Transplantation In CR1 Research Articles

Real-Life Management of FLT3-Mutated AML: Single-Centre Experience over 24 Years.

We analyzed 140 patients with a median age of 51 years; 21% had WBC ≥ 100 × 109/L, and 52% had an NPM1 co-mutation. Until 2018, 101 patients received chemotherapy; thereafter, 39 received 3+7+midostaurin. The overall CR rate was 64%, higher in NPM1 mutant patients (73%). Univariate analysis showed that NPM1 mutation (p = 0.032) and WBC < 100 × 109/L (p = 0.013) positively influenced the response, with a trend for FLT3i administration (p = 0.052). Multivariate analysis confirmed WBC count as an independent prognostic factor (p = 0.017). In CR1, 41/90 patients underwent allogeneic and 18 autologous transplantation. The median EFS was 1.1 vs. 1.6 years in autografted and allografted patients, respectively (p = 0.9). The one-year non-relapse mortality was 0.00% for autologous and 28% for allogeneic transplants (p = 0.007); CIR at 1 and 3 years was higher in autologous transplants (39% vs. 15% and 57% vs. 21%, p = 0.004). The median survival was not reached in the FLT3i group. Overall, 69 patients received stem cell transplantation (18 autologous, 51 allogeneic). Post-transplant FLT3i was resumed in eight patients, all alive after a median of 65 months. Allogeneic transplantation is crucial in FLT3-mutated AML, but the next challenge will be to identify which patients can benefit from transplants in CR1 and in which to intensify post-transplant therapy.

Leukemic Stem Cells (LSCs) As Peri-Transplant MRD Assessment in AML Patients Undergoing Allogeneic Stem Cell Transplantation in CR

Background: Several studies have shown that the leukemic stem cells (LSCs: CD34 +CD38 -CD45RA +/Combi-6 +) play a crucial role in the development of relapses in AML patients (pts). LSCs are less sensitive to conventional therapy; moreover, their phenotypical characteristics may allow immune evasion promoting relapses after allo-SCT. Although ELN guidelines recommend including LSCs into MRD assessment, this approach has not yet been studied extensively in the allogeneic setting. Here we suggested that peri-transplant LSCs detection may provide additional prognostic information to conventional (c)MRD in AML pts allografted in CR. Methods: 90 pts (male, n=46; median, 60.5 years, 19-76) with AML in CR and available pre-transplant cMRD data (multicolor flow cytometry, “different from normal” approach, according to ELN guidelines), who received allografts (matched, n=73; mismatched, n=17) during 2019-2022 years at the Department of Stem Cell Transplantation at University Medical Centre Hamburg were included. LSCs were assessed according to Zeijlemaker et al. 2019 before and after transplant at days +30 and +100. Both methods (cMRD and LSCs detection) were investigated solely and combined for their prognostic impact. Results: Majority of pts had de novo AML (76%), adverse ELN risk (48%), received matched grafts (related, n=73, 81%; unrelated, n=17, 19%) and MAC regimen (n=55, 61%). ATG was used for GvHD prophylaxis in 70 pts (78%). There were 47 cMRD neg (52%) and 43 cMRD pos (48%) pts. LSCs were detected in 39 (56%) pts with a median proportion of 0.01% (0.005-0.37%) of WBC. There was no correlation between LSCs proportion and cMRD status. The cMRD pos pts were more frequently LSCs pos (67% vs 33%), and cMRD neg were more frequently LSCs neg (33% vs 67%, p=0.002). Before allo-SCT, 34 pts (38%) were cMRD neg/LSCs neg, 26 pts (29%) experienced cMRD pos/LSCs pos, 17 pts (19%) had cMRD neg/LSCs pos and 13 pts (14%) had cMRD pos/LSCs neg. The conformity between both assays was 67%. During a median follow up of 10 months (1-29) there were 17 mortalities, 13 relapses and 11 NRM events. The 1-year OS and LFS were significantly better in LSCs neg than in LSCs pos pts: 91% (77-97%) vs 73% (55-86%, p=0.012) and 88% (72-96%) vs 52% (35-68%, p=0.001), respectively. This was due to a higher relapse rate in LSCs pos group: 33% (18-52%) vs 4% (1-20%, p=0.002). The median time to relapse was 180 days (40-395). The difference in NRM was not significant. The area under the ROC curve for relapses was 0.74 (0.61-0.88, p=0.006). Regarding the combined used of LSCs/cMRD, the best 1-year OS (p=0.038) and LFS (p=0.002) were observed for the double negative group: 94% (77-99%) and 88% (65-97%); followed by cMRD pos/LSCs neg: 86% (59-96%) and 86% (61-97%); cMRD neg/LSCs pos: 77% (43-94%) and 71% (39-90%); and the double positive group: 63% (43-79%) and 42% (25-61%)., respectively ( Figure 1). This was due to in the differing relapse rate that was highest in cMRD neg/LSCs pos group: 47% (17-79%), followed by double positive: 29% (14-50%), double negative: 7% (1-32%), and cMRD pos/LSCs neg group: 0% (p=0.02). Post-transplant cMRD/LSCs data on days +30 and +100 were available in 70 consecutive pts. The post-transplant conversion rates (positive &amp;gt; negative) for LSCs, cMRD and cMRD/LSCs were 49%, 61%, and 63%, respectively. The majority of pts converted at day +30. We observed a higher conversion rate to LSC neg status after MAC vs RIC (12/16, 75% vs 5/11, 45%, p=0.12). Of nine pts who were MRD pos at day +30, six were LSC neg and three were LSC pos. One MRD pos/LSC neg pts died due to NRM while remaining five pts survived without relapse. All three MRD pos/LSC pos pts developed relapses with two mortalities. Conclusion: Peri-transplant detection of LSCs has a strong predictive value for early post-transplant relapses in AML pts. This approach can improve pre-transplant risk assessment for cMRD pos patients by defining a population with better survival and low relapses (cMRD pos/LSCs neg) and one with worse survival and more relapses (cMRD pos/LSCs pos). The post-transplant clearance of residual disease is associated with better survival regardless of the flow strategy being used (cMRD, LSCs, or both). Pts with persisting cMRD early after allo-SCT may be subdivided into different risk groups according to their LSCs status. Figure 1. Leukemia-free survival according to pre-transplant cMRD/LSCs status in 90 AML patients.

Impact of PTPN11 Mutations in De Novo, Secondary and Relapsed/Refractory Acute Myeloid Leukemia

Background Somatic mutations in the protein phosphatase non-receptor type 11 ( PTPN11) gene occur frequently in children with juvenile myelomonocytic leukemia and less commonly in adults with AML, being present in less than 5% of reported cases. Uncertainty exists regarding the prognostic impact of PTPN11 mutations in AML, largely owing to their observed rarity. Some retrospective studies have identified PTPN11 mutations as deleterious prognostic markers in AML, though others have noted that their negative impact is mitigated by concurrent NPM1 mutations, which frequently co-occur. We analyzed the outcomes of patients at our institution with AML and PTPN11 mutations in order to add to the literature regarding the relevance of this mutation. Methods We conducted a retrospective case series of patients at a single-center, tertiary-care institution who were diagnosed with AML between January 1 st, 2020 and June 1 st, 2023. Inclusion criteria included: 18 years of age or older, primary follow-up at the study institution, documented diagnosis of AML and identification of a PTPN11 mutation by NGS. Outcomes of interest included cytogenetic and molecular profiles, response to induction or salvage therapy, progression-free survival (PFS) and overall survival (OS). Results Twenty-two (12 men and 10 women) patients with PTPN11 mutant AML were identified. The median age at diagnosis was 60 years (range, 31-89 years). Nineteen patients had a PTPN11 mutation identified at diagnosis and 3 had a PTPN11 mutation appear at the time of relapse. Nine patients with de novo AML had PTPN11 mutations identified at diagnosis. Six were female and the average age at diagnosis was 60 years (range, 44-89 years). The most common co-occurring mutations were NPM1 (8 patients), DNMT3A (3 patients), TET2 (2 patients) and FLT3-TKD (2 patients). Cytogenetics were normal or non-adverse in 8 patients, and complex/adverse-risk in 1 patient. Seven patients received treatment - 4 with intensive chemotherapy and 3 with a hypomethylating agent (HMA) + venetoclax. Treatment response was CR/CRi in 6 patients (85.7%). At a median follow-up of 195 days, median PFS and OS were not reached. Two patients relapsed at 76 and 139 days after response. No patients received an allogeneic transplant in first remission. Ten patients with therapy-related or secondary-AML (t/s-AML) were identified, all with PTPN11 mutations noted at the time of AML diagnosis. Two patients had preceding MDS and 3 had preceding MDS/MPN. Median age was 63 years (range, 31-70 years). The most common co-occurring mutations were RUNX1 (5 patients), FLT3-ITD (2 patients) and NRAS/KRAS (3 patients). Chromosome 7 abnormalities were present in 4 of 5 patients with RUNX1 mutations. Cytogenetics were complex or adverse-risk in 9 patients. Eight patients received treatment - 6 with intensive chemotherapy and 2 with HMA + venetoclax. Treatment response was CR/CRi in 3 patients (37.5%). Median PFS was 183 days and median OS in treated patients was 307 days. The only patient with an ongoing response at the time of data cut-off received an allogeneic transplantation in CR1. Three patients with AML had emergence of a PTPN11 mutation at the time of relapse, at 245, 343 and 2262 days after initial diagnosis. PTPN11 was the only new mutation identified in 2 patients, and emerged in conjunction with an NRAS and KDM6A mutation in 1 patient. One patient received treatment, attaining a CRi after HMA + venetoclax, but relapsed 112 days later. The other 2 patients passed at 10 and 21 days after relapse. Conclusions PTPN11 mutations were relatively rare, occurring in only 22 patients with AML during a 3.5-year time span. Stark differences were noted in patients with de novo AML versus t/s-AML and PTPN11 mutations. De novo AML patients frequently demonstrated NPM1 mutations and a normal karyotype, while t/s-AML patients frequently had RUNX1 and FLT3 mutations, as well as adverse cytogenetics. Although the impact of PTPN11 mutations in AML may be influenced by concurrent NPM1 mutations or cytogenetic characteristics, the context of AML may ultimately have the largest impact.

Outcome of Risk- and Response-Adapted Post-Remission Therapy in Patients with NPM1 AML Treated Intensively

Introduction: Molecular assessment of measurable residual disease (MRD) is a powerful prognostic tool to identify high risk of relapse. Specifically, large studies have shown that MRD negativity of NPM1 after two cycles of intensive chemotherapy (IC) predicts long term remission. The translation of MRD results to treatment decisions such as treatment augmentation (MRD erasing) and referral to an allogeneic stem cell transplant (allo-SCT) is still lacking. The purpose of this study is to report the outcome of AML patients with NPM1 mutation who received IC and achieved remission, in whom NPM1 MRD post cycle 2 of IC, combined with FLT3-ITD status, were used systematically to decide whether patients were to complete intensive consolidations or refer to alloSCT. Methods: This is a retrospective analysis from 3 large hospitals in Israel. Patients were treated with 7+3 for induction and a repeat induction based on day 14 marrow. Midostaurin was added for FLT3mut leukemia since 2018. Consolidation consisted of 3-4 HiDAC cycles at doses of 1-3 g/msqrX6. Gemtuzumab ozogamicin and maintenance with FLT3 inhibitors or CC486 could be added. NPM1 transcript levels (normalized to ABL copies) were collected at diagnosis, after 2 cycles of IC, at the end of IC cycles and during follow-up. Patients were transplanted if a donor was available and any of the following: NPM1 transcript level was not reduced by 3 logs by the end of second cycle chemotherapy, absolute level was &amp;gt;1%, poor risk AML (ELN 2017 guidelines) or high AR FLT3-ITD mutation was present. Patients were followed for relapse (type and timing) and whether a second remission was achieved, as well as for EFS and overall survival. Results: A database search yielded 90 patients with NPM1 AML who were treated according the abovementioned protocol between 5/2015 and 11/2022 and achieved remission, with a median follow-up of 872 days (range 103-2751). Forty-seven patients were to receive consolidation cycles without transplantation in CR1, based on the aforementioned criteria. All but one patient (death from sepsis) completed treatment cycles. During follow-up, 21 (45%) patients relapsed at a median of 343 days. Two patients died while in CR1 during follow-up (extensive burns; sudden death at home). In a subgroup analysis of patients &amp;lt;60y (N=28), there were 11 events (9 relapses and 2 deaths), whereas in patients &amp;gt;60y (N=19) there were 13 events (12 relapses and 1 death during follow-up). Of note, 4 patients &amp;gt;60y were treated with CC486, of whom only 1 relapsed. Of the 18 patients who relapsed and received further treatment (3 had palliative care only), only 1 patient did not enter CR2 (died during salvage). The other 17 patients entered CR2 after salvage regimen (N=7, 4 were qPCR MRDneg, 5 were subsequently transplanted in CR2) or after upfront alloSCT without any salvage regimen (N=10, 4 were qPCR MRDneg). Forty-three patients were planned for alloSCT at CR1 (27 - inadequate molecular response, 16 - ELN risk group). Only one of these patients failed to undergo alloSCT in CR1 as she relapsed. The other 42 patients underwent alloSCT at CR1. In this group of patients, the median progression-free survival was 5 years, with no difference in patients above or below the age of 60. One half of the events (9/18) were relapses and the other half were deaths in remission, almost all were GVHD associated (figure1). Discussion: NPM1 mut AML without FLT3 is still considered by the ELN to have favorable outcome and most patients are not being transplanted at CR1. Yet, many relapse. This study evaluated the outcome of AML patients according to molecular risk stratification and alloSCT consideration by the end of cycle 2 of IC. In line with previous publications, younger patients with standard-risk AML and with adequate molecular response had a favorable outcome, with &amp;gt;60% of them having a disease-free long-term survival without transplantation. Moreover, even in a case of relapse, patients can achieve CR2 with MRDneg and attain long-term remission (90% OS in long-term follow-up). Older patients have a less favorable outcome even when they achieve adequate molecular response with two thirds of them experiencing relapse. Hence, the potential long-term outcome without transplantation needs to be balanced by the high risk of relapse. Nevertheless, even these patients can be successfully treated with either a salvage regimen or immediate transplantation, and &amp;gt;40% of them can be long-term survivors.

Safety and Efficacy of Azacitidine and Chidamide Maintenance after Allogeneic Hematopoietic Stem Cell Transplantation for Patients with High-Risk Acute Myeloid Leukemia: Interim Analysis of a Prospective, Multicenter, Single-Arm, Phase Ⅱ Clinical Trial

Background Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the potentially curative therapy for AML, the relapse rate after HSCT is high with 30-60% for patients with high-risk AML. Maintenance therapy with efficacy and low toxicity is needed to mitigate relapse. It has been reported that histone deacetylases inhibitor chidamide exhibits anti-tumor activity against AML cells, and is able to elicit anti-tumor immune response in mouse models. However, efficacy and safety of chidamide as maintenance therapy following allo-HSCT for patients with AML have not been reported. Therefore, we designed a multicenter, single arm, phase II clinical trial for high-risk AML patients to use azacitidine combined with chidamide as maintenance therapy post allo-HSCT to prevent relapse. Methods In this multicenter, single arm, phase II clinical trial, patients aged 18-60 years with high-risk AML, defined as the European LeukemiaNet (ELN) 2017 adverse risk group, refractory, relapsed or secondary AML were given AZA and chidamide as maintenance therapy after 60 days post transplantation (NCT05270200). AZA was given at 100mg/day (days 1-5) for 6 cycles and chidamide 5mg daily (days 1-28) with a cycle of 28 days for up to 2 years. The dose of AZA was amended at 50mg/m 2/day (days 1-3) from Dec 23,2022 due to occurrence of thrombocytopenia. If PLT was below 50×10 9/L or grade 3/4 non-hematological toxicity occurs, maintenance should be interrupted or delayed until PLT count was greater than 75×10 9/L or the non-hematological toxicity resolved to ≦ grade 1. Primary objectives were safety and one year cumulative incidence of relapse. Secondary objections were relapse-free survival (RFS), overall survival (OS) and incidence of severity of acute and chronic graft-versus-host disease (GVHD). Results From February 12,2022 to June 30,2023, seven patients were enrolled, with a median age of 46 years（28-60), four patients (57%) were female. One patient (14%) received matched sibling donor transplantation, six patients (86%) received haploidentical donor transplantation. Five patients (71%) received myeloablative and 2/7 (29%) reduced intensity conditioning regimen. Six (86%) were in ELN 2017 adverse risk with three patients harboring KMT2A rearrangement, one patient with TP53 mutation, one patient with -7, one patient with RUNX1 mutation, while one patient (14%) was diagnosed as secondary AML with broad extramedullary infiltration. All but one patients entered transplant in CR, while five patients (83%) were MRD negative and one patient (17%) were positive. The baseline patient characteristics are summarized in Table1. Outcome data were updated as of June 30,2023 (Figure1). The median time to start maintenance therapy after transplantation was 77 days (range 64-80). The median follow-up time was 9.9 months, only one patient relapsed and the accumulative incidence of relapse of one year was 16.7%（95%CI,0.4%-64.1%). The relapsed patient diagnosed with MLL-AF10 rearrangement had extramedullary infiltration of left tonsil, gum and neck lymph nodes at 197 days post transplantation while bone marrow remained in MRD negative remission. AZA/chidamide were well tolerated, with no severe adverse event was recorded. Two grade 3/4 non-hematologic adverse events were observed, with one increased bilirubin due to cGVHD and one pneumonia. Two patients (29%) experienced grade4 thrombocytopenia requiring platelet transfusion. After amendment of AZA dose, no grade4 thrombocytopenia was recorded. No one discontinued treatment due to toxicity. During follow-up, none of patients had aGVHD. Three patients (43%) experienced mild or moderate cGVHD, no severe cGVHD was observed. The median OS was not reached, with six months and one year OS both of 100%. The median RFS is not reached, with six months and one year RFS of 100% and 83.3%(95%CI,35.9%-99.6%). Conclusions Preliminary results suggest that maintenance of AZA combined with chidamide post allo-HSCT in patients with high-risk AML exhibits promising efficacy and well-tolerated. Recruitment of patients with high-risk AML post allo-HSCT for this trial is ongoing. Disclosures No relevant conflicts of interest to declare.

The Benefit of Allogeneic Transplant in 1 st Complete Remission in NPM1 Mutated AML with or without FLT3 ITD Is Restricted to Those Testing MRD Positive after Induction - an Analysis of the UK NCRI AML17 and AML19 Studies

Background While there is accumulating evidence that measurable residual disease (MRD) negative patients with intermediate risk AML may not benefit from allogeneic transplantation in 1 st complete remission (CR1-allo), many consider the presence of a FLT3 Internal Tandem Duplication (ITD) an indication for this procedure. However, the studies supporting this practice were mainly performed before the development of sensitive molecular MRD techniques (Schlenk NEJM 2008).The UK NCRI AML17 and AML19 trials studied, then incorporated, MRD by RT-qPCR into the management of patients with NPM1 mutated AML. Methods NCRI AML17 (April 2009 to December 2014) and AML19 (November 2015 to November 2020) were sequential prospective randomised trials for younger adults (18 - 60 years) with newly diagnosed AML. In AML17, decisions regarding CR1-allo were made using a validated risk score incorporating baseline factors and response to induction. In AML19, for patients with NPM1 mutated AML ( NPM1mut) the protocol recommended CR1-allo only in patients testing MRD positive in the peripheral blood (PB) post cycle 2 (PC2), regardless of other baseline risk factors such as FLT3 ITD, based on findings from AML17 (Ivey et al, NEJM 2016). Both trials were performed prior to the availability of midostaurin and FLT3 ITD MRD assays. Here we compare the outcomes of patients with NPM1mut in these trials and assess the benefit of CR1-allo according to FLT3 ITD and molecular MRD status. Time-to-event variables are analysed using the Kaplan-Meier method, and the impact of alloSCT assessed using time-dependent Cox regression and visualised with Simon-Makuch plots. Molecular relapses were included as relapse events, and alloSCT performed after molecular relapse was not considered as CR1. Results 737 patients with NPM1mutAML who achieved CR/CRi and had a valid PC2 PB MRD result were included in the analysis. 60/348 (17%) patients from AML17 and 83/389 (21%) from AML19 tested PB PC2 MRD positive. Overall, CR1-allo was performed in 20% of patients in AML17 and 25% in AML19. Of the MRD positive patients CR1-allo was performed in 16/60 (27%) in AML17 compared to 50/83 (60%) in AML19 where these patients were recommended for transplant. CR1-allo was performed in 18% and 16% of MRD negative patients in AML17 and AML19 respectively. In AML17, as previously reported (Ivey et al, NEJM 2016), patients who were MRD+ had poor outcomes, with 3-year cumulative incidence of relapse (CIR) of 84% and overall survival (OS) of 25%. These outcomes were improved in AML19, with 3y CIR 50% and 3y OS 51%. Across both trials, CR1-allo was associated with a significant survival benefit in MRD+ patients (3y OS 61% vs 24%, HR 0.42, 95%CI 0.26-0.69, p&amp;lt;0.001, Figure A). Patients who were MRD negative had excellent outcomes in both trials (3y CIR 33% and 24% and 3y OS 75% and 83% for AML17 and AML19 respectively). AlloSCT in CR1 provided no survival advantage for MRD- patients (HR 0.83, 95%CI 0.51-1.34, p=0.4). There were a total of 286 patients with NPM1mutFLT3 ITD mut AML with a PC2 PB MRD result across both trials. 81/286 (28%) were PB PC2 MRD+ of whom 32/81 (40%) received CR1-allo (28% in AML17 and 49% in AML19). Outcomes in these high-risk patients were improved in AML19, with 3y CIR 91% vs 68% and 3y OS 22% and 31% for AML17 and AML19 respectively. Those who received CR1-allo had improved outcomes (3y OS 45% vs 18%, HR 0.52, 95% CI 0.29-0.93, p=0.03) consistent with the overall MRD+ population. In the 70% of NPM1mutFLT3 ITD mut AML patients who achieved PB PC2 MRD-, outcomes were encouraging in both AML17 (3y CIR 37%, 3y OS 75%) and AML19 (3y CIR 27%, 3y OS 80%). CR1-allo was performed in 20% (19% in AML17, 21% in AML19), with no survival benefit for transplant (HR 0.80, 95% CI 0.37-1.72, p=0.6, Figure B). There remained no benefit when restricted to those with high (&amp;gt;0.5) FLT3 ITD allelic ratio (HR 0.63, 95% CI 0.2 - 2.23, p = 0.50) and there was also no evidence of an interaction between allelic ratio and benefit from transplant for MRD negative patients (p=0.86). Conclusion Molecular MRD can be used to stratify decision making concerning post remission therapy in patients with NPM1mut AML. Patients who achieve MRD negativity in the peripheral blood by the end of course 2 are at low risk of relapse and we found no evidence of benefit from allogeneic transplant in CR1, including in the subset with FLT3 ITD. This finding contrasts with MRD+ patients where there was a significant survival benefit for CR1 transplant.

The Genomic Landscape and Its Clinical Implication in NPM1-Mutated AML Patients: A Study within the AMLSG 09-09 Clinical Trial

Background: Mutations in the Nucleophosmin 1 gene ( NPM1 mut ) represent one of the most common genetic lesions in acute myeloid leukemia (AML).Based on its characteristic clinico-pathologic features, NPM1 mutAML has been recognized as a distinct entity among the category “AML with recurrent genetic abnormalities”. According to the ELN 2022 genetic risk-stratification, NPM1 mut AML, in the absence of FLT3-ITD mutation, is associated with a favorable prognosis. However, a significant proportion of these patients (pts) relapse after intensive therapy suggesting that other co-mutations may have an impact on outcome. Aims: To comprehensively characterize the genomic landscape and leukemogenic trajectoriesin a large cohort of NPM1 mut AML pts and to investigate its prognostic and predictive impact on outcome. Methods: Targeted DNA sequencing (mean read depth: 1817) on the entire coding region of 263 genes was performed in 568 NPM1 mut AML pts (median age: 58.7 years; 18-60 years, n=317; &amp;gt;60 years, n=251). All pts were enrolled in the randomized open-label Phase 3 AMLSG 09-09 trial [NCT00893399; Döhner H et al. Lancet Haematol 2023]. In this trial, pts were assigned to intensive chemotherapy plus all- trans retinoic acid with or without gemtuzumab ozogamicin; none of the pts received midostaurin. Results: In total n=3,058 variants (variant allele frequency of ≥1%) were identified in 195/263 genes. The median number of co-mutations was 3 (range 0-11). The most common co-mutated genes were DNMT3A (49.5%), FLT3-TKD (42.8%) PTPN11 (24.8%), NRAS (22.7%) TET2 (21.7%), IDH2 (21.3%), IDH1 (18%), and FLT3-ITD (17.3%). DNMT3AR882 hotspot mutations occurred more frequently in younger pts (36.6% vs 17.1%), while there was no difference for DNMT3AnonR882 mutations between the two age groups (21.8% and 21.9%). An age-dependent difference was also identified for mutations in myelodysplasia-related genes ( ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and ZRSR2) as defined by the ICC, occurring with a higher incidence in older pts (30.3% vs 12.3% in younger pts). Analyzing the mutational pattern of co-mutations, we found statistically significant tertiary gene-gene interactions: e.g., NPM1- NFE2- STAG2 (p&amp;lt;.001), NPM1- IDH2- SRSF2 (p&amp;lt;.001), NPM1- CEBPA- TET2 (p&amp;lt;.001), NPM1- DNMT3AR882- NRAS (p=.002), and NPM1- ASXL1- SRSF2 (p=.004); mutual exclusivities were identified for NPM1- DNMT3AR882- DNMT3AnonR882 (p&amp;lt;.001), NPM1- IDH2- TET2 (p&amp;lt;.001), NPM1- DNMT3AR882- SRSF2 (p&amp;lt;.001), NPM1- IDH1- TET2 (p&amp;lt;.001), and NPM1- FLT3-ITD- KRAS (p&amp;lt;.002). Correlating co-mutation data with outcome, we found that DNMT3AR882 hotspot mutations confer inferior event-free (EFS) and overall survival (OS) only in younger pts (EFS, p&amp;lt;.001 vs p=.11, Figure 1a; OS, p=.003 vs p=.8), whereas DNMT3AnonR882 mutations did not impact prognosis within the two age groups. We also found a negative prognostic impact of IDH1 mutations which was restricted to younger pts (EFS, p=.05), whereas IDH2 mutations were associated with superior EFS in older pts (p=.04) and superior OS in both groups (p=.05 and p=.03). Of note, co-mutations occurring in one or more of the myelodysplasia-related genes did not impact EFS or OS (Figure 1b). In multivariable analysis (all pts) including age, WBC, LDH, allogeneic transplantation in CR1, and mutations with an incidence of at least 3% as covariables, age (HR,1.03; p&amp;lt;.001), DNMT3AR882 (HR, 1.86; p&amp;lt;.001), FLT3-ITD (HR, 1.54; p=.012), IDH1 (HR, 1.48; p=.009), MYC (HR, 1.83; p=.032), and WT1 (HR, 1.73; p=.012), were associated with an inferior EFS, while SMC3 mutation showed favorable EFS (HR, 0.44; p=.019). To further study the leukemogenic trajectories, we used an oncogenetic tree modeling algorithm, which yielded a tree with several main branches including DNMT3AR882, DNMT3AnonR882, FLT3-TKD , IDH1, IDH2, PTPN11, and TET2. These mutations might represent initiating events which predispose to additional events with further distinct branches. Conclusions: Our study provides comprehensive data on the genomic landscape and its clinical impact in pts with NPM1mut AML fit for intensive chemotherapy. The co-mutational pattern clearly differs between younger and older NPM1 mutAML pts. Using this large dataset allowed the identification of secondary and tertiary gene-gene interactions with significant impact on outcome. Further data analysis is ongoing and will be presented at the meeting.

Dose Reduced Chemotherapy in Sequence with Blinatumomab for Newly Diagnosed Older Patients with Ph/BCR::ABL Negative B-Precursor Adult Lymphoblastic Leukemia (ALL): Preliminary Results of the GMALL Bold Trial

Older patients (pts) with newly diagnosed ALL are ineligible for unmodified pediatric-based therapies. Although results are improved with age-adapted, dose-reduced regimens including MRD-based treatment modification, there is much space for further improvement.Therefore, the GMALL study group developed a trial to evaluate Blinatumomab, a CD19 directed bi-specific T-cell engager, in sequence with chemotherapy in this patient population with high medical need (NCT 03480438). Importantly, Blinatumomab replaced three cycles of standard consolidation chemotherapy.Pts aged 56 - 76 years (yrs) with CD19-positive, Ph-neg B-precursor ALL wereeligible. The primary endpoint was complete hematologic remission (CR) afterinduction (1 cycle chemo, 1 cycle Blinatumomab) and the key secondary endpoint was molecular response (table 1). The efficacy population included pts treated with dose reduced and shortened induction I (IP1) and Blinatumomab 1 or early death (ED). Induction was followed by 3 further Blinatumomab cycles alternating with age adapted consolidation cycles (HDMTX/ASP, HDAC, reinduction and maintenance) according to GMALL protocols for older pts (Gökbuget et al, ASH 2021). The median age was 66 (56-76) yrs. 21% had pro-B-ALL and 79% c/preB subtype. 40% had comorbidities according to the Charlson Score; most frequent were diabetes (13%) myocardial infarction (10%) or vascular diseases (10%). 50 pts were evaluable for IP1: 76% achieved CR/CRu and 2 pts (4%) died due to infections. 33% (N=11) had a molecular response and 18% MolCR (table 1). 47 pts were evaluable for the primary endpoint after Blinatumomab 1: CR/CRu was observed in 85%; 2 experienced ED (4%; those mentioned above; no additional ED). 88% of the CR pts had a molecular response (82% MolCR). The median follow-up is 757 (61-1584) days. Overall Survival (OS) after 1 and 3 yrs was 80% and 67% for the efficacy population (figure 1). The resp results for the total population were 82% and 65%. The 3y OS was 69% for c/pre-B-ALL and 58% for pro-B-ALL (p&amp;gt;.05). 3y OS was 81% for pts aged 55-65 yrs and 53% for those older than 65 yrs (p=.025). Only three pts received an allogeneic stem cell transplantation in CR1. 6 pts relapsed, 2 pt developed a secondary malignancy (Colon Ca, MDS) and 3 pts died in CR (1 HLH, 1 arterial disease, 1 Covid19). EFS was 60% at 3 yrs. We compared the results with those of the current GMALL standard therapy for older pts with B-precursor ALL (N=186) (Gökbuget et al, ASH 2022). Patient characteristics were similar. CR rates after induction were 85% vs 78% for BOLD vs standard (p&amp;gt;.05). Molecular CR rates in pts with hematologic CR were 82% vs 55% (p=.006). OS at 3 yrs was 67% and 49% (p=0.08) and Remission Duration (RD) was 83% vs 58% (p=0.055). Overall tolerability and efficacy of the regimen was very promising with a high hematologic and molecular response rate; mortality in induction and consolidation was low. In comparison with the current standard therapy the MRD response rates were significantly better. OS and RD was superior despite the omission of several chemotherapy cycles in contrast to other trials with unmodified chemotherapy but additional cycles of Blinatumomab. An ongoing randomized trial (NCT04994717) compares an even more dose reduced combination of Blina and chemotherapy with standard of care. This is an independent academic trial initiated by the GMALL Study Group which received free supply of Blinatumomab and financial support by Amgen.

Outcomes in Mantle Cell Lymphoma with Central Nervous System Involvement - a Dual Center Study

Background Central nervous system (CNS) involvement is a rare complication (&amp;lt;5% of cases) of mantle cell lymphoma (MCL) and is associated with poor outcomes, highlighting the need for novel treatment approaches. We report the outcomes of a large cohort of patients (pts) with CNS MCL from Mayo Clinic and Memorial Sloan Kettering Cancer Center (MSKCC). Methods MCL pts with CNS involvement seen at Mayo Clinic and MSKCC between 1/2000-1/2021 were included. CNS involvement was defined by histologically confirmed CNS MCL, CSF analysis demonstrating lymphoma cells, and/or neuroimaging findings compatible with CNS lymphoma. Medical records were reviewed for baseline characteristics, treatment, and outcomes. First-line MCL chemotherapy was categorized into higher intensity chemotherapy (i.e., anthracycline-based +/- high-dose cytarabine), moderate intensity chemotherapy (i.e., bendamustine-based regimens or single agent chemotherapy), and other. CNS treatment regimens were categorized as intrathecal (IT) therapy alone, systemic therapy (with CNS penetration such as IV cytarabine or IV methotrexate) with/without IT therapy, regimens with Bruton's tyrosine kinase inhibitors (BTKi), chimeric antigen receptor T cell (CAR-T) therapy, or radiation alone. Kaplan-Meier method was used for time to event analysis. Forest plots were developed using univariable Cox proportional hazards models. Results Seventy patients were included in the cohort, 34 from MSKCC and 36 from Mayo Clinic. Median age at MCL diagnosis was 65 years (range 56-72) and 52 were male (74%). MIPI score was available in 60 pts: low (n=10, 17%), intermediate (n=20, 33%), and high (n=30, 50%) risk. First line therapy included: higher intensity chemotherapy (n=42, 60%), moderate intensity chemotherapy (n=25, 36%) and other (n=3, 4%). Twenty-five (36%) pts underwent autologous hematopoietic cell transplantation in CR1. Median time from initial MCL diagnosis to CNS involvement was 24 months (m) (range 0-167). Four (6%) pts had CNS involvement at initial diagnosis. Abnormal CNS imaging was reported in 53 (76%) pts: leptomeningeal (n=37), leptomeningeal and parenchymal (n=4), parenchymal (n=8), orbital (n=4). The most common regimen following CNS diagnosis was systemic therapy with or without IT therapy (n=34, 54%) followed by treatment including BTKi (n=13, 21%), IT alone (n=10, 16%), radiation alone (n=3, 5%), and treatment including CAR-T (n=3, 5%). Three patients elected hospice care and four patients had missing/unknown CNS treatment. The overall CNS response to therapy was available in 54 patients: CR in 22 (41%) pts, PR in 8 (15%), SD in 11 (20%), and PD in 13 (24%) pts. Of the 70 patients, 63 died. Median follow up was 6.9 years (range: 1.6-11.2) from initial MCL diagnosis and 2.1 years from CNS diagnosis (range: 0.4-7.9). Median OS from MCL diagnosis was 3.4 years (95% CI: 2.4-4.6). In univariable Cox models, sex, stage, performance status, Ki67, or first line systemic chemotherapy type were not significantly associated with OS from MCL diagnosis. Low risk MIPI score (score &amp;lt; 5.7) was associated with favorable OS (HR 0.31, 94% CI: 0.12-0.77; p value 0.01) compared to high risk. First-line treatment and treatment intensity were not associated with a significant difference in OS. Median PFS for the first CNS-directed therapy was 2.4 m (95% CI: 1.7-4.3). Cause of death was disease-related in a majority (n=49, 78%) of pts and therapy-related in 10% (n=6). The remaining 8 deaths had cause of death reported as missing or other (13%). Median OS from CNS involvement was 5.1 m (95% CI: 3.3-10.0) (Figure 1). When assessing OS from time of CNS diagnosis, treatment regimens incorporating BTK inhibitors were associated with a more favorable OS compared to systemic therapy +/- IT therapy (HR=0.37, 95% CI: 0.16-0.89, p value=0.03) (Figure 2). Conclusions Our dual center series confirms patients with CNS involvement by MCL have poor outcomes. When evaluating OS from the time of CNS diagnosis, novel therapies, including BTKi and CAR-T, may be more effective than CNS-penetrant chemotherapy for treatment of CNS relapse suggesting newer therapeutic approaches are required to improve outcomes.

Characteristics and clinical outcomes of patients with acute myeloid leukemia with inv(3)(q21q26.2) or t(3;3)(q21;q26.2).

Acute myeloid leukemia (AML) with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) has a very poor prognosis. Determinants of clinical outcomes and optimal treatment remain uncertain. We retrospectively reviewed 108 cases of AML with inv(3)/t(3;3) and evaluated clinicopathological characteristics and clinical outcomes: 53 newly diagnosed (ND) AML and 55 relapsed/refractory (R/R) AML. Median age was 55 years. White blood cell (WBC) count ≥20x109/L and platelet count ≥140x109/L was observed in 25% and 32% of ND patients, respectively. Anomalies involving chromosome 7 were identified in 56% of patients. The most frequently mutated genes were SF3B1, PTPN11, NRAS, KRAS and ASXL1. In ND patients, the composite complete remission (CRc) rate was 46% overall; 46% with high-intensity treatments and 47% with lowintensity treatments. The 30-day mortality was 14% and 0%, with high- and low-intensity treatment, respectively. In R/R patients, the CRc rate was 14%. Venetoclax based-regimens were associated with a CRc rate of 33%. The 3-year overall survival (OS) was 8.8% and 7.1% in ND and R/R patients, respectively. The 3-year cumulative incidence of relapse was 81.7% overall. Older age, high WBC, high peripheral blast count, secondary AML and KRAS, ASXL1, DNMT3A mutations were associated with worse OS in univariable analyses. The 5-year OS rates were 44% and 6% with or without hematopoietic stem cell transplantation in CR1, respectively. AML with inv(3)/t(3;3) is associated with low CR rates, very high risk of relapse and dismal long-term survival. Intensive chemotherapy and hy pomethylating agents provide similar rates of remission and patients achieving CR benefit from hematopoietic stem cell transplantation in first CR.

Allogeneic Blood or Marrow Transplantation with High-Dose Post-Transplantation Cyclophosphamide for Acute Lymphoblastic Leukemia in Patients Age ≥55 Years

Patients age ≥55 years with acute lymphoblastic leukemia (ALL) fare poorly with conventional chemotherapy, with a 5-year overall survival (OS) of ∼20%. Tyrosine kinase inhibitors and novel B cell-targeted therapies can improve outcomes, but rates of relapse and death in remission remain high. Allogeneic blood or marrow transplantation (alloBMT) provides an alternative consolidation strategy, and post-transplantation cyclophosphamide (PTCy) facilitates HLA-mismatched transplantations with low rates of nonrelapse mortality (NRM) and graft-versus-host disease (GVHD). The transplantation database at Johns Hopkins was queried for patients age ≥55 years who underwent alloBMT for ALL using PTCy. The database included 77 such patients. Most received reduced-intensity conditioning (RIC) (88.3%), were in first complete remission (CR1) (85.7%), and had B-lineage disease (90.9%). For the entire cohort, 5-year relapse-free survival (RFS) and overall survival (OS) were 46% (95% confidence interval [CI], 34% to 57%) and 49% (95% CI, 37% to 60%), respectively. Grade III-IV acute GVHD occurred in only 3% of patients, and chronic GVHD occurred in 13%. In multivariable analysis, myeloablative conditioning led to worse RFS (hazard ratio [HR], 4.65; P=.001), whereas transplantation in CR1 (HR, .30; P=.004) and transplantation for Philadelphia chromosome-positive (Ph+) ALL versus T-ALL (HR, .29; P=.03) were associated with improved RFS. Of the 54 patients who underwent RIC alloBMT in CR1 for B-ALL, the 5-year RFS and OS were 62% (95% CI, 47% to 74%) and 65% (95% CI, 51% to 77%), respectively, with a 5-year relapse incidence of 16% (95% CI, 7% to 27%) and an NRM of 24% (95% CI, 13% to 36%). RIC alloBMT with PTCy in CR1 represents a promising consolidation strategy for B-ALL patients age ≥55 years.

Adolescent and Young Adults with ALL Who Complete Therapy on DFCI Consortium ALL Trials Have Excellent Long-Term Overall Survival

Background: Adolescent and young adult (AYA) patients (pts) with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL) have good outcomes when treated on pediatric regimens but still face worse survival compared to younger children (Siegel JAMA Onc 2018). Pediatric patients who do not complete ALL treatment, particularly planned asparaginase (ASP), have inferior oncologic outcomes (Silverman Blood 1997). In the CALBG 10403 trial of a pediatric-inspired regimen in AYAs 17-39 years (yrs), only 39% of pts completed planned treatment (Stock Blood 2019). We aimed to describe the prevalence of treatment failure, reasons for treatment non-completion, and their effect on survival among patients treated on Dana-Farber Cancer Institute (DFCI) ALL Consortium protocols. Methods: We identified Philadelphia chromosome negative (Ph-) pts aged 1-49 yrs treated on 4 sequential multi-center DFCI Consortium protocols between 2000 and 2018 (00-001, 05-001, 01-175, 06-254). Additional consecutive Ph- pts treated as per these protocols were identified by chart review. All pts were intended to receive 30 continuous weeks (wks) of ASP during consolidation. Treatment failure was defined as induction failure, induction death, relapse/progression on therapy, and remission death on therapy. Treatment non-completion was defined as transplant in first complete remission (CR), withdrawal due to toxicity or other reasons, loss to follow up, and ineligible status. Treatment completion was defined as no exit from treatment protocol before its completion, approximately 2 yrs from complete remission (CR). Per protocol, no patients were recommended for allogeneic hematopoietic stem cell transplant (HSCT) in CR1. ASP completion was defined as receiving at least 26 wks of ASP during consolidation (Silverman, Blood 2001). The protocols allowed for truncation of ASP for toxicity without exit from protocol. Median follow-up time was calculated using the reverse Kaplan Meier indicator. The chi square test was used to compare proportions between groups. Overall survival (OS) among groups was compared using the log rank test. Results: A total of 1,480 pts were identified: 1,149 children (< 15 yrs, median age 4.5 yrs) and 331 AYAs (15-49 yrs, median age 24 yrs). Median follow-up was 7.9 yrs. Treatment completion rate was lower among AYAs than children (61.3% vs. 89.9%, p < 0.001) (Table 1). This was driven by higher treatment failure rates among AYAs than children (19.9% vs. 5.5%) as well as higher treatment non-completion rates (19.0% vs. 4.6%), primarily driven by transplants in CR1 among AYAs. Treatment completion rates were lower among older (30-49 yrs) AYAs compared to younger (15-29 yrs) AYAs (50.5% vs. 65.7%, p = 0.009). Among 1235 pts who completed treatment, 1086 (87.9%) received ³26 weeks of ASP. ASP completion rate was lower among AYAs vs. children (79.2% vs. 89.6%, p < 0.001). A higher percentage of AYAs discontinued ASP because of toxicity than children (11.9% vs. 5.5%, p = 0.01). In a landmark analysis of patients who survived and had follow-up for at least 2 years from diagnosis, AYAs who completed treatment (with or without ASP completion) had an estimated 5-year OS of 92.7% (95% Confidence Interval (CI): 87.5%, 95.8%), while children who completed treatment had a 5-year OS of 97.9% (95% CI: 96.7%, 98.6%) (Log-rank test p = 0.002) (Figure 1). Patients alive at 2 years who failed or did not complete treatment had worse survival outcomes with a 5-year OS of 70.5% (95% CI: 53.9%, 82.1%) among AYAs and 76.1% (95% CI: 62.2%, 85.5%) among children (Log-rank test p = 0.598) Conclusions: AYAs in our cohort completed protocol treatment at higher rates than previously reported trials. Among AYAs who completed treatment protocol, oncologic outcomes were excellent (5-year OS above 90%) and comparable to (although statistically lower than) those of children. AYAs had higher treatment failure rates, likely due to more aggressive disease biology. AYAs had lower ASP completion rates and higher ASP discontinuation rates due to toxicity compared to children; the etiology and impact of that on survival will need to be further investigated. Introduction of novel agents to improve remission induction rates and prevent early relapse in AYAs might help further improve oncologic outcomes for this population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Do Adult Philadelphia-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) Patients Require Allogeneic Transplant in First Remission (CR1)?

Introduction: Ph+ ALL has long been considered a high risk leukemia with poor outcomes when multi-agent chemotherapy is used alone. Allogeneic transplantation is considered by many the only chance of cure in this population. After reviewing data at Princess Margaret Cancer Centre (PMCC) in 2016, we found no overall survival (OS) difference between transplanted and non-transplanted Ph+ ALL patients. Thereafter, only relapsed or refractory patients were transplanted. We sought to determine the outcomes of non-transplanted Ph+ ALL patients who received a modified pediatric regimen (without asparaginase) with imatinib. Methods: A retrospective chart review of Ph+ ALL treated at PMCC from 2001 to 2019 was undertaken. Patient demographic data, disease characteristics, response, and course, as well as treatment information, were collected and a descriptive summary was presented using counts/proportions and median/IQR or range as appropriate. OS/RFS rates were calculated using the Kaplan-Meier product-limit method, and the impact of covariates of interest were assessed using the Log-rank test. Results: 158 Ph+ ALL patients were identified since 2001. 56 patients (35.4%) received a transplant in CR1, while 102 (64.6%) did not. All patients received a modified pediatric-inspired regimen typically with imatinib (Table 1). Median follow up was 38 months (range 1 to 229 months). 144/158 patients achieved a CR with first induction (91%). N=6 patients died during induction (3.8%). Overall survival for all patients at 3 and 4 years, was 61.8% (95% CI 53.4-69.1%) and 54.1% (95% CI 45.5-61.9%) respectively. Overall RFS at 3 and 4 years, was 51.7% (95% CI 43.3-59.4%) and 46.3% (95% CI 37.9-54.2%) respectively. When stratified by transplant in CR1, 3-year OS was 49.8% (95% CI 36.1-62.0%) in transplanted patients vs 69.2% (95% CI 49.3-69.9%) in non-transplanted patients; p=0.145 (Figure 1). There was no significant difference in RFS at 3 years in transplanted (46.4% [95% CI 33.0-58.7%]) vs non-transplanted (55% [95% CI 44.2-64.6%]) patients; p=0.89. A 6-month PCR level indicating a molecular 3 log (or deeper) reduction (MR3) in BCR-ABL1 transcripts predicted a statistically significant improved 3-year RFS of 71.4% (95% CI 40.6-88.2%) vs those who had achieved only an MR2 (25% [95% CI 0.9%-66.5%] p=0.037). Overall, 48 patients relapsed. Of these, 13 received blinatumomab +/- a tyrosine kinase inhibitor (TKI) after relapse and 12/13 (92.3%) achieved a second CR, including one patient who had relapsed post-transplant. Of the 12 who achieved a CR2, 5 went on to an allogeneic transplant. Conclusion: Using a modified pediatric regimen and imatinib, there was no difference in overall survival between transplanted and non-transplanted Ph+ ALL patients, provided that they achieved an MR3 (or deeper) at 6 months. In those who were not transplanted in CR1 and subsequently relapsed, blinatumomab + TKI was a successful salvage regimen. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Post-Allograft Romidepsin Maintenance Mitigates Relapse Risk and Stimulates the Graft-Versus-Malignancy Effect through Enhanced NK-Cell Cytotoxicity in Patients with Aggressive T-Cell Malignancies in a Phase I/II Trial

Background: For patients with high risk, and relapsed/refractory T-cell malignancies allogeneic stem cell transplant (allo-SCT) is the only available potentially curative therapy. The efficacy of allo-SCT is limited in this population by high rates of relapse, with rates up to 55-60% post-allo-SCT. We designed a phase I/II trial, evaluating the combination of the histone deacetylases inhibitor romidepsin (rom) with FluBu conditioning, followed by romidepsin maintenance (m-rom) in patients receiving allo-SCT for T-cell malignancies (NCT02512497). Here we present an evaluation of the stimulatory effects of m-rom on the graft-versus-malignancy effect through NK-cells post-allo-SCT in the context of clinical results. Methods: This is a phase I/II clinical trial of patients with T-leukemia/lymphoma in at least a partial remission requiring an allo-SCT, <70 years of age, with a MRD/MUD donor. Patients received BuFlu (AUC 20000 or 16000) with rom, followed by tacrolimus/methotrexate GVHD prophylaxis with ATG for MUDs. An expansion cohort of up to 30 patients (total) was included. M-rom was initiated between day +28 and +100 for 1 year (2nd year optional), with built in dose reductions for toxicity. The effect of m-rom on NK-cell cytotoxicity was assessed on samples taken pre-transplant, and 1, 3, 6, 12 months post allo-SCT. NK cytotoxicity was assessed by isolating mononuclear cells from patient samples at each timepoint, comparing those on m-rom (n=10) versus those who did not receive m-Rom (n=5). Cells were targeted against K562 and T-cell lymphoma targets using the calcein-AM assay. Fine-Gray models were used to estimate PFS, OS, and cumulative incidence, and compare survival across groups. Results: To date, 28 patients have been enrolled, with a median age at transplant of 55, 50% female, 75% received MUD donor, and 68% utilized PB marrow source with 32% receiving BM. 16/28 (57%) had a diagnosis of T-cell leukemia, while 12/28 (42%) had a diagnosis of lymphoma. These included: T-ALL (18%), ETP-ALL (14%), ATLL (4%), T-PLL (21%), CTCL (7%), and PTCL (36%). 18% of patients entered transplant in a PR, while the remaining entered transplant in CR1 (61%) or CR2+ (21%). With a median follow-up time of 12 months, the median OS is 40 months (95% CI: 7.5-not reached), with a 1 and 3 year OS probability of 67% and 56%. The median PFS is 28.2 months (95% CI: 6.5-not reached), with 1 and 3-year PFS of 58% and 32%. Cumulative incidence (CI) of NRM at day 100 and 1 year were 15.6% and 19.8%. CI of grade II-IV aGHVD and extensive cGVHD were 42.9% and 19.1%. The CI of relapse (CIR) was 22.2% at 1 year (95% CI: 7.7-41.3%). There was no difference between PFS among patients with MRD versus those without MRD prior to transplant (p=0.71), and no difference in 1-year CIR (p=0.83). PFS at 1 year was substantially better in the lymphoma versus leukemia patients (78% vs 44%, p=0.02), though CIR at 1 year was not significantly different (13% vs 29%, p=0.12). No patients with PTCL relapsed, and 4/6 patients with T-PLL are alive, disease free. 16/28 (57%) of patients received m-rom with a median number of 12 cycles (range 1-39). 8 patients experienced grade 3/4 adverse events (AE), and 1 patient discontinued m-rom due to toxicity, unlikely related to romidepsin (loss of CD3 chimerism). NK-cytotoxicity was significantly higher at each time point in patients who received m-rom compared to those who did not (p<0.01). Further, when NK-cytotoxicity was assessed between the two groups after starting maintenance, NK-cytotoxicity in the m-rom group was significantly higher than in those without m-rom (p<0.0001) (Figure). Studies evaluating NK-cytotoxicity against patient T-cells are ongoing and will be presented at the ASH meeting. Conclusions: BuFluRom with m-rom is effective at decreasing relapse in patients with T-cell malignancies, with 1-year CI relapse below expected relapse rates for this set of diseases. NK-cell cytotoxicity data in a large sample set of trial patients demonstrates that m-rom enhances NK-cell cytotoxicity post allo-SCT, augmenting the GVL effect and likely accounting for at a minimum, some of the decrease in relapse seen on this trial. These results suggest long-term romidepsin past one year may decrease late relapse. Long-term follow-up is needed to evaluate these results, but these results suggest the BuFluRom regimen with m-rom should be strongly considered in patients receiving allo-SCT for T-cell malignancies to mitigate relapse. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Allogeneic Blood or Marrow Transplantation (AlloBMT) with High-Dose Post-Transplantation Cyclophosphamide (PTCy) for Acute Lymphoblastic Leukemia (ALL) in Patients Aged ≥ 55: Best Results in B ALL in First Remission (CR1) with Reduced-Intensity Conditioning (RIC)

Background: Older patients with ALL fare poorly with conventional chemotherapy. Patients aged 55-65 on E2993 and ≥ 60 treated with Hyper-CVAD have 5-year overall survival (OS) of just 21% and 20%, respectively (Sive. BJH. 2012 and O'Brien. Cancer. 2008). Recently, HyperCVD with inotuzumab +/- blinatumomab in patients ≥ 60 years old with Ph- B ALL demonstrated an improved 5-year OS of 47% with 38% of patients dying in remission (Short. Blood. 2021). AlloBMT provides an alternative consolidation strategy. Registry studies in ALL patients ≥ 60 years old and B ALL patients ≥ 55 years old who underwent alloBMT with RIC in CR1 demonstrated 5 and 3-year OS of 42% and 45%, respectively (Roth-Guepin. Oncotarget. 2017 and Rosko. Am J Hematol. 2017). These studies utilized heterogenous conditioning and graft-versus-host disease (GVHD) prophylaxis regimens. The use of high-dose post-transplantation cyclophosphamide as GVHD prophylaxis facilitates transplants in older adults with low rates of non-relapse mortality, GVHD, and the use of HLA haploidentical donors (Kasamon. JCO. 2015). Methods: The bone marrow transplant database at Johns Hopkins was queried for patients ≥ 55 years old who received a first alloBMT using PTCy from January 2008-January 2021. Characteristics of patients were summarized and compared using Fisher's exact test for categorical variables. Estimators of OS and relapse-free survival (RFS) were reported using the Kaplan-Meier method. Differences in time-to-event outcomes were estimated using Cox proportional hazards model, or Fine and Gray's model for cumulative incidence of relapse (CIR)/nonrelapse mortality (NRM) considering competing risks. Results: A total of 77 patients aged ≥ 55 underwent a first alloBMT with PTCy for ALL. The vast majority were performed in CR1 (85.7%), utilized RIC (88.3%), and were performed for B ALL (90.9%). Demographics and transplant characteristics are presented in Table 1. RIC consisted of fludarabine, cyclophosphamide and total body irradiation followed by PTCy-based GVHD prophylaxis as previously described (Kasamon. BBMT. 2008). Relapse-free survival (RFS) and OS at 5 years for the entire cohort were 46% (95% CI 34-57) and 49% (95% CI 37-60), respectively, with a 5-year CIR of 27% (95% CI 18-38) and NRM of 28% (95% CI 18-39). The cumulative incidences of grade 3-4 acute GVHD at 1 year and chronic GVHD at 3 years were 3% (95% CI, 0% to 9%) and 13% (95% CI 5% to 21%), respectively. In univariate analysis, the use of myeloablative conditioning led to worse RFS (HR 0.25, p=0.0004); while the absence of MRD (HR 2.93, p=0.008), transplant in CR1 (HR 3.81, p=0.0004), and transplant for Ph+ ALL vs. T ALL (HR 3.15, p=0.03) led to improved RFS. Subsequent analysis focusing on the 54 patients receiving RIC alloBMT in CR1 for B ALL demonstrated RFS and OS at 5 years of 61% (95% CI 46-73) and 64% (95% CI 49-76), respectively, (see Figure 1) with a 5-year CIR of 16% (95% CI 7-27) and NRM 24% (95% CI 13-36), although just 7% at 1 year. For B ALL patients transplanted with RIC in CR1, 3-year NRM was higher among patients who received a peripheral blood stem cell transplant (55%, 95% CI 18% to 81%), those treated with rituximab pre-transplant (36%, 95% CI 16% to 57%), and those who received ≥100 mg/m2 of doxorubicin equivalent for ALL (67%, 95% CI 19% to 90%). Outcomes did not differ among the 20% of patients who received pre-transplant blinatumomab compared to those who did not. Among the 23 Ph+ B ALL patients transplanted with RIC in CR1 following treatment with a 2nd or 3rd generation tyrosine kinase inhibitor (TKI), the 5-year CIR was 5% (95% CI, 0% to 22%). Conclusions: RIC AlloBMT with PTCy in CR1 represents a promising consolidation strategy for B ALL patients ≥ 55 years old. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real-World Outcomes and Adverse Events of Elderly Patients with Ph-Negative Acute Lymphoblastic Leukemia Treated with a Pediatric-Inspired Protocol

Poor outcomes in elderly patients with Acute Lymphoblastic Leukemia (ALL) result from the disease's adverse biology and poor tolerance to chemotherapy, leading to dose reductions, treatment delays, and high rates of early death and treatment-related mortality. Some reports indicate that pediatric-inspired chemotherapy protocols can be safely and efficiently used in older adults, resulting in improved median overall survival (mOS) ranging from 17 to 40 months. Despite such reports, front-line implementation of pediatric-inspired approaches to elderly patients with ALL remains a topic of discussion. Our goal is to estimate OS and define adverse events (AEs) in patients with ALL, aged > 60 years, and treated with a pediatric-inspired protocol. Methods All newly diagnosed patients aged > 60 years with Ph-negative ALL who received induction chemotherapy with a modified, asparaginase-intense, pediatric-inspired regimen between January 2002 and January 2022 were included. The treatment regimen consisted of induction, central nervous system prophylaxis, 7 cycles of intensification, and 24 cycles of maintenance. During these 20 years, we switched from native to pegylated E.coli asparaginase. Standard descriptive statistics were used to summarize patients’ demographics and outcomes of interest. 95% confidence intervals were provided where possible. Fisher's exact test was used to assess the impact of categorical covariates of interest on induction mortality. Using Fine-Gray methods, the Multivariable Cox proportional hazards regression model was used to determine the joint effect of potential factors for outcomes. P<0.05 was considered significant. Results A total of 76 patients were included. Patient and disease characteristics are presented in table 1. The median dose of Peg-asparaginase and L- asparaginase were 935 iu/m2 (477-1,111 iu/m2) and 5,944 iu/m2 (4,388-15,000 iu/m2) respectively. AEs rates found were severe pancreatitis 3.9%, thrombosis at any time during treatment 43.2%, hypofibrinogenemia <1g/L 30.6%, CTCAE grade IV transaminases, and total bilirubin 35.2%, and 17.3% respectively. The induction mortality rate was 12% (N=9) and the complete remission rate after induction (CR1) was achieved at 79% (n=60). Allogeneic hematopoietic stem cell transplantation in CR1 was carried out for 9.2% (N=7). The median follow-up among survivors was 49.7 months (range: 9-155) and the mOS was 35.1 months (95%CI: >19.3) (figure 1). OS rate at 1 and 4 years was 73.6% (95%CI: 62 - 82) and 42.2% (95%CI: 29.3 - 54.6) respectively, with a cumulative incidence of relapse from the date of diagnosis at 12 months of 12% (95% CI: 5.8 - 20). Leukemia-free survival rate at 4 years was 42.4% (95% IC 30 - 53). For the patients with early mortality, 5 patients had L-asparaginase, 3 patients had no asparaginase, and one Peg-asparaginase (11.11%). In contrast, in the no early mortality group, 46 (68.6%) patients received L-asparaginase, 2 (2.9%) patients had no asparaginase, and 19 (28.3%) patients received Peg-asparaginase (p=0.011). In univariate analysis, variables significantly associated with worse OS were: older age [<70 years old (n=46) median OS 70.8 months (95%CI >31.1) vs >70 years old (n=30)14.4 months (95%CI 9.2-54.2) (p=0.016)], higher WBC count [<11x10e9/L (n=54) median OS was 70 months (95%CI 27-NA), while in those with WBC >11x10e9/L (n=22) was 17.2 months (95%IC 6-31) (p= 0.004)], and no asparaginase given [OS at 12 months was: 85% (95%CI 60.4 -94.9) in patients treated with Peg-asparaginase; 72.4% (95%CI 57.9-82.6) in patients treated with L-asparaginase, and 40% (95%CI 5.2-75.3) in patients that did not receive asparaginase (p=0.0021). In multivariable analysis, younger age and lower WBC remained independent significant prognostic factors for increased OS [Patients <70 years old HR 2.67 (95% CI[1.38 - 5.17], p=0.0034) and patients with WBC <11x10e9/L HR 2.5 (95% CI [1.30- 4.82], p= 0.007)]. Conclusions The use of a pediatric-inspired chemotherapy protocol is shown to be effective and well tolerated in patients with Ph-negative ALL aged >60 years. Although AE rates were not negligible, outcomes were excellent and, early mortality improved over prior reports (Marc Poch Martell et al, BJH 2013, early mortality 20%). Further research will be needed to understand how the outcomes could be improved further using newer targeted treatments. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

AML-513 The Role of FLT3 Inhibitors in Patients With Acute Myeloid Leukemia (AML) and T(6;9)(P22;Q34)

Efficacy of FLT3 inhibitors (FLT3-i) in patients with AML and t(6;9)(p22;q34)/DEK-NUP214 is not well-established. We compared overall survival (OS) and event-free survival (EFS) of AML patients with t(6;9) who received frontline FLT3-i, regardless of their FLT3 mutation status. We evaluated patients with AML or high-risk myelodysplastic syndrome (HR-MDS) seen in our center between 1995-2021. Among 9936 patients, 55 patients (0.5%) had t(6;9) (48 AML, 7 HR-MDS). Patients were divided according to their induction regimen with (n:5) or without FLT3-i (n:48). Among 47 patients, 35 were FLT3-ITD+, 5 had both ITD and TKD mutations. ITD allelic ratio (AR) was known for 28 (80%) patients (AR range: 0.01-0.95) with 11 (31%) patients having an AR ≥0.5. Age was well-balanced across both groups with median of 41 years. Ninety-two percent had ECOG performance status of 0-1 on presentation. Most patients in FLT3-i group (80%) and non-FLT3-i group (77%) received intensive chemotherapy. Sorafenib was used in 62% and quizartinib in 24% of cases. All patients in FLT3-i group and 71% in non-FLT3-i group were FLT3-ITD+. All patients in FLT3-i group achieved CR/CRi (60% MRD negative) as compared to 52% of non-FLT3-i group, and 60% of FLT3-i group had transplantation in CR1 (vs. 21% of non-FLT3-i). All groups received 1 cycle of therapy to reach CR/CRi. With median follow up of 47 months, 2-year OS and EFS were higher in FLT3-i than non-FLT3-i cohort (80% and 60% vs. 41% and 20%, respectively, p=0.2 for OS and 0.1 for EFS). Addition of FLT3-i improved 2-year EFS in FLT3-ITD+ patients (60% vs. 15% in non-FLT3-i regimen, p=0.07). Two-year OS and EFS were lower in FLT3-ITD+ patients than wild-type FLT3 patients (44% and 22% vs. 58% and 42%, respectively; p=0.4 for OS and 0.3 for EFS), regardless of FLT3-i therapy during induction. CR/CRi rate was similar between FLT3-ITD+ and wild-type FLT3 patients (57%) but more wild-type FLT3 patients received transplantation in CR1 (42%) than FLT3-ITD+ (23%). FLT3 mutation status does not impact survival in patients with t(6;9). Addition of FLT3-i in subset of patients with FLT3-ITD mutation is beneficial and should be further evaluated.

P365: INCORPORATION OF NELARABINE (NEL), PEGYLATED ASPARAGINASE (PEG) AND VENETOCLAX (VEN) IN THE FRONTLINE THERAPY OF ADULT PATIENTS WITH T-ACUTE LYMPHOBLASTIC LEUKEMIA/T-LYMPHOBLASTIC LYMPHOMA (T-ALL/LBL)

Background: NEL is effective for patients (pts) with relapsed T-ALL/LBL but its incorporation into the front-line therapy has not been investigated. In children, addition of NEL to the induction regimen improved disease-free survival (DFS) but not overall survival (OS) (Dunsmore KP, JCO, 2020). VEN has shown preclinical and clinical activity in relapsed T-ALL/LBL. Aims: We investigated addition of NEL and PEG into the hyperCVAD (HCVAD) regimen in adult pts with T-ALL/LBL. We then explored the safety and efficacy of addition of VEN to this regimen. Methods: Pts with previously untreated or minimally pre-treated T-ALL/LBL were eligible if they had an ECOG PS ≤3, creatinine ≤ 2 mg/dL, bilirubin ≤ 2 mg/dL and ALT/AST ≤ 4 x ULN. Pts received 8 cycles of HCVAD (cycles 1,3, 5, 7) alternating with high dose ara-C and methotrexate (MTX) (cycles 2, 4, 6, 8) at approximately 3 weeks intervals. 2 cycles of NEL (650 mg/m% daily x 5) were initially administered after the 8 cycles (cohort 1) but later moved to after cycle 4 (cohort 2) and then PEG (1500 IU/m2 capped at 3750 IU) was added on day 5 of NEL cycles (cohort 3). More recently, VEN 400 mg daily on the first 7 days of each of 8 cycles of therapy was added (cohort 4) and this was later adjusted to be given for 7 days on the induction cycle and reduced to 3 days per cycle in pts with ETP-ALL or with persistent MRD with no VEN after cycle 1 in all other pts (cohort 5) Pts with ETP-ALL were referred for allogeneic stem cell transplant in CR. After the completion of the intensive phase, all pts in all cohorts received 30 cycles of maintenance with monthly POMP and early intensification with NEL/PEG on cycles 6 and 7 and late intensification with MTX/PEG in cycle 18 and HCVAD on cycle 19. All pts received 8 intrathecal doses of MTX alternating with ara-C and mediastinal radiation was considered in pts with balky mediastinal disease. Results: Between 8/2007 and 12/2021. 120 pts were enrolled in the 5 study cohorts sequentially (cohort 1= 30, 2= 49, 3=17, 4=16, 5=8)(Table). 74 pts had T-ALL, 45 T-LBL and 1 biphenotypic T/myeloid leukemia. Median age was 35 yrs (range 18-78), 93 pts were male (78%) and 106 pts (88%) had PS 0-1. In pts with T-ALL, median bone marrow blast % was 81% (range, 20-97%). 6 pts (5%) had CNS disease. Cytogenetics was diploid in 77 pts (64%), abnormal in 34 (28%), and unavailable in 9 pts (7.5%). Pts were further characterized as thymic (n=53), early T-cell precursor (ETP; n=23), near ETP (N=19) mature (n=11), not otherwise specified (NOS; n=11), and early-non-ETP (n=3). 25 pts had received 1-2 prior cycles of therapy prior to enrollment with 18 having achieved CR. 30-day mortality was 0%. 106 pts (88%) had ≥ one grade 3/4 non-hematological treatment-emergent adverse events (TEAE) with the most frequent grade 3/4 TEAEs being neutropenic infections in 92 pts (77%) and elevated liver enzymes in 25 pts (21%). Overall response rate (CR/CRi/PR) was 97% with CR/CRp in 95/102 pts (93%), PR in 4 (4%), and no response in 3 (3%). The median no. of cycles to response (including negative PET scans) was 1 (range 1-10). CR/CRp rate in T-ALL was 88% and T-LBL was 100%. At a median follow-up of 48 months (mo; 2-168), 79 pts (66%) are alive with a median PFS and OS of 135 and 135 mo (Figure) and 73 pts (61%) remain in CR. Image:Summary/Conclusion: Addition of NEL/PEG cycles to the HCVAD regimen is feasible and may be beneficial. Addition of VEN to each cycle is associated with significant myelosuppression. Lower doses of VEN may benefit selected pts.

Allogeneic transplant compared to pediatric-inspired therapy for Philadelphia chromosome-negative adolescent and adult ALL in first complete remission.

Pediatric-inspired non-transplant regimens for adolescent and adult ALL patients are becoming standard in many institutions. We aimed to compare a cohort of patients receiving a pediatric-inspired protocol to a cohort of patients treated with adult type ALL therapy followed by allografting after achieving CR1. Eighty-five adolescent and adult ALL patients treated with CALGB 19802 protocol who received MSD transplant in CR1 were retrospectively compared to a matched cohort of 72 adolescent and adult ALL patients treated with a modified version of Children's Cancer Group (CCG) 1900 protocol. The five years OS in the allo-HCT cohort was 63.1% compared to 80.2% in the pediatric-inspired chemotherapy arm (P = 0.03). The five years EFS in the allo-HCT arm was 58.8% compared to 61.6% in the pediatric-inspired chemotherapy arm (P = 0.07). The five years DFS in the allo-HCT arm was 58.8% as compared to 71.9% in the pediatric-inspired chemotherapy arm (P = 0.07). The relapse rate in the allo-HCT cohort was 30.58% compared to 21.68% in the pediatric-inspired chemotherapy arm (P = 0.16). The NRM in the allo-HCT cohort was 10.59 as compared to 6.45 in the pediatric-inspired chemotherapy arm (P = 0.3). For adolescent and adult patients with Ph-negative ALL, pediatric-inspired chemotherapy resulted in higher OS compared to allo-HCT.

Outcomes of Patients with AML Treated with CPX-351 Based on the 2017 ELN Risk Stratification

Outcomes of Patients with AML Treated with CPX-351 Based on the 2017 ELN Risk Stratification