 aberrations (mutated and/or TP53 deletion by FISH). Forty-eight pts received IRV. Best response to IRV was 96% and CR of 92%. After part 2, the best ORR remained unaltered, 96% (92% CR and 4% PR). The median number of cycles of triplet IRV to reach best response was 8 cycles (range 2-12). Fifteen pts (30%) did not receive part 2 chemotherapy, two pts (4%) received 1 cycle, 16 pts (32%) 2 cycles and 13 pts (26%) got 4 cycles of chemotherapy. With a median follow up of 24 months, the median PFS and OS were not reached (2 year 92% and 90% respectively). The median PFS and OS was not reached and not significantly different in pts with high and low Ki-67% or with/without TP53 aberrations or among pts with low, medium or high-risk categories. The median PFS and OS was inferior in blastoid/pleomorphic MCL pts compared to classic MCL pts (p=0.01 and 0.03 respectively). Thirteen pts (26%) came off study - 5 for adverse events, 3 for on study deaths, and 2 for patient choice, 2 patients lost to follow up and one for disease progression. Overall, 5 pts died (3 on trial and 2 pts died off study, one due to progressive disease and another due to COVID pneumonia). Grade 3-4 toxicities on part 1 were 10% myelosuppression and 10% each with fatigue, myalgia and rashes and 3% mucositis. One pt developed grade 3 atrial flutter on part 1. None had grade 3-4 bleeding/bruising. Conclusions - Chemotherapy-free induction with IRV induced durable and deep responses in young MCL pts in the frontline setting. WINDOW-2 approach suggests that pts with low risk MCL do not need chemotherapy but further follow up is warranted. This combined modality treatment approach significantly improves outcomes of young MCL pts across all risk groups. Detailed molecular analyses will be reported. (Figure Presented).
ABSTRACT
Background: Acute Kidney Injury (AKI) affects up to one in two critically ill patients. The cellular mechanisms of kidney tubule repair after acute kidney injury are poorly characterized in humans. Methods: We recruited 5 patients admitted to the Geneva University Hospital's Intensive Care Unit for severe COVID19 and experiencing AKI. For each of them, a kidney biopsy was performed before the planned withdrawal of resuscitation measures. We further applied single-cell RNA sequencing to analyze the kidney in the first days after acute injury. Results: After data processing and quality control, we obtained 20,165 single-cell transcriptomes. The most prominent finding in the snRNAseq analyses was in the proximal tubule (PT) compartment. We defined two cell populations corresponding to mature and undifferentiated PT cells, connected by two cell state transitions (Figure 1). Undifferentiated PT cells display an injured pattern characterized by metabolic impairment, reduction of the tubule transport function, and expression of injury markers confirmed in immunochemistry. We found that tubule repair follows two converging patterns involving the plasticity of mature tubule cells and the expansion and differentiation of progenitor-like cells. Tubule repair by cell plasticity displayed substantial similarities among mice and men and determined the transient expansion of undifferentiated tubule cells with altered functional and metabolic properties. Progenitorlike cells marked by PROM1 proliferated in response to injury and followed a differentiation process characterized by the sequential activation of the WNT, NOTCH, and HIPPO signaling pathways. Conclusions: Here we generated the first map of PT injury and repair in humans. Taken together, our analyses reveal cell states transitions and fundamental cellular hierarchies underlying kidney injury and repair in patients.
ABSTRACT
Introduction: WhiMSICAL (Waldenström's Macroglobulinemia Study Involving CArt-wheeL) is the first global Waldenström's Macroglobulinemia (WM) registry capturing patient-derived data to complement scarce clinical trials data in this rare cancer (Tohidi-Esfahani et al, Am J Hematol 2021). The registry was interrogated to identify real-world first line treatment outcomes, quality of life (QoL) and coronavirus disease 2019 (COVID-19) data. Methods: The registry captures data through www.cart-wheel.org, an online rare cancer database, utilizing a tailored questionnaire developed by clinician and patient investigators. WM patients complete consent online, then enter symptom, pathology, treatment, QoL (EORTC QLQ-C30) and COVID-19 data, and can return to update their data on an ongoing basis. Recruitment is driven by social media messaging by the International Waldenström's Macroglobulinemia Foundation investigators. Time to next treatment (TTNT) was assessed from start of first therapy to start of second therapy. Patients without a documented second therapy were censored at the time of last edit to their account. COVID-19 questions included testing, disease severity, vaccination and impact on WM management. Results: As of July 2021, 558 patients from 20 countries have participated in the registry, predominantly from USA (50%), Australia (22%) and the UK (9%). Median age at diagnosis was 61 years (range 24-83) with male predominance (61%). 371 patients documented first-line therapies, with a total of 54 unique therapeutic combinations listed. The seven most common therapies were: bendamustine rituximab (BR, n=94), rituximab monotherapy (Rit., n=52), dexamethasone rituximab cyclophosphamide (DRC, n=33), ibrutinib (n=25), bortezomib dexamethasone rituximab (n=15), rituximab cyclophosphamide vincristine prednisolone (n=14) and chlorambucil (n=10). Comparison of TTNT was limited to the four most common first-line therapies: BR, Rit., DRC, with zanubrutinib (n=5) and ibrutinib plus rituximab (n=2) adding to the first line Bruton tyrosine Kinase inhibitor (BTKi) cohort (n=32). Median ages for the BR, BTKi, DRC and Rit. cohorts were 65, 66, 61 & 65 years, respectively. More patients in the BR cohort listed comorbidities (37%), with BTKi-treated patients reporting the least (19%). Pre-treatment disease burden (median IgM and hemoglobin) trended to being higher in the BR and DRC cohorts (figure 1B-D, IgM p=0.24, Hb p=0.27). At median follow up ranging from 31 to 39 months, BR had superior TTNT to DRC (median: not reached and 104 months, p=0.007, figure 1C) and Rit. (median 26 months, p < 0.0001, figure 1D), and trended to superiority compared to BTKi (median not reached, p=0.08, figure 1B). Median TTNT for the entire cohort (n=371) was 108 months (median follow up 55 months, figure 1A). Assessment of QoL was conducted in all patients (any line of treatment) and compared between patients currently on BTKi therapy (n=64) and patients not exposed to BTKi and treated within the last 12 months (n=84). The expanded BTKi cohort reported better QoL, with mean EORTC QLQ-C30 global scale of 82 ± 14.4 compared to the BTKi-naïve cohort mean 73.4 ± 20.9, p=0.005. This was despite more prior lines of treatment (median 2 [IQR 1-4] compared to 1 [IQR 1-1];p<0.0001). 324 (58%) patients responded to the COVID-19 questions. 144/324 (44%) had undergone testing for COVID-19, with 11 (8%) returning a positive result;none after vaccination. Median length of symptoms was seven days (range 2-30), with two hospitalized, one requiring intensive care. Both hospitalized patients were on second line ibrutinib. Of 211 responses regarding vaccination status, 15 (7%) were not vaccinated, eight due to availability, five due to personal choice and two due to clinician advice. Regarding impact of the pandemic on their WM management, 5% had treatment schedule disruption and 53% reported reduced face-to-face consultations. Conclusion: The WhiMSICAL registry provides a scientifically robust and ethically approved portal for the patients' voice. The data highligh the real-world efficacy of combination chemoimmunotherapy, particularly first-line BR, and suggest a better QoL with BTKi than other therapies. As this global data platform grows, the breadth of data allows for new insights into WM with patient reported outcomes advancing knowledge and facilitating treatment decisions for clinicians and patients. [Formula presented] Disclosures: D'Sa: Sanofi: Honoraria;BeiGene: Honoraria, Research Funding;Janssen Cilag: Honoraria, Research Funding. Kersten: Roche: Consultancy, Honoraria, Other: Travel support, Research Funding;Miltenyi Biotec: Consultancy, Honoraria, Other: Travel support;Novartis: Consultancy, Honoraria, Other: Travel support;BMS/Celgene: Consultancy, Honoraria;Takeda: Research Funding;Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support, Research Funding;Celgene: Research Funding. Thomas: Acerta Pharma: Research Funding;Ascentage Pharma: Research Funding;BeiGene: Membership on an entity's Board of Directors or advisory committees;BMS: Research Funding;Pharmacyclics: Membership on an entity's Board of Directors or advisory committees;X4 Pharma: Research Funding;Genentech: Research Funding. Palomba: Ceramedix: Honoraria;Rheos: Honoraria;Nektar: Honoraria;Priothera: Honoraria;Lygenesis: Honoraria;WindMIL: Honoraria;Wolters Kluwer: Patents & Royalties;Juno: Patents & Royalties;BeiGene: Consultancy;Kite: Consultancy;Magenta: Honoraria;Seres: Honoraria, Other: Stock, Patents & Royalties, Research Funding;PCYC: Consultancy;Notch: Honoraria, Other: Stock;Novartis: Consultancy;Pluto: Honoraria. Olszewski: Acrotech Pharma: Research Funding;Celldex Therapeutics: Research Funding;TG Therapeutics: Research Funding;PrecisionBio: Research Funding;Genentech, Inc.: Research Funding;Genmab: Research Funding. Trotman: PCYC: Research Funding;roche: Research Funding;BMS: Research Funding;TAKEDA: Research Funding;JANSSEN: Research Funding;beigene: Research Funding.