ALBERT

Description: Background: In their seminal paper SWOG described the expected EMR for patients by age enrolled on clinical trials in AML (Appelbaum et al Blood 2006; 107: 3481-5). We sought to contrast these to population based outcomes. Methods: Using case listing session of SEER 18 (1973-2010) we identified patients (pt) 18 years of age and older diagnosed (dx) from 1990-2005 with AML (Site recode ICD-O-3/WHO 2008 Acute Myeloid Leukemia which includes ICD-0-3 9861/3, 9873/3, 9920/3, 9910/3, 9840/3, 9891/3, 9867/3, and 9895/3 and includes all FAB and WHO subtypes except M3 ). This was done in order to match the accrual periods of the SWOG studies. We then examined the EMR of pt with non-M3 AML and compared them to those reported by SWOG. EMR in SEER was defined as death within 0 to 1 month from dx; EMR in the SWOG studies was defined as death within 30 days of initiation of induction chemotherapy. Analyses were conducted with SEER*Stat 8.1.2, Microsoft Excel 2007 and GraphPad Prism 6. All p-values were 2-sided. Results: 26,272 pt were identified within SEER and 955 pt were in the SWOG EMR cohort. 54% of patients were male in SEER and 55% were male in SWOG; 85% of patients were white in SEER and 89% were white in SWOG. The EMR was 38.6% (10,130) in the SEER cohort; EMR was 12.2% (116) in the SWOG cohort (chi-squared with Yates correction p

Description: Background: Haploidentical hematopoietic cell transplantation (haplo-HCT) has emerged as a popular alternative to traditional HLA-matched hematopoietic cell transplant. As the number of haplo-HCT's rises, investigating the factors that may affect outcomes is necessary in order to improve overall survival and reduce transplant-related mortality. The optimal dose of CD34+ cells used during haplo-HCT to ensure favorable outcomes using PTCy has not yet been reported though a range of 2 to 5.00x106 cells/kg is commonly used.Furthermore, the optimal dose of CD3+ cells is unknown however recent data has suggested less than 3.00x108 cells/kg may prevent the development of acute GVHD. The importance of studying the impact of CD34+/CD3+ cell dosing may help to improve outcomes in this setting. Methods: We retrospectively analyzed adult patients at USC Norris Cancer Hospital (age ≥ 21) who received haplo-HCT from 2014 to 2019. The primary end-point assessed was 1-year GVHD-free/relapse-free survival (GRFS) defined as grade 3-4 acute GVHD, systemic therapy-requiring chronic GVHD, relapse, or death in the first post-HCT year. Secondary end-points included 1-, 2-, and 3-year relapse-related mortality (RRM) and overall survival (OS) in addition to 1-year transplant related mortality (TRM) and incidence of both acute and chronic GVHD. Results: A total of 67 adult haplo-HCT recipients were reviewed. Of the patients evaluated, approximately 50% (n = 33) were male and 49% (n = 32) were female. The age range was 21-71 years old (median = 44), and the most common underlying hematologic disorders included AML (40%), ALL (38%), aplastic anemia (7.7%), and others (MDS, lymphoma, myelofibrosis, and HLH) (13.8%). 67% of patients received myeloablative conditioning regimens while 33% received reduced intensity regimens. 70% (n = 47) of patients received peripheral blood as a stem cell source with 30% (n = 20) receiving bone marrow. The mean CD34+ dose infused was 6.07x106 cells/kg and the mean CD3+ dose was 2.94x108 cells/kg. The mean time to recovery of platelets, neutrophils, and lymphocytes was 25, 18, and 37 days respectively. CD34+ stem cells ≥5.00x106 cells/kg was significantly associated with shorter time to lymphocyte recovery (p = 0.0265) though recovery less than 30 days was not significantly associated with OS (p = 0.5268). Incidence of 1-year GRFS was 71% (n= 46) and 1-, 2-, and 3-year RRM were 4.6%, 6%, and 7.7% respectively. 1-year TRM was 15.3% with 50% of deaths from acute GVHD. 1-, 2-, and 3-year OS were 80%, 78%, and 77% respectively. Factors significantly associated with increased mortality included use of RIC regimen (p = 0.004) and disease status at time of transplant (p = 0.04). Cumulative incidence of GVHD was 63% (n = 42) with 33% (n = 22) and 30% of patients (n = 20) with acute and chronic GVHD respectively. Lack of mild chronic GVHD was associated with increased mortality (p = 0.0029) and use of a myeloablative regimen (p = 0.0029) was significantly associated with GVHD. Subgroup analysis of those who received CD34+ dose ≥7.00x106 cells/kg (n = 24) and ≥10x106 cells/kg (n = 7) were found to have 1-year OS of 87.5% and 85.7% compared with 77% and 80% in those that received lower doses (p= 0.2229 and p = 1.00) respectively however this was not found to be significantly associated with increased incidence of GVHD, relapse, or mortality. Discussion: Our results demonstrate improved outcomes specifically 71% survived 1 year without experiencing at least 1 GRFS event compared with 24-35% reported by CIBMTR, Holtan et al 2015, and Solh et al 2016 with 3-year OS of 77% when compared with a previously reported 48%. The mean CD34+ cell dose of our population is higher than the standard range which may account for the improved outcomes however the dosing of CD34+/CD3+ cells were not significantly associated with our primary and secondary end-points. It was significantly associated, however, with shorter time to lymphocyte recovery, a factor that has been reported to be associated with decreased RRM and therefore improved OS. Furthermore, subgroup analysis of higher CD34+ dose did show a better 1-year OS though this was not statistically significant. Limitations of this study include small sample size and short follow-up period. Further research with a prospective study identifying the optimal CD34+/CD3+ cell dose in addition to comprehensive evaluation of immune recovery is warranted in order to improve haplo-HCT outcomes. Figure Disclosures Yaghmour: Jazz Pharmaceutical company: Consultancy, Speakers Bureau; Astella company: Speakers Bureau; Takeda: Speakers Bureau.

Description: Introduction: Haploidentical hematopoietic stem cell transplantation (HSCT) is a potentially curative intervention for various malignant and non-malignant hematological conditions. Its use has led to the near universal availability of donors, but major challenges compared to HLA-matched related donor (MRD) and HLA-matched unrelated donor (MUD) transplants still exist. Although the most frequently discussed complication of haploidentical HSCT is graft rejection or severe/fatal graft-versus-host disease (GVHD), infection remains a significant cause of morbidity and mortality compared to other forms of transplant. Methods: This was a retrospective, single institution study that analyzed the outcomes of 187 patients with various hematological diseases who received allogeneic HSCT with haplo donor transplants, MRD transplants, or MUD transplants from 2011-2018. Conditioning regimens included combinations of fludarabine, busulfan, cyclophosphamide, melphalan, antithymocyte globulin, and total body irradiation. GVHD prophylaxis included either the combination of cyclosporine, tacrolimus, and mycophenolate mofetil (MMF) or tacrolimus and methotrexate (MTX). All patients received anti-viral prophylaxis with acyclovir, anti-fungal prophylaxis with either an azole or echinocandin, and anti-bacterial prophylaxis with trimethoprim-sulfamethoxazole or levofloxacin if the absolute neutrophil count (ANC) was 0.05). Rates of chronic GVHD were also similar between the two groups at 45% in haplo patients and 48% in non-haplo patients (p 〉0.05). The 100-day infection-related mortality rate following transplant was significantly higher in the haploidentical group at 9% compared to 1% in the non-haploidentical group (p = 0.03, Figure 1). In addition, the 1-year rate of infection-related mortality after transplant was also significantly increased at 16% vs. 4% in the haplo vs. non-haplo groups, respectively (p = 0.01, Figure 2). The proportion of patients who experienced bacterial and fungal infections over this time period was comparable between the two groups (41% vs. 42% for bacterial infections and 18% vs. 12% for fungal infections in haploidentical patients vs. non-haploidentical patients, p 〉0.05 for both) while the incidence rate of viral infections was significantly higher in the haplo group at 72% vs. 38% in the non-haplo group (p 〈 0.001). However, all cases of infection-related mortality were due to bacterial and fungal infections rather than viral with 27% of bacterial or fungal infections leading to patient death in haploidentical patients compared to 7% in non-haploidentical patients (p = 0.02, Figure 3). Conclusion: The results of our study showed that compared to non-haplo transplant recipients, patients who underwent haplo transplants had significantly increased risks of 100-day and 1-year mortality secondary to infections. This finding is supported by prior data demonstrating that there is a longer time to immune reconstitution, specifically of the T-cell subset and dendritic cell subgroup, in the haploidentical population (Chang et. al. Journal of Clinical Immunology 2011). Furthermore, our results showed that the increased risk of infection-related mortality is not due to higher rates of acute or chronic GVHD, implying that the risk may be due to haploidentical transplantation itself as opposed to increased amounts of immunosuppressive therapy. While there was a greater incidence rate of viral infections amongst haploidentical patients, no viral infections led to mortality in either transplant group. In contrast, despite similar rates of bacterial and fungal infections between haploidentical and non-haploidentical patients, these infections led to death more often in the haplo population. These findings are important in considering future approaches to infection prophylaxis and treatment in haploidentical transplant recipients. Disclosures No relevant conflicts of interest to declare.

Description: The outcomes after Haploidentical HCT with Fludarabine (Flu)/Cyclophosphamide (Cy)/TBI and PTCY as pioneered by the Hopkins group have been associated with higher risk of relapse and delayed immune reconstitution. Multiple groups have explored the potential benefits of more intensive conditioning regimens with or without TBI. However, none of these regimens to our knowledge has exploited the immunogenic properties of pre-transplant low dose Cy while avoiding the immune-suppressive effect of TBI. Additionally, there is limited knowledge regarding immune reconstitution post haploidentical HCT with the use of mobilized peripheral blood stem cells. Accordingly, we designed a protocol modification of the Hopkins regimen by replacing TBI with Melphalan (Mel) without adding Thiotepa in contrast to the MD Anderson regimen (Ciurea et al). We hypothesized that the immunogenic properties of pre-transplant low dose Cy along with the immunomodulatory effects of Mel would enhance early post-transplant engraftment and early peripheral T cell recovery through enhanced cytokine release and antigen alloreactivity We examined the clinical outcomes and immune reconstitution recovery of 12 consecutive haploidentical HCT patients with high-risk hematological malignancies. Patient and graft characteristics are as shown in table-1. The conditioning regimen was low dose Cy 14.5 mg/m2 on day -6 & day -5, Flu 30 mg/m2 on days -6 to Days -2 and Mel 70 mg/m2 on day -3 & -2. Graft versus host disease prophylaxis (GVHD) was PTCY 50 mg/Kg on day +3 and day +4 along with Tacrolimus and Mycophenolate starting at day +5 as previously described by the Hopkins group. An immune reconstitution panel of absolute lymphocyte count (ALC), CD3, CD4, CD8, Activated T cell (CD3-HLA Dr + T cells) & NK cell (CD56/16) was performed by 4 color flow-cytometry on days +60, +120 and +180 post HCT. Chimerism studies were performed at day +30 and +100 post HCT by variable number tandem repeat PCR analysis of peripheral blood & bone marrow. All of the patients were treated according to an institutional protocol and records were reviewed retrospectively after IRB approval. All patients engrafted with a median time to engraftment of 17 days (range 12-23). Chimerism studies revealed enhanced engraftment with 100% donor in bone marrow (unsorted) and peripheral blood (CD3, CD33 & CD 56) at day +30 in all 12 patients. All patients with active disease at time of transplant (5 Pts) achieved complete remission at day +30 evaluation. Post HCT immune recovery is shown in table 2. There was significant early recovery at day + 60 of the median ALC and all T cell subsets. This recovery was most pronounced in activated T cells. While we have observed a progressive reduction in the median number of early activated T cells at day 120 & 180, the number of helper T cells (CD4) and NK cells (CD56/16) did not decline (Figure 1). With a median duration of follow up of 261 days (range 62-390), the overall survival at day 100 and projected one year survival is 96% and 81% respectively. Only one of 12 patients had relapsed. Acute GVHD grade 2-4 developed in six of 12 patients, two of whom were grade 3-4. Chronic GVHD developed in four patients (1 serositis, 1 pericardial effusion and 2 nephrotic range proteinuria). Cytokine storm developed in 5/12 patients after stem cell infusion and resolved after PTCY. BK cystitis developed in four patients but continuous bladder irrigation was only required in two patients. All cases of BK cystitis were transient and resolved with supportive measures. CMV reactivation occurred in 9/12 patients; no CMV disease or CMV mortality was observed. Aspergillus antigen positivity in serum occurred in 4 /12 but only two developed clinical fungal infection. Conclusion: In this limited series of patients with high- risk hematological malignancies who underwent haploidentical HCT with low dose Cy/Flu/Mel and PTCY, the regimen was well tolerated and resulted in effective disease control. The regimen has also demonstrated enhanced early engraftment and robust immune recovery in comparison to other studies, table 3. However, it is not clear if this enhanced immune recovery is related to the conditioning regimen modification or the use of mobilized stem cells. The results are intriguing and need further confirmation. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 5058 Background: The presence of elevated nucleated red blood cells (NRBC) in the peripheral blood smear points towards the presence of myelodysplastic syndrome (MDS) or myelophthisis. The intent of our study was to assess the prognostic implication of the presence of increased NRBC in patients with MDS. Methods: Retrospective single institution chart review over a period of 10 years from 2000 to 2010. Our study population comprised 288 diagnosed cases of MDS whose diagnoses were made by bone marrow (BM) examination. Results: 174 patients were male (60.4%) and 114 were female (39.6%). Average age at diagnosis of MDS was 71.92 years. 204 patients were Caucasian (70.8%), 69 patients were African-American (23.9%), 1 patient was Hispanic, 2 patients were Asian, and race was not documented in 12 patients. 117 patients had intermediate-1 IPSS (40.6%), 79 had low IPSS (27.4%), 54 patients had intermediate-2 IPSS (18.7%), 26 patients had high IPSS (9.0%), and 12 patients had unknown IPSS. 131 patients (45.5%) had undetectable NRBC in their peripheral smear prior to their initial diagnostic BM examination. 13 out of these 131 patients (9.92%) progressed to acute myeloid leukemia (AML). 157 patients (54.5%) had one or more NRBC in their peripheral smear prior to their diagnostic BM examination. 27 out of these 157 patients (17.19%) progressed to AML. Survival in days was available in 59 patients. 19 out of 59 patients had undetectable NRBC in their peripheral smear prior to their initial diagnostic BM examination with an average survival of 1,256.2 days. Only one patient in this group underwent allogeneic matched unrelated peripheral stem cell transplantation (PSCT) with a survival of 2,532 days. 40 out of 59 patients had one or more NRBC in their peripheral smear prior to their diagnostic BM examination with an average survival of 850.4 days. Only 3 patients in this group underwent allogeneic matched PSCT (2 related and 1 unrelated) with an average survival of 924.3 days. Conclusions: The presence of nucleated red blood cells in the peripheral blood smear of patients with MDS seems to be a marker of more aggressive disease, higher rates of progression to AML and portends worse survival. To our knowledge this is the first study documenting the prognostic implication of NRBC in the peripheral circulation of patients with MDS. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 5245 Introduction: The myelodysplastic syndromes (MDS) comprise a heterogeneous group of malignant stem cell disorders characterized by dysplastic and ineffective blood cell production and a variable risk of transformation to acute leukemia (AML). Treatment of MDS with immunomodulatory drugs and eryrthropoitin is a well known risk factor for venous thromboembolic disease (VTE) and has been cited in several reports. However, the frequency of VTE in MDS patients as an independent risk factor regardless of treatment modalities has not been characterized before. Methods: We reviewed all cases of MDS diagnosed between 2000 and 2010 in our institution and did a retrospective analysis on the incidence of VTE in these patients prior or during different modalities and also according to different MDS subtypes and prognostic scores. The study also sub-classified the VTE according to being provoked or not. Results: Between 2000 and 2010, 291 patients were diagnosed with MDS in our institution. Seventeen (5.8%) patients developed VTE. Of these patients, 4(23.5%) had unprovoked VTE compared to 13(76.5%) with provoked VTE. All patients with unprovoked VTE (100%) had their venous event prior to the MDS diagnosis with a median time of 154 days (range 5–150 days). 75% (3 patients) of these patients had an intermediate-1 IPSS group and 25% (1 patient) belonged to the low risk group. In the group of patients with provoked VTE, 6 (46.2%) patients had the venous event prior to MDS diagnosis with a median time of 434 days (range 90–943 days). 83.3% (5 patients) had an intermediate-1 IPSS group and 16.7% (1 patient) belonged to the high risk group. On the other hand, 7 (53.8%) patients had provoked VTE after the MDS diagnosis with a median time of 294 days (range 14–718 days). Treatment modalities during which these VTE occurred were as follows, 3 (42.8%) patients were on erythropoietin stimulating agents (ESA), 1 (14.2%) patient was on revlimid, 2 (28.5%) patients were on active chemotherapy, and 1 (14.2%) patient was on no treatment. The IPSS group distribution for post MDS diagnosis patients with provoked VTE was as follows: 0% in the low risk group, 28.5% belonged to intermediate-1 risk group, 28.5% belonged to intermediate-2 risk group and 43% belonged to the high risk group. In patients with unprovoked VTE, the median age was 77.7 years (range 76–81 years) with equal distribution between males and females (50% each). In patients with provoked VTE, the median age was 69.6 years (range 56–85 years) with 46.1% males and 53.9% females. Discussion: The results of this study shows an increased risk of VTE in patients with MDS (5.8%) compared to that in the general population which is reported to occur in about 1 per 1000 persons per year. It also shows that all the unprovoked VTE events occurred prior to the MDS diagnosis with a median time of around 5 months. Due to this finding, we recommend that part of the workup for unprovoked VTE in the elderly population (as the mean age for unprovoked VTE was 77.7 years) include at least a CBCD and a peripheral smear to rule out cytopenias or morphologic changes suggestive of MDS. Since 46.2% of the provoked VTE happened before MDS diagnosis, we also recommend checking a CBCD in the elderly population (as the mean age for provoked VTE was 69.6 years) due to its low cost and especially if the provoking factor for VTE was not strong enough. Since 42.8% of patients with provoked VTE were on ESA during the event, we encourage aggressive VTE prophylaxis in moderate/high risk situations for these patients. The study did not show a higher prevalence of the intermediate-2 or high IPSS risk groups among patients with unprovoked (0%) or provoked VTE (46%). However, we encourage further research to study the prognostic significance of VTE in MDS patients and its relationship to progression to AML and to overall survival. Conclusion: Our study showed that a higher risk of VTE is present in patients with MDS compared to the general population and we recommend that aggressive VTE prophylaxis be given in moderate/high risk situations especially for patients who are taking ESA. We also recommend further research to be done on the prognostic significance of VTE in patients with MDS regarding overall survival and progression to AML. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction: The presence of the Philadelphia chromosome has historically been associated with a poor prognosis in patients with acute lymphoblastic leukemia (ALL). Prior studies had demonstrated that the 5-year overall survival (OS) rate among adult patients with Philadelphia-chromosome positive (Ph+) ALL was 25% compared to 41% in Philadelphia-chromosome negative (Ph-) ALL (Moorman et. al. Blood 2007). While hematopoietic stem cell transplantation (HSCT) has long been regarded as the standard of care for adult Ph+ ALL patients despite its significant transplant-related morbidity and mortality, its benefit is less clear in the era of newer-generation tyrosine kinase inhibitors (TKI) such as dasatinib. Methods: We conducted a retrospective study at a single urban transplant center with academic affiliation to analyze the outcomes of adult patients diagnosed with Ph+ ALL between 2005-2018. Patients were treated with either combination chemotherapy plus dasatinib or combination chemotherapy plus dasatinib and allogeneic HSCT. Chemotherapy regimens included hyper-CVAD, Berlin-Frankfurt-Munster-like (BFM-like) protocol, and a regimen developed at the University of Southern California (USC ALL regimen) using pegaspargase (Douer et. al. Journal of Clinical Oncology 2014). All patients in both the transplant group and the non-transplant group received TKI therapy with dasatinib throughout their treatment courses; in the former, patients received dasatinib both prior to and following their transplants. Statistical analysis was performed using the Fisher Exact Probability Test with p-values 30 x 109/L at the time of diagnosis. When comparing rates of OS and RFS between transplant vs. non-transplant patients in this group, there was also no significant difference. Conclusion: This study showed that in the management of adult Ph+ ALL patients, there was no significant difference in OS or RFS between patients who underwent allogeneic HSCT compared to those who received only combination chemotherapy with dasatinib. In addition, prior studies of Ph+ ALL patients treated with either chemotherapy alone or chemotherapy followed by HSCT concluded that the OS rates were approximately 50%, 35%, and 30% at the 1-year, 2-year, and 3-year marks, respectively (Rowe et. al. Blood 2005). Our analysis, however, demonstrated improved rates of survival at all time points for this patient population with the addition of dasatinib. Subgroup analysis of patients with a WBC 〉30 x 109/L at the time of diagnosis also showed no significant difference in OS between transplant and non-transplant patients despite previous reports showing a survival benefit from HSCT (Huang et. al. Blood 2016). This may be attributed to the fact that our patients received the newer and more potent agent dasatinib compared to imatinib in these prior studies. Since allogeneic HSCT demonstrated no survival benefit in our study and can also introduce risks of serious infectious complications, venoocculsive disease (VOD), and graft-versus-host disease (GVHD) that contribute to patient morbidity and mortality, it may serve a less beneficial role for the Ph+ ALL population in the era of newer-generation TKIs. Disclosures No relevant conflicts of interest to declare.

Description: Introduction: Venetoclax (VEN) in combination with a hypomethylating agents (HMA) is associated with a high rate of composite remission (complete remission [CR] and complete remission with incomplete recovery [CRi]) among older and unfit patients with untreated AML. However, data regarding the activity of VEN-HMA in those patients with favorable-risk AML is limited, particularly in those with core-binding factor (CBF) alterations. Although more frequent among younger patients, favorable-risk alterations are also observed among older patients, often unfit for intensive regimens. Even among the subset of older patients (〉60 years) with favorable-risk AML eligible for intensive regimens, long-term outcomes are poorer in comparison to younger patients. Methods: We retrospectively analyzed outcomes of 46 patients with favorable-risk AML who underwent therapy with VEN-HMA between 2016-2020 at 4 academic cancer centers in US. Favorable-risk AML was defined by the presence of either CBF [t(8;21) and inv(16) or t(16;16)], NPM1 mutation in the absence of FLT-3 ITD mutations; or bi-allelic CEBPA mutations. Results: Forty-six patients with favorable risk AML were treated with HMA-VEN, including 26 (57%) with newly diagnosed (ND) and 20 (43%) with relapsed/refractory (R/R) AML (Table1). Ten (22%) patients had CBF, 21 (46%) had NPM1 mutations (NPM1m), and 13 (28%) had bi-allelic CEBPA mutations (CEBPAm). The median age was 70 years, and 54% were females. Patients with R/R AML were younger than ND patients (56 vs. 72 yrs, p=0.003). Twenty (44%) patients had secondary or therapy-related AML, including half of ND patients. The median lines of prior therapy were 2(1-4) in patients with R/R AML, including 6 (30%) who had failed prior allogeneic HCT. Eleven (24%) patients had received HMA prior to HMA-VEN therapy, including 1 patient in the ND cohort for prior MDS. Eleven (24%) patients received azacitidine in combination with VEN, while the rest (76%) of patients received decitabine, including 14 patients who received 10-day decitabine during the first cycle. The CR/CRi rate among the whole cohort was 80%, including 52% CR and 28% CRi. There was no statistically significant difference in CR/CRi rate between ND and R/R patients (88% vs. 70%, P =0.15). However, patients with history of prior HMA exposure had lower response rate compared to HMA-naïve patients (55% vs. 88%, p= 0.025). No difference in response was observed based on the favorable genetic alteration subgroups (80% in CBF vs. 86% in NPM1m vs. 77% in CEBPAm, p=0.44). Furthermore, no difference in response was observed according to patient age (p= 0.83), AML types (de novo vs. secondary; p= 0.47), prior transplant (p=1.00), or the type and schedule of HMA (P=0.66). Among the responders who had MRD assessment done (n= 26), 22 (85%) achieved MRD negativity by multicolor flow cytometry. Post response, 13 (35%) patients underwent allogeneic transplant consolidation. The median overall survival (OS) for the whole cohort was 18 months (12.5-NA). Median leukemia-free survival (LFS) was 13.2 months (7-20.2) for all responders, 11.2 months (1.7-NA) for ND responders, and 14.0 months (1-NA) for RR responders (p=0.986). The 30- and 60-day mortality for the whole cohort was 0% and 9%, respectively. Conclusion: In patients with favorable-risk AML, VEN-HMA combination is associated with a highly promising CR/CRi rate, with durable responses. The majority of responders achieved MRD negativity. Patients with prior use of HMA had lower response rate with VEN-HMA, nonetheless, over half of these patients responded despite most being treated in the R/R setting. Disclosures Pullarkat: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genetech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dova: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stein:Stemline: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Marcucci:Abbvie: Speakers Bureau; Merck: Other: Research Support (Investigation Initiated Clinical Trial); Novartis: Speakers Bureau; Pfizer: Other: Research Support (Investigation Initiated Clinical Trial); Takeda: Other: Research Support (Investigation Initiated Clinical Trial); Iaso Bio: Membership on an entity's Board of Directors or advisory committees. Yaghmour:Novartis: 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; Astellas: Consultancy, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau. Bhatt:Omeros: Consultancy; Agios: Consultancy; Rigel: Consultancy; Tolero: Research Funding; Pfizer: Research Funding; Abbvie: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Partnership for health analytic research: Consultancy; Takeda: Consultancy; Jazz: Research Funding; National Marrow Donor Program: Research Funding; Oncoceutics: Other. Fathi:Takeda: Consultancy, Research Funding; Jazz: Consultancy; Forty Seven: Consultancy; Daiichi Sankyo: Consultancy; Amphivena: Consultancy; Blueprint: Consultancy; Kura Oncology: Consultancy; Boston Biomedical: Consultancy; Astellas: Consultancy; Trovagene: Consultancy; Novartis: Consultancy; PTC Therapeutics: Consultancy; Agios: Consultancy, Research Funding; BMS/Celgene: Consultancy, Research Funding; Kite: Consultancy; Pfizer: Consultancy; Trillium: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Abbvie: Consultancy; Newlink Genetics: Consultancy.

Description: Introduction: Measuring minimal residual disease (MRD) is an essential component of directing treatment and predicting outcomes in patients with acute lymphoblastic leukemia (ALL). Current methods used to detect MRD in patients with ALL include multiparameter flow cytometry (Flow), allele-specific and mutation-specific quantitative polymerase chain reaction, and more recently next-generation sequencing (NGS)-based methods. While flow cytometry remains standard of care for ALL MRD evaluation in most institutions, quantification of MRD with higher sensitivity assays could potentially improve early detection of clinical relapse resulting in better survival outcomes. The clonoSEQ NGS-based platform (Adaptive Biotechnologies, Seattle WA) tracks tumor specific V(D)J rearrangements in lymphoid malignancies and can detect MRD at less than 10-6 (0.0001%) level. Here we describe a real-world practice-based comparison of the impact of MRD testing by clonoSEQ and Flow on clinical outcomes in ALL. Methods: We retrospectively evaluated 45 adult patients with confirmed ALL admitted to the Norris Cancer Center (University of Southern California) between November 2017 and June 2020. In all patients, the presence/absence [(+)/(-)] of MRD was evaluated on bone marrow aspirates by both the clonoSEQ assay (clonoSEQ MRD) and by a flow cytometry-based COG ALL MRD assay (Flow). Descriptive statistics were used to characterize the cohort. The Fisher's exact test was used to describe groups with categorical outcomes. A p-value of 〈 0.05 was considered statistically significant. Results: Forty-five patients included in our study were aged 20 to 67 (median age 38), with 67% (30/45) males, 82% diagnosed with B-ALL (13% Ph-positive, 36% Ph-like, 51% Ph- negative),13% with T-ALL, and 5% with mixed-phenotype leukemia. Three patients were excluded from the analysis due to insufficient sampling. Among 38% (16/42) of patients with original Flow(-)/clonoSEQ(+) MRD, 31% (5/16) eventually became Flow(+) and later clinically relapsed, and 19% (3/16) received blinatumomab as a bridge to allogeneic hematopoietic cell transplantation (allo-HCT) and 2 remain in clinical remission (CR), 1 died from other medical complications. 11/14 Ph-like patients were analyzed post-induction. Post-induction clonoSEQ MRD status was used to direct these Ph-like B-ALL patients to allo-HCT (if positive, 8/11 patients) or to continue chemotherapy (if negative, 3/11 patients). Among 8/11 patients who underwent allo-HCT, 3/8 relapsed, while 5/8 remain in CR. All 3/11 patients who continued chemotherapy without allo-HCT, based on the clonoSEQ(-) MRD, remain in CR. Comparative post-induction clonoSEQ/Flow MRD data was available for 12 patients. Among these, 25% (3/12) were Flow(+)/clonoSEQ(+), 25% (3/12) were Flow(-)/clonoSEQ(+), and 50% (6/12) were Flow(-)/clonoSEQ(-), with the 12-month disease-free survival (DFS) rates of 33%, 100%, and 50%, respectively. Conclusions: Adult ALL is commonly associated with high relapse rates, often requiring therapy intensification with other agents or allo-HCT. We observed a trend towards a lower relapse rate and better outcomes with early treatment with blinatumomab and/or allo-HCT. Patients with post-induction clonoSEQ(-) MRD, who continued chemotherapy without allo-HCT or immunotherapy maintained molecular CR for 〉 1 year after diagnosis. Our data supports the clinical benefit of early molecular MRD evaluation with clonoSEQ to guide subsequent additional treatment (to reduce/eliminate MRD) or defer allo-HCT in MRD(-) patients. It is also important to note that a substantial subset of our unique adult population had high risk disease, whereas previous studies have focused on pediatric populations. Due to the small number of patients included, this analysis was mainly descriptive, and a larger patient cohort would be needed to better evaluate the clinical impact of MRD testing in adult ALL. Disclosures Yaghmour: Jazz:Consultancy, Speakers Bureau;Astellas:Consultancy, Speakers Bureau;Takeda:Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Alexion:Consultancy, Speakers Bureau;Agios: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.Varnavski:Adaptive Biotechnologies:Current Employment.

Description: Background: Cytomegalovirus (CMV) is a major cause of morbidity in allogeneic hematopoietic stem cell transplant (HSCT) patients. Marty et al. 2017 showed that letermovir is effective in preventing CMV reactivation in high-risk HSCT patients, though only 16% were haplo-identical. Recently, Karam et al. 2019 showed decreased rates of CMV reactivation in haplo-identical HSCT using letermovir in unselected high-risk patients. The effects of letermovir on other transplant-related outcomes including overall survival (OS), relapse free survival (RFS), and Graft-versus-host-disease (GVHD)-free-/relapse-free survival (GRFS), however, are not as well-known. With the increased use of post-transplant cyclophosphamide (PTCy) as GVHD prophylaxis in all transplant types, letermovir use may need to be broadened as those that are T-cell depleted are also at increased risk of CMV reactivation. Methods: We retrospectively analyzed adult patients at USC Norris Cancer Hospital (age ≥ 18) who received allo-HSCT from 2018 to 2020. Recipients who were CMV positive, received T-cell depleting therapies such as PTCy for GVHD prophylaxis and/or ATG in the conditioning regimen, and those who fulfilled the criteria in Marty et al. 2017 were categorized as high-risk. Patients were considered to have CMV reactivation if they had clinically significant serum CMV viremia or organ involvement by day+100. Letermovir was initiated on day+21 for high-risk patients. The primary end-point assessed was day+100 CMV reactivation. Secondary end-points included 1-year OS, 1-year RFS, 1-year transplant-related mortality (TRM), and 1-year GRFS, defined as grade 3-4 acute GVHD, systemic therapy-requiring chronic GVHD, relapse, or death in the 1-year post-HSCT period. Results: A total of 116 adult HSCT recipients were reviewed. 51% were male and 49% were female. The donor sources comprised of 27% match related, 28% match-unrelated, and 49% haplo-identical. Most common diseases included AML (38%), ALL (38%) and MDS (8%). 64% received myeloablative conditioning regimens while 36% received reduced intensity regimens. Furthermore, 92% of patients received peripheral blood with 8% receiving bone marrow. 70% of patients at time of transplant were in CR1 or had stable disease. 61% of patients received letermovir prophylaxis (n=71), all high-risk, and 39% did not (n=45). 13 high-risk patients did not receive letermovir due to insurance limitations and were included in the non-letermovir group. 85% (n =60) received T-cell depleting therapies in the letermovir group compared to 51% (n=23). 90% (n=64) were CMV positive in the letermovir group and 64% (n= 29) were positive in the non-letermovir group. Both groups were similar in regard to the incidence of GVHD. The only factors significantly associated with CMV reactivation were haplo-HSCT, CMV recipient positivity, use of PTCy as GVHD prophylaxis and/or ATG in conditioning regimen, risk status, and GVHD (p = 0.054, p = .017, p = 0.003, p = 0.050, and p = 0.024 respectively). In a subset analysis of all high-risk patients, CMV reactivation was 32% in the letermovir group and 69% in the non-letermovir group (p = 0.03). All other factors were not significantly associated with outcomes. CMV reactivation in the letermovir group was (32%) compared to the non-letermovir group (29%). 1-year OS, 1-year TRM, 1-year RFS, and 1-year GRFS were 85%, 13.2%, 87%, and 60% respectively in the letermovir group compared with 88%, 10%, 90%, and 56% in the non-letermovir group, though not statistically significant. Discussion: Our study confirms improved CMV reactivation outcomes with use of letermovir in high-risk patients. Furthermore, all end-points were similar between both groups, despite increased usage of myeloablative conditioning overall and more high-risk patients in the letermovir group, indicating improved 1-year OS, TRM, and GRFS compared with historical outcomes. Although the primary and secondary end-points were not statistically significant, it may be clinically meaningful, as our center has demonstrated similar outcomes amongst those who were high-risk and received letermovir and those who were low-risk and did not. This suggests broadened use of letermovir may be needed in the prevention of CMV reactivation and the improvement in overall outcomes. Further studies using letermovir in low risk patients may be necessary to investigate improved outcomes in the allo-HSCT setting. Disclosures Yaghmour: Jazz: Consultancy, Speakers Bureau; Novartis: 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; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau.