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The proceedings contain 35 papers. The topics discussed include: germline variants and prognostic factors for cutaneous melanoma in children and adolescents;association between polygenic risk score and multiple primary melanoma;Porocarcinoma: an epidemiological, clinical, and dermoscopic 20-year study;primary cutaneous melanoma and COVID-19: a hospital-based study;atypical spitz tumors: an epidemiological, clinical and dermoscopic multicenter study with 16 years of follow-up;pediatric melanoma: an epidemiological, clinical and dermoscopic multicenter study;recurrence-free survival prediction in melanoma patients by exploiting artificial intelligence techniques on melanoma whole slide images;ultra-high frequency ultrasound and machine learning approaches for the differential diagnosis of melanocytic lesions;and genetic determinants of response to therapy in a real-world setting of advanced/metastatic melanoma patients: whole-exome sequencing and CFDNA analysis.
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Ablation includes ethanol injection, radiofrequency ablation (RFA), microwave ablation (MWA), etc. Ablation can be potentially curative, minimally invasive and easily repeatable for recurrence. RFA has been the most widely used ablation technique for liver tumors. The new-generation MWA system incorporating antenna cooling and high-power generation has attracted attention. It can create a more predictable ablation zone and a larger ablation volume in a shorter procedure time. Many high-volume centers have introduced new-generation MWA in Japan. However, many studies failed to show that new-generation MWA is superior to RFA in terms of local control and overall survival. In MWA, clinical data have been insufficient compared with those of RFA. There has been keen competition between surgical resection and ablation for almost 40 years since the era of ethanol injection. In 2021, SURF trial revealed that overall survival and recurrence-free survival were not significantly different between surgical resection and RFA. SURF trial was a multicenter randomized controlled trial in which 49 major centers in Japan enrolled patients with good hepatic function (Child-Pugh scores <= 7) and primary HCC of largest diameter <= 3 cm, and <= 3 nodules during the 6-year period of 2009-2015. The registered patients were followed for at least 5 years. As the result of SURF trial and other comparative studies, the revised Japanese clinical practice guidelines in 2021 treats hepatic resection and ablation equally for patients with <= 3 lesions, <= 3 cm in diameter. Recently, the combination of systemic and locoregional therapies has been attracting much attention. Systemic therapy using molecular targeted agents or immune checkpoint inhibitors is used for advanced HCC which cannot be treated by surgery or ablation. On the other hand, some locoregional therapies, such as hepatectomy and ablation, are potentially curative, but they cannot be indicated for advanced HCC. Combination of both therapies is an approach to improve the prognosis of advanced HCC, which is not indicated for curative treatment. Systemic therapy is used to shrink the tumor, and then locoregional therapies are performed to eradicate it. The combination may build a new strategy for advanced HCC. Ablation is highly operator-dependent. The skills and outcomes are very different from operator to operator. Before the pandemic of COVID-19, we held domestic and international training programs for intermediate and advanced doctors and hands-on seminars for young doctors. These were activities to exchange knowledge and experience and standardize the procedure. During the pandemic, we cannot get together. Since August 2020, we have conducted Japan Ablation Webinar 8 times with a total of 1,566 participants. We have also conducted International Ablation Webinar 4 times with a total of 1,272 participated doctors. Education is important to acquire skills and knowledge for successful ablation. We have established Japan Academy of Tumor Ablation (JATA) this year. There are two triggers. One is that SURF trial revealed that there is no difference between hepatectomy and ablation. The other is that ablation for lung, bone and soft tissue and kidney cancers has become reimbursed with health insurance since this September.
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INTRODUCTION: Patient often experience delays in operative care due to access issues, comorbidities, and other personal reasons. However, during the recent COVID pandemic, hospital resources were severely limited and all patients were forced to endure unprecedented delays, including colon and rectal cancer patients. The oncologic implications of these delays are unknown. METHOD(S): Adult patients who underwent surgery for colon and rectal cancer between January and September of 2020 were retrospectively reviewed. Patients with stage 4 disease were excluded. Patients were categorized as regular or extended interval if time to operation was less than or greater than 40 days for colon cancer and 80 days for rectal cancer. RESULT(S): A total of 186 patients were included, 123 colon cancer and 63 rectal cancer. In the colon cancer group, there were 65 regular interval and 58 prolonged interval patients. There were no significant differences in post-operative, 30-day, or 90-day post-operative outcomes between the two interval groups. During the follow up period (regular vs prolonged: 468.7 +/- 238.3 vs 414.2 +/- 235.5, p = 0.005) there was a higher rate of recurrence in the prolonged group (4.6% vs 17.2%, p = 0.023). Cox regression controlling for disease stage, procedure performed, and resection score demonstrated a significant difference in recurrence-free survival (HR = 7.544, p = 0.007). In the rectal cancer group, there were 48 regular interval and 15 prolonged interval patients. There were no significant differences in postoperative, 30-day, or 90-day outcomes between the two interval groups. During the follow up period (regular vs prolonged: 574.0 +/- 237.3 vs 569.3 +/- 252.2, p = 0.687) there was no difference in recurrence (16.7% vs 26.7%, p = 0.389), but recurrence-free survival was significantly longer in the regular interval group (543.9 +/- 241.6 vs 493.1 +/- 237.4, p = 0.009). However, Cox regression controlling for disease stage, neoadjuvant chemotherapy, procedure performed, resection score demonstrated no difference in recurrence-free survival (HR = 1.403, p = 0.662). CONCLUSION(S): A prolonged time to surgery, greater than 40 days, was associated with decreased recurrence-free survival for color cancer patients. In rectal cancer, no significant reduction in recurrence-free survival was observed despite a longer time to surgery interval in the prolonged group. In events when resources are limited, colon cancer patients may benefit from prioritized treatment and rectal cancer patients may be able to tolerate longer delays without significant impacts on recurrence-free survival.
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Background: Mammographic screening programmes reduce breast cancer mortality, but detect many small tumours with favourable biological features which may not progress during a woman's lifetime. Screen-detected cancers are treated with standard surgery and adjuvant therapies, with associated morbidities. There is a need to reduce overtreatment of good prognosis tumours and numerous studies have evaluated the omission of radiotherapy in this context. However, there is little evidence to support surgical de-escalation, although percutaneous minimally invasive treatment approaches have been described. Vacuum-assisted excision (VAE) is in widespread use for management of benign lesions and lesions of uncertain malignant potential. SMALL (ISRCTN 12240119) is designed to determine the feasibility of using this approach for treatment of small invasive tumours detected within the UK NHS Breast Screening Programme (BSP). Method(s): SMALL is a phase III multicentre randomised trial comparing standard surgery with VAE for screendetected good prognosis cancers. The main eligibility criteria are age >=47 years, unifocal grade 1 tumours with maximum diameter 15mm, which are strongly ER/PR+ve and HER2-ve, with negative clinical/radiological axillary staging. Patients are randomised 2:1 in favour of VAE or surgery;with no axillary surgery in the VAE arm. Completeness of excision is assessed radiologically, and if excision is incomplete, patients undergo open surgery. Adjuvant radiotherapy and endocrine therapy are mandated in the VAE arm but may be omitted following surgery. Co-primary end-points are: 1. Noninferiority comparison of the requirement for a second procedure following excision 2. Single arm analysis of local recurrence (LR) at 5 years following VAE Recruitment of 800 patients will permit demonstration of 10% non-inferiority of VAE for requirement of a second procedure. This ensures sufficient patients for single arm analysis of LR rates, where expected LR free survival is 99% at 5 years, with an undesirable survival probability after VAE of 97%. To ensure that the trial as a whole only has 5% alpha, the significance level for each co-primary outcome is set at 2.5% with 90% power. The Data Monitoring Committee will monitor LR events to ensure these do not exceed 3% per year. Secondary outcome measures include time to ipsilateral recurrence, overall survival, complications, quality of life and health economic analysis. A novel feature of SMALL is the integration of a QuinteT Recruitment Intervention (QRI), which aims to optimise recruitment to the study. Recruitment challenges are identified by analysing recruiter/patient interviews and audiorecordings of trial discussions, and by review of trial screening logs, eligibility and recruitment data and study documentation. Solutions to address these are developed collaboratively, including individual/group recruiter feedback and recruitment tips documents. Result(s): SMALL opened in December 2019, but recruitment halted in 2020 for 5 months due to COVID-19. At 7st July 2022, 142 patients had been randomised from 26 centres, with a randomisation rate of approximately 45%, and a per site recruitment rate of 0.4-0.5 patients/month, approaching the feasibility recruitment target of 144 patients. Drawing from preliminary QRI findings and insights from patient representatives, a recruitment tips document has been circulated (on providing balanced information about treatments, encouraging recruiters to engage with patient preferences, and explaining randomisation). Individual recruiter feedback has commenced, with wider feedback delivered across sites via recruitment training workshops. Conclusion(s): Despite pandemic-related challenges, SMALL has an excellent recruitment rate to date and is expected to have a global impact on treatment of breast cancer within mammographic screening programmes.
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Background: We aimed to evaluate the role of plasma fibrinogen and D-dimer as prognostic biomarkers in patients with non-muscle invasive bladder cancer (NMIBC). Method(s): The prospective study included 35 patients (30 males) with newly diagnosed NMIBC with no history of thromboembolic event or anti-coagulant intake or active infection and underwent complete trans-urethral resection between September 2020 and December 2021. Patients with deranged hepato-renal functions, refractory hypertension or diagnosed with COVID-19 infection with in one-month before surgery or routine follow-up were excluded. Follow-up was done as per NCCN guidelines. Fibrinogen and D-dimer levels were measured with in seven days of surgery or follow-up and analyzed for recurrence-free survival (RFS) and progression-free survival (PFS). Cox regression analyses were adopted to assess the influence of these two parameters on RFS and PFS. Result(s): The mean age was 53.9 years with a median follow-up of 9-months. Nine had recurrence of which six had progression. The cut-off values of fibrinogen and D-dimer were 402.5 mg/dl and 0.55 microg/ml, respectively. Kaplan-Meier analysis demonstrated that high fibrinogen and D-dimer levels were significantly related to poor RFS and PFS (p < 0.001). On multivariate analysis only fibrinogen and D-dimer retained their significance for RFS (p = 0.026 and 0.014, respectively) and PFS (p = 0.027 and 0.042, respectively). High levels of fibrinogen and D-dimer were also present in patients who had recurrence or progression at follow-up visits compared to rest of the patients. Conclusion(s): High levels of fibrinogen and D-dimer may indicate worse prognosis in patients with NMIBC, suggesting that these two can be used as prognostic biomarkers.Copyright © 2023, The Author(s).
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Background: Rituximab is one of the second-line treatments for ITP. At present, there are few studies on low-dose rituximab, lacking of a large number of prospective and randomized trials to support the efficacy and safety of lowdose rituximab, especially in children's ITP. Influenced by COVID-19, we used two low-dose rituximab regimens before and after March 2020 for second-line treatment of children's ITP. Aims: To compare the efficacy and safety of two different regimens for low-dose rituximab of children patients with chronic /refractory ITP, so as to provide basis for clinical treatment. Methods: 83 children patients were enrolled in this study and non-randomly assigned to receive 100mg/200mg (body weight 30kg) rituximab weekly for 4 weeks (group A, 53 cases) or a single dose of 375mg / m2 rituximab (group B, 30cases). The study was follow-up for at least half a year. Results: The baseline data of group A and B were the same. For group A: Overall and complete response (OR and CR) rates were 35.8% and 15%, respectively;the side effects rate is 3.8%. In responders, the median time to response was 4 (1 -12) weeks, with a median follow-up time of 12 (6 ∼ 36) months, 6 of 19 responders (31.6%) relapsed. For group B: OR and CR rates were 36.7% and 23%, respectively;the side effects rate is 10%. In responders, the median time to response was 1 (1 ∼ 4) weeks, with a median follow-up time of 11.5 (6 ∼ 17) months, 4 of 11 responders (36.4%) relapsed. No significant difference in the OR, NR, relapse free survival and incidence of side effects was observed in patients between the two groups. Image: Summary/Conclusion: The two low-dose rituximab regimens in the treatment of ITP in children both are safe and effective;The single-agent scheme is more recommended because of easier use and not increasing safety events.
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Background: Severe SARS-CoV-2 infections associated with high mortality rates are reported in a higher percentage of patients (pts) with hematologic malignancies compared to general population. In chronic myeloid leukemia (CML), pts with uncontrolled disease have a higher mortality risk. The impact of SARS-CoV-2 infection on CML pts in treatment-free remission (TFR) has not been studied so far. In particular, as immune control of residual disease may be important for TFR, the concern is that the infection could induce loss of TFR. Aims: To evaluate the outcome of SARS-CoV-2 infection in CML pts in TFR and assess any impact on maintenance of TFR. Methods: From March 2020 to December 2021, the CANDID study organized by the international CML Foundation has collected data on COVID-19 positive CML pts worldwide. Details on the registry were presented recently (Pagano ASH 2021). For this sub-analysis on pts in TFR additional information were collected including;molecular remission status (BCR::ABL1 ratios) before, during and after SARS-CoV-2 infection covering at least 6 months. For molecular analyses, BCR::ABL1 ratios were classified according to Cross et al (Leukemia 2015). In addition, ratios of 0% without indication of sensitivity were allocated as MR4 i.e. 0.01%IS. PCR outlier results were identified using the ROUT method by nonlinear regression with a maximum false discovery rate (FDR) of 1% (Motulsky et al 2006). Time to molecular relapse (MR) was measured from the date of COVID-19 diagnosis to the date of MR defined as loss of major molecular remission (MMR, BCR::ABL1 >0.1%IS) or the date of last molecular test. Molecular relapse-free survival (MRFS) and overall survival (OS) were estimated with the Kaplan-Meier method. The statistical difference between groups was performed using log-rank test. Results: By December 2021, 1050 COVID-19 positive CML pts were registered. 95 pts were in TFR at the time point of SARS-CoV-2 infection of which 89 (93.68%) recovered and 6 deceased (6.32%). Median age of TFR pts was 57 years, male were 51 (53.68%). Median time from CML diagnosis to reporting date was 13 years (range 3.7-27.0 years). TFR duration was 2.83 years in median (range 0.5 months - 10.1 years) including 19 pts with a duration < 1 year. From the 89 recovered TFR pts, 74 pts completed the 6-month follow up (83%), a further 6 pts with molecular follow-up of 3-5 months after COVID-19 diagnosis were still in TFR, 9 pts were lost to follow-up. Of 74 pts with complete reports, 69 pts remained in TFR (93%) and 5 pts lost TFR. For 71 pts, PCR results were obtained before, during and after infection. With the ROUT method 10 pts demonstrated outlier PCR tests, 61 pts demonstrated stable PCR results. There was no statistically significant difference in PCR results before and during/after infection (p>0.2). MRFS for these 71 pts 15 months after COVID-19 diagnosis was 86%. Probability of TFR loss was higher in pts with a TFR duration < 6 months compared to pts with TFR duration >6 months (27% vs 10%, Fig 1A). Additionally, there were no statistically differences in hospitalization rate (16% vs 23%, p=0.12) and severity of COVID-19 symptoms (12.6% vs 12%, p=0.87) comparing TFR and TKI treated pts. OS of COVID-19 positive TFR pts did not differ from COVID-19 positive pts on TKI therapy (HR 1.1, CI 0.47-2.54) (Fig 1B). Summary/Conclusion: In this sub-analysis of the CANDID study, CML pts in TFR had similar severity and survival to CML pts who were on TKI therapy and there was no evidence of an increased risk of TFR loss after SARS-CoV-2 infection.
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Introduction: It was aimed to evaluate the efficacy, local control and survival in patients with inoperable primary or metastatic lung cancer who underwent stereotactic body radiotherapy (SBRT) using the Cyberknife-M6 (CK-M6) with lung optimized treatment (LOT) module. Methods: Ethics committee (no: 2018-7/6) and scientific research project (OUAP (T) 2019/1) approval were obtained. 23 lesions of 21 patients were treated between April 2019 to December 2020 at our department. The patients were immobilized in the supine position by wearing a Synchrony vest, with the hands at their sides. A planning 4D-CT was obtained in a free breathing modality. The gross target volumes was created both on the full-inhale and full-exhale phases and internal target volume (ITV) was created. By taking an image of patients on the treatment device, tracking modality was selected according to the visibility of the target. Zero-View tracking was applied in 10 patients, 1-View in 10 patients, 2-View in 1 patients. 3 to 5 mm margin added for planning target volume (PTV) according to tracking method. Median ITV and PTV was 9,38 (2-52,34) and 20,27 (9,25-82,7) cc, respectively. An InCise2 multileaf collimator optimized by the Monte Carlo algoritm was used in all patients. A pair of the orthogonal kV X-ray imaging systems were used for simultaneous target tracking. Median prescribed dose was 48 Gy in 4 fractions (30-54 Gy in 3-6 fractions) administered consecutively or every other day. Prescription isodose covering 95% of PTV was 82,5% (77,4-99,3). Median conformity and homogeneity index was 1,17 (1,02-1,77) and 1,22 (1,09-1,29), respectively. Median BED10 was 100 Gy (53,62-151,2) and median beam on time was 26 minutes (12-42). Results: Patients were evaluated on January 2022. The median follow-up was 21 months (2-33). The median age was 68 (53-80) and 40% of the cases were adenocarcinoma. Two patients diagnosed with radiologically. Median lesion size was 13 mm (9-27). SBRT was applied to 13 primary tumors, 3 lung metastases and 7 lymph nodes. At initial evaluation, complete, partial and stable response was found 30%, 65% and 5%, respectively. During the follow-up, 3 patients locally recurred at a median of 11 months (9-14). The median and one-year local recurrence free survival was 22 months, and 89%. Acute and late grade 1-2 pulmonary complications was seen in 10 patients in a median of 7 months (2-13). While the cause of death in 6 cases was existent cardiac morbidity, covid19 pneumonia, lung infection (2) and progression (2), it was unknown in 1 patient. The median and one-year survival was 23 months and 95%. Conclusions: LOT module of the CK-M6 Xsight lung tracking system allows for the application of fiducial-free motion management strategies. The advantage of our study is that the most appropriate tracking modality can be selected prospectively before treatment. In our study, excellent local control with a median survival of 23 months for primary and metastatic lung cancer. With a median treatment time 26 minutes, noninvasive CK-M6 based SBRT was efficient, safe and comfortable treatment in lung cancer. Keywords: lung cancer, Cyberknife-M6, stereotactic body radiotherapy
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Background: Mammographic screening programmes reduce breast cancer mortality but detect many small tumours with favourable biology which may not progress. These are treated with surgery and adjuvant therapies, but associated morbidities mean there is a need to reduce overtreatment. Minimally invasive treatments such as vacuum-assisted excision (VAE) have been described but there is no prospective randomised evidence to support their routine use. SMALL (ISRCTN 12240119) is designed to establish the feasibility of using VAE to treat small tumours detected within the UK NHS Breast Screening Programme (BSP). Methods: Phase III multicenter randomized trial comparing surgery with VAE for screen-detected good prognosis cancers. Eligibility criteria are age ≥47 years, unifocal grade 1 tumors (maximum diameter 15mm), strongly ER/PR+ve and HER2-ve, with negative axillary staging. Patients are randomized 2:1 to VAE or surgery, with no axillary surgery in the VAE arm. Excision is assessed radiologically, and if incomplete, patients undergo surgery. Adjuvant radiotherapy and endocrine therapy are mandated in the VAE arm. Coprimary end-points are: (1) Non-inferiority comparison of the requirement for a second procedure. (2) Single-arm analysis of local recurrence (LR) at 5 years after VAE. Recruitment of 800 patients will permit demonstration of 10% non-inferiority of VAE for requirement of a second procedure, ensuring sufficient patients for single arm analysis of LR rates, where expected LR free survival is 99% at 5 years, with an undesirable survival probability after VAE of 97%. The DMC will monitor LR events to ensure these do not exceed 3% per year. Secondary outcome measures include time to ipsilateral recurrence, overall survival, complications, quality of life and health economic analysis. A QuinteT Recruitment Intervention (QRI) is integrated throughout SMALL to optimize recruitment and informed consent. Recruitment challenges are identified by analyzing recruiter/ patient interviews, audio-recordings of trial discussions, and by review of screening, eligibility and recruitment data and study documentation. Solutions are developed collaboratively, including recruiter feedback and recruitment tips documents. Results: SMALL opened in December 2019, but recruitment halted for 5 months due to COVID-19. At 11th February 2022, 91 patients had been recruited from 22 centers, with an approached/consented ration of 50%. Drawing from preliminary QRI findings, a recruitment tips document has been circulated (on discussing SMALL, providing balanced information on treatment options and explaining randomization). Individual recruiter feedback has commenced, with wider feedback planned shortly. Conclusion: Despite pandemic-related challenges, SMALL has excellent recruitment to date and is expected to have a global impact on treatment of screen-detected breast cancer.
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Background: Rituximab (RTX) achieved high remission-induction and sustained maintenance rates for patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) [1], [2]. However, RTX is an expensive medication, which may potentially lead to serious side effects. Defning the best dose regimen for maintenance in AAV is still an unmet need. Objectives: The aim of the present study is to compare the effects of ultra-low dose RTX (500 mg or 1000 mg once per year) to standard low dose RTX (500 or 1000 mg twice per year) as remission-maintenance therapy in AAV patients. Methods: We included consecutive AAV patients (classifed as GPA and MPA [3]) referring to four different Rheumatology centers in Italy. We assessed all AAV patients who successfully achieved disease remission (BVASv3=0) with conventional RTX or cyclophosphamide regimens and have been subsequently treated with RTX for maintenance of remission. All included patients received at least three maintenance infusions with either 1000 mg or 500 mg, twice per year (standard low dose) or once per year (ultra-low dose). After a period of 18 months, we assessed the remission rate, damage (VDI), glucocorticoids intake, ANCA status, B-cells depletion and serum IgG levels. Results: From January 2011 to December 2021, 83 AAV patients (mean age 51±16, 49.4% female, 95.2% ANCA positive, 65.8% anti PR3, 34.2% anti MPO), 61 classifed as GPA and 22 MPA, achieved complete disease remission with conventional RTX induction regimen. After 7 [6-9] months, 29.9% patients started maintenance treatment with ultra-low dose RTX (once per year), while 70.1% patients with standard low dose (twice per year), for 18 months. No signifcant differences at baseline were noted between patients receiving ultra-low dose when compared to those treated with conventional low-dose. At the end of observation period, a disease fare was observed in 22.7% of the low-dose group, and 21.2% in those treated with the standard dose (p=0.881). Relapse-free survival was comparable between the two group (log-rank p=0.818, Figure 1). When comparing AAV patients treated with ultra-low dose regimen to those treated with low-dose, no differences were noted in negative ANCA rate (72.2% vs 67.1%, p=0.262), ANCA titer (0 [0-7.8] vs 0 [0-50] UI/mL, p=0.232), B-cells depletion rate (70.6% vs 75%, p=0.725), mean serum IgG (811 [146-922] vs 680 [429-861] mg/dL, p=0.367), mean daily glucocorticoid dosage (2.5 [0-5] vs 3.75 [0-5] mg/d, p=0.647), VDI (4 [1-5] vs 2 [1-4], p=0.098), hypogammaglobulinaemia rate (31.8% vs 36.5%, p=0.697) and deaths (4.5% vs 5.8%, p=0.831). Although not signifcant, patients treated with ultra-low dose had lower severe infection rate (10.5% vs 26.8%, p=0.154). Notably, in the all cohort 5 deaths were related to COVID19 pneumonia. Conclusion: Reduced exposure to RTX was not associated with an impaired efficacy of maintenance therapy in patients with AAV. Remission maintenance with ultra-low dose RTX is a safe and more cost-effective option.
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Background:. Mammographic screening programmes have been shown to reduce breast cancer mortality. However, they detect many small tumours with favourable biological features which may not progress during a woman's lifetime. These are treated with standard surgery and adjuvant therapies, which have associated morbidities. Thus, there is a need to reduce overtreatment of good prognosis tumours found by screening. Minimally invasive treatment approaches have been described but there is no prospective randomised evidence to support their routine use. Vacuum-assisted excision (VAE) is in widespread use for management of benign lesions and lesions of uncertain malignant potential. SMALL (ISRCTN 12240119) is designed to determine the feasibility of using this approach for treatment of small invasive tumours detected within the UK NHS Breast Screening Programme (BSP). Methods:. SMALL is a phase III multicentre randomised trial comparing standard surgery with VAE for screen-detected good prognosis breast cancers. The main eligibility criteria are age ≥47 years, screen-detected unifocal grade 1 tumours with maximum diameter 15mm, which are strongly ER/PR+ve and HER2-ve, with negative clinical/radiological axillary staging. Patients are randomised 2:1 in favour of VAE or surgery;with no axillary surgery in S the VAE arm. Completeness of excision is assessed radiologically, and if excision is incomplete, patients undergo open surgery. Adjuvant radiotherapy and endocrine therapy are mandated in the VAE arm but may be omitted following surgery. Co-primary end-points are:1.Non-inferiority comparison of the requirement for a second procedure following excision2.Single arm analysis of local recurrence (LR) at 5 years following VAE. Recruitment of 800 patients over 4 years will permit demonstration of 10% non-inferiority of VAE for requirement of a second procedure. This ensures sufficient patients for single arm analysis of LR rates, where expected LR free survival is 99% at 5 years, with an undesirable survival probability after VAE of 97%. To ensure that the trial as a whole only has 5% alpha, the significance level for each co-primary outcome is set at 2.5% with 90% power. The Data Monitoring Committee will monitor LR events to ensure these do not exceed 3% per year. Secondary outcome measures include time to ipsilateral recurrence, overall survival, complications, quality of life and health economic analysis. A QuinteT Recruitment Intervention (QRI) is integrated throughout SMALL to optimise recruitment and informed consent. Recruitment challenges are identified by analysing recruiter/patient interviews and audio-recordings of trial discussions, and by review of screening, eligibility and recruitment data and study documentation. Solutions to address these are developed collaboratively, including individual/group recruiter feedback and recruitment tips documents. Results:. SMALL opened in December 2019, but recruitment halted in 2020 due to suspension of the NHS BSP for 5 months due to COVID-19. As of 1st July 2021, 55 patients had been approached in 10 centres, with 33 patients randomised (randomisation rate 60%). A further 23 centres are in set-up, with 8 suspended due to the pandemic. Drawing from preliminary QRI findings and insights from patient representatives, a recruitment tips document has been circulated (on introducing and discussing SMALL, providing balanced information. on treatment options and explaining randomisation). individual recruiter feedback has commenced, with wider feedback planned shortly. Conclusion:. Despite pandemic-related challenges, SMALL has an excellent recruitment rate to date and is expected to have a global impact on treatment of breast cancer within mammographic screening programmes. SMALL is funded by the UK NIHR HTA programme, award 17/42/32.
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Introduction: The use of high-dose post-transplant cyclophosphamide (PTCY) has revolutionized graft-versus-host disease (GVHD) prophylaxis and allowed to successfully reconsider haplotransplant in recent years. As this strategy significantly reduces the incidence of both acute and chronic GVHD, PTCY has been thereafter considered not only in matched settings but also as sole GVHD prophylaxis, at least when considering myeloablative allotransplant using matched sibling (MSD) or unrelated (MUD) donors and bone marrow as source of graft. Here, PTCY, as a sole GVHD prophylaxis, was tested in a reduced-intensity conditioning (RIC) setting, using peripheral blood stem cells (PBSC) as source of graft considering that this platform is currently broadly used worldwide in adults. Methods: This prospective monocentric phase 2 study was designed with the main objective to demonstrate the feasibility and safety of using only PTCY (without cyclosporine A nor mycophenolate mofetyl after transplant) in adults (18-70 years old) eligible for a RIC PBSC transplant with MSD or MUD. The Baltimore platform with 2 days of PTCY 50mg/kg/day on days 3 and 4 post infusion was considered as conditioning regimen, using fludarabine for lymphoid disease or clofarabine for myeloid disease. The primary objective was to appreciate the incidence of corticosteroid-resistant acute grade 3-4 GVHD (CR 3-4 GVHD) within 100 days post-transplant. According to statistical rules, patients have to be included in a step by step fashion (3, 3, 6, 15, 15 and 17 patients) for a total of 59 evaluable patients (meaning having received PTCY), in order to stop the protocol soon enough in case of excessive rate of deleterious severe acute GVHD (graded according to Mount Sinai International Consortium). Thus, the trial had to be stopped in case of documentation of > 2 CR 3-4 GVHD for the first 3 patients, >3 CR 3-4 GVHD for the first 6 patients, > 4 CR 3-4 GVHD for the first 12 patients, > 6 3-4 CR GVHD for the first 27 patients, > 8 CR 3-4 GVHD for the first 42 patients and finally as soon as > 9 CR 3-4 GVHD for the last included patients. All patients gave informed consent. The trial was registered at ClinicalTrials.gov Identifier: NCT03263767. Results: The results of the first 27 first patients (males n=17 and female n=10;median age: 59 years old (yo), range: 26-70) are reported here. They were included between February 2018 and November 2020. Diagnoses were AML (N=8), MDS (N=5), CMML (N=2), myelofibrosis (N=5), CML (N=1), DLBCL (N=1), T-cell lymphoma (N=1), Philadelphia positive B-ALL (N=1), CLL (N=1), lymphoblastic lymphoma (N=1) and mixed phenotype acute leukemia (N=1). Donors were MSD in 10 cases and MUD in 17. Only one primary graft failure was documented in a 61 yo MDS patient with active disease at transplant. He is however still alive in response after autologous reconstitution. With a median follow-up of 17.6 months (range: 10-42) for alive patients at the time of analysis (July 2021), 1-year and 2-year survivals were 80.9+7% and 74.7+9%, respectively, for both OS et DFS. GVHD-free/relapse-free survival (GRFS) at 1-year and 2-year was 58.7+9% and 52.2+10%, respectively. Three relapses (11%) and 6 deaths occurred. Deaths were due to acute GVHD in 4 patients (including 1 with sepsis and 1 with SARS-COVID 19 infection) and relapse in 2. Grade 2, 3 and 4 acute GVHD occurred in 11, 1 and 4 patients, respectively, for a total of 59% of grade 2-4 acute GVHD. CR 3-4 GVHD was observed in all of 5 patients with acute grade 3-4 GVHD and 4 died related to GVHD. Moderate/severe chronic GVHD occurred in 5/22 (22.7%) evaluable patients, including 4 still on immunosuppressive therapy at 40, 28, 25 and 16 months post-transplant. Overall non-relapse mortality (NRM) was 14.8% and related to acute GVHD. However, the number of cases conducting to stop the protocol was not reached. Conclusion: PTCY as a sole GVHD prophylaxis is here demonstrated as possible and relatively safe for adults receiving a matched PBSC Baltimore-based RIC allograft. The very good survivals reported he e may be related to a strong GVL effect associated with the high incidence of acute GVHD. However, because of this high incidence and the fact that NRM was related to GVHD after this first analysis, we have now made an amendment to test the addition to PTCY of one day of anti-thymoglobulin (ATG) 2.5 mg/kg on day-2 for the next 32 patients to be included. This second cohort receiving PTCY+ATG as a sole prophylaxis is ongoing.
ABSTRACT
Background: Recurrence is a risk factor for the prognosis of lung squamous carcinoma (LUSC). DNA methylation levels of RNAs are also associated with LUSC prognosis. This study aimed to construct a prognostic model with high performance in predicting LUSC prognosis using the methylation levels of lncRNAs and genes. Methods: The differentially expressed RNAs (DERs) and differentially methylated RNAs (DMRs) between the recurrent and non-recurrent LUSC tissues in The Cancer Genome Atlas (TCGA; training dataset) were identified. Weighted correlation network analysis was performed to identify co-methylation networks. Differentially methylated genes and lncRNAs with opposite expression-methylation levels were used for the screening of prognosis-associated RNAs. The prognostic model was constructed and its performance was validated in the GSE39279 dataset. Results: A total of 664 DERs and 981 DMRs (including 972 genes) in recurrent LUSC tissues were identified. Three co-methylation modules, including 226 differentially methylated genes, were significantly associated with LUSC. Among prognosis-associated RNAs, 18 DERs/DMRs with opposite methylation-expression levels were included in the methylation prognostic risk model. LUSC patients with high risk scores had a poor prognosis compared with patients who had low risk scores (TCGA: HR = 3.856, 95% CI [2.297-6.471]; GSE39279: HR = 3.040, 95% CI [1.435-6.437]). This model had a high accuracy in predicting the prognosis (AUC = 0.903 and 0.800, respectively), equivalent to the nomogram model inclusive of clinical variables. Conclusions: Referring to the methylation levels of the 16-RNAs might help to predict the survival outcomes in LUSC.
ABSTRACT
Background: Venetoclax combined with hypomethylating agents is a new standard of care for newly diagnosed patients with acute myeloid leukemia (AML) 75 years or older, or unfit for intensive chemotherapy. As precision therapy in AML expanded with the addition of venetoclax among others in the therapeutic armamentarium of AML, efficacy and safety reports in ethnic minorities are limited, with a background of well recognized inter-ethnic differences in drug response. Phase III data from VIALE-A, as well as VIALE-C, was limited for the Arab population as no site opened in the Arab world. We herein report our experience on the use of venetoclax with azacitidine in patients with newly diagnosed or relapsed/refractory AML in the Arab population. Methods: Retrospective-single center review on the use of Azacitidine with venetoclax in older patients (aged ≥60 years) with newly diagnosed AML, not eligible for intensive chemotherapy;secondary AML and relapsed or refractory AML. All patients self-identified of Arabic ethnicity. Patients who received previous BCL2-inhibitor therapy were excluded. Patients who received at least one dose of treatment (Azacitidine ≥3 days, >14 days of venetoclax) were included in the intention to treat analysis. Patients typically received azacitidine 75 mg/m2 intravenously for 7 days with oral venetoclax 400 mg daily for induction, with appropriate dose adjustment for concomitant use of azoles. This is followed by the same regimen in consolidation, with adjustment according to response and side effects at the treating physician's discretion. The primary endpoint was overall survival. The secondary endpoints include response rate, safety, and relapse-free survival. Results: Between July 2019, and July 2021, we identified 19 patients;13 (68%) had newly diagnosed AML (ND-AML), and 6 (32%) had relapsed or refractory AML (R/R AML). The median age was 70 years (17-82). In the ND-AML, most patients had an adverse ELN 2017 AML (69%) with 23% having either intermediate or adverse AML (Negative for CBF, NPM1, FLT3-ITD and biCEBPA, but missing NGS data for adverse mutations Tp53/ASXL1 and RUNX1). Only one patient was classified as intermediate-risk AML. The overall response rate in the ND-AML was 77%, with 46% achieving complete remission (CR), and 23% CR with incomplete count recovery (CRi) [Table]. One patient achieved PR after the first cycle (blast 7% by morphology and 1.5% by flow cytometry) and did not have a subsequent bone marrow evaluation, however had a full count recovery. Among the responders in the ND-AML cohort, 4 deaths were noted. One death was related to COVID-19 associated pneumonia, one due to graft failure (at day 42 post Haplo-SCT), one due to septic shock, and one was related to relapse disease. The overall survival and relapse-free survival for ND-AML were 5.6 months for both [Figure]. In the R/R AML, 66% had prior HMA exposure, and all patients did receive high-intensity chemotherapy. The median number of prior treatments was 3 (1-5). the response rate was 80% (4/5), with 60% achieving CR. All patients are still alive with a median follow-up of 7.6 months. One patient had progressive disease. One patient is early to evaluate and was not included in the response analysis [Table]. The 30-day mortality was zero in both ND-AML and R/R AML cohorts. Conclusions: In a majority of adverse risk ND-AML, and in heavily pretreated R/R AML, the response rate and overall survival is comparable to what has been previously reported. Our data support the use of this regimen in older patients with newly diagnosed AML, patients with relapsed or refractory disease, and those with adverse-risk features. This analysis is limited by the small number of patients, and by the lack of ELN 2017 favorable-risk AML. Future prospective and randomized studies are needed to clarify activity and safety in the Arab population, as well as in the high-risk AML subset. [Formula presented] Disclosures: No relevant conflicts of interest to declare.
ABSTRACT
Introduction: Hypofractionated radiotherapy (HF-RT) has been used in the UK as a non-surgical treatment for locally advanced laryngeal cancer (LALC) in the past. HF-RT has been readopted in some departments during the COVID-19 pandemic due to having a shorter overall treatment time and fewer attendances. This study explores the outcomes of a cohort of patients treated from 2003 to 2012 at Aberdeen Royal Infirmary (Scotland, UK). Materials and Methods: 36 patients received HF-RT (55 Gy in 20 fractions) through 2D or 3D conformal radiotherapy, 7 of them received concurrent cisplatin (CRT). Overall survival (OS), locoregional recurrence free survival (LRFS), progression free survival (PFS), laryngectomy free survival (LFS), disease specific survival (DSS) and late toxicity data were analysed in patients treated with HF-RT at 1-year (1Y), 2-year (2Y) and 5-year (5Y). The same outcomes were measured between the RT and CRT group for any differences. Results: The mean follow-up durationwas 43.0 months. OS at 1Y, 2Y and 5Y was 69.4%, 52.8% and 30.6%. LRFS at 1Y, 2Y and 5Y was 63.9%, 47.2% and 25.0%. PFS at 1Y, 2Y and 5Y was 63.9%, 44.4% and 25.0%. LFS at 1Y, 2Y and 5Y was 69.4%, 50.0% and 27.8%. DSS at 1Y, 2Y and 5Y was 63.9%, 52.8% and 30.6%. During the period of treatment and up to 5Y follow up, 41.7% of patients required an NG tube for feeding and 25% required a PEG tube at any point. 22.2% of patients required long term enteral feeding via PEG tube beyond 5Y. No significant differences were found in the survival outcomes or alternative feeding route outcomes between patients treated by RT alone or CRT. Conclusions: HF-RT constitutes an alternative for the treatment of LALC with acceptable local control and toxicity. Further investigation is needed in the comparison of this regime with standard fractionation and its application with modern radiotherapy techniques
ABSTRACT
Background: Currently, asymptomatic patients with CLL/SLL are observed without treatment until development of symptoms or cytopenias. Historically, early intervention studies in patients with CLL/SLL with non-specific chemoimmunotherapy agents have not resulted in an overall survival (OS) benefit and have resulted in toxicity. The introduction of targeted therapies, such as venetoclax (an oral BCL2 inhibitor;V) and obinutuzumab (an intravenous anti-CD20 monoclonal antibody;O), have provided tolerable/efficacious options for patients with CLL. In the CLL14 study, symptomatic patients with CLL receiving frontline therapy with VO had longer progression-free survival (PFS) and deeper remissions [more undetectable minimal residual disease (uMRD)] compared with those receiving chlorambucil and O (Fischer 2019). The CLL-International Prognostic Index (CLL-IPI;Table 1) is a validated prognostic model to predict which patients are at highest risk of a shorter time to first therapy and shorter OS. A score of ≥4 is considered high-risk on this scale. We aim to use VO as early intervention in asymptomatic, high-risk CLL patients, assessed by CLL-IPI, to potentially improve OS and thus alter the natural history of the disease. Methods: On 12/14/20, we activated the S1925 study (NCT#04269902 ) for adult patients with CLL or SLL, who were diagnosed within 12 months of enrollment. Eligible patients have a CLL-IPI score ≥4 (Table 1) or complex cytogenetics (≥3 cytogenetic abnormalities) and do not meet any criteria for initiation of treatment by the International Working Group for CLL (IWCLL;Hallek 2018) guidelines. Enrolled patients are randomized in a 2:1 manner to early versus delayed (at the time IWCLL indication for treatment is met) therapy with VO (Figure 1). VO is administered as previously described (Fischer 2019). The primary endpoint is OS. We hypothesize that early intervention with VO will improve the rate of 6-year OS from 60% to 80%. This design requires 222 eligible patients for 88% power (2-sided a=0.05) for the primary comparison. To allow for 10% ineligibility, we will enroll 247 patients. Estimated accrual time is 4 years. Secondary endpoints include: rates of response, PFS, and relapse-free survival;safety;time to second CLL-directed therapy;and quality of life (assessed by FACT-Leukemia). As COVID19 is an infection with particularly high morbidity and mortality in patients with CLL, incidence of this infection and complications including death will be recorded and compared between patients followed on the early versus delayed intervention arms. The primary translational objective is to evaluate the prognostic association between OS and peripheral blood MRD status at 15 months after treatment initiation by flow cytometry. Secondary translational objectives include describing the association of other clinical outcomes, baseline prognostic factors, and IWCLL-defined response with MRD status at multiple timepoints. Current Status: At the time of submission, 7 patients have been registered and randomized per protocol. Accrual is ongoing. [Formula presented] Disclosures: Stephens: Adaptive: Membership on an entity's Board of Directors or advisory committees;TG Therapeutics: Membership on an entity's Board of Directors or advisory committees;Epizyme: Membership on an entity's Board of Directors or advisory committees;Beigene: Membership on an entity's Board of Directors or advisory committees;Innate Pharma: Membership on an entity's Board of Directors or advisory committees;AstraZeneca: Consultancy;CSL Behring: Consultancy;Celgene: Consultancy;Novartis: Research Funding;Abbvie: Consultancy;JUNO: Research Funding;Arqule: Research Funding;Mingsight: Research Funding;Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding. Moseley: BioSight Ltd: Consultancy. Hill: AbbVie: Consultancy, Honoraria, Research Funding;Gentenech: Consultancy, Honoraria, Research Funding;Beigene: Consultancy, Honoraria, Research Funding;Pfizer: Consultancy, Honoraria;Kite, Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding;Karyopharm: Consultancy, Honoraria, Research Funding;AstraZenica: Consultancy, Honoraria;Celgene (BMS): Consultancy, Honoraria, Research Funding;Novartis: Consultancy, Honoraria, Research Funding;Epizyme: Consultancy, Honoraria;Incyte/Morphysis: Consultancy, Honoraria, Research Funding. Pagel: Pharmacyclics/AbbVie: Consultancy;Actinium Pharmaceuticals: Consultancy;Incyte/MorphoSys: Consultancy;BeiGene: Consultancy;Epizyme: Consultancy;Kite, a Gilead Company: Consultancy;AstraZeneca: Consultancy;Gilead: Consultancy;MEI Pharma: Consultancy. Shadman: Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding;Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune, Mustang Bio and Atara Biotherapeutics: Consultancy. Danilov: Genentech: Consultancy, Honoraria, Research Funding;Takeda Oncology: Research Funding;TG Therapeutics: Consultancy, Research Funding;Abbvie: Consultancy, Honoraria;Beigene: Consultancy, Honoraria;Pharmacyclics: Consultancy, Honoraria;Gilead Sciences: Research Funding;Bristol-Meyers-Squibb: Honoraria, Research Funding;Rigel Pharm: Honoraria;Bayer Oncology: Consultancy, Honoraria, Research Funding;SecuraBio: Research Funding;Astra Zeneca: Consultancy, Honoraria, Research Funding. Mato: Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding;DTRM BioPharma: Consultancy, Research Funding;Acerta/AstraZeneca: Consultancy, Research Funding;Sunesis: Consultancy, Research Funding;BeiGene: Consultancy, Research Funding;Johnson and Johnson: Consultancy, Research Funding;Genentech: Consultancy, Research Funding;AbbVie: Consultancy, Research Funding;Nurix: Research Funding;Genmab: Research Funding;LOXO: Consultancy, Research Funding;Janssen: Consultancy, Research Funding;AstraZeneca: Consultancy;Adaptive Biotechnologies: Consultancy, Research Funding;MSKCC: Current Employment;TG Therapeutics: Consultancy, Other: DSMB, Research Funding. Brander: Juno Therapeutics/Celgene/Bristol Myers Squibb: Research Funding;Pfizer: Consultancy, Other: Biosimilars outcomes research panel;TG Therapeutics: Consultancy, Research Funding;Novartis: Research Funding;ArQule/Merck: Consultancy;Verastem: Consultancy;BeiGene: Research Funding;ArQule: Research Funding;NCCN: Other: panel member;AstraZeneca: Research Funding;Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding;LOXO: Research Funding;Ascentage: Research Funding;Genentech: Consultancy, Research Funding;DTRM: Research Funding;MEI Pharma: Research Funding;AbbVie: Consultancy, Other: informCLL registry steering committee, Research Funding. Coutre: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees;Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Data Safety Monitoring Committee, Research Funding;Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees;Acerta: Other: Data Safety Monitoring Committee, Research Funding. O'Brien: Kite, Regeneron, Acerta, Caribou, Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis: Research Funding;Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc., Vaniam Group LLC, AbbVie, Alexion, Verastem, Juno Therapeutics, Vida Ventures, Autolus, Johnson and Johnson, Merck, Bristol Myers Squibb, NOVA Research Company, El Lill: Consultancy. Erba: AbbVie Inc;Agios Pharmaceuticals Inc;Bristol Myers Squibb;Celgene, a Bristol Myers Squibb company;Incyte Corporation;Jazz Pharmaceuticals Inc;Novartis: Speakers Bureau;AbbVie Inc: Other: Independent review committee;AbbVie Inc;Agios Pharmaceuticals Inc;ALX Oncology;Amgen Inc;Daiichi Sankyo Inc;FORMA Therapeutics;Forty Seven Inc;Gilead Sciences Inc;GlycoMimetics Inc;ImmunoGen Inc;Jazz Pharmaceuticals Inc;MacroGenics Inc;Novartis;PTC Therapeutics: Research Funding;AbbVie Inc;Agios Pharmaceuticals Inc;Astellas;Bristol Myers Squibb;Celgene, a Bristol Myers Squibb company;Daiichi Sankyo Inc;Genentech, a member of the Roche Group;GlycoMimetics Inc;Incyte Corporation;Jazz Pharmaceuticals Inc;Kura Oncology;Nov: Other: Advisory Committee. OffLabel Disclosure: The trial studies early intervention with venetoclax and obinutuzumab in patients with CLL/SLL who are asymptomatic and observation would be standardly recommended.
ABSTRACT
Background. Treatment-free remission (TFR) has become a new treatment goal for chronic myeloid leukemia (CML) patients. However, usually abrupt tyrosine kinase inhibitors (TKIs) therapy discontinuation has been successful only in about half of eligible patients and it can cause burdening TKI withdrawal syndrome (TWS) in about 30% of them. Moreover, any robust clinical or biological factor predictive for successful TFR has not been identified yet. On top of that, sustainable deep molecular response (DMR) as the main prerequisite for TKI discontinuation attempt is achieved only in 20-40% of patients. The majority of CML patients, therefore, need to be treated with the effective and well-tolerated drug for a long time or even life-long. Study design and methods. With the recognition of all these aspects, we designed a nationwide prospective investigator-initiated phase II clinical trial HALF (ClinicalTrials.gov NCT04147533) in order to evaluate efficacy and safety of TKI discontinuation after previous two-step dose reduction in patients with CML in DMR (Fig. 1). Step-wise TKI dose reduction, i.e. half of the standard during the first 6 months after study entry, and the same dose given alternatively (every other day) during the next 6 months, was derived from pharmacokinetics and experimental data as well as from clinical trials' results. We assume that the step-wise and eventually meaningful TKI dose reduction enables a higher rate of patients achieving successful TFR with less pronounce TWS, or even would represent a more reasonable and safer alternative to the complete and sudden TKI interruption. This unique nationwide academic project has been facilitated by hematological patients care centralization in the Czech Republic. A primary study objective is to evaluate the proportion of patients in major molecular response (MMR) at 6 and 12 months and in TFR at 18, 24, and 36 months after the study enrollment, respectively, and molecular recurrence-free survival at all mentioned time points as well. Main secondary and exploratory objectives are: to evaluate the proportion of patients loosing MMR and in whom MMR and MR4.0 would be re-achieved after TKI re-introduction, time to MMR and MR4.0 re-achievement, FFS, PFS, OS, TWS, and QoL assessment, predictive factors for successful TFR identification, quantification of BCR-ABL1 using digital droplet PCR at both the DNA and mRNA levels, immunological profiling, BCR-ABL1 kinetics mathematical modeling, assessment of TKI pharmacokinetics, clonal hematopoiesis and pharmaco-economics. Results. The study was launched in December 2019;however, due to the COVID-19 outbreak, patients' recruitment started on June 16, 2020. Here, characteristics of the first 74 patients included in the study until April 2021 are presented. There were 37 males and 37 females, with median age at the time of diagnosis of 53 years (range, 23-74) and at the time of the study entry of 67 years (range, 35-86). A median time of CML disease, TKI treatment, and DMR duration before the study initiation was as follows: 9.9 years (range, 4.4-22.5), 9.8 years (range, 4.2-20.2), and 7.3 years (range, 3.2-18.3), respectively. The ELTS score was low, intermediate, high and unknown in 62.2%, 21.6%, 13.5%, and 2.7% of patients, respectively. At the time of study entry, 58 patients (79.5%) were treated with imatinib, 10 (13.7%) with nilotinib, and 5 (6.8%) with dasatinib, respectively, whereas in 63 patients (86.3%) it was in the first line of therapy. With almost half of patients (48.6%), the TKI dose was already reduced at the time of study entry. With 10 (13.5%) patients, interferon-α treatment preceded TKI administration. At the time of this preparation, on July 26, 2021, altogether 102 patients (from planned 150) have been enrolled in the study;48 of them (47.1%) have already moved to the second de-escalation phase and 9 (8.8%) patients to the TFR phase. There were 2 cases of confirmed MMR loss (both in month 8 after the study entry) and no patient experienced symptoms resembling TWS. Conclusions. Despite the COVID-19 pandemic, the HALF study was successfully launched and initiated in the majority of centers, with 102 already included patients and continuing intensive enrolment. Based on our very preliminary results, the step-wise dose reduction seems to be an effective and safe approach. More included patients, longer follow-up and further analyses are needed in order to reach all set up objectives. [Formula presented] Disclosures: Žácková: Angelini: Consultancy, Speakers Bureau;Novartis: Speakers Bureau. Faber: Angelini: Consultancy, Other: conference fees, Research Funding, Speakers Bureau;Bristol-Myers Squibb: Consultancy, Other: conference fees, Research Funding, Speakers Bureau;Novartis: Consultancy, Other: conference fees, Research Funding, Speakers Bureau;Pfizer: Other: conference fees;TERUMO: Other: conference fees. Bělohlávková: Novartis: Consultancy;BMS/Celgene: Consultancy. Horňák: Angelini: Honoraria. Svobodník: Roche: Speakers Bureau;Janssen-Cilag: Speakers Bureau. Machová Poláková: Incyte: Consultancy;Angelini: Consultancy;Novartis: Research Funding. Mayer: Principia: Research Funding.
ABSTRACT
On behalf of the GRAALL group, the Czech Republic ALL group, the Finland ALL group and the EWALL group. Introduction. Treatment of older patients (pts) with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) remains an unmet medical need. Inotuzumab ozogamicin (INO), an anti-CD22 antibody conjugated to calicheamicin, is approved for the treatment of relapsed/refractory BCP-ALL in adults, sinusoidal obstruction syndrome (SOS) being the major adverse event associated with INO. A previous first line study conducted by the MDACC in pts 60 years or older successfully used INO in combination with a lower intensity version of the hyper-CVAD (mini-hyper-CVD). Due to the occurrence of SOS, the total doses were fixed at 1.3 mg/m² for cycle 1 followed by 3 cycles at 1 mg/m² (Kantarjian H et al. Lancet Oncol, 2018). Here, we aimed to assess the activity and safety of fractionated INO at a reduced dosage in combination with low-intensity chemotherapy as frontline therapy for older pts with CD22+ Philadelphia chromosome-negative (Ph-neg) BCP-ALL. Methods. EWALL-INO is a single arm prospective phase 2 multicentric study conducted in European centers belonging to the EWALL group. Eligibility criteria were pts aged 55y or older, performance status ≤2, and newly diagnosed CD22+ (20% or more of positive blast cells) Ph-neg BCP-ALL without central nervous system involvement. After a prephase including 5 days (D) of dexamethasone (DEX) 10mg per D and a single intrathecal injection (IT), the induction regimen was begun and split in 2 parts. Induction part I (Induc1) consisted of one triple IT, vincristine (VCR) 2 mg (1 mg over 70y) D1 D8 D15 D22 and DEX 20 mg D1D2 D8D9 D15D16 D22D23 combined with 3 injections of INO (0.8 mg/m² D1, 0.5 mg/m² D8 and D15). Induction part II (Induc2) was offered to pts in CR or CRp (CR with platelets < 100 G/l) after Induc1 or as salvage therapy. Induc2 consisted of DEX 20mg D1D8, cyclophosphamide (CY) 300 mg/m² D1 to D3, one triple IT D2 and 2 injections of INO (0.5 mg/m² D1 and D8). Pts in CR/CRp were programmed to receive 6 blocks of consolidation (Ara-C 1.5g/m²/12h adapted to renal clearance D1D2 and DEX 10mg/12h D1D2, cycles 1 and 4;Methotrexate (MTX) 1.5 g/m² over 24h D1, VCR 1 or 2 mg D1, one triple IT D2 and 6-mercaptopurin (6-MP) D1 to D7, cycles 2 and 5;CY 500 mg/m² D1D2, VP16 75 mg/m² D1D2, one triple IT D2 and MTX 25 mg/m² D1, cycles 3 and 6) followed by a POMP maintenance (VCR, 6-MP, MTX, DEX) during 18 months. Allograft was allowed after at least 3 blocks of consolidation at the discretion of the investigators. The evaluable population was pts who received at least 1 dose of INO. Analyses were by modified intention to treat and performed JUN 28, 2021. All pts gave informed consent. The study is registered at ClinicalTrials.gov under the NCT number: NCT03249870. Results. Between DEC 29, 2017 and JUN 22, 2021, 115 pts (out of 130 planned pts) were enrolled including 6 pts with screen failure. The first 90 eligible pts (up to MAR 1, 2021) were considered for this analysis to obtain a minimum of 4 months follow-up. Median age was 69y (range 55-84) and median follow-up for alive pts was 1.18 years (range 0.3-3.5). At time of analysis, 90 and 88 pts had started induc1 and induc2, respectively. Treatment related mortality was 2.2% (2/90) and CR/CRp rate was 85.5% (77/90, 6 CRp) after induc1. Three cases relapsed between induc1 and induc2 and 5 pts were salvaged by induc2 allowing to a CR/CRp rate of 87.7% (79/90, 8 CRp) after induc2. One pts died from refractory disease during induc2. One, 2, 3 4 and 5 injections of INO were administered to 2 (2.2%), 2(2.2%), 11 (12.2%), 2 (2.2%) and 73 pts (81.1%) respectively. Only 6 pts were allografted. One-year OS was estimated to be 78.5% (95%CI 68-85.9) and median OS was not reached. One-year relapse free survival was 74.5% (95CI 63.5-82.6) (Figure 1). Grade 3-4 liver toxicity was observed in 8 pts (8.8%) during the study including 3 pts (3.3%) developing SOS, 2 related to INO during induc1 and one occurred after transplant. Twenty-nine pts died during the follow-up, 16 from relapses (overall incidence 18%) and 13 from adverse events (overall incidence 14.4%), including one COVID19 fatal infection during consolidation. Conclusion. Fractionated inotuzumab ozogamicin at reduced doses (0.8/0.5/0.5/0.5 mg/m²) combined with low-intensity chemotherapy is a very active and well tolerated frontline therapy for older patients with CD22+ Ph-neg BCP-ALL. [Formula presented] Disclosures: Doubek: Janssen-Cilag, AbbVie, AstraZeneca, Amgen, Gilead, Novartis: Honoraria, Research Funding. Huguet: Novartis: Other: Advisor;Jazz Pharmaceuticals: Other: Advisor;Celgene: Other: Advisor;BMS: Other: Advisor;Amgen: Other: Advisor;Pfizer: Other: Advisor. Raffoux: ABBVIE: Consultancy;PFIZER: Consultancy;CELGENE/BMS: Consultancy;ASTELLAS: Consultancy. Boissel: CELGENE: Honoraria;Servier: Consultancy, Honoraria;Incyte: Honoraria;Amgen: Consultancy, Honoraria, Research Funding;Novartis: Consultancy, Honoraria, Research Funding;Bristol-Myers Squibb: Honoraria, Research Funding;PFIZER: Consultancy, Honoraria;JAZZ Pharma: Honoraria, Research Funding;SANOFI: Honoraria. Dombret: Amgen: Honoraria, Research Funding;Incyte: Honoraria, Research Funding;Jazz Pharmaceuticals: Honoraria, Research Funding;Novartis: Research Funding;Pfizer: Honoraria, Research Funding;Servier: Research Funding;Abbvie: Honoraria;BMS-Celgene: Honoraria;Daiichi Sankyo: Honoraria. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. OffLabel Disclosure: Inotuzumab ozogamicin as first line therapy in newly diagnosed CD22+ Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia
ABSTRACT
Background During 2020, the novel COVID-19 pandemic lead to cryopreservation of allogeneic hematopoietic stem cell (HSCT) grafts based on NMDP and EBMT recommendations, to secure grafts before start of conditioning chemotherapy. We examined the impact of this change in practice on patient outcomes. Methods We retrospectively analyzed the outcomes of 483 patients who received HSCT between Aug 2017 and Aug 2020, at Princess Margaret Cancer Centre, Canada, comparing the outcomes between those who received cryopreserved (CRYO, n=135) or fresh peripheral blood stem cell grafts (FRESH, n=348). Median follow-up: 12.3 months. Probability of overall survival (OS) was calculated using the Kaplan-Meier product-limit method and heterogeneity of time-to-event distribution functions were compared by the log-rank test. Cumulative incidences of aGvHD and cGvHD, relapse, and non-relapse mortality (NRM) were estimated using the cumulative incidence method considering competing risk, and groups were compared using Gray's test. Death was considered as a competing event for relapse, aGvHD and cGvHD, and relapse was considered a competing event for NRM, aGvHD and cGvHD. Results Median age was 58y;54.5% were males. Acute myeloid leukemia was commonest HSCT indication (n=248, 49.1%). Donors: MUD 10/10 n=233;MUD 9/10 (MMUD) n=48, matched related donor (MRD) n=112, Haploidentical n=88. Transplant conditioning: 79 (23%) and 23 (17%) patients received myeloablative conditioning (MAC) in the FRESH and the CRYO groups, respectively (p ns). In the FRESH group, 253 (73%) patients and 114 (84%) patients in the CRYO group received ATG followed by posttransplant cyclophosphamide (PTCy) and Cylosporine GvHD prophylaxis. OS at the 2y timepoint, FRESH group (n=348), was 67.0% (61.1-72.3%), compared to 48.7% (38.1-58.4%) for patients in the CRYO group (n=135), p=0.002, Figure 1a. This was mainly due to MRD cohort outcomes: 2y OS in MRD FRESH group (n=65), was 85.2% (73.3-92.0%), compared to 45.1% (29.9-59.1%) in MRD CRYO group (n=47), p<0.001, Figure 2a. Multivariate analysis (MVA) for OS, significant factors were increasing patient age, DRI high/v.-high, HCT-CI ≥ 3, Donors: Haplo and MMUD, cryopreservation, Table 1. NRM at 1y for FRESH (n=348) 17% (13.2-21.2) vs CRYO (n=135) 22.1 % (14.8-30.4), p ns. However, in the MRD cohort, NRM at 1y for FRESH group (n=65), was 1.5% (0.1-7.4%), compared to 15.4% (6.6-27.4%) for CRYO group (n=47), p=0.003, Figure 2b. On MVA, NRM adverse significant factors were patient age, DRI high/v.-high, Donors: Haplo and MMUD, Table 1. Cumulative incidence (CI) of relapse at 2y for FRESH 22.4% (17.5-27.7) vs CRYO 27.0 % (18.8-35.9) p=0.07. The CI of moderate-severe cGvHD at 1y for FRESH group (n=315) was 21.5% and 10.8% in the CRYO group, p=0.027, Figure 1c. Patients with FRESH 10/10 MUDs (n=180), had CI of moderate-severe cGvHD at 1y of 20.6%, compared to CRYO 10/10 MUDs (n=35), 6.0% p ns for MUDs;FRESH MRD (n=64) CI was 30.1%;and CRYO MRD (n=43) 10.3%, p=0.008 for MRD, Figure 1d. On MVA, significant adverse factors for chronic GvHD were increasing donor age, male recipient/female donor, whilst graft CRYO was protective, Table 1. GvHD-and Relapse free Survival (GRFS) at 2y for FRESH 54.0% (47.9-59.6) vs CRYO 43.4% (33.4-53.0) p<0.05, Figure 1b. However, in the MRD cohort, GRFS at 2y in FRESH group (n=65), was 74.2% (61.3-83.4%), compared to 40.7% (26.3-54.6%) for CRYO group (n=47), p=0.001;other donor types no difference, Figure 1c. On MVA, significant factors correlated with worse GRFS were: DRI high and very-high, cryopreservation, Donors: Haplo and MMUD, Table 1. Compared to FRESH group, CRYO group experienced reduced cGvHD, delay in neutrophil engraftment, higher graft failure and increased CMV reactivation, with no difference in relapse incidence or acute GvHD. Conclusion Cryopreservation was associated with inferior outcomes post-HSCT particularly in the MRD cohort, possibly due to combination ATG and post-transplant cyclophosphamide impacting differential tolerance to cryopreservation on components of the stem ce l graft;further studies are warranted to elucidate mechanisms for this observation. [Formula presented] Disclosures: Law: Novartis: Consultancy;Actinium Pharmaceuticals: Research Funding. Lipton: Bristol Myers Squibb, Ariad, Pfizer, Novartis: Consultancy, Research Funding. Kim: Bristol-Meier Squibb: Research Funding;Paladin: Honoraria, Research Funding;Pfizer: Honoraria, Research Funding;Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mattsson: MattssonAB medical: Current Employment, Current holder of individual stocks in a privately-held company.