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Introduction Venetoclax has transformed the treatment landscape in hematologic malignancies, especially in elderly population. With high rates of remission, deep and durable responses, and safe toxicity profile, venetoclax in combination therapy has been extremely effective, garnering accelerated approval and becoming standard of care in lymphoid and myeloid malignancies. Areas covered The role of venetoclax in the intrinsic apoptotic pathway is covered. This includes preclinical and clinical experience of venetoclax monotherapy and combination therapy in relapsed/refractory and frontline CLL, AML, ALL and high-risk MDS, with an emphasis on key clinical trials and efficacy of combination regimens in distinct mutational landscapes. Strategies to mitigate myelosuppression, manage dose adjustments and infectious complications are addressed. Expert opinion Targeting BCL-2 offers a safe and highly effective adjunct to available therapies in hematologic malignancies. Despite success and frequent utilization of venetoclax, several resistance mechanisms have been elucidated, prompting development of novel combinatorial strategies. Further, on-target myelosuppression of venetoclax is a key obstacle in clinical practice, requiring diligent monitoring and practice-based knowledge of dose modifications. Despite these limitations, venetoclax has gained tremendous popularity in hematologic-oncology, becoming an integral component of numerous combination regimes, with ongoing plethora of clinical trials encompassing standard chemotherapy, targeted agents and immune-based approaches.

Introduction: Recent FDA approvals of novel therapies and hypomethylating agents/venetoclax (HMA-ven) has transformed AML therapy. CR with partial hematological recovery (CRh), defined as bone marrow blasts 0.5×109/L, and platelet count >50×109/L, was used as a surrogate marker for efficacy due to limited data on HMA-ven. We evaluated the impact of CRh on pts treated with 10-day decitabine and venetoclax (DEC10-VEN, NCT03404193). Method: Patients with newly diagnosed AML aged >60 years or patients with secondary AML and antecedent hematological disorder were included. Decitabine 20 mg/m2 IV for 10 days with oral venetoclax 400 mg daily was administered for induction and decitabine (5 days) with daily venetoclax for consolidation. Responses initially recorded were complete response (CR), CR with incomplete hematologic recovery (CRi), and morphologically leukemia-free state (MLFS), according to ELN 2017 criteria. Pts who achieved CRi and MLFS were re-classified to CRh. Outcomes evaluated were overall survival (OS) and event-free survival (EFS). Full protocol and interim results have been published (DiNardo et al. Lancet Haematol. 2020;7:e724–36) Results: From January 2018 to February 2021, 125 patients (79 [63%] newly diagnosed, 46 [37%] secondary AML) with a median age of 71 yrs (range 48–89) were included. 69 (55%) pts achieved CR, 11 (8%) pts achieved CRh, 14 (11%) pts achieved CRi, 10 (8%) pts achieved MLFS, and 21 (17%) pts were refractory. Of the 11 CRh pts, 8 (73%) patients were previously classified as CRi and 3 (27%) as MLFS. Among pts achieving CR, the median OS was 24.5 mo, and median EFS was 18.0 mo. CRh was achieved with a median of 1 (range 1–3) cycles. Median OS of CRh vs CRi was 16.9 vs 5.8 mo (HR: 0.47, 95% CI: 0.19–1.13, p=.06), and CRh vs MLFS was 16.9 vs 6.2 mo (HR: 0.34, 95% CI: 0.13–0.93, p=.007). Median EFS of pts with CRh vs CRi was 14.1 vs 5.8 mo (HR: 0.49, 95%CI: 0.21–1.14, p=.08); CRh vs MLFS was 14.1 vs 6.2 mo (HR: 0.37, 95% CI: 0.14–1.01, p=.016). Pts achieving CRh had durable remission with a duration of response of 6.0 vs 2.5 mo with CRi and 1 mo with MLFS. Conclusion: In pts with newly diagnosed and secondary AML treated with DEC10-VEN, pts achieving CRh had a trend toward improved OS and EFS compared with CRi or MLFS.

INTRODUCTION: Myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN RS-T), formerly called refractory anemia with ring sideroblasts and thrombocytosis (RARS-T), is a disease entity characterized by the presence of anemia, thrombocytosis, bone marrow dysplasia with ring sideroblasts and large atypical megakaryocytes. Given the rarity of MDS/MPN-RS-T, there is little data on the efficacy and clinical outcomes of different therapies in this patient population. Prior case reports and series suggest treatment with erythropoietin-stimulating agents (ESAs) and lenalidomide can be effective in this disease, but there is no data detailing the activity of hypomethylating agents (HMA). The aim of this study is to evaluate the outcomes with HMAs in patients with MDS/MPN-RS-T. MATERIALS AND METHODS: A retrospective review was conducted of patients presenting to MD Anderson Cancer Center between March 2005 and January 2020 at with the diagnosis of MPS/MPN RS-T per World Health Organization (WHO) criteria and 52 patients were identified. Of the 52 patients, 16 patients had received either decitabine or azacitidine in the course of their disease. Of those, 4 were excluded for either receiving HMAs prior to presentation or proceeding to transplant after only 1 cycle of HMA. The data presented is on the remaining 12 patients. Outcomes evaluated included erythroid response, duration of response, response rate, disease progression, overall survival (OS) and progression free survival (PFS). Disease progression was defined as increasing transfusion dependence, development of myelofibrosis (MF) or transformation to acute myeloid leukemia (AML). Overall survival was defined as time from the date of treatment initiation to the date of last follow-up or censorship date. Progression-free survival was defined as the time from the date of starting treatment to the date of progression of disease. RESULTS: Twelve patients who received HMAs with WHO defined MDS/MPN RS-T were included. Median age was 66 years (51-77) with 7 males (58%). Patient characteristics are detailed in Table 1. Ten patients (83%) were transfusion dependent at the time of HMA therapy initiation. The median number of prior therapies was 2 (range 0-5). A total of 6 patients had received prior ESAs and 3 had received prior lenalidomide. HMAs were used as 1st line treatment in 2 patients (17%), 2nd line in 2 patients (17%), 3rd line in 3 patients (25%), 4th line in 4 patients (33%), 5th line in 1 patient (8%) and 6th line in 1 patient (8%). Nine patients (75%) received azacitidine (of which 1 was in conjunction with ruxolitinib), 2 patients (17%) received decitabine, and 1 patient (8%) received decitabine and then azacitidine (in combination with an investigational agent). Median duration of treatment was 8.5 months (range 0-53). Response was achieved in 3 patients with an overall response rate (ORR) of 25%. Per 2015 International Working Group (IWG) MDS/MPN overlap syndrome response criteria, 1 patient achieved complete response (CR) and 2 patients reached hematological improvement in the erythrocyte lineage (HI-E). Median duration of response was 7 months (range 4-21). For the remaining 9 patients, 2 remain on HMA therapy with stable disease, 1 died during treatment, 3 developed failure/loss of response and proceeded to allogeneic stem cell transplantation and 3 had disease progression, with a median follow-up time of 38 months; median OS from therapy initiation was 46 months (Figure 1). Disease progression was seen in a total of 5 patients (42%, 2 patients from the responder group), with increased transfusion dependence in 1 patient (8%), worsening cytogenetics in 1 patient (8%), increased bone marrow blast count in 1 patient (8%), development of myelofibrosis after 8 months in 1 patient (8%) after introduction of HMA therapy and transformation to AML in 1 patient (8%) 46 months after initiating HMAs (Table 2). CONCLUSION: Treatment with HMAs can induce responses in up to 25% of patients, including transfusion independence, even in heavily pre-treated patients with prior exposure to lenalidomide, with a median response duration of 7 months. Disclosures Sasaki: Daiichi Sankyo: Consultancy; Otsuka: Honoraria; Pfizer Japan: Consultancy; Novartis: Consultancy, Research Funding. Jabbour:Genentech: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding. Pemmaraju:MustangBio: Honoraria; DAVA Oncology: Honoraria; Affymetrix: Other: Grant Support, Research Funding; Blueprint Medicines: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; SagerStrong Foundation: Other: Grant Support; Novartis: Honoraria, Research Funding; Celgene: Honoraria; Daiichi Sankyo: Research Funding; Plexxikon: Research Funding; Samus Therapeutics: Research Funding; Roche Diagnostics: Honoraria; AbbVie: Honoraria, Research Funding; LFB Biotechnologies: Honoraria; Incyte Corporation: Honoraria; Pacylex Pharmaceuticals: Consultancy; Cellectis: Research Funding. Kadia:Cyclacel: Research Funding; Amgen: Research Funding; Novartis: Honoraria; Ascentage: Research Funding; Celgene: Research Funding; Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Incyte: Research Funding; JAZZ: Honoraria, Research Funding; Cellenkos: Research Funding; Pulmotec: Research Funding; Genentech: Honoraria, Research Funding; Astra Zeneca: Research Funding; Astellas: Research Funding. Ravandi:Abbvie: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria. Daver:Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. Borthakur:PTC Therapeutics: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Abbvie: Research Funding; Jannsen: Research Funding; GSK: Research Funding; Cyclacel: Research Funding; BioLine Rx: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; Polaris: Research Funding; Treadwell Therapeutics: Consultancy; Nkarta Therapeutics: Consultancy; BioTherix: Consultancy; BioLine Rx: Consultancy; PTC Therapeutics: Consultancy; Xbiotech USA: Research Funding; Argenx: Consultancy; FTC Therapeutics: Consultancy; Curio Science LLC: Consultancy; Oncoceutics: Research Funding. Verstovsek:Genentech: Research Funding; CTI Biopharma Corp: Research Funding; NS Pharma: Research Funding; Novartis: Consultancy, Research Funding; Roche: Research Funding; Incyte Corporation: Consultancy, Research Funding; PharmaEssentia: Research Funding; Protagonist Therapeutics: Research Funding; AstraZeneca: Research Funding; Promedior: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Sierra Oncology: Consultancy, Research Funding; ItalPharma: Research Funding; Blueprint Medicines Corp: Research Funding. Bose:Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Astellas Pharmaceuticals: Research Funding; Pfizer, Inc.: Research Funding; Kartos Therapeutics: Honoraria, Research Funding; NS Pharma: Research Funding; Promedior, Inc.: Research Funding; Constellation Pharmaceuticals: Research Funding; CTI BioPharma: Honoraria, Research Funding; Blueprint Medicines Corporation: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding. Kantarjian:Novartis: Research Funding; AbbVie: Honoraria, Research Funding; Takeda: Honoraria; Astex: Research Funding; Daiichi-Sankyo: Research Funding; Immunogen: Research Funding; Cyclacel: Research Funding; Ariad: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; BMS: Research Funding; Agios: Honoraria, Research Funding; Jazz Pharma: Research Funding. Garcia-Manero:Jazz Pharmaceuticals: Consultancy; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Amphivena Therapeutics: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; H3 Biomedicine: Research Funding; Onconova: Research Funding.

7025 Background: Patients (pts) with AML frequently encounter life-threatening complications requiring transfer to an intensive care unit (ICU). Methods: Retrospective analysis of 145 adults with AML requiring ICU admission at our tertiary cancer center 2018-19. Use of life-sustaining therapies (LSTs) and overall survival (OS) were reported using descriptive statistics. Logistic regression was used to identify risk factors for in-hospital death. Results: Median age was 64 yrs (range 18-86). 47% of pts had an ECOG status of ≥ 2 with a median of at least 1 comorbidity (Table). 117 pts (81%) had active leukemia at admission. 68 pts (47%) had poor-risk cytogenetics (CG) and 32 (22%) had TP53-mutated disease. 61 (42%), 27 (19%) and 57 pts (39%) were receiving 1st, 2nd and ≥ 3rd line therapy. 33 (23%) and 70 pts (48%) were receiving intensive and lower-intensity chemotherapy, respectively, and 77 pts (53%) were concurrently on venetoclax. Most common indications for admission were sepsis (32%), respiratory failure (24%) and leukocytosis (12%); Table outlines additional ICU admission details. Median OS from the date of ICU admission was 2.0 months (mo) for the entire cohort and 6.9, 1.6 and 1.2 mo in pts with favorable-, intermediate- and poor-risk CG. Median OS of pts receiving frontline vs. ≥ 2nd line therapy was 4.2 vs. 1.4 mo (P

B cell prolymphocytic leukemia is a rare and aggressive disorder often with high risk features including TP53 mutation, deletion 17p and complex karyotype. There is scarcity of data regarding treatment and existing therapies induce short lived remissions. Ibrutinib, a Bruton tyrosine kinase inhibitor, has had success in some patients with high risk features. Venetoclax, a BCL-2 inhibitor, has primarily been used in the relapsed setting. We present a case of B PLL with deletion 17p and mutated TP53 treated with ibrutinib and venetoclax in the frontline setting which resulted in measurable/minimal residual disease negative remission for approximately three years.

To evaluate patients presenting with Tetralogy of Fallot with absent pulmonary valve syndrome to a tertiary care hospital and their surgical management.The retrospective study was conducted at Congenital Cardiac Services, Aga Khan University Hospital, Karachi, Pakistan, and comprised data of Tetralogy of Fallot patients between April 2007 and June 2012. Data was analysed together with follow-up echocardiography. Variables assessed included demographics, imaging, operative technique, complications, post-operative recovery and follow-up echocardiography. SPSS 17 was used for statistical analysis.Of the 204 patients, 6 (3%) had undergone surgical correction for Tetralogy of Fallot with absent pulmonary valve syndrome. All 6(100%) patients underwent complete repair. Median age for surgery was 8.5 years (range: 0.5-29 years). Of the different surgical strategies used, Contegra and Bioprosthetic valve placement had satisfactory outcome with minimal gradient at Right Ventricular Outflow Tract, good ventricular function and mild valvular regurgitation. One (16.6%) patient with Trans Annular Patch developed post-operative Right Ventricle Outflow Tract gradient of 80mmHg with moderate pulmonary regurgitation. One (16.6%) patient with monocusp valve developed free pulmonary regurgitation at 6 months. The other 4(66.6%) patients are currently free from any complications or re-intervention.Early surgery is preferred in symptomatic patients. The repair depends upon achieving integrity of pulmonary circulation which is best achieved by using right ventricle to pulmonary artery conduit or inserting a pulmonary valve.

BackgroundCardiopulmonary bypass is associated with systemic inflammatory response. Steroids suppress this response, although the therapeutic evidence remains controversial. We hypothesised that intravenous steroids in children undergoing open-heart surgery would decrease inflammation leading to better early post-operative outcomes. We conducted a randomised controlled trial to evaluate the trends in the levels of immunomodulators and their effects on clinical parameters.ObjectiveTo assess the effects of intravenous steroids on early post-operative inflammatory markers and clinical parameters in children undergoing open-heart surgery.Materials and methodsA randomised controlled trial involving 152 patients, from one month up to 18 years of age, who underwent open-heart surgery for congenital heart disease from April 2010–2012 was carried out. Patients were randomised and administered either three scheduled intravenous pulse doses of dexamethasone (1 mg/kg) or placebo. Blood samples were drawn at four time intervals and serum levels of inflammatory cytokines – Interleukin-6, 8, 10, 18, and tumour necrosis factor-alpha – were measured. Clinical parameters were also assessed.ResultsBlood cytokine levels were compared between the dexamethasone (n=65) and placebo (n=64) groups. Interleukin-6 levels were lower at 6 and 24 hours post-operatively (pConclusionDexamethasone caused quantitative suppression of Interleukin-6 and increased Interleukin-10 activation, contributing to reduced immunopathology, but it did not translate into clinical benefit in the short term.

Air embolism entering the systemic arterial system originating from the pulmonary circuit itself is an extremely rare occurrence. We report the case of an 18-year-old female undergoing correction of an atrial septal defect, who had an air embolism that is believed to have originated from the right superior pulmonary vein. Although the exact mechanism of air entry remains a matter of speculation, several plausible hypotheses are proposed and discussed. Injury to a pulmonary vein may lead to air entry with migration to the left atrium and ultimately to systemic embolism.

Aggressive angiomyxoma is a rare, myofibroblastic tumour, of pelvi-perineum of young women. It is a slow growing, low grade neoplasm with a high risk of recurrence following initial resection. Aggressive angiomyxoma is often clinically misdiagnosed because of its variable presentation as a soft tissue mass of the vulva, perianal region, buttock or pelvis. It displays translevator extension with growth around the perineal structures. Fewer than 150 cases have been reported in the literature since 1983. Imaging is important to determine the extent of the lesion. We present layered configuration of the mass on ultrasound and Magnetic Resonance Imaging in a 40 years old woman with a left pelvi- perineal mass since 5 years. Histapathology after excision gave a diagnosis of Aggressive Angiomyxoma.

To evaluate the midterm results of Contegra conduit.The retrospective study comprised patient record at Aga Khan University Hospital, Karachi, of conduits implanted between May 2007 and June 2012. Data collection was made from the clinical notes and from serial echocardiograms by a single cardiologist. The last followup echocardiography was done at the time of data collection in June 2012. SPSS 19 was used for statistical analysis.A total of 18 conduits had been implanted (16-22 mm) during the study period. Median age at the time of surgery was 9 years (range: 2.5-16 years). Early mortality was seen in 3 (16.66%) patients, but none was Contegra related. Of the remaining 15 patients, 2 (13.33%) with a diagnosis of Pulmonary Atresia-Ventricular Septal Defect with hypoplastic peripheral Pulmonary Arteries (PA), developed severe distal pressure gradient (50 mmHg) across Contegra over a median period of 18 months (range: 12-24 months), with resultant severe regurgitation and needed percutaneous intervention. There was no thrombosis, calcification, anuerysmal dilation or late deaths.At midterm followup, Contegra conduit was associated with low re-intervention rates with satisfactory haemodynamic results. However, long-term durability must be determined for this conduit, especially in patients with Pulmonary Atresia-Ventricular Septal Defect with hypoplastic peripheral Pulmonary Arteries.

The focus of this study is to share the experience and outcomes of Contegra graft implantation in the paediatric and adult population in Pakistan.Between May 2007 and July 2011, 16 patients, underwent implantation of a Contegra valved conduit. All operations were performed through a median sternotomy with cardiopulmonary bypass. Indications included: Pulmonary atresia with ventricular septal defect (n = 11), Tetralogy of Fallot with absent Pulmonary Valve (PV) syndrome (n = 2), double outlet right ventricle, transposition of great arteries and pulmonary stenosis (n = 1), isolated aortic valve disease (n = 1) and a pseudo-aneurysm with infective endocarditis (n = 1).Conduit sizes varied between 16-22 mm.The three in hospital deaths were unrelated to the Contegra valved conduit. One patient was lost to follow up. Of the 12 survivors, 10 are currently free from re-operation or complications related to the conduit while one needed distal pulmonary artery dilatation owing to critical stenosis and another had severe Valvular regurgitation. Echocardiographic evaluation of the Contegra valved conduit demonstrated no haemodynamically significant valve regurgitation in 10 patients.In this small review of 16 operations using the Contegra valved conduit for Right Venticular Outflow Tract (RVOT) reconstruction in the paediatric population, we observed good post operative results concerning conduit function. The Contegra conduit provides an excellent substitute to the homograft with satisfactory early and mid-term results though long-term results are awaited in Pakistan.

To examine the outcomes of surgical repair of atrial septal defects in paediatric and adult patients.The retrospective study comprised data of 84 patients who had undergone surgical correction of atrial septal defect at the Aga Khan University Hospital, Karachi, between June 2006 and December 2011. All patients with isolated atrial septal defect (ostium secundum, ostium primum and sinus venosus with or without partial anomalous pulmonary venous connection) were included. Clinical and transthoracic echocardiographic data was reviewed. SPSS 17 was used for statistical analysis.There were no deaths in the study population. The mean time for follow-up was 6.5 +/- 9.9 months. Most of the patients (n = 80; 95.2%) were in NewYork Heart Association class I at follow-up, while the remaining 4 (4.8%) were in New York Heart Association class II. Post-operatively, 8 (9.5%) patients developed brief episodes of arrhythmias. There were 3 (3.57%) patients who were re-admitted within 30 days; 2 (66.7%) had superficial wound infection, while 1 (33.3%) had to be re-opened because of cardiac tamponade.Surgical repair of atrial septal defects is a safe procedure which is associated with excellent results and low morbidity.