Strong impact of the COVID-19 pandemic on fetal development and chromosomal abnormalities

Background/Objectives: To date, not many studies have been conducted to examine the role of COVID-19 on gestation and fetal development. During COVID-19, pregnant women had difficulty accessing prenatal screening and care due to pandemics restrictions and lockdowns. In this retrospective study we aimed to assess the effect of the SARS-CoV-2 outbreak on fetal development in both prenatal and postnatal outcomes pre-and pre-COVID-19 pandemics in Northern Cyprus. Method(s): A total number of 61 aborted materials were karyotyped during the pre-pandemic period (January 2017 and March 2020) whereas 24 samples were analysed during the peripandemic period (March 2020-November 2021). On the other hand, 25 new-borns blood samples during the pre-pandemic and 44 samples during the pre-pandemic period were analysed. Result(s): No statistically significant difference found in health and abnormal aborted material karyotypes between two periods. On the other hand, a statistical significance was observed in postnatal chromosomal abnormalities (P = 0.04) after two long pandemic lockdowns, which are known as the first and the second waves, dramatically indicating that no baby with Down syndrome was between 2017-2020 whereas seven babies with Down Syndrome were born as consequences of without taking precaution against lockdowns. Conclusion(s): Overall, prenatal care is failed which resulting increased postnatal chromosomal abnormality due to heavy flight restrictions, economic inflation instability, limited access to medical services during COVID-19 pandemic lockdowns in Northern Cyprus.

Mild Androgen Insensitivity Syndrome presenting in male with infertility and sexual difficulties

Androgen insensitivity syndrome has a wide spectrum of presentations. It results from a mutation in androgen receptor (AR) gene. It ranges from mild androgen insensitivity syndrome (MAIS) which is the mildest form to complete androgen insensitivity syndrome (CAIS). In case of MAIS, the abnormality that can be observed appears to be male infertility and sexual difficulties including premature ejaculation and erectile dysfunction. In this case report, we discuss a case of MAIS in a 37-year-old male who presented with infertility, premature ejaculation, and secondary erectile dysfunction.Copyright © 2023, Ibn Sina Trust. All rights reserved.

POST-MORTEM MRI to INVESTIGATE PERINATAL LOSS at COUNTIES MANUKAU HEALTH, AUCKLAND, NEW ZEALAND

Background: Magnetic Resonance Imaging (MRI) may be useful as an alternative to perinatal post-mortem autopsy. Our service has high rates of perinatal loss, and low rates of post-mortem autopsy. We have offered post-mortem MRI for the last 5 years, however how MRI is currently being used, have not been reviewed. Aim(s): To describe: (i) the number of perinatal post-mortem MRIs performed, (ii) the reasons for offering MRI, (iii) whether the MRI was contributory to diagnosing cause of perinatal loss or adding extra information. Method(s): Cases were identified crosschecking perinatal loss and radiology data from 2010 to 2021. Anonymised summaries of clinical notes and investigation results of all cases were reviewed by two multidisciplinary groups, each of whom had MRI reports for half of the cases. Congruency of final classification of cause of death was compared and groups reported for each case whether MRI provided new information. Result(s): Between 2018 and 2021 there were 426 perinatal losses, of which 17 were investigated with MRI. In all cases MRI was offered after parents declined autopsy and was performed in addition to other investigations (maternal blood tests, placental karyotype, and histology). MRI changed the final PDC code in 1 case, provided additional findings in 2 cases, confirmed antenatally diagnosed anomalies in 4 cases and was non-contributory to diagnosing cause of death in 11/17 cases. Conclusion(s): In our service, post-mortem MRI has been used infrequently as part of the investigations into perinatal loss. When used, it has been most useful in confirming presence of structural anomalies diagnosed antenatally. Conclusion(s): High COVID-19 community prevalence was associated with increased MROP numbers at our clinical site, but inferences are limited by a lack of standardisation of operative reporting.

The eXtraordinarY BABIES STUDY: EARLY SOCIAL COMMUNICATION SKILLS IN INFANTS WITH SEX CHROMOSOME TRISOMY (SCT)

Purpose of Study: The eXtraordinarY Babies Study is a natural history study of health and neurodevelopment in infants with a prenatal diagnosis of SCT. Given the increased risk for social difficulties and autism in SCT in later childhood and beyond, the study explores trajectories of early social communication development to identify early predictors of outcomes, and relationship of social communication skills to developmental profiles. Methods Used: A subset of 56 participants (XXY=43, XYY=4, XXX=9) from the eXtraordinarY Babies Study completed the Autism Diagnostic Observation Schedule- 2nd edition (ADOS-2), Toddler Module as part of the 12-month visit and The Bayley-3 Scales of Infant and Toddler Development. The ADOS-2 provides ratings of 0 (typical development), 1 (mild atypicality), and 2 (atypical) for communication, social interaction, and other behavior items, and an algorithm classifies total score into categories of: Little-No Concern, Mild-Moderate Concern, Moderate-Severe Concern. Analyses were limited to those who completed the assessment prior to COVID19 mask/shield requirements. Summary of Results: High rates of delayed or atypical development of early social communication skills were identified, with >75% of the sample showing scores of 1 or 2 in frequency of babbling, spontaneous vocalizations, gesture use, and pointing. 58% of the sample showed unusual eye contact and vocalizations. Over 50% received atypical scores on items assessing the quality of eye contact. Participants showed few restricted and repetitive behaviors. Results of ADOS-2 total scores: Little-no concern 50%, Mild-Moderate concern 35.7%, Moderate-severe concern 14.3%. No one was assigned a clinical diagnosis of ASD. For this group, Bayley-3 results showed average Cognitive (scaled score 10.8 sd1.9) and Fine motor skills (9.3 sd2.3), followed by lower Receptive (8.2 sd2.4) and Expressive Language (8.9 sd3.0) and below average Gross Motor skills (7.9 sd2.6). Receptive language scores negatively correlated with ADOS-2 Social Affect (r= -.38, p = < .001) and Overall Total (r= -.41, p = < .001). Conclusion(s): Even at an early age, toddlers with SCT are at increased risk for language, communication, and social interaction delays. While no participants were diagnosed with ASD at 12 months of age, social communication deficits known to be "red flags" for later diagnosis of ASD were seen in a subset of young children with SCT. Prospective follow-up will allow us to determine the trajectory of these deficits and those that may predict higher risk for more significant clinical symptoms.

IBRUTINIB PLUS VENETOCLAX IN PATIENTS WITH COMPLEX KARYOTYPE AND CHRONIC LYMPHOCYTIC LEUKEMIA

Background: In the largest study of Baliakas et al. (2019) the presence of at least 5 abnormalities, was associated with dismal clinical outcome, independently of the somatic hypermutation status and TP53 status. The presence of 3 or 4 aberrations is defined as clinically relevant in the absence of TP53. Studies by Kittai (2021) and Al-Sawaf (2020) showed the impact of karyotypic complexity on survival in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib or venetoclax. The complex karyotype (CK) is a topic that is being intensively researched, both in the aspect of increasing karyotypic complexity stratification and clonal evolution. Optimal therapy for patients with CLL has not yet been developed. The combination therapy of ibrutinib and venetoclax was superior to chlorambucil and obinutuzumab in terms of undetectable minimal residual disease (MRD) responses according to data from the GLOW trial (Tunir, 2021). The importance of achieving a complete response with undetectable MRD as the goal of therapy in CLL was proposed (Montserrat, 2005). Aims: The aim of our study is to evaluate the effectiveness of therapy with ibrutinib and venetoclax in combination for the patients with CLL and CK. Methods: This ambilinear observational study included patients with CLL with high genetic complexity (high-CK), defined as >=5 aberrations or CK (>=3 aberrations) in combination with a 17p deletion (CK+del17p). The first retrospective cohort included patients treated with ibrutinib monotherapy (Imono) to progression or intolerable toxicity since May 2015. The second prospective cohort included patients receiving ibrutinib in combination with venetoclax (IVen) since July 2019. Venetoclax therapy was started at the 3rd month of ibrutinib (from the escalation phase). Combination therapy was continued until a complete response, defined as three consecutive PET-CT-negative and MRD-negative results 3 months apart. If this criterion was not achieved at 24th month of therapy, venetoclax was discontinued and ibrutinib continued indefinitely. Results: Seventy-nine patients are included in the study. Twenty-nine patients in the first cohort and 50 patients in the second cohort. The characteristic is presented in Table. At the current follow-up periods, there were no significant differences in PFS and OS regarding a follow-up period <= 24 months (with the exception of death from COVID-19, since patients were not observed at parallel time intervals). In the group of patients treated with Imono, the majority of patients achieved partial remission or partial remission with lymphocytosis by 12 months. In 21 patients from Iven group, with a median follow-up of 7.4 months, a complete remission was achieved (72.4%);of these, 8 had unmeasurable MRD. Four patients did not complete the escalation period. There was a significant difference in the median MRD response achieved between 3 (log10>10) and 12 (log10<0,1) months in IVen group (p=0,03). In 2 patient from the IVen group progression of the disease was noted. Summary/Conclusion: Combination therapy with ibrutinib and venetoclax is an effective oral regimen for high-risk patients with complex karyotype disorders. PFS in both groups is currently not significantly different, which is obviously due to the short follow-up period. Patients receiving the IVen regimen achieve a significantly better response, which paves the way for allogeneic transplantation in these patients.

FEASIBILITY OF HAEMATOPOIETIC STEM CELL MOBILIZATION AFTER CONSOLIDATION WITH GEMTUZUMAB OZOGAMICIN AND INTERMEDIATE-DOSES ARA-C AND DAUNORUBICIN IN AML

Background: Gemtuzumab ozogamicin (GO), an anti-CD33 immunoconjugate Antibody is currently approved in combination with 7 + 3 in low- and intermediate risk acute myeloid leukaemia (AML). These patients are candidate for consolidation with autologous stem cell transplantation (ASCT) particularly when MRD- is obtained. GO can improve the rate of MRD negativity. There are limited data on the effect of its addition on the mobilization of Hemopoietic Stem Cells (HSC). Aims: To assess the feasibility of mobilization of HSC after re-introduction into market of GO at 3mg/m2 in 2019. Methods: We retrospectively studied AML patients undergoing 3+7 + GO induction and Ara-C + Daunorubicine + GO, consolidation (doses are derived from label instructions and ALFA0701 study) and mobilization on day +20 using GCSF 10μg/kg. CD34+ were monitored, and patients were harvested when a threshold of 20 cells/μL was reached in peripheral blood. Results: In 2020 and 2021, also considering constrains caused by COVID-19 pandemics, we attempted mobilization in our 3 Italian centres of 14 patients with a diagnosis of CD33+ de novo-AML. The median age was 52 years (range 29-65 yrs.), 4 were males and 10 females;11 patients carried a mutation of NPM1 and all had a normal karyotype except one with t(10p12;11q14) (Table 1). All received 3+7+GO induction and achieved a CR. Therefore, we started consolidation (total ARA-C 8g/m2) + GO as inpatient. Ten patients (71%) reached the established threshold of 20 CD34+ /μL and were successfully harvested, while 4 patients (29%) failed mobilization. The median day of apheresis was D+26 from the start to chemotherapy (range 22- 39). The median number of circulating CD34+ cells on the day of collection was 35.9 cells/μL (range 20-2153 cells/μL). The median CD34+ harvested was 4.65 x 106/kg (range 1.8- 44.6 x 106/kg). In our cohort, 4 patients (28% of the entire cohort and 40% of the harvested patients) underwent ASCT, 3 achieved favourable engraftment, while in the last patient ASCT is ongoing. Several reasons prevented ASCT in the remaining 6 patients: 3 patients underwent allogeneic SCT (2 had positive MRD on harvested apheresis;1 was reclassified as high-risk ELN2017 due to RUNX1 mutation resulting from NGS panel), 2 refused ASCT and one suffered early relapse. Summary/Conclusion: In our patients, the addition of GO did not impair HSC mobilization and harvesting that was reached in about 71% of cases, similarly to the AML-10 trial of the EORTC and GIMEMA Leukemia Groups where 70% of patients were successfully harvested. Our data are particularly interesting because in the pivotal ALFA0701 study, only one patient underwent Autologous- SCT, but in the control arm. An important limit of our case-series is that only 4 patients were auto-transplanted, so we have scant data on engraftment. In particular, evaluating day to engraftment of platelets would be interesting, given the known increase of thrombocytopaenia in patients treated with GO. In conclusion, mobilization with GO is feasible and further studies are warranted to evaluate the effects of fractioned doses of GO on HSC mobilization and ASCT outcome;the ongoing trial GIMEMA AML1819 - EudraCT number 2019-003871-20 - will prospectively assess the effect of GO, but with lower doses of ARA-C (total ARA-C 6 g/m2). (Table Presented).

HYPEREOSINOPHILIC SYNDROME FOLLOWING the BNT162B2 (BIONTECH/PFIZER) VACCINATION

Background: Some reports of small vessel vasculitis following nSARS-CoV2 vaccination are reported in the literature (1, 2). Objectives: We purpose to report the case of small-medium vessel vasculitis after BNT162b2 (BioNTech/Pfzer) vaccination. Methods: We present the case of a 48 years old man with an unremarkable history who underwent BNT162b2 vaccination. Results: Five days after the frst shot of BNT162b2 vaccine, the patient refer the onset of left inguinal adenopathy, and erythematous dermatitis of the trunk. Ultrasound of the groin found increase bilateral inguinal lymph nodes with reactive characters. Contextually, erythematous, itchy and painful nodular lesions appear in the lower and upper limbs as well as acrocyanosis and paresthesia in the right hand and foot. The tests performed showed thrombocytopenia and eosinophilia. While, CRP, search for fecal parasites, pANCA, cANCA, ANA, RAST test, serum tryptase were all absent. Haematological evaluation, bone marrow biopsy, karyotype and molecular biology (FIP1L1/PDGFRa), were performed, all results negative. The patient was admitted in Internal Medicine ward for worsening of skin lesions and of acrocyanosis with gangrenous lesions at the tips of the fourth fnger of the right hand. An angio-CT showed an occlusion of the right ulnar artery. At electromyography an axonal sensory neuropathy was found. The skin biopsy showed fbrinoid necrosis of venules of the superfcial vascular plexus associated with numerous eosinophils, lymphocytes and karyorrhetic debris (Figure 1). High-resolution CT scan described diffuse minimal accentuation of the interstitial texture with micronodular aspects and some ground glass appearance. The diagnosis of hypereosinophilic syndrome was made. Therapy with Methylprednisolone 500 mg/daily for 3 days then Prednisone 1 mg/kg daily in association with IL-5 inhibitor (mepolizumab) with good clinical response, in addition to anticoagulation with warfarin was started. Conclusion: To our knowledge this might be the frst case of (HES) following COVID vaccine. As our experience, due to the short commercialization of anti-nSARs-CoV2 vaccines, is limited further studies are needed to explore the possible effect on small-medium vessels.

Rare Form of Congenital Cystic Bronchiectasis in a Filipino Adult

Background: Tuberculosis remains to be the most common lung infection in the Philippines. Compliance to medication leads to significant improvement. A portion of the population however remains untreated leading to complication such as bronchiectasis. In the approach to treatment, etiologies such as a possible genetic abnormality must be considered aside from a post inciting event. Case: This is a case of D.A. 20 year old, female who came in due to difficulty of breathing. She grew up having recurrent upper and lower respiratory tract infection. She was previously treated with pulmonary tuberculosis for 6 months last 2011. She was initially admitted at the COVID wards during the surge because any patient with pulmonary complains with bilateral infiltrates will be tagged as COVID suspect until a negative RT PCR result becomes available. She was admitted with complains of difficulty of breathing with desaturation. Her body mass index is 12.8 which is underweight. Pertinent physical examination shows bilateral coarse crackles with clubbing which suggest a chronic disease. Complete work up was done. Echocardiography which revealed an ejection fraction of 74%, severe pulmonary hypertension with dilated right atrium and right ventricle. Chest radiography revealed bronchiectatic changes with infiltrates while a confirmatory chest computed tomography scan revealed post infection pulmonary fibrosis with cystic bronchiectasis both lung fields. Spirometry revealed a severe obstructive ventilatory defect with no response to bronchodilator and a probable restrictive ventilatory defect which explains why the patient had higher frequency of admissions. Paranasal sinus xray to rule out Kartagener's syndrome was done which revealed normal results. Microbiologic studies such as sputum TB culture and sputum gene xpert was negative. The sputum culture revealed Stenotrophomonas maltophilia which was treated with intravenous antibiotics. To rule out other possible differentials for the cystic bronchiectasis, karyotyping was facilitated which revealed a normal female karyotype (46 XX). She was managed as a case of cor pulmonale, post tuberculous bronchiectasis, bacterial pneumonia, with considerations of mucociliary defects such as cystic fibrosis. It was unfortunate that a sweat chloride test was not done as it was not available in the country. Conclusion: In a country with endemic infectious pulmonary diseases such as tuberculosis, there is an anticipated sequelae of post infection bronchiectasis and fibrosis. Even if resources are scare and diagnostic tests are limited, repeated lung infection in a young patient warrants further investigation as congenital causes of structural lung diseases may initially present as an infectious process. (Figure Presented).

Blinatumomab and inotuzumab ozogamicin for acute lymphoblastic leukaemia: data from the South East Scotland Cancer Network

Current therapy for adults with B-cell acute lymphoblastic leukaemia (B-ALL) remains suboptimal, despite good initial remission rates. Adults with relapsed or refractory B-ALL (R/R B-ALL) represent a challenge with historically poor outcome;the introduction of targeted agents has expanded options but there is no consensus management. Blinatumomab is a bispecific T-cell engager antibody construct against CD19 (Scottish Medicine consortium, SMC, approval February 2020);inotuzumab is a monoclonal anti-CD22 antibody conjugated to calicheamicin (SMC approval May 2018). Trial data have shown both agents improved remission rates and survival when compared with standard chemotherapy with manageable toxicity profiles, although adverse events including neurological toxicity and cytokine release syndrome (CRS) have been reported. We describe the experience of blinatumomab and inotuzumab in a BCSH level three unit from February 2017 to August 2021. Eleven patients-six male, five female, mean age 41.5 years (range 22-55) received a monoclonal antibody;blinatumomab ( n = 8) and inotuzumab ( n = 3). Ten had B-ALL and one had mixed lineage leukaemia (MLL). All patients were Philadelphia negative. Cytogenetic abnormalities were present in four cases-Inv(20), trisomy 21 (patient with Down syndrome), tetraploidy with isochromosome 17q and one with a complex karyotype. Further molecular information was available for nine cases, and all were negative for TCF3-PBX1 t(1;19), ETV6-RUNX1 t(12;21) and KMT2A rearrangements (including the case with MLL). Four patients received blinatumomab due to refractory BALL. Two (50%) went on to receive an allogeneic transplant in CR1 (one MRD negative and the other MRD below limit of quantification). Both patients were able to maintain a performance status of 0-1 pretransplant. One patient (25%) died due to SARS-COV-2 infection and the fourth patient's care was lost to follow-up. Four patients received blinatumomab due to relapsed BALL, two had undergone allogeneic transplant in CR1. Two patients (50%) died of progressive B-ALL. One patient is currently on UKALL 2011 regimen B maintenance B2 (comorbidities preclude allogeneic transplant), the other patient remains in molecular remission having failed lymphocyte collection for chimeric antigen (CAR) T-cell therapy. Three patients received inotuzumab for relapsed B-ALL. Two (66%) had a previous allogeneic transplant in CR1-one of whom went on to receive donor lymphocyte infusion (DLI) postinotuzumab while the other patient went on to have a second allogeneic transplant. The third patient relapsed on maintenance chemotherapy and has been referred for allogeneic transplant. Infective episodes occurred in 45% (all received blinatumomab) including one death from SARS-COV-2 pneumonitis. Following blinatumomab CRS and neurotoxicity (tonic-clonic seizures) occurred (both n = 1). No significant toxicities were observed in the three patients who received inotuzumab, although this likely reflects small patient numbers rather than a true difference between the two agents. Despite improved responses in R/R B-ALL with these therapies as single agents for the majority they do not offer cure. While toxicity was recorded it did not negatively impact PS. CAR T-cell therapy has demonstrated high initial remission rates in heavily treated B-ALL patients, including previous targeted therapy. Optimal sequencing of therapies remains to be defined alongside depth of response and duration of measurement.

Ibrutinib plus rituximab and venetoclax (IRV) followed by risk-stratified observation or short course R-hyper CVAD/MTX in young patients with previously untreated mantle cell lymphoma-phase-II WINDOW-2 clinical trial

Background - The WINDOW-1 regimen introduced first-line ibrutinib with rituximab (IR) followed by 4 cycles of R-HCVAD for younger mantle cell lymphoma (MCL) patients (pts) demonstrating 90% CR on IR alone and we aimed to improve the CR rate with the addition of venetoclax. We therefore investigated the efficacy and safety of IR and venetoclax (IRV) followed by risk-stratified observation or short course R-HCVAD/MTX-ARA-C as consolidation in previously untreated young patients with mantle cell lymphoma (MCL). Our aim was to use a triplet chemotherapy-free induction to reduce the toxicity, complications and minimize chemotherapy exposure in MCL pts. Methods - We enrolled 50 previously untreated pts in this single institution, single arm, phase II clinical trial - NCT03710772. Pts received IR induction (Part-1) for initial 4 cycles. Pts were restaged at cycle 4 and received IRV for up to eight cycles (Cycle 5 to Cycle 12) starting with ramp up venetoclax dosing in Cycle 5. All pts who achieved CR prior to cycle 12 continued to receive IRV for 4 cycles (maximum 12 cycles) and then moved to part 2. Pts were stratified into three disease risk groups: high, moderate and low risk categories from the baseline data for assignment to R-HCVAD/MTX-ARA-C as consolidation in part 2 (4 cycles, 2 cycles, or no chemotherapy for high, medium and low risk pts respectively). Briefly, low risk pts were those with Ki-67 ≤30%, largest tumor mass <3 cm, low MIPI score and no features of high risk disease (Ki-67 ≥50%, mutations in the TP53, NSD2 or in NOTCH genes, complex karyotype or del17p, MYC positive, or largest tumor diameter >5 cm or blastoid/pleomorphic histology or if they remain in PR after 12 cycles of part 1. Medium risk are pts which did not belong to low or high-risk category. Those who experienced progression on part 1 went to part 2 and get 4 cycles of part 2. Patient were taken off protocol but not off study, if they remained in PR after 4 cycles of chemotherapy, these patients were followed up for time to next treatment and progression free survival on subsequent therapies. After part 2 consolidation, all pts received 2 years of IRV maintenance. The primary objective was to assess CR rates after IRV induction. Adverse events were coded as per CTCAE version 4. Molecular studies are being performed. Results - Among the 50 pts, the median age was 57 years (range - 35-65). There were 20 pts in high-risk group, 20 pts in intermediate-risk group and 10 pts in low-risk group. High Ki-67 (≥30%) in 18/50 (36%) pts. Eighteen (36%) had high and intermediate risk simplified MIPI scores. Six (12%) pts had aggressive MCL (blastoid/pleomorphic). Among the 24 TP53 evaluable pts, eight pts (33%) had TP53 aberrations (mutated and/or TP53 deletion by FISH). Forty-eight pts received IRV. Best response to IRV was 96% and CR of 92%. After part 2, the best ORR remained unaltered, 96% (92% CR and 4% PR). The median number of cycles of triplet IRV to reach best response was 8 cycles (range 2-12). Fifteen pts (30%) did not receive part 2 chemotherapy, two pts (4%) received 1 cycle, 16 pts (32%) 2 cycles and 13 pts (26%) got 4 cycles of chemotherapy. With a median follow up of 24 months, the median PFS and OS were not reached (2 year 92% and 90% respectively). The median PFS and OS was not reached and not significantly different in pts with high and low Ki-67% or with/without TP53 aberrations or among pts with low, medium or high-risk categories. The median PFS and OS was inferior in blastoid/pleomorphic MCL pts compared to classic MCL pts (p=0.01 and 0.03 respectively). Thirteen pts (26%) came off study - 5 for adverse events, 3 for on study deaths, and 2 for patient choice, 2 patients lost to follow up and one for disease progression. Overall, 5 pts died (3 on trial and 2 pts died off study, one due to progressive disease and another due to COVID pneumonia). Grade 3-4 toxicities on part 1 were 10% myelosuppression and 10% each with fatigue, myalgia and rashes and 3% mucositis. One pt developed grade 3 atrial flutter on part 1. None had grade 3-4 bleeding/bruising. Conclusions - Chemotherapy-free induction with IRV induced durable and deep responses in young MCL pts in the frontline setting. WINDOW-2 approach suggests that pts with low risk MCL do not need chemotherapy but further follow up is warranted. This combined modality treatment approach significantly improves outcomes of young MCL pts across all risk groups. Detailed molecular analyses will be reported. (Figure Presented).

The selective bruton tyrosine kinase (BTK) inhibitor TG-1701 as monotherapy and in combination with ublituximab and umbralisib (U2) in patients with B-cell malignancies

Introduction: TG-1701 is an irreversible, selective, novel Bruton's tyrosine kinase inhibitor (BTKi) administered once daily (QD). BTK inhibitors, as well as the U2 combination (anti-CD20 mAb ublituximab + the PI3Kδ-CK1ϵ inhibitor umbralisib), are highly efficacious in chronic lymphocytic leukemia (CLL), each of which have been previously demonstrated to be superior over standard chemoimmunotherapy. Treatment with a more selective BTK inhibitor could result in improved efficacy and safety outcomes compared with ibrutinib (ALPINE study, EHA 2021), and we hypothesized that dual blockade of the B-cell receptor (BCR) pathway through combination of TG-1701 with U2 may confer greater depth of response compared to either regimen alone. Methods: Patients with CLL and non-Hodgkin lymphoma (NHL) were enrolled in an ongoing Phase 1 study. After characterizing the safety profile of TG-1701 monotherapy, a parallel dose escalation arm of TG-1701+U2 was implemented. Select dose levels of TG-1701 monotherapy and TG-1701+U2 were also expanded. All patients were treated until disease progression, unacceptable toxicity, or investigator/patient decision to withdraw. Safety was evaluated in all treated patients, and efficacy was evaluated in all treated patients who had at least 1 post-baseline assessment. TG-1701 monotherapy data were previously presented;herein we present data from the TG-1701+U2 dose escalation/expansion and the TG-1701 monotherapy CLL expansion cohorts Results: As of July 2021, 142 patients were treated with TG-1701, 36 of whom were enrolled in the TG-1701+U2 arm. The median # of prior therapies across all treated patients was 1 (range, 0-10) and all patients were BTKi-naïve. Among the 36 patients treated with U2+1701, 19 were evaluable for efficacy and safety (17 too early to evaluate). The median age was 69 years (range 47-81), and 56% were male. TG-1701+U2 was well tolerated at 4 different dose levels without dose-limiting toxicities. The most common (>30%) all-causality, all grade treatment-emergent adverse events (TEAEs) were diarrhea (53%) contusion (42%), nausea (37%), hypertension, ALT/AST increase, and fatigue (all 32% each) with TG-1701+U2. Grade 3/4 AEs >15% were limited to ALT/AST increase (21%). Dose reduction occurred in 1 patient due to an AE, and 4 patients discontinued at least 1 study drug due to an AE: 2 discontinued umbralisib, 1 discontinued umbralisib and TG-1701, and 1 discontinued all 3 agents. At the data cut-off, overall response rate (ORR) was 84% (4 CR and 12 PR) among 19 evaluable patients, with remaining patients awaiting post-baseline assessment. In the monotherapy CLL-specific cohorts (200 mg QD, n=20;and 300 mg QD, n=20), 40 pts were evaluable for safety, and 39 for efficacy (1 pt withdrew due to COVID prior to first response assessment). The median age was 71 (range 49-86), and 43% were male. The most common TEAEs were increased ALT/AST (all grades: 18%;grade ≥3: 3%), followed by diarrhea (all grades: 15%;grade ≥3: none), and neutropenia (all grades: 13%;grades ≥3: 13%). There were no cases of atrial fibrillation, major bleeding, or ventricular tachyarrhythmia in the CLL cohorts at a median follow-up of 12.8 months (range 2.5 - 20.8). TEAEs leading to TG-1701 dose reduction occurred in 1 (3%) patient. No patients in the 200 mg or 300 mg CLL cohorts have discontinued due to AEs. In patients with anemia and thrombocytopenia at baseline, sustained improvement in hematologic variables was observed. The ORR among 39 patients was 97% (all PR/PR-L). Lymphocytosis resolved to normal value or <50% of baseline in 69% (24 of 35 of patients with lymphocytosis). Consistent response rates were observed across all subgroups, including the following high-risk genomic features: del17p/TP53 mutations, unmutated immunoglobulin heavy-chain variable-region (IGHV), and complex karyotype (defined as 3 ≤cytogenetic abnormalities). The median duration of response has not been reached in either cohort. Best change in tumor burden from baseline in patients with CLL is presented in Figure 1. C nclusions: TG-1701 exhibits an encouraging safety and efficacy profile as monotherapy in patients with CLL and additionally shows promising activity and a manageable tolerability profile in combination with U2. Future registration trials are being planned in CLL with TG-1701. Recruitment to this study (NCT03671590) continues. (Figure Presented).

TG-1701, a selective bruton tyrosine kinase (BTK) inhibitor, as monotherapy and in combination with ublituximab and umbralisib (U2) in patients with chronic lymphocytic leukemia

Introduction: TG-1701 is a selective, covalent BTK inhibitor administered once daily (QD). Both the 'U2' combination (anti-CD20 mAb ublituximab+the PI3Kd-CK1e inhibitor umbralisib) and BTK inhibitors are highly efficacious in treatment- naïve (TN) and relapsed/refractory (R/R) CLL, each having previously demonstrated superiority over standard chemoimmunotherapy. Here, we report results for patients treated with TG-1701 alone or in combination with U2 from an ongoing Phase 1 study, with a focus on patients with CLL. Methods: Patients with R/R CLL and B-cell non-Hodgkin lymphoma were enrolled in an ongoing Phase 1 study initially evaluating dose escalation (DE) of oral TG-1701 QD continuously administered in 28-day cycles (100, 200, 300, and 400 mg). After characterizing the safety profile of TG-1701 monotherapy, we implemented a parallel DE arm of TG-1701+U2. Select dose levels of TG-1701 monotherapy were also expanded. All patients were treated until disease progression, unacceptable toxicity, or investigator/patient decision to withdraw. Safety was evaluated in all treated patients, and efficacy was evaluated in all treated patients with CLL who had at least 1 post-baseline assessment. Results: As of 30 April 2021, 125 patients were treated with TG-1701, 49 of whom had CLL. Enrollment was: 25 patients in the monotherapy DE arm (6 with CLL), 61 in the 200-mg disease-specific cohorts (20 CLL [5 TN], 21 mantle cell lymphoma [MCL, 4 TN], 20 Waldenström's macroglobulinemia [WM, 8 TN]), 20 in the 300-mg CLL cohort (4 TN), and 19 in the 1701+U2 DE arm (3 with CLL). Patients with MCL or WM in the 200-mg disease-specific cohorts were excluded from this analysis. The median # of prior therapies among CLL patients was 1 (range, 0-5) and all patients were BTKi-naïve. TG-1701 was well-tolerated and the maximum tolerated dose for monotherapy was not reached up to 400mg (near 100% saturation of the BTK at all dose levels studied). In the DE arms, the most common all-causality treatment-emergent adverse events (TEAE) were constipation (32%), increased ALT (28%), bruising (28%), and upper respiratory tract infection (28% of patients) with TG-1701 monotherapy;diarrhea (53%) and bruising (42%) with TG-1701+U2. Grade 3/4 AEs were limited. In the CLL-specific cohorts, the most common TEAE was increased ALT/AST (all grades, 17.5%;grade 3, 2.5%;grade ≥4, none), followed by diarrhea (all grades, 12.5%;grade ≥3, none), and COVID-19 (all grades, 12.5%;grade 3-4, none;grade 5, 7.5%). There were no cases of atrial fibrillation, major bleeding, or ventricular tachyarrhythmia in the CLL cohorts at a median follow-up of 10.5 months. TEAEs leading to TG-1701 dose reduction occurred in 7.5% of patients. TEAEs leading to treatment discontinuation occurred in 7.5% of patients (all COVID-19). At the data cut-off, 48 patients with CLL were evaluable for response, including nine in DE. ORR was 95.6% for TG-1701 monotherapy (all PR/PR-L) and 100% for TG-1701+U2 (all PR). The median duration of response has not been reached in either cohort. The best change from baseline in tumor burden in patients with CLL is presented in Figure 1, and treatment exposure and response duration data are presented in Figure 2 below. In patients with anemia and thrombocytopenia at baseline, sustained improvement in hematologic variables was observed in the 200- and 300-mg cohorts. Lymphocytosis was observed in 70% of the monotherapy patients, with a resolution to normal or <50% of baseline in 57.1%. Consistent response rates were observed across all subgroups, including age and high-risk genomic features, such as del17p/TP53, unmutated immunoglobulin heavy-chain variable-region (IGHV), and complex karyotype (defined as three or more cytogenetic abnormalities). Time to event data will be reported at the time of presentation. Conclusions: TG-1701 exhibits an encouraging safety and efficacy profile in patients with CLL, with promising activity and a manageable tolerability profile as monotherapy and in combination with U2 (Figure 1). Future registration trials ar being planned in CLL with TG-1701. Recruitment to this study (NCT03671590) continues.

Preliminary results of the FILO phase 2 trial for untreated fit patients with intermediate risk chronic lymphocytic leukemia comparing ibrutinib plus venetoclax (IV) vs. FCR

With the emergence of targeted therapies, defining the best strategy for the treatment of previously untreated CLL patients remains challenging. The aim of this phase 2 study was to compare the efficacy of an association with ibrutinib and venetoclax (IV) to the standard FCR regimen in fit patients with intermediate-risk CLL defined by either unmutated IGHV status, 11q deletion, or complex karyotype in the absence of TP53 abnormality. Patients were randomized 1:1 between two treatment arms, i.e. FCR 6 cycles or IV. After a lead-in phase of ibrutinib as a single agent from the month (M)1 to M3, the total duration of treatment with IV was based on the response achieved at M9;if bone marrow (BM) MRD was <0.01% using flow cytometry, the treatment was continued for 6 additional months until M15 and then stopped;if BM MRD at M9 was ≥0.01%, the treatment with IV was continued for 18 additional months until M27. The primary endpoint was the percentage of patients with BM MRD <0.01% at M27 in both arms. We present here the preliminary results on the first evaluation done at M9 including CT-scan, BM biopsy, and MRD assessment in PB and BM after the inclusion of all the 120 patients as initially planned. One hundred and twenty patients were enrolled from September 2019 to February 2021. The median age was 59 [34-72] and 61 [34-74] years in the FCR and IV arms, respectively. The characteristics of the patients were well-balanced between the 2 arms in terms of gender (male 72% FCR, 74% IV), PS ECOG 0-1 (59% FCR, 68% IV), and Binet stage (A, B, and C 15, 64, 21% for FCR;8.5, 59, and 32% for IV). No major difference in terms of cytogenetic features was noted, all patients but one had unmutated IGHV. At the time of data cut-off for this interim analysis, the median follow-up for all cohort was 12.7 [4.5.9-21.4] months. The frequency of patients presenting all grades adverse events (AE) so far was 90% (grade ≥3: 45%) in the FCR arm and 80% (grade ≥3: 45%) in the IV arm. The rate of infusion-related reactions (IRR) in the FCR arm was 35% on cycle 1-day 1 (14% grade 3-4);for the IV arm, 5% of patients experienced tumor lysis syndrome (TLS) (grade 3 for 1 patient). Ibrutinib doses were reduced for seven patients (four permanently stopped and three resumed at a lower dose because of toxicities (digestive, hepatic, or hematological). Venetoclax was permanently discontinued before M9 in four patients (digestive toxicities and grade 4 neutropenia). Fifty-two serious adverse events were reported of which 22 were in the IV arm (among them one sudden death, one ischemic stroke, one acute coronary syndrome, two atrial fibrillations, two TLS, two acute renal failures, one hepatitis, one neutropenia, two COVID pneumonitis, and one osteoporotic fracture) and 30 in the FCR arm (among them five febrile neutropenia, one hemolytic anemia, one thrombocytopenia, three IRR, three TLS, three COVID pneumonitis, one acute myeloid leukemia, one myelodysplasic syndrome). All patients with COVID pneumonitis had a favorable evolution with the need for intensive care and convalescent plasma for three of them. The first 85 patients included in the study have reached M9 and among them, nine prematurely discontinued the study, (one active hemolysis, one ischemic stroke, one TLS, one hepatitis, and one sudden death in the IV arm;three hematologic toxicities and one early progression in the FCR arm). In the evaluated patients (n=74), 69% of patients in the FCR arm and 43% of patients in the IV arm achieved bone BM MRD <0.01%. The complete (CR, CRi) and partial response rates were 56 and 44% in the FCR arm and 74 and 26% in the IV arm, respectively. In conclusion, preliminary results show a lower BM MRD rate in the IV arm compared to the FCR arm at M9, with toxicity that remains significant and relatively similar between the two arms. However, BM MRD rate may improve after longer exposure to the IV combination and the analysis of the primary endpoint at M27 will be decisive in determining the best therapeutic strategy.

A new translocation partner for CBFB in acute myeloid leukemia, t(10;16)(p13;q22)

Cytogenetic abnormalities involving chromosome 16 are found in 5– 8% of acute myeloid leukemia (AML). These are typically a pericentric inversion inv(16)(p13.1q22) or a translocation, t(16;16)(p13.1;q22), involving the MYH11 and CBFB genes localized to chromosome 16p13.1 and 16q22, respectively. In addition, less common rearrangements include deletion of the long arm of chromosome 16, del(16) (q22), and cryptic insertions involving the MYH11 and the CBFB genes with otherwise normal karyotypes. In this report, we present the first AML case with a new translocation involving the CBFB gene. The more common CBFB - MYH11 fusion product resulting from the inversion and/or translocation of chromosome(s) 16 leads to an AML with monocytic and granulocytic differentiation and abnormal eosinophil component with large, purple to violet color eosinophilic granules. This entity typically corresponds to the adult AML-M4Eo in French-American- British (FAB) Classification and now called AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22);CBFB-MYH1 in the new 2017 WHO Classification. Patients may present with myeloid sarcoma at initial diagnosis or at relapse. We present a case of an 80-year-old male with a history of prostate cancer post radiotherapy who was referred for COVID-19 testing. A complete blood count with differential revealed neutropenia and a macrocytic anemia. A bone marrow biopsy and a bone marrow aspirate confirmed a diagnosis of AML with 33% blasts including myeloblasts and promonocytes. Interphase fluorescence in situ hybridization (FISH) analysis with a break-apart probe for CBFB showed an abnormal hybridization pattern consistent with rearrangement of CBFB in 66% of nuclei. Chromosome analysis revealed an abnormal karyotype with two related clones: 47,XY, t(10;16)(p13;q22),+22[4]/48,idem,+8[16]. Sequential GTG-FISH confirmed that the 3’ region of CBFB was translocated to 10p13 in the t(10;16) and the 5’ region remained on 16q. Based on the karyotype, the patient’s bone barrow exhibits clonal evolution having acquired additional chromosome abnormalities (trisomy 22 and trisomy 8). Molecular studies by next generation sequencing showed NRAS p.Gln61Lys mutation with a VAF of 11.21%. No genomic alterations were detected in KIT, KRAS or FLT3 genes. AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22) is associated with a high rate of complete remission and favorable overall survival when treated with intensive consolidation therapy. However, their prognostic advantage may be affected by additional cytogenetic abnormalities and/or other gene mutations. Specifically, trisomy 22, is a frequent abnormality additional to inv(16) detected as a secondary finding which has been associated with an improved outcome when compared to the prognosis associated with inv(16) alone. Furthermore, KIT (in 30–40%), FLT3 (in 14%), NRAS (in 45%) and KRAS (in 13%) mutations are common in this AML type. The prognostic implications of KIT mutation (especially involving exon 8) do not appear to be significantly poor prognostic compared to other AML types. On the other hand FLT3-TKD mutations and trisomy 8 are associated with a worse outcome. The patient is currently receiving Vidaza 75 mg/m2, days 1–7 of a 28 days cycle with Venetoclax mg daily of a 28-day cycle and his clinical prognosis is currently unclear. Further analysis by DNA sequencing may help to characterize the molecular nature of the fusion gene product resulting from the novel t(10;16)(p13;q22). To the best of our knowledge, this is the first reported case of an AML patient with translocation t(10;16)(p13;q22) involving the CBFB gene. Given the rarity and lack of additional information regarding the effects of this abnormality, the prognosis and survival cannot be predicted.

6th International Congress of Medical Genetics

The proceedings contain 108 papers. The topics discussed include: toll-like receptor 3 c.1377C/T and -7C/A polymorphisms in COVID-19 infection;a cleft palate with 49, XXXXY karyotype: A case report;a case with atypical autism and hereditary motor sensory neuropathy;investigation of genetic etiology in gastrointestinal cancer patients with next generation sequencing method;a rare disease associated with the CDK13 gene: CHHDFIDD;a case report of pericentric inversion, inv (21) (p12;q22) in repeated pregnancy loss;a case of rare CYP26B1-related craniosynostosis in a Turkish female patient;a novel homozygous mutation in CYP11A1 gene in 46, XX patient with P450scc deficiency;and a novel homozygous variant in SUOX gene causes classic isolated sulfite oxidase deficiency: a case report.

Preliminary Results of the Filo Phase 2 Trial for Untreated Fit Patients with Intermediate Risk Chronic Lymphocytic Leukemia Comparing Ibrutinib Plus Venetoclax (IV) Versus FCR

With the emergence of targeted therapies, defining the best strategy for the treatment of previously untreated CLL patients remains challenging. The aim of this phase 2 study was to compare the efficacy of an association with ibrutinib and venetoclax (IV) to the standard FCR regimen in fit patients with intermediate risk CLL defined by either unmutated IGHV status, 11q deletion or complex karyotype in the absence of TP53 abnormality. Patients were randomized 1:1 between two treatment arms, ie FCR 6 cycles or IV. After a lead-in phase of ibrutinib as a single agent from month (M)1 to M3, the total duration of treatment with IV was based on the response achieved at M9;if bone marrow (BM) MRD was < 0.01% using flow cytometry, the treatment was continued for 6 additional months until M15 and then stopped;if BM MRD at M9 was ≥ 0.01%, the treatment with IV was continued for 18 additional months until M27. The primary endpoint was the percentage of patients with BM MRD < 0.01% at M27 in both arms. We present here the preliminary results on the first evaluation done at M9 including CT-scan, BM biopsy and MRD assessment in PB and BM after the inclusion of all the 120 patients as initially planned. One hundred and twenty patients were enrolled from September 2019 to February 2021. The median age was 59 [34-72] and 61 [34-74] years in the FCR and IV arms, respectively. The characteristics of the patients were well balanced between the 2 arms in terms of gender (male 72% FCR, 74% IV), PS ECOG 0-1 (59% FCR, 68% IV) and Binet stage (A, B and C 15%, 64%, 21% for FCR;8.5%, 59% and 32% for IV). No major difference in terms of cytogenetic features was noted, all patients but one had unmutated IGHV. At the time of data cut-off for this interim analysis, the median follow-up for the all cohort was 11 [2.9 - 19.8] months. The frequency of all grades adverse events (AE) observed so far was 53% (grade 3-4, 24%) in the FCR arm and 47% (grade 3-4, 17%) in the IV arm. The rate of infusion-related reactions (IRR) in the FCR arm was 35% on cycle 1-day 1 (14% grade 3-4);for the IV arm, 6% of patients experienced tumor lysis syndrome (TLS) (grade 4 for 4 patients). ibrutinib doses were reduced for 7 patients (4 permanently stopped and 3 resumed at a lower dose because of toxicities (digestive, hepatic or haematological)). Venetoclax was permanently discontinued before M9 in 4 patients (digestive toxicities and grade 4 neutropenia). Forty serious adverse events were reported of which 15 in the IV arm (1 sudden death, 1 ischemic stroke, 2 atrial fibrillations, 2 clinical TLS, 1 hepatitis, 1 neutropenia, 4 COVID pneumonitis and one osteoporotic fracture) and 25 in the FCR arm (2 neutropenias, 1 anemia, 1 thrombocytopenia, 1 autoimmune haemolytic anemia, 3 IRR, 4 TLS, 2 COVID pneumonitis, 4 fever episodes of undetermined origin, 1 community-acquired pneumonia, 1 gastrointestinal toxicity, 1 confusion, 2 chest pains, 1 acute myeloid leukemia, 1 myelodysplasic syndrome). The patients with COVID pneumonitis had a favorable evolution with the need for intensive care and convalescent plasma for 3 of them. The first 60 patients included in the study have reached M9 and among them, 6 prematurely discontinued the study, 3 in each arm (active hemolysis, ischemic stroke and sudden death in the IV arm;2 grade 4 hematologic toxicities and 1 early progression in the FCR arm). In the evaluated patients (n=54), 71% of patients in the FCR arm and 48% of patients in the IV arm achieved bone BM MRD < 0.01%. The complete (CR, CRi) and partial response rates were 54% and 46% in the FCR arm and 76% and 24% in the IV arm respectively. In conclusion, the preliminary results show a lower BM MRD rate in the IV arm compared to the FCR arm at M9, with a toxicity that remains significant and relatively similar between the two arms. However, BM MRD rate should improve after longer exposure to the IV combination and the analysis of the primary endpoint at M27 will be decisive in determining the best therapeutic strategy. Disclosures: Quinquenel: Abbvie: Honoraria;Jansse : Honoraria;AstraZeneca: Honoraria. Laribi: Le Mans Hospital: Research Funding;Novartis: Other: Personal Fees, Research Funding;Takeda: Other: Personal Fees, Research Funding;BeiGene: Other: Personal Fees;IQONE: Other: Personal Fees;AbbVie: Other: Personal Fees, Research Funding;Astellas Phama, Inc.: Other: Personal Fees;AstraZeneca: Other: Personal Fees;Jansen: Research Funding. Cymbalista: Lilly-LOXO: Honoraria, Membership on an entity's Board of Directors or advisory committees;Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees;ASTRA ZENECA: Honoraria, Membership on an entity's Board of Directors or advisory committees;Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees;Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Leblond: AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Lilly: Consultancy;AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support;Roche: Honoraria;Amgen: Honoraria;Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees;Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dartigeas: Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress;Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress;Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress. Ferrant: Janssen: Other: Travel, Accommodations, Expenses;AbbVie: Honoraria, Other: Travel, Accommodations, Expenses;AstraZeneca: Honoraria. de Guibert: Janssen: Consultancy, Honoraria;AbbVie: Consultancy, Honoraria;Gilead: Consultancy, Honoraria. Feugier: Astrazeneca: Consultancy, Honoraria;Gilead: Consultancy, Honoraria;Abbvie: Consultancy, Honoraria;Amgen: Honoraria;Janssen: Consultancy, Honoraria. Cartron: Roche, Celgene-BMS: Consultancy;Danofi, Gilead, Novartis, Jansen, Roche, Celgene-BMS, Abbvie, Takeda: Honoraria. Ysebaert: Abbvie, AstraZeneca, Janssen, Roche: Other: Advisory Board, Research Funding.

COVID-19 Outcomes Among Participants in the NHLBI Myelodysplastic Syndromes (MDS) Natural History Study

Introduction: The NHLBI MDS Natural History Study (NCT02775383) is an ongoing prospective cohort study conducted across 144 sites in the U.S. and Israel intended to establish a data and biospecimen repository to advance the understanding of MDS. In response to the COVID-19 pandemic, the study also collected data on COVID-19 infection and management. Here, we report a summary of COVID-19 outcomes from participants in this study and the impact of the pandemic on study operations. Methods: This prospective cohort study initiated in June, 2016 is enrolling patients (pts) undergoing diagnostic work up for suspected or newly diagnosed MDS or MDS/myeloproliferative neoplasms (MPNs) in the setting of cytopenia. Study enrollment was paused from Mar. 27, 2020 to May 18, 2020 due to COVID-19. Previously untreated pts underwent a bone marrow assessment with a centralized histopathology review at enrollment for assignment to a longitudinal cohort (MDS, MDS/MPN overlap, idiopathic cytopenia of undetermined significance (ICUS), acute myeloid leukemia (AML) with <30% blasts, or “At-Risk” (pts with sub-threshold dysplasia, select karyotype, or select genetic mutations) for follow-up every six months;or a cross-sectional cohort (other cytopenia or cancers) with no further follow-up. COVID-19 outcomes, including tests, status, hospitalizations and treatments for COVID-19, were collected for all eligible pts. Protocol deviations related to COVID-19 were also collected. Fisher's exact test was used for comparing the proportions of pts tested or positive between groups. Results: Of 758 eligible pts with available COVID-19 data, 507 (67%) were assigned to the longitudinal cohort and 251 (33%) to the cross-sectional cohort or are pending assignment. Among longitudinal pts, 74 (15%) had ICUS, 240 (47%) MDS, 47 (9%) MDS/MPN overlap, 11 (2%) AML with <30% blasts, and 135 (27%) At-Risk for MDS. The median age over all pts was 72 years (range=21-95) and 66% were male, 92% White, 4% Black, 2% Asian, and 2% other. Among 244 pts (32%) tested for COVID-19 (Table 1), 23 (9%) were positive. Twelve (>50% of the positive pts) were in Wisconsin, California (CA), and Missouri (Figure 1), with 8 identified from Sep. to Dec. 2020, which overlaps with third waves of COVID-19 reported in CA and in the Midwest. Tests from 17 (74%) of the 23 pts were based on a polymerase chain reaction (PCR) assay. The proportion of pts positive were similar between pooled disease (ICUS, MDS, MDS/MPN, AML <30%), At-Risk, and cross-sectional groups (8%, 8%, 16%, respectively;Table 2) but the proportions tested differed significantly (39%, 28%, and 25%, respectively, p=0.004). Among all positive pts, 21 (91%) are recovering or have recovered (16 with sequelae), 1 (4%) died, and 1 outcome is unknown (Table 1). The one participant who died had MDS with excess blasts-1 (MDS-EB1, 5-9% blasts). Eight pts (35% of positive pts) required hospitalization (median duration of 7 days (range=2-17)) or treatment (tx) in response to COVID-19, 7 of whom required both. In the 8 pts who required tx for COVID-19, 4 reported Remdesivir-use, 3 of whom were diagnosed with MDS or MDS/MPN overlap. The study monthly accrual rates were similar when compared pre- vs. post-study pause (23 vs. 22 pts, respectively) but the rate of missed follow-up visits increased from 5% to 11% post-pause. About half (49%) of the 144 COVID-19-related study deviations occurred during the months the study was paused. Conclusions: In this analysis of 758 pts with MDS and related conditions, the largest reported for these diagnoses, the COVID-19 mortality rate (13%) in MDS was lower than has been reported in a smaller (n=61) case study (39%, Feld et al Blood 2020) but is similar to the rates for MDS observed annually each year prior to study pause (range=11-19%) and to the rate reported in a larger (n=2186) observational study of cancer patients (16%, Rivera et al Cancer Discov 2020). Infection rates were similar across disease groups. The pandemic also resulted in substantial study-specific challenges, including incre sed rate of deviations, the study being paused, and difficulty sourcing material for biospecimen processing. Data on vaccine efficacy and rates of pts with long-haul symptoms post-COVID may be of interest in future work. [Formula presented] Disclosures: Padron: BMS: Research Funding;Kura: Research Funding;Taiho: Honoraria;Stemline: Honoraria;Blueprint: Honoraria;Incyte: Research Funding. Komrokji: Novartis: Honoraria;Geron: Honoraria;Acceleron: Honoraria;Agios: Honoraria, Speakers Bureau;Abbvie: Honoraria, Speakers Bureau;JAZZ: Honoraria, Speakers Bureau;BMS: Honoraria, Speakers Bureau. Saber: Govt. COI: Other. Al Baghdadi: Bristol-Myers Squibb: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees;AstraZeneca: Current holder of individual stocks in a privately-held company;Epizyme: Current holder of individual stocks in a privately-held company;Heron Therapeutics: Current holder of individual stocks in a privately-held company;Morphosys: Membership on an entity's Board of Directors or advisory committees;Karyopharm: Membership on an entity's Board of Directors or advisory committees;Cardinal Health: Membership on an entity's Board of Directors or advisory committees. DeZern: Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees;Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees;Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees;Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sekeres: Novartis: Membership on an entity's Board of Directors or advisory committees;Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees;BMS: Membership on an entity's Board of Directors or advisory committees.

Inhibition of De Novo Pyrimidine Synthesis Depletes Acute Myleogenous Leukemia Stem Cells (LSCs) Burden and Triggers Apoptosis and Differentiation Associated with Oxidative Stress

Background: De novo nucleotide synthesis is necessary to meet the enormous demand for nucleotides, other macromolecules associated with acute myeloid leukemia (AML) progression 1, 2, 34. Hence, we hypothesized that targeting de novo nucleotide synthesis would lead to the depletion of the nucleotide pool, pyrimidine starvation and increase oxidative stress preferentially in leukemic cells compared to their non-malignant counterparts, impacting proliferative and differentiation pathways. Emvododstat (PTC299) is an inhibitor of dihydroorotate dehydrogenase (DHODH), a rate-limiting enzyme for de novo pyrimidine nucleotide synthesis that is currently in a clinical trial for the treatment of AML. Objectives: The goals of these studies were to understand the emvododstat-mediated effects on leukemia growth, differentiation and impact on Leukemia Stem Cells(LSCs). Comprehensive analyses of mitochondrial function, metabolic signaling in PI3K/AKT pathways, apoptotic signatures, and DNA damage responses were carried out. The rationale for clinical testing emvododstat was confirmed in an AML-PDX model. Results: Emvododstat treatment in cytarabine-resistant AML cells and primary AML blasts induced apoptosis, differentiation, and reduced proliferation, with corresponding decreased in cell number and increases in annexin V- and CD14-positive cells. Indeed, the inhibition of de novo nucleotide synthesis compromises the dynamic metabolic landscape and mitochondrial function, as indicated by alterations in the oxygen consumption rate (OCR) and mitochondrial ROS/membrane potential and corresponding differentiation, apoptosis, and/or inhibition of proliferation of LSCs. These effects can be reversed by the addition of exogenous uridine and orotate. Further immunoblotting and mass cytometry (CyTOF) analyses demonstrated changes in apoptotic and cell signaling proteins (cleaved PARP, cleaved caspase-3) and DNA damage responses (TP53, γH2AX) and PI3/AKT pathway downregulation in response to emvododstat. Importantly, emvododstat treatment reduced leukemic cell burden in a mouse model of AML PDX ( Complex karyotype, mutation in ASXL1, IDH2, NRAS), decreased levels of leukemia stem cells frequency (1 in 522,460 Vs 1 in 3,623,599 in vehicle vs emvododstat treated mice), and improved survival. The median survival 40 days vs. 30 days, P=0.0002 in primary transplantation and 36 days vs 53.5 days, P=0.005 in secondary transpantation in a PDX mouse model of human AML. This corresponded with a reduction in the bone marrow burden of leukemia and increased expression of differentiation markers in mice treated with emvododstat (Fig. 1). These data demonstrate effect of emvododstat on mitochondrial functions. Conclusion: Inhibition of de novo pyrimidine synthesis triggers differentiation, apoptosis, and depletes LSCs in AML models. Emvododstat is a novel dihydroorotate dehydrogenase inhibitor being tested in a clinical trial for the treatment of myeloid malignancies and COVID-19. Keywords: AML, emvododstat, DHODH, apoptosis, differentiation References: 1 Thomas, D. & Majeti, R. Biology and relevance of human acute myeloid leukemia stem cells. Blood 129, 1577-1585, doi:10.1182/blood-2016-10-696054 (2017). 2 Quek, L. et al. Genetically distinct leukemic stem cells in human CD34- acute myeloid leukemia are arrested at a hemopoietic precursor-like stage. The Journal of experimental medicine 213, 1513-1535, doi:10.1084/jem.20151775 (2016). 3 Villa, E., Ali, E. S., Sahu, U. & Ben-Sahra, I. Cancer Cells Tune the Signaling Pathways to Empower de Novo Synthesis of Nucleotides. Cancers (Basel) 11, doi:10.3390/cancers11050688 (2019). 4 DeBerardinis, R. J. & Chandel, N. S. Fundamentals of cancer metabolism. Sci Adv 2, e1600200, doi:10.1126/sciadv.1600200 (2016). [Formula presented] Disclosures: Weetall: PTC therapeutics: Current Employment. Sheedy: PTC therapeutics: Current Employment. Ray: PTC therapeutics: Current Employment. Andreeff: Karyopharm: Research Funding;AstraZeneca: Research Funding;Oxford Biomedica UK: Research Funding;Aptose: Consultancy;Daiich -Sankyo: Consultancy, Research Funding;Syndax: Consultancy;Breast Cancer Research Foundation: Research Funding;Reata, Aptose, Eutropics, SentiBio;Chimerix, Oncolyze: Current holder of individual stocks in a privately-held company;Novartis, Cancer UK;Leukemia & Lymphoma Society (LLS), German Research Council;NCI-RDCRN (Rare Disease Clin Network), CLL Foundation;Novartis: Membership on an entity's Board of Directors or advisory committees;Senti-Bio: Consultancy;Medicxi: Consultancy;ONO Pharmaceuticals: Research Funding;Amgen: Research Funding;Glycomimetics: Consultancy. Borthakur: ArgenX: Membership on an entity's Board of Directors or advisory committees;Protagonist: Consultancy;Astex: Research Funding;University of Texas MD Anderson Cancer Center: Current Employment;Ryvu: Research Funding;Takeda: Membership on an entity's Board of Directors or advisory committees;Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees;GSK: Consultancy.

CPX-351 for Acute Myeloid Leukaemia: Real World Results Are Comparable to Trial Outcomes and Exceeds Them in Non-Adverse Risk Patients- a Multicentre Experience from West Midlands Hospitals on Behalf of West Midlands Research Consortium ( WMRC) UK

Patients with secondary AML or MDS derived AML have poor outcomes compared to de-novo AML. The benefits of intensive chemotherapy without anticipated transplant consolidation have been previously doubted. Outcomes in USA trial centres have not often been closely replicable in real world settings. From November 2018 CPX-351 has been available in the UK for secondary AML, therapy related AML, AML with MDS related Karyotype (AML-MRC) and licensed but not funded for AML with myelodysplastic related changes. Objectives Here we report our experience specifically on patient outcomes and toxicity across 5 Hospitals in West Midlands, UK Methods Patients receiving CPX 351 outcomes were evaluated retrospectively from 2018 to 2021. Baseline genetics, CPX 351 indications, patient's comorbidities, overall survival, remission status, number of cycles delivered, early mortality, reasons for early discontinuation, intensive care admission and time for neutrophil recovery (>0.5) was recorded. Time-to-event outcomes reported here are from a data cut on 01-06-21 Results In a total cohort of 57 patients baseline characteristics are shown on table 1 and compared with the original trial CPX-351 group. Median follow up was 376 days (range 21 to 1248 days). The mean age was 63, 17 patients were under 60, 31 males and 26 females. The most common indication for CPX-351 was AML with antecedent MDS/MPN 51% (N=29), therapy related 14% (N=8), MDS related karyotype (AML-MRC) 19% (N=11) and 16% (N=9) other patients. Mean Charleston co-morbidity score was 2.7 (range 0-6), 10.5% (N=6) had previous non myeloid malignancies, 8.7% (N=5) had prior ischaemic heart disease, only 3.5% (N=2) had ejection fractions under 50%. The most common mutations were TP53 21% (N=12), ASXL1 15.7% (N=9), TET2 15.7% (N=9), IDH2 10.5% (N=6), RUNX1 10.5% (N=6), SRSF2 7% (N=4), JAK2 3.5% (N=2), FLT3 5% (N=3), NPM1 5%(N=3) and IDH1 5% (N=3). MRC cytogenetic risk was adverse in 19 patients (33%), intermediate in 35 patients (61%) and favourable in 3 patients (5%). 30 patients (53%) had adverse European Leukaemia Network classification, 17 (30%) had intermediate and 10 (17%) had favourable. 30-day mortality was 3/57 (5%), 60-day mortality was 6 (10.5%) comparable to the 5.9% and 10.6% rates for the original trial. 9% or 5/57 patients were admitted to ITU with 2 survivors beyond 60 days. Neutropenic fever requiring antibiotics was 100% whereas only 5/57 (9%) had radiological evidence of fungal infection. Only one patient died from COVID 19. The mean time to neutrophil recovery was 35 days with a range of 12 to 84 days. 29 patients completed 1 cycle, 25 completed 2 cycles, only 3 completed 3 cycles. The reasons for stopping were death, refractory disease, drop in performance status, alternative chemotherapy chosen or moving to transplantation (39%). Composite remission rate including CRi was 61% 36/57, adverse ELN group demonstrated 50% 15/30, intermediate 76% 13/17 and favourable 80% 8/10. Mutated P53 was associated with a 50% 6/12 rate whereas in wild type P53 the remission rate was 60% 30/45. Overall median survival from diagnosis was 429 days [95% CI 274 to 788 days]. To compare with the original trial, we removed the under 60s and those with less than 1 year follow up, in this cohort of 30 patients the median survival was 289 days (9.5 months) with 95% CI of 255 to 476 days. P53 mutated patients had an estimated median survival of 257 days versus wild type p53 with 524 days hazard ratio of 2.418 (CI 1.077 to 5.248) with p value of 0.032. Median survival for ELN groups was 373 days (adverse), 413 days (intermediate) and not reached for favourable. Of the 36 patients who achieved a remission, 22 went on to receive an allogenic transplant with follow from 254 to 1248 days, median survival estimated 706 days (95% CI 429-not reached). Patients in remission who haven't received a transplant have a similar estimated survival of 788 days (305-not reached) pending longer follow up. Conclusion This is the first UK multicentre analysis to show comparable results to the landmark trial ( edian survival 9.5 months in equivalent cases). The improved overall remission rate 61% versus the 47% in the trial and the longer median survival 14 months versus 9.5 months in the trial is expected given the younger age and increase in favourable risk genetics. This study therefore supplies further data of CPX-351 efficacy in younger patients not included in the original studies and may now be used as a standard comparator arm. [Formula presented] Disclosures: No relevant conflicts of interest to declare.

High Rates of Undetectable Minimal Residual Disease Remissions with Time-Limited Bendamustine, Rituximab, and Venetoclax (BR-VR) in Untreated Chronic Lymphocytic Leukemia (CLL)

Background: Despite the efficacy of venetoclax (VEN) in frontline CLL, optimal combination regimens and duration of treatment remain unclear. We hypothesized that cytoreduction with bendamustine/rituximab (BR) induction followed by venetoclax/rituximab (VR) consolidation for a fixed 1-year duration would be associated with an increased rate of undetectable minimal residual disease (uMRD) compared to historical controls and a reduction in the risk of tumor lysis syndrome (TLS). Here we report data from an ongoing phase 2 multicenter, US, single-arm, open-label study (NCT03609593) designed to assess the safety and efficacy of BR-VR in previously untreated CLL patients (pts). Methods: Previously untreated CLL/SLL pts ≥ 18 years requiring therapy per iwCLL criteria initially received 3 cycles of bendamustine 50-90 mg/m 2 daily for 2 days and rituximab 375 mg/m 2 every 28 days for 3 cycles. Following BR, VEN was initiated with a standard dose escalation from 20 mg to 400 mg daily over 5 weeks. This was followed by 6 cycles of VR with rituximab given monthly and 5 cycles of VEN alone (12 cycles of VEN in total). Additional eligibility included: ECOG PS ≤ 2, hemoglobin ≥8g/dL, ANC ≥1000/mm 3, and platelets ≥50,000/mm 3. Response was assessed by 2018 iwCLL criteria with uMRD testing by central flow cytometry at a level of <10 -4 in peripheral blood (PB) and bone marrow (BM). The primary endpoint was objective response rate (ORR). Secondary endpoints included uMRD rate, time to uMRD, and adverse events (AEs) assessed by CTCAE v 5.0. Results: As of data cutoff on 30 May 2021, 26 pts were accrued with additional recruitment ongoing. Baseline demographics were as follows: male/female (16/10), median age 60 yrs (range 44-77). Baseline prognostic studies showed unmutated IGHV in 16 (62%) pts, TP53 aberrant (either del(17p) and/or TP53 mutation) in 1 (4%) pt, del(11q) in 3 (12%) pts, and complex karyotype in 4 (15%) pts. TLS risk among 24 evaluable pts at baseline was high (H) in 3 (12.5%), medium (M) in 15 (62.5%), and low (L) in 6 (25%). At a median follow-up of 12.9 mo. (range, 1.9-27.5), 23 pts remain on study. Of 12 pts with at least 15 mo. follow-up (completing all therapy), the ORR was 100% (92% CR/CRi, 8% PR [due to small residual nodes]). 3 pts died on study (2 due to COVID-19 and 1 developed newly metastatic squamous cell carcinoma and taken off study after achieving a CR post-VEN ramp-up). Bendamustine was administered at doses of 50 mg/m 2 in 47%, 70 mg/m 2 in 11%, and 90mg/m 2 in 42% of pts. In 20 evaluable pts, response assessments after cytoreduction with BR demonstrated 15% of pts achieved CR/CRi and 85% achieved PR. For evaluable pts at 16 mo., uMRD (<0.01%) in the PB and BM was observed in 100% (10/10) and 90% (9/10) of pts, respectively. MRD was intermediate (0.01% - <1.0%) in 10% (1 patient) in BM (Figure 1 ORR and MRD). Median time to uMRD was 12 mo. (range 3-15) in PB and 14 mo. (range 5.5-15) in BM. The most common treatment-emergent AEs during BR induction were (any grade/grade ≥3) anemia in 6/2 (21%/7%) pts, nausea in 6/0 (21%/0%), neutropenia in 5/2 (18%/7%), rash in 5/0 (18%/0%), constipation 4/0 (14%/0%), and transaminitis in 3/0 (11%/0%). 2 pts (7%) developed febrile neutropenia during BR. Emergent AEs during VEN treatment included diarrhea in 10/0 (36%/0%) pts, neutropenia in 6/3 (21%/11%), leukopenia in 5/2 (18%/7%), and nausea in 4/0 (14%/0%). TLS risk was substantially reduced after BR lead-in. Of 3 H-risk pts at baseline, none remained H-risk after BR;of 15 M-risk pts, only 1 remained M-risk, with the remainder at L-risk (94% reduction in H- or M- risk TLS). Conclusions: BR-VR is a safe and well-tolerated regimen in untreated CLL pts. BR debulking substantially reduces TLS risk, and this sequential strategy achieves high rates of PB and BM uMRD across all prognostic risk groups. [Formula presented] Disclosures: Hill: Celgene (BMS): Consultancy, Honoraria, Research Funding;AstraZenica: Consultancy, Honoraria;Pfizer: Consultancy, Honoraria;Gentenech: Consultancy, Honoraria, Research Funding;AbbVie: Consultancy, Honoraria, Research Funding;Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding;Karyopharm: Consultancy, Honoraria, Research Funding;Beigene: Consultancy, Honoraria, Research Funding;Epizyme: Consultancy, Honoraria;Novartis: Consultancy, Honoraria, Research Funding;Incyte/Morphysis: Consultancy, Honoraria, Research Funding. Jurcic: AbbVie, BMS/Celgene, Novartis: Consultancy;AbbVie, Arog Pharmaceuticals, Astellas, BMS/Celgene, Forma Therapeutics, Genentech, Gilead Sciences, PTC Therapeutics, Syros Pharmaceuticals: Research Funding. Heaney: CTI: Honoraria, Research Funding;Blueprint: Honoraria, Research Funding;Novartis: Honoraria;Sierra Oncology: Research Funding;Cogent: Research Funding;BMS: Research Funding;Kartos: Research Funding. Lamanna: MingSight Pharmaceuticals, Inc.: Research Funding;Gilead Sciences, Inc.: Consultancy;AbbVie: Consultancy, Research Funding;AstraZeneca: Consultancy, Research Funding;Juno Therapeutics, Inc.: Research Funding;Oncternal Therapeutics: Research Funding;Celgene Corporation: Consultancy;Genentech, Inc.: Consultancy, Research Funding;Verastem Oncology: Research Funding;TG Therapeutics, Inc: Research Funding;Janssen Pharmaceuticals, Inc.: Consultancy;BeiGene: Consultancy;Pharmacyclics: Consultancy. OffLabel Disclosure: Venetoclax, Bendamustine, and Rituximab are all FDA approved for use in first-line CLL. The combination of these three agents and dosing schedule utilized in this clinical trial is novel and therefore technically reflects an off-label use.