Liquid biopsy testing in metastatic or advanced breast cancer patients during the COVID-19 pandemic

Objective: During the COVID-19 pandemic, cancer patients had restricted access to standard of care tissue biopsy. Liquid biopsy assays using next generation sequencing technology provides a less invasive method for determining circulating tumour mutations (ctDNA) associated with targeted treatments or prognosis. As part of deploying technology to help cancer patients obtain molecular testing, a clinical program was initiated to offer liquid biopsy testing for Canadian patients with advanced or metastatic breast cancer. Method(s): Blood was drawn in two 10 mL StreckTM DNA BCTs and sent to the CAP/CLIA/DAP accredited Imagia Canexia Health laboratory for testing using the clinically validated Follow ItTM liquid biopsy assay. Plasma was isolated using a double spin protocol and plasma cell-free DNA (cfDNA) extracted using an optimized Promega Maxwell RSC method. Extracted cfDNA was amplified using the multiplex amplicon-based hotspot 30 or 38 gene panel and sequenced. An inhouse developed bioinformatics pipeline and reporting platform were used to identify pathogenic single nucleotide variants (SNVs), indels (insertions and deletions), and gene amplification. Included in the panel are genes associated with metastatic breast cancer: AKT1, BRAF, ERBB2, ESR1, KRAS, PIK3CA, TP53. Result(s): To identify biomarkers, 1214 metastatic or advanced breast cancer patient cfDNA samples were tested. There were 15 cases sent for repeat testing. We reported 48% of samples harboring pathogenic ctDNA mutations in TP53 (22%), PIK3CA (19%), ESR1 (18%), AKT1 (2%), ERBB2 (1.5%). Co-occurring variants were identified in samples with ESR1/PIK3CA as well as TP53/PIK3CA (both p-values <0.001). Interestingly, 29% of samples with mutated ESR1 harbored >= 2 ESR1 ctDNA mutations. In 56% of cases, previous molecular testing indicated the cancer subtype as hormone receptor (ER, PR) positive with/without HER2 negative status. In this specific subgroup, 49% harbored ctDNA mutations with 63% of those being PIK3CA and/or ESR1 mutations. Conclusion(s): A population of Canadian women with metastatic breast cancer were tested using a liquid biopsy gene panel during the COVID-19 pandemic for identification of biomarkers for targeted therapeutic options. Over 50% of the samples were identified as hormone positive, with greater than 60% harboring PIK3CA and ESR1 ctDNA mutations. Studies have shown that metastatic PIK3CA mutated ER-positive/HER2-negative tumors are predictive to respond to alpelisib therapy and have FDA and Health Canada approval. Additionally, ESR1 mutations are associated with acquired resistance to antiestrogen therapies, and interestingly we identified 29% of ESR1 mutated samples with multiple mutations possibly indicating resistance subclones. In future studies, longitudinal monitoring for presence of multiple targetable and resistance mutations could be utilized to predict or improve clinical management.

Hairy Cell Leukemia in a Filipino Male during the COVID-19 Pandemic - Report of a Rare Case

Hairy cell leukemia (HCL) is a rare, chronic, mature B-cell lymphoproliferative disorder accounting for 2% of all leukemias. In this paper, we would like to present our experience in the management of HCL in a financially limited setting where other diagnostic tests and chemotherapy are unavailable. The case report aims to emphasize the recognition of the distinctive morphology of hairy cells in the peripheral blood in the consideration of the initial diagnosis. A 60-year-old Filipino male was incidentally found to have anemia, thrombocytopenia and an absolute neutrophilic count below 1,000 in a pre-operative clearance for elective herniorrhaphy. Blood smear revealed atypical lymphocytes with hair like cytoplasmic projections. CT-scan of the abdomen showed splenomegaly and prominent paraaortic nodes. Flow cytometry of the bone marrow aspirate was consistent with an involvement of a Mature B cell neoplasm markers CD19, CD20, CD22 and surface immunoglobulin lambda and hairy cell leukemia markers CD11c, CD103 and CD25. He responded to six-weekly sessions of Cladribine with remission of the bone marrow and hematologic parameters. HCL is a rare type of a mature B cell neoplasm characterized by pancytopenia, splenomegaly, bone marrow fibrosis and the presence of atypical lymphoid cells with hairy projections in blood, bone marrow and spleen. Immunophenotyping express CD11c, CD103, CD123, and CD25. BRAF V600E mutation is the disease defining genetic event. Cladribine and Pentostatin are the first line of treatment. Cases of leukemia can be easily overlooked because of the mild derangement in the complete blood count. A meticulous differential review of the atypical lymphocyte, is the first step in the diagnosis of this rare disease.Copyright © 2022, Philippine College of Physicians. All rights reserved.

Twitterchats as a means to educate patients with CRC and caregivers and stimulate collaborations

Background: During the COVID-19 pandemic, Twitter has been instrumental in accelerating knowledge dissemination and forging collaborations within the medical community and amongst patient advocates. Tweetchats within Twitter are scheduled conversations on a specific topic. In oncology, Tweetchats have been used by cancer advocates to spread awareness and for patient and caregiver education. A colorectal cancer (CRC) specific tweetchat did not previously exist. This describes the creation, and experiences with a CRC specific tweetchat. Method(s): The #CRCTrialsChat tweetchat was created by a patient advocate for colorectal cancer patients, caregivers and clinicians to meet and exchange clinical trial-related information. Two gastrointestinal (GI) medical oncologists and two radiation oncologists were enlisted as moderators. The topic for each session is chosen by the patient advocate, who creates an outline and divides the content, which is designed to last a one hour session. The idea is to create engaging, technical, but easy to understand content. Each moderator then works on the answers to their assigned section, which is edited to fit tweet character limit. Sessions may also have guest moderators with expertise on a specific topic. Through tweeting, moderators answer specific questions that come up during the session and later. Result(s): To date, we have had four sessions covering the following topics: Clinical trial basics, CRC Updates from ASCO22, ClinicalTrialFinders and BRAF-mutated tumors. The content created has been simple and engaging, the format has functioned smoothly, and the reach of #CRCTrialsChat has been steadily increasing. After the most recent session on BRAF in September 2022, the @CRCTrialsChat has 281 followers, 17K impressions and 14.6K profile visits, a reflection of its excellent content. From a clinician perspective, this is a great format to interact with colleagues, discuss enrolling trials and also become familiar with using Twitter. Conclusion(s): A CRC clinical trial focused tweetchat is an engaging way to deliver trial-related content to an audience of clinicians, patients and caregivers. The current format appears to be an effective way to create and disseminate information. Future sessions will focus on ctDNA, molecular markers such as KRAS and HER2, and rectal cancer trials. Our hope is that #CRCTrialsChat will stimulate continued patient and clinician engagement, increase awareness of clinical trials, enhance trial participation and initiate patient-centric research and collaborations.

HER2 copy number variation in non-small cell lung cancer (NSCLC)

Background: The value of increased HER2 gene copy number (GCN) in NSCLC is unclear. In this study we defined its frequency and characterized a cohort of patients harboring it. Methods: Patients with stage IIIB/IV NSCLC enrolled in the Gustave Roussy MSN study (NCT02105168) between Oct. 2009 and Feb. 2016 were screened by FISH (positivity defined as HER2 GCN to centromeres ratio ≥ 2) and tested for other molecular alterations. Descriptive analyses of clinical-pathological data were performed, progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier method. Results: HER2 FISH tested positive in 22 of 250 screened patients (9%). Median age was 60 years (range 47-80), 68% (n=15) were male, 91% (n=20) were current or former tobacco smokers (median exposure 47 pack-year), 64% (n=14) had adenocarcinoma, 18% (n=4) squamous cell and 18% (n=4) large cell carcinoma. 91% (n=20) had an ECOG PS of 0 or 1. Stage IV with extra-thoracic involvement was the most common clinical presentation (64%, n=14). Overall, 95% of patients (n=21) had 1 or 2 metastatic sites at diagnosis (bone 32%, lung 27%, nodes 18%, liver 18%, brain 18%). In 9 patients (41%) 12 concurrent molecular alterations were detected: 5 KRAS mutation (3 G12C, 1 G12D, 1 G61H), 2 HER2 exon 20 insertion, 1 EGFR exon 19 deletion, 1 BRAF V600E mutation, 1 ALK rearrangement, 1 FGFR1 and 1 MET amplification. 18 patients received first-line platinum-based chemotherapy, with 33% (95% CI 16-56) objective response rate and 83% (95% CI 61-94) disease control rate. After a median follow-up of 28 months (95% CI 23-45), median PFS and OS were 5.9 (95% CI 3.4-11.0) and 15.3 (95% CI 10.3-NR) months, respectively. Median PFS was longer in patients with higher GCN. As further line of treatment, 5 patients received trastuzumab: 4 in combination with chemotherapy and 1 as monotherapy, with 1 stabilization of disease as best response. 3 patients received nivolumab (1 partial response and 1 stable disease) and 3 a targeted therapy (anti ALK, EGFR, BRAF). Conclusions: Increased HER2 GCN was found in 9% of patients with unresectable NSCLC, was not correlated to particular clinical characteristics, but frequently occurred with other molecular alterations. Its clinical actionability and the correlation with protein expression deserve further characterization. Clinical trial identification: NCT02105168. Legal entity responsible for the study: Gustave Roussy. Funding: Has not received any funding. Disclosure: M. Tagliamento: Other, Personal, Other, Travel grants: Roche, Bristol-Myers Squibb, AstraZeneca, Takeda, Eli Lilly;Other, Personal, Writing Engagements, Honoraria as medical writer: Novartis, Amgen. E. Auclin: Financial Interests, Personal, Advisory Board: Amgen, Sanofi. E. Rouleau: Financial Interests, Institutional, Advisory Board: AstraZeneca, Roche, Amgen, GSK;Financial Interests, Institutional, Invited Speaker: Clovis, BMS;Financial Interests, Institutional, Funding, Data base: AstraZeneca. A. Bayle: Non-Financial Interests, Institutional, Other, Principal/Sub-Investigator of Clinical Trials: AbbVie, Adaptimmune, Adlai Nortye USA Inc, Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Astex Pharmaceuticals, AstraZeneca Ab, Aveo, Basilea Pharmaceutica International Ltd, Bayer Healthcare Ag, Bbb Technologies Bv, BeiGene, BicycleTx Ltd, Non-Financial Interests, Institutional, Research Grant: AstraZeneca, BMS, Boehringer Ingelheim, GSK, INCA, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi;Financial Interests, Institutional, Other, drug supplied: AstraZeneca, Bayer, BMS, Boehringer Ingelheim, GSK, MedImmune, Merck, NH TherAGuiX, Pfizer, Roche. F. Barlesi: Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Novartis, Merck, Mirati, MSD, Pierre Fabre, Pfizer, Sanofi-Aventis, Seattle Genetics, Takeda;Non-Financial Interests, Principal Investigator: AstraZeneca, BMS, Merck, Pierre Fabre, F. Hoffmann-La Roche Ltd. D. Planchard: Financial I terests, Personal, Advisory Board: AstraZeneca, BMS, Merck, Novartis, Pfizer, Roche, Samsung, Celgene, AbbVie, Daiichi Sankyo, Janssen;Financial Interests, Personal, Invited Speaker: AstraZeneca, Novartis, Pfizer, priME Oncology, Peer CME, Samsung, AbbVie, Janssen;Non-Financial Interests, Principal Investigator, Institutional financial interests: AstraZeneca, BMS, Merck, Novartis, Pfizer, Roche, Daiichi Sankyo, Sanofi-Aventis, Pierre Fabre;Non-Financial Interests, Principal Investigator: AbbVie, Sanofi, Janssen. B. Besse: Financial Interests, Institutional, Funding: 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Celgene, Cergentis, Cristal Therapeutics, Daiichi Sankyo, Eli Lilly, GSK, Janssen, Onxeo, Ose Immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals;Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical, EISAI, Genzyme Corporation, Inivata, Ipsen, Turning Point Therapeutics. L. Mezquita: Financial Interests, Personal, Advisory Board: Takeda, AstraZeneca, Roche;Financial Interests, Personal, Invited Speaker: Roche, BMS, AstraZeneca, Takeda;Financial Interests, Personal, Research Grant, SEOM Beca Retorno 2019: BI;Financial Interests, Personal, Research Grant, ESMO TR Research Fellowship 2019: BMS;Financial Interests, Institutional, Research Grant, COVID research Grant: Amgen;Financial Interests, Institutional, Invited Speaker: Inivata, Stilla. All other authors have declared no conflicts of interest.

Three-years real-world evidence of adjuvant dabrafenib plus trametinib (DT) in patients with resected melanoma in Spain (GEM 1901 - DESCRIBE-AD)

Background: DT combination has shown efficacy in the adjuvant setting for BRAF-mutated melanoma (BMM) patients (pts) in clinical trials. Previous reports from DESCRIBE-AD resulted in promising overall survival (OS) rates at 12 months. Methods: An observational retrospective study was carried out in 25 GEM sites in Spain. Histologically confirmed and resected BMM pts previously treated with DT according to standard clinical practice in the adjuvant setting were included. Only surgical resection was allowed as a prior treatment to DT. DT discontinuation rate and time to treatment discontinuation were the primary objective. Secondary objectives included safety and efficacy of the combination. Here, we report 3-year results for OS. Results: From 10/2020 to 03/2021, 65 pts were included. Median age was 58 years, 55% were male and 60%, 25%, and 14% had an ECOG PS 0/1/Uk respectively, one patient presented ECOG 3. Allocation of stage IIIA, IIIB and IIIC according to TNM AJCC 7th edition was 29%, 26% and 32%, respectively. There were 3 pts diagnosed at stage I/II but considered of risk, and 2 pts with stage IV but completely resected, all considered for adjuvant DT. Ulceration was present in 40%, Breslow ≥2 mm in 71%, and nodes were microscopically and macroscopically affected in 39% and 22% of pts, respectively. Only 9.2% of pts discontinued DT prematurely due to toxicity and 21.2% had dose reductions to manage toxicity. After a median follow-up of 36.2 m (range: 13-51.1), the overall OS rate at 3-years was 83.5% (95% CI: 74.5-93.5). According to AJCC 7 stage at diagnosis, the 3-years OS rate was 95.2% (95% CI: 86.6-100), 75% (56-100), and 76.8% (60.7-97.2) for stage I-II-IIIA, IIIB, and IIIC-IV respectively. Throughout the study period 11 (16.9%) pts died, of which 10 died due to disease progression and one due to COVID-19 infection. Conclusions: Adjuvant treatment with DT for melanoma achieved good treatment compliance and has proven efficacy in the real world. Adjuvant DT has a clinical impact in survival in line with previous clinical trial COMBI-AD. Editorial acknowledgement: We acknowledge Mfar Clinical Research staff for their assistance in the development of this . Legal entity responsible for the study: Grupo Español Multidisciplinar en Melanoma (GEM). Funding: Grupo Español Multidisciplinar en Melanoma (GEM) as Sponsor with Industry partner NOVARTIS. Disclosure: P. Cerezuela-Fuentes: Financial Interests, Personal, Other, Consultancy, conference,congress attendance/infrastructure: BMS, MSD, Pierre Fabre, Roche, Sanofi, SunPharma. J. Martín-Liberal: Financial Interests, Personal, Other, Lecture fees: Astellas, MSD;Financial Interests, Personal, Other, Lecture fees, advisory fees: Bristol Myers Squibb, Novartis, Pierre Fabre, Pfizer, Roche, Sanofi;Non-Financial Interests, Personal, Member, membership or affiliation: ASCO, ESMO, SEOM, GEM, EORTC, SOGUG, GEIS. L.A. Fernández-Morales: Financial Interests, Personal, Invited Speaker, Speak at sponsored meetings: BMS, MSD, Pierre-Fabre, Roche;Financial Interests, Personal, Other, Speak at sponsored meetings and advisory role: Novartis. J. Medina Martinez: Financial Interests, Personal, Other, Speaker, consultancy or advisory role or similar activity: Novartis, Roche, Pierre Fabre, BMS, MSD, Sanofi. M. Quindós: Financial Interests, Personal, Other, speaker, consultancy and advisory: AstraZeneca, GSK, Merck Sharp & Dohme, Novartis, PharmaMar, Roche, Bristol Myers Squibb, Pierre Fabre;Financial Interests, Institutional, Other, Clinical trials: Merck Sharp & Dohme, Roche, Bristol Myers Squibb. A. García Castaño: Non-Financial Interests, Advisory Role: Bristol, MSD, Novartis. T. Puértolas: Financial Interests, Personal, Invited Speaker, Speaker and advisory role: BMS, Novartis;Financial Interests, Personal, Invited Speaker: Roche, MSD, Sun-Pharma;Financial Interests, Personal, Other, Speaker and advisory role: Pierre-Fabre;Financial Interests, Personal, Advisory Role: Sanofi;Financial Interests, Institutional, Other, Clinical trial: Roche, BMS, Apexi en Inc, Aduro Biotech, Alkermes Inc;Non-Financial Interests, Institutional, Other, congresses inscriptions: Lilly, Sun-Pharma, Novartis, Roche, MSD;Non-Financial Interests, Institutional, Leadership Role, Vocal: GEM (Grupo Español Multidisciplinar de Melanoma);Non-Financial Interests, Institutional, Affiliate: SEOM (Sociedad Española de Oncología Médica), GEM (Grupo Español Multidisciplinar de Melanoma). P. Ayala de Miguel: Financial Interests, Personal, Invited Speaker, Public speaking: Novartis, Merck Sharp & Dohme, Sanofi, Pierre-Fabré. B. Campos: Financial Interests, Personal, Other, Speaker or advisory role: Roche, BMS, Sanofi, Novartis, Pierre-Fabre, Sun Pharma;Financial Interests, Personal, Other, Speaker role: AstraZeneca, Merck, ROVI, Leo Pharma. E. Espinosa: Financial Interests, Personal, Advisory Role, Advisory: BMS, MSD;Financial Interests, Personal, Other, Advisory, educational activities: Novartis;Financial Interests, Personal, Invited Speaker, Advisory, educational activities: Pierre Fabre;Financial Interests, Personal, Funding, Funding for translational investigation: Roche;Non-Financial Interests, Personal, Member, Vicepresident: Grupo Español Multidisciplinario de Melanoma. A. Rodríguez-Lescure: Financial Interests, Personal, Advisory Role: Pfizer, Novartis, ROCHE, AstraZeneca, Daiichi Sankyo, Seagen;Financial Interests, Personal, Invited Speaker, Public speaking: Pierre-Fabre;Financial Interests, Institutional, Research Grant, Grant for Clinical Trials: BMS, Lilly, Roche, Novartis, Amgen, Pzifer, Zimeworks, AstraZeneca, G1 Therapeutics, Bayer. L. Espasa Font: Financial Interests, Personal, Full or part-time Employment: Novartis. G. Belaustegui Ferrández: Financial Interests, Personal, Full or part-time Employment: Novartis. All other authors have declared no conflicts of interest.

Long-term survival in advanced melanoma for patients treated with nivolumab plus ipilimumab in CheckMate 067

Background: Durable clinical benefit has been achieved with nivolumab (NIVO) + ipilimumab (IPI), including an overall survival (OS) of 49% and a melanoma-specific survival (MSS) of 56%, with median MSS not reached (NR) at 6.5-y minimum follow-up. Here we report sustained efficacy outcomes at 7.5 y. Methods: Patients (pts) with previously untreated, unresectable stage III/IV melanoma were randomly assigned 1:1:1 and stratified by PD-L1 status, BRAF mutation status, and metastasis stage to receive NIVO 1 mg/kg + IPI 3 mg/kg for 4 doses Q3W, followed by NIVO 3 mg/kg Q2W (n = 314);NIVO 3 mg/kg Q2W + placebo (n = 316);or IPI 3 mg/kg Q3W for 4 doses + placebo (n = 315) until progression or unacceptable toxicity. Co-primary endpoints were progression-free survival (PFS) and OS with NIVO + IPI or NIVO alone versus IPI. Results: With a minimum follow-up of 7.5 y, median OS remained stable at 72.1 mo (NIVO + IPI), 36.9 mo (NIVO), and 19.9 mo (IPI);median MSS was NR, 49.4 mo, and 21.9 mo, respectively (Table). While the objective response rate remained stable at 58% (NIVO + IPI), 45% (NIVO), and 19% (IPI), median duration of response had now been reached for NIVO at 90.8 mo and remains NR and 19.2 mo for NIVO + IPI and IPI, respectively. Subsequent systemic therapy was received by 36%, 49%, and 66% of NIVO + IPI-, NIVO-, and IPI-treated patients, respectively, and median time to that therapy was NR (95% CI, 45.9-NR), 24.7 mo (16.0-38.7), and 8.0 mo (6.5-8.7). Of patients alive at 7.5 y, 106/138 (77%, NIVO + IPI), 80/115 (70%, NIVO), and 27/60 (45%, IPI) were off treatment and had never received subsequent systemic therapy. No change to the safety summary was observed with additional follow-up;updated health-related quality of life data will be reported. Of the 10 new deaths since the 6.5-y follow-up (ie, 5 NIVO + IPI;3 NIVO;2 IPI), none were treatment-related;4 were due to melanoma progression;1 was due to an unknown cause;and 5 were due to other causes, but not associated with a COVID diagnosis. Conclusions: The 7.5-y follow-up continues to demonstrate the durability of responses with NIVO + IPI and an ongoing survival plateau. A substantial difference in median OS and MSS between patients treated with NIVO + IPI or NIVO was observed in descriptive analyses.

Treatment (TX) of advanced melanoma during the Coronavirus Disease 2019 (COVID-19) pandemic in Kaiser Permanente Northern California (KPNC)

The COVID-19 pandemic brought with it TX changes for many patients (pts) with AMEL, as it did for other pts with cancer. The long-term impacts of mandated area lockdowns, social distancing, medical society guidelines, and patient preference will not be fully understood for some time. The first step to learning from the pandemic is to assess how AMEL care was rendered in 2020. We performed a retrospective analysis of systemic TX for AMEL in KPNC, an integrated community healthcare system with approximately 4 million pts and about 150 de novo diagnoses of AMEL annually. We performed a chart review of pts with AMEL who were treated with standard of care systemic therapy, either immune-checkpoint inhibitors (ICI) or BRAF/MEK inhibitors (BRAF/MEKi), from January 1 to March 15, 2020, as a control group, and between March 15 and May 20, during the first wave of the COVID-19 pandemic in California with follow-up through November 4, 2020. Between January 1 and March 15, 26 pts started palliative ICI of whom 11 started combination PD1 (PD1i) and CTLA4 inhibitors. Among 15 pts who started on single-agent PD1i, 14 pts received short-interval TX (SIT), while 1 started long-interval TX (LIT). All 21 pts who started perioperative PD1i pre-pandemic, started on SIT. Between March 15 and May 20, 21 pts started palliative ICI, of whom only 3 started combination TX. Among pts who started palliative single-agent PD1i 40% started on LIT in this initial phase of the pandemic. 27 pts started perioperative ICI during this time. We found 3 started with neoadjuvant therapy and 78% started on LIT. Among 78 pts who were already on palliative single-agent ICI at the start of the COVID-19 pandemic, 15% remained on SIT and 24% changed to LIT. Sixteen pts (21%) also interrupted palliative ICI between March 15 and April 15 after a median time on TX of 45 weeks and for 63% the cited reason for interruption on chart review was the COVID 19 pandemic. Three of these pts who stopped ICI changed to BRAF/MEKi, the remainder continue in active follow-up as of November 2020. Among 72 pts already receiving perioperative ICI in March 2020, 19% remained on SIT, 35% changed to LIT, and 11% were already on LIT. 39% of pts interrupted perioperative ICI after a median time of 20 weeks on TX and 46% of these cited COVID 19 as the reason for interruption. Three pts have since resumed peri-operative TX, but the others remain in active follow-up off therapy. Between 3/15 and 5/30/2020, we noted a 325% increase in pts started on BRAF/MEKi;69% of pts received therapy for palliative intent. The start of the COVID-19 pandemic saw many different changes in AMEL TX in KPNC, with increased use of single-agent ICI, LIT, and oral therapy, in line with public health guidance, oncology societal guidelines and patient preference. It will be important to assess the long-term outcomes relating to these changes, including the impact of early discontinuation of ICI, to help guide future Melanoma care during and after the pandemic.

Immune reconstitution in patients with classical hairy cell leukemia during BRAF inhibitor treatment

For patients with classical hairy cell leukemia (HCL) standard treatment options such as purine analogues (PA) achieve a durable response, but are associated with severe immunosuppression. In particular, PAs cause long-lasting depletion of CD4+-lymphocytes. The BRAF inhibitor vemu-rafenib is effective in HCL but its use in first line treatment is currently limited to select clinical situations such as active infection. There is a lack of clinical data on the impact of BRAF inhibitors on immune function or response to vaccines in HCL. Here, we report the use of vemurafenib in four patients with HCL during the coronavirus disease 2019 (COVID-19) pandemic with detailed immune monitoring during treatment. All patients responded to BRAFi with normalization of peripheral blood counts. None of the patients developed neutropenia or severe infection. We observed stable CD4+ and CD8+ T-lymphocyte counts while receiving vemurafenib (median treatment duration 131 days). Immunoglobulin levels were normal in all patients without decline. 3 out of 4 patients received the SARS-CoV-2 vaccination (Pfizer-BioNTech) during vemuraf-enib treatment. The IgG antibody levels against the spike-protein of SARS-CoV-2 were detectable in 3 out of 3 patients (2-12 weeks after the second vaccination). Our findings suggest that BRAF inhibitors have limited effect on cellular and humoral immune function. The findings may support the use of BRAF inhibitors during the current pandemic to avoid the potentially detrimental effects of PA and thus minimize COVID-19 related morbidity and mortality in patients without SARS-CoV-2 vaccination.