Begna, Kebede H.

Background: Venetoclax (Ven) in combination with hypomethylating agent (HMA) is the preferred treatment for elderly/unfit patients with newly-diagnosed acute myeloid leukemia (AML). Current prognostication for AML is based on European LeukemiaNet (ELN) genetic risk stratification which has limited applicability in patients treated with Ven-HMA ( Blood, 2022). Accordingly, our primary objective was to determine predictors of treatment response and survival outcomes in treatment-naïve AML patients receiving Ven-HMA. Methods: Our study population was recruited from Mayo Clinic (MN, FL, AZ), after institutional review board approval and based on documentation of newly-diagnosed AML treated with Ven-HMA outside of clinical trials between November 2018 and April 2023. Cytogenetic and molecular studies were performed by conventional karyotype, and next-generation sequencing, respectively. Response was assessed according to the 2022 ELN criteria Results: Patient characteristics A total of 301 newly-diagnosed AML patients (median age 73 years, 66% male, 62% de novo) received a median of 3 cycles (range 1-48) of azacitidine 75 mg/m2 days 1-7 ( n=100) or decitabine 20 mg/m2 days 1-5 ( n=201) with Ven. ELN 2022 cytogenetic risk included favorable (1%, n=4), intermediate (61%, n=184) or adverse (38%, n=113). Mutations involved TP53 in 77/301 (25%), ASXL1 in 54/279 (19%), RUNX1 in 54/296 (18%), NPM1 in 44/299 (15%), DNMT3A in 40/296 (13%), K/NRAS in 41/296 (14%), IDH1 in 20/301 (6%), IDH2 in 30/301 (10%), FLT3-ITD in 25/301 (8%) and DDX41 in 9/247 (4%) of informative cases. Predictors of response Complete remission, with (CR) or without (CRi), count recovery, was documented in 182 (60%) patients, including CR in 36% and measurable residual disease (MRD) negative by flow cytometry in 77% of 105 informative cases that achieved CR/CRi. Median time to CR/CRi was 1.4 months. In univariate analysis, CR/CRi was more likely to occur in the presence of NPM1 mutation, (86% vs. 56%; p < .01), IDH2 mutation, (80% vs. 58%; p = .02), DNMT3A mutation, (78% vs. 57%; p = .01), or DDX41 mutation, (100% vs. 58%; p <.01), and in the absence of adverse karyotype, (71% vs. 42%; p < .01), TP53 mutation, (67% vs. 40%; p <.01), FLT3-ITD mutation, (63% vs. 36%; p = .01), or RUNX1 mutation, (64% vs. 44%; p = .01); in multivariable analysis, adverse karyotype, ( p < .01), FLT3-ITD ( p < .01), RUNX1 ( p < .01), NPM1 ( p = .03), IDH2 ( p = .04), and DDX41, ( p = .01) mutations remained significant. Predictors of survival After a median follow-up of 8.5 months (range 0.5-56), 13.2 months for living patients, 174 (58%) deaths, 73 relapses (40% of those achieving CR/CRi), and 41 (14%; including 35 in CR/CRi) allogeneic hematopoietic stem cell tranplants (AHSCT) were documented. In univariate analysis of pre-treatment variables, thrombocytopenia < 100 x 10 9/l, (HR 1.5, 95% CI 1.03-2.2; p = .03), adverse karyotype, (HR 2.8, 95% CI 2.1-3.8; p < .01) TP53 mutation, (HR 2.5, 95% CI 1.8-3.5; p < .01), or absence of IDH2 mutation, (HR 3.5, 95% CI 1.7-7.6; p < .01) predicted inferior survival. Failure to achieve CR/CRi (HR 4.5, 95% CI 3.3-6.1; p < .01) was also associated with inferior survival and in multivariable analysis, failure to achieve CR/CRi, (HR 3.4, 95% CI 2.5-4.8; p< .01), presence of adverse karyotype, (HR 1.6, 95% CI 1.1-2.6; p = .02), TP53 mutation, (HR 1.6, 95% CI 1.002-2.4; p = .04), and absence of IDH2 mutation (HR 2.2, 95% CI 1.004-4.7; p = .04) were identified as risk factors for survival. Subsequent HR-weighted scoring resulted in three-tiered risk stratification: low (0-1 point; n= 130), intermediate (2-3 points; n= 105), and high (4-5 points; n= 66), with respective median survival (3-year rate) of 28.9 (48%), 9.6 (6%), and 3.1 (0%) months ( p < .01) (Figure). AHSCT had an independent favorable impact on survival (HR 0.3, 95% CI 0.1-0.6; p < .01), most apparent in low ( p =0.04), and intermediate ( p <.01), as opposed to high ( p = .06) risk. Conclusions: In the current single institutional series of Ven-HMA treated newly-diagnosed AML, response to Ven-HMA was the foremost predictor of survival. Additional risk factors for survival included adverse karyotype, presence of TP53 and absence of IDH2 mutations. These observations allowed for a three-tiered genetics-enhanced survival model with CR/CRi as a backbone, and also confirmed survival advantage from AHSCT, regardless of risk category.

Background: According to the international consensus classification (ICC), diagnosis of myelodysplastic syndromes (MDS) with del(5q) requires presence of i) del5q, alone or associated with no more than one other cytogenetic abnormality, exclusive of -7/del(7q), ii) <5% bone marrow (BM) and <2% circulating blasts, and iii) the absence of “multi-hit” TP53 ( Arber et al. Blood 2022;140: 1200). We have recently reported on TP53 variant allele frequency (VAF) ≥22% being the sole genetic predictor of inferior survival in MDS-del(5q) (Fleti. et al. AJH 2023;98:E76). In the current study, we examined the additional prognostic impact of therapy-related setting, in the context of TP53 VAF and other risk factors. Methods : The current study included patients with MDS-del(5q) who were seen at the Mayo Clinic or Moffitt Cancer Center, USA. Diagnosis of MDS-del(5q) and therapy-related qualification was according to ICC criteria ( Arber et al. Blood 2022;140: 1200), with the exception that patients with biallelic or multi-hit TP53 were included to allow unbiased analysis of impact on prognosis. Patient selection was based on availability of mutation information from next-generation sequencing (NGS). The latter was assessed either at diagnosis or at different time points during the disease course, but at least 3 months before leukemic transformation. Otherwise, all analyses, including estimation of overall and leukemia-free survival, were based on variables collected at time of initial diagnosis of MDS-del(5q). TP53 mutation VAF threshold of 22% was considered based on our previously published report cited above. Age cutoff at 67 years was determined by ROC analysis. Conventional statistical methods were applied using JMP Pro 16.0.0 software (SAS Institute, Cary, NC, USA). Results: A total of 210 patients (median age 72 years; 65% females), meeting the above-stipulated criteria for MDS-del(5q), were considered: 172 primary and 38 therapy-related. Table 1 outlines clinical and laboratory characteristics obtained at the time of diagnosis: 42% were transfusion-dependent, 69% had hemoglobin level <10 g/dL, 30% platelet count <150 x 10(9)/L, and 15% carried additional cytogenetic abnormality. NGS data performed either at diagnosis or at least 3 months prior to leukemic transformation was available in 146 patients; the most frequent mutations were TP53 (21%), SF3B1 (16%), DNMT3A (12%), TET2 (12%), ASXL1 (10%), and JAK2 (7%) (Table 1). At a median follow-up of 3.9 years (range 0.002-18.5) for living patients, 95 (45%) deaths and 34 (16%) leukemic transformations were recorded; treatment undertaken included lenalidomide in 162 (77%) cases. NGS data-exclusive multivariable analysis that included all 210 patients identified therapy-related setting (p<0.01; HR 2.9; Figure 1a), age >67 years (p=0.01; HR 1.8), transfusion-dependency (p=0.04; HR 1.5), and platelet count <150 x 10(9)/L (p=0.03; HR 1.6), as independent predictors of inferior survival. The significant effect of age and platelet count was sustained when analysis was limited to patients with primary MDS-del(5q) but lost when applied to therapy-related disease. NGS data-inclusive multivariable analysis, which was applicable to the subset of 146 patients, identified, as risk factors, therapy-related setting (p<0.01; HR 2.3) and TP53 VAF ≥22% (p<0.01; HR 2.4; Figure 1b) while age >67 years sustained borderline significance (p=0.07; HR 1.8). Figure 1c depicts survival data based on the presence or absence of TP53 VAF ≥22% and therapy-related qualification; low-risk with no risk factors (N=112; median survival 11.7 years; 5/10-year survival 73%/52%) and high-risk with one or both risk factors (N=34; median survival 4 years; 5/10-year survival 42%/14%); leukemia-free survival was affected by TP53 VAF ≥22% (p<0.01) but not therapy-related setting (p=0.13). Conclusions : The current study highlights TP53 VAF and therapy-related setting as the most prominent risk factors for survival in MDS-del(5q) and proposes a simple risk model that distinguishes patients with a projected 10-year survival that exceeds 50%, in the absence of both risk factors, and plummets to 14%, in the presence of one of the two risk factors. Accordingly, allogeneic stem cell transplant might be deferred in the former instance while it should be pursued sooner than later, in the latter instance.

BACKGROUND: Recently proposed World Health Organization (WHO, 5 th edition) and International Consensus Classification (ICC) recognized myeloid neoplasms (MN) harboring TP53-mutated ( TP53mut) as a separate entity. However, there are critical differences between the two classifications regarding allelic-status, variance allele frequency (VAF) cut-off and blast categories, that may lead to under- or overestimation of the risk. METHODS: We analyzed MN harboring TP53mut (VAF ≥2%, n=536) managed at Mayo Clinic (USA) and South Australia Health Network (Australia). ICC (Arber et al, Blood 2022) and WHO (Bluebook, Beta v2) definitions were used to stratify MN harboring TP53mut. RESULTS: Of 536 cases, 379 (71%) had myelodysplastic syndromes (MDS) (<20% blasts) and 157 (29%) had acute myeloid leukemia (AML). Using WHO, 160 (42%) of 379 were classified as MDS-bi TP53 as they harbored 2 TP53mut (n=115; 30%) or 1 TP53mut plus confirmed loss of heterozygosity (LOH) or copy neutral LOH (cnLOH) of TP53 locus (n=45; 12%). Sixty-two (16%) TP53mut MDS with VAF >49% were classified as presumptive MDS-bi TP53. Of the 157 cases with 1 TP53mut VAF ≤49%, 17 confirmed to have an intact wild-type TP53 copy and were classified as monoallelic. While 140 (89%) cases did not have copy number variation (CNV) analysis. We next evaluated the number of TP53mut cases classified differently by WHO and ICC. As WHO does not recognize TP53mut AML as a separate entity, 157 (29%) TP53mut AML were not classifiable. 46% (174/379) of the TP53mut MDS including 48 (30%), 12 (19%) and 79 (65%) of bi TP53, presumptive bi TP53 and monoallelic TP53mut MDS according to WHO were classified differently by ICC ( Figure 1A). Discordance between the two classifications were predominantly driven by: (i) The difference in VAF cut-off. Sixty patients (11%) with TP53mut VAF <10% were excluded from the ICC classification of TP53mut MN as it mandates TP53mut VAF cut-off ≥10%. 11 (18%) and 41 (68%) of these had bi TP53, monoallelic TP53mut MDS by WHO criteria while 8 (13%) had AML. Importantly, within the VAF <10% cohort, median overall survival (OS) of 2 TP53mut or 1 TP53mut with 17p13.1 (hereafter 17p) deletion or complex karyotype (CK, n=30) was significantly poor compared to 1 TP53mut VAF <10% (11.6 vs 32.4 months; P =0.002, Figure 1B), suggesting that ICC may underestimate the poor prognosis of multi-hit or multi-hit equivalent TP53mut MN with VAF <10%. (ii) The difference in bone marrow blast cut-off. The underlying assumption by WHO is that prognosis of bi TP53mut MDS is poor irrespective of blast percentage category (0-9% vs 10-19%). In contrast, ICC considers that TP53mut MDS/AML (blasts 10-19%) is associated with poor prognosis irrespective of TP53 allelic status. Median OS of TP53mut MDS with 10-19% blasts was significantly poor compared to blast 0-9% (6.4 vs 11.6 months, P <0.0001). Second, median OS of bi TP53mut was significantly poor than monoallelic TP53mut in MDS- blast 0-9% (10.1 vs 15.9 months; P =0.0001) but not in blasts 10-19% (6.8 vs 6.2 months; P =0.19). Hence, exclusion of monoallelic TP53mut MDS with blast 10-19% as TP53mut MN from the WHO classification may underestimate the poor prognosis. (iii) The difference in the definition of biallelic and multi-hit TP53 loss. 35 cases with 1 TP53mut VAF ≤49%, had 17p deletion but did not have CNV analysis to confirm the loss of TP53 locus and could not be classified further using WHO. ICC classified 18 (50%) of these cases as multi-hit. Median OS of 1 TP53mut VAF ≤49%, and 17p deletion on karyotype was significantly poor than 1 TP53mut (VAF ≤49%without 17p deletion on karyotype (6.4 vs 14.6 months, P =0.001). (iv) The difference in the definition of multi-hit equivalent. 32% (33/104) WHO defined monoallelic cases without available CNV data, were classified as multi-hit-equivalent by ICC as they harbored CK. However, WHO does not consider CK as presumptive evidence of bi TP53. Median OS of 1 TP53mut VAF ≤49% with CK was significantly poor compared to 1 TP53mut without CK (8.2 vs 26.9 months, P =0.0008). CONCLUSION: Our study provides evidence that poor prognosis of ‘multi-hit’ TP53 with VAF <10% is underestimated by ICC. On the other hand, poor prognosis of monoallelic TP53 MDS with 10-19% blasts as well as 1 TP53mut VAF ≤49% in the presence of CK is underestimated by WHO. These data suggest that both classifications can be further refined.

Background In unfit patients (pts) with newly diagnosed (ND) AML, long-term survival remains short (mOS 14.7 months) despite improved responses (CR 37% and CR/CRi 66%) with azacitidine (AZA) and venetoclax (VEN) (VIALE-A, DiNardo NEJM 2020). In a pooled analysis of AZA-VEN in ND AML pts with poor risk cytogenetics the response rates were higher in TP53wt pts (CR/CRi 70%) compared with TP53mut pts (CR/CRi 41%) (Pollyea Clin Cancer Res 2022). The measurable residual disease (MRD)-negative rate was 41% in AZA-VEN treated pts in VIALE-A which was associated with improved survival (Pratz JCO 2022). Pivekimab sunirine (PVEK, IMGN632) is a first-in-class antibody-drug conjugate (ADC) comprising a high-affinity CD123 antibody, cleavable linker, and an indolinobenzodiazepine pseudodimer (IGN) payload. The novel IGN payload alkylates DNA and causes single strand breaks without crosslinking (Kovtun Blood Adv 2018). Methods This is an ongoing, open-label, multicenter, Phase 1b/2 study of PVEK in combination with AZA +VEN in adults with ND CD123-positive AML (any CD123+ expression by local flow cytometry or IHC). Pts received the recommended phase 2 dose of PVEK 0.045 mg/kg IV on D7 + AZA 75 mg/m 2 SC or IV daily on D1-7 + VEN up to 400 mg PO daily for 14 to 28 days (based on cohort assignment) in a 28-day cycle. Bone marrow assessment was performed at D14 (cohort 1) or D21 (cohort 2) of cycle 1 to determine VEN duration. The primary endpoints are composite CR rate (CCR [CR+CRh+CRp+CRi]), MRD rate (assessed centrally [Hematologics, Inc.] by flow cytometry; <0.1% defined as negative) and duration of remission. Key secondary endpoints are safety, pharmacokinetics and immunogenicity. Responses were determined using ELN 2017 criteria (with the addition of CRh) and a 14-day post-marrow count recovery window. Results As of July 17, 2023, data is available for 50 ND pts (n=25 per cohort) treated with PVEK+AZA+VEN and are aggregately reported here. The median age was 74 years (range, 46-83), 42% were ≥ 75 years old, 26% had secondary AML, 64% were ELN 2017 adverse risk, and 38% had a TP53mut. The most common non-hematologic treatment-emergent adverse events (TEAE) (all grades [grade 3+]) seen in > 20% of all pts were febrile neutropenia (44% [38%]), constipation (42% [2%]), peripheral edema (36% [4%]), diarrhea (36% [2%]), hypophosphatemia (32% [0%], nausea (28% [4%]), and hypokalemia (24% [2%]). No veno-occlusive disease (VOD) events were reported. In responders, the median time to achieve absolute neutrophil count ≥500/µL and platelet count ≥50,000/µL was 35.5 days (range, 20-55) and 22 days (range, 20-55), respectively. The median post-remission cycle delay (beyond cycle day 28) was 14 days. Two pts discontinued PVEK due to a TEAE (edema; marrow aplasia). The 60-day mortality was 4%. In the ITT population (N=50) the CR rate was 52% (26/50), and the CCR rate was 66% (33/50). In pts ≥ 75 years old, the CCR rate was 76% (16/21). In pts known to be TP53wt, both the CR and CCR rate was 88% (22/25). Additional response subsets in Table 1. Twenty-one pts received 9-14 days of VEN, 9 pts received 15-21 days of VEN and 20 pts received ≥ 22 days of VEN in cycle 1; of those who received ≤ 14 days of VEN the CR rate was 71% (15/21) and the CCR rate was 76% (16/21). Of the 26 pts who achieved CCR and had an MRD-evaluable sample, 73% (19/26) achieved MRD negativity (CCR MRD-, <0.1% residual blasts); notably all had undetectable MRD levels (lower level of detection is 0.02%). MRD-negativity was achieved rapidly with a median of 1.7 months (range, 0.8-4.5). CCR MRD- rates were high across major molecular subsets, including FLT3 (ITD/TKD) at 100% (7/7), IDH1/2 at 89% (8/9), and NPM1 at 89% (8/9), as well as ELN risk groups (intermediate 80% [8/10]; adverse 64% [9/14]). Conclusion With a manageable safety profile in pts with ND AML, the PVEK+AZA+VEN triplet demonstrated anti-leukemia activity with robust CR rates and early MRD negative responses in a cohort enriched for adverse disease characteristics (64% ELN adverse risk; 38% TP53mut). Encouraging CCR MRD- rates were observed across cytogenetic/molecular subsets, and the majority of responding pts achieved early and deep remissions, which may translate to improved clinical outcomes. The regimen was well tolerated with no new safety signals, and the addition of PVEK to the AZA-VEN backbone did not appear to meaningfully prolong count recovery.

AbstractThe World Health Organization (WHO) classification system categorizes advanced systemic mastocytosis (SM‐Adv) into aggressive SM (ASM), mast cell leukemia (MCL), and SM with associated hematological neoplasm (SM‐AHN). By contrast, the International Consensus Classification (ICC) requires “immature” MC cytomorphology for the diagnosis of MCL and limits SM‐AHN to myeloid neoplasms (SM‐AMN). The current study includes 329 patients with SM‐Adv (median age 65 years, range 18–88; males 58%): WHO subcategories SM‐AHN (N = 212; 64%), ASM (N = 99; 30%), and MCL (N = 18; 6%); ICC subcategories SM‐AMN (N = 190; 64%), ASM (N = 99; 33%), and MCL (N = 9; 3%); WHO‐defined MCL with “mature” MC cytomorphology and SM‐AHN associated with lymphoid neoplasms were operationally labeled as “MCL‐mature” (N = 9) and SM‐ALN (N = 22), respectively, and distinguished from ICC‐defined MCL and SM‐AMN. Multivariable analysis that included the Mayo alliance risk factors for survival in SM (age >60 years, anemia, thrombocytopenia, increased alkaline phosphatase) revealed more accurate survival prediction with the ICC versus WHO classification order: (i) survival was significantly worse with MCL‐immature versus MCL‐mature (hazard ratio [HR] 15; p < .01), (ii) prognostic distinction between MCL and SM‐AHN/AMN was confirmed in the context of ICC (HR 9.3; p < .01) but not WHO classification order (p = .99), (iii) survival was similar between MCL‐mature and SM‐AMN (p = .18), and (iv) SM‐AMN (HR 1.7; p < .01) but not SM‐ALN (p = .37) was prognostically distinct from ASM. The current study provides evidence for the independent prognostic contribution of both the ICC system for SM‐Adv and the Mayo alliance risk factors for survival in SM.

Abstract We surveyed the performance of ponatinib, as salvage therapy, in a real-world setting of chronic phase chronic myeloid leukemia (CML-CP). Among 55 consecutive patients (median age 49 years) with relapsed/refractory CML-CP, 35 (64%) had failed ≥ 3 tyrosine kinase inhibitors (TKIs), 35 (64%) were pre-treated with nilotinib, and 14 (28%) harbored ABL1T315I. At start of ponatinib (median dose 30 mg/day), 40 patients were already in complete hematologic (CHR), 4 in complete cytogenetic (CCyR), 3 in major molecular (MMR) remission, while 8 had not achieved CHR (NR). Ponatinib improved the depth of response in 13 (33%), 3 (75%), 2 (66%), and 4 (50%) patients with CHR, CCyR, MMR, and NR, respectively (p = 0.02). At a median follow-up of 42 months, 13 (23%) deaths, 5 (9%) blast transformations, and 25 (45%) allogeneic transplants were recorded. Five/10-year post-ponatinib survival was 77%/58% with no significant difference when patients were stratified by allogeneic transplant (p = 0.94), ponatinib-induced deeper response (p = 0.28), or a post-ponatinib ≥ CCyR vs CHR remission state (p = 0.25). ABL1T315I was detrimental to survival (p = 0.04) but did not appear to affect response. Prior exposure to nilotinib was associated with higher risk of arterial occlusive events (AOEs; 11% vs 0%; age-adjusted p = 0.04). Ponatinib starting/maintenance dose (45 vs 15 mg/day) did not influence either treatment response or AOEs. Our observations support the use of a lower starting/maintenance dose for ponatinib in relapsed/refractory CML-CP but a survival advantage for deeper responses was not apparent and treatment might not overcome the detrimental impact of ABL1T315I on survival. The association between prior exposure to nilotinib and a higher risk of post-ponatinib AOEs requires further validation.

TPS7089 Background: Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative overlap neoplasm (MDS/MPN) that can be further divided into MD (WBC < 13 x 109/L) and MP (≥13 x 109/L) subtypes. MP-CMML is enriched in RAS pathway mutations ( NRAS, CBL, KRAS, PTPN11 and NF1), has a shorter median survival (19 vs 36 months), has a higher rate of acute myeloid leukemia (AML) transformation (40% vs 10%) and has a unique transcriptomic and epigenetic composition. These RAS pathway mutations promote selective PLK1 overexpression, a mitotic checkpoint kinase. Given the relative inefficacy of hypomethylating agents (HMA) in MP-CMML and previously demonstrated in vitro and in vivo efficacy data for PLK1 inhibition on MP-CMML with RAS pathway mutations, we designed a phase 1 clinical trial testing the safety of onvansertib, a novel, orally bioavailable, PLK1 inhibitor in relapsed/refractory MP-CMML. Methods: This is an investigator-initiated, prospective, open-label, phase I study of onvansertib in MP-CMML relapsed/refractory (RR) or intolerant to existing therapies including HMA and hydroxyurea. The primary endpoint is characterization of safety. Secondary endpoints include efficacy as defined by the 2015 MDS/MPN International Working Group criteria, volumetric spleen response and symptom response via assessment with MPN-SAF-TSS. Inclusion criteria include MP-CMML RR following hydroxyurea or at least 4-cycles of HMA or intolerance of treatment with either, platelets ≥ 20,000/m3 and Cockcroft-Gault creatinine clearance ≥ 60 mL/min/m2. Hydroxyurea may continue for the first 28 days on study. Onvansertib will be given orally on days 1 through 21 of a 28-day cycle with a Bayesian optimal interval design to assess the safety and recommended phase II dose. Exploratory end points include targeting efficacy, impact of PLK1 and KMT2A expression and interactions with ASXL1 and TET2 mutations. Twenty-five patients will be enrolled at Mayo Clinic in Minnesota, with enrollment open since November 2022. Clinical trial information: NCT05549661 .

e15640 Background: The standard management of locally advanced rectal cancer (LARC) is neo-adjuvant concurrent chemo radiation (CCRT) followed by total meso-rectal excision. Recently there is an increased interest in total neo-adjuvant treatment (TNT). Most patients with rectal cancer in developing countries present in advanced stage for several reasons including lack of resources and delayed health seeking behavior. Most patients are not able to get standard management. This study tries to assess treatment patterns and outcomes in LARC. Methods: A cross-sectional study was conducted in patients with LARC that are treated at TASH from Jan 1, 2020 up to Sept. 2022. The data was collected from Patient’s cards using a pre-structured format that included demographic data, laboratory, pathological and imaging information. Data analysis was conducted by using IBM SPSS version 25. Results: 100 patients were included in the study, 51% were male. The median (range) age at diagnosis was 45.5 (20-86) years. 81% of patients came to our center without getting any oncologic treatment and 75.3% of them were presented on a multi-disciplinary tumor board for their treatment decision. Upfront surgery was decided in 48.1% (39/81) of patients. Standard neo-adjuvant treatment of either TNT or CCRT was decided in 23.4% (19/81) and 8.6% (7/81) of patients respectively. There is no significant association between tumor location, TNM stage, mesorectal fascia status and first treatment decision. Only 12 (14.8%) patients were able to finish their whole treatment plan. The most common reason for not finishing all treatment was prolonged radiation waiting time, with the median (range) waiting time of 10 ± 7.1 (1-26) months. From 81 treatment naive patients, 79 were decided to have surgery; and 59.5% (47/79) underwent the planned surgery with 89.9% R0 resection rate. R0 resection rate in patients who undergo upfront surgery was 91.2% (31/34). Neo-adjuvant chemotherapy was given to 34.6% (28/81); and only 18% (5/28) underwent subsequent surgery. The most common reason for not undergoing subsequent surgery was disease progression 43.5% (10/23) during or after finishing the neo-adjuvant chemotherapy. Only 24% of the study participants received radiotherapy. From the patients who took radiotherapy, only two patients received short course radiotherapy. Conclusions: Treatment decisions for rectal cancer in our study did not conform to standard treatment recommendations. Upfront surgery maybe a better option than neoadjuvant chemotherapy, since timely administration of standard neoadjuvant treatment is not possible. Alternative radiotherapy treatment options like short course radiotherapy may be better in resource limited setting to alleviate the longer radiotherapy waiting time.