Low-intensity Regimens Research Articles

Comorbidities in transplant recipients with acute myeloid leukemia receiving low-intensity conditioning regimens: an ALWP EBMT study.

Older age and a high burden of comorbidities often drive the selection of low-intensity conditioning regimens in allogeneic hematopoietic stem cell transplantation recipients. However, the impact of comorbidities in the low-intensity conditioning setting is unclear. We sought to determine the contribution of individual comorbidities and their cumulative burden on the risk of nonrelapse mortality (NRM) among patients receiving low-intensity regimens. In a retrospective analysis of adults (≥18 years) who underwent transplantation for acute myeloid leukemia in the first complete remission between 2008 and 2018, we studied recipients of low-intensity regimens as defined by the transplantation conditioning intensity (TCI) scale. Multivariable Cox models were constructed to study associations of comorbidities with NRM. Comorbidities identified as putative risk factors in the low-TCI setting were included in combined multivariable regression models assessed for overall survival, NRM, and relapse. A total of 1663 patients with a median age of 61 years received low-TCI regimens. Cardiac comorbidity (including arrhythmia/valvular disease) and psychiatric disease were associated with increased NRM risk (hazard ratio [HR], 1.54; 95% confidence interval [CI], 1.13-2.09 and HR, 1.69; 95%CI, 1.02-2.82, respectively). Moderate pulmonary dysfunction, though prevalent, was not associated with increased NRM. In a combined model, cardiac, psychiatric, renal, and inflammatory bowel diseases were independently associated with adverse transplantation outcomes. These findings may inform patient and regimen selection and reinforce the need for further investigation of cardioprotective transplantation approaches.

Treatment responses, outcomes, and prognostic factors associated with them in patients with secondary acute myeloid leukemia

Objective: To evaluate treatment responses, outcomes, and prognostic factors in adults with secondary acute myeloid leukemia (sAML) . Methods: Between January 2008 and February 2021, date of consecutive cases of younger than 65 years of adults with sAML were assessed retrospectively. Clinical characteristics at diagnosis, treatment responses, recurrence, and survival were evaluated. Logistic regression and Cox proportional hazards model were employed to determine significant prognostic indicators for treatment response and survival. Results: 155 patients were recruited, including 38, 46, 57, 14 patients belonging to t-AML, and AML with unexplained cytopenia, post-MDS-AML, and post-MPN-AML, respectively. In the 152 evaluable patients, the rate of MLFS after the initial induction regimen was 47.4%, 57.9%, 54.3%, 40.0%, and 23.1% in the four groups (P=0.076) . The total rate of MLFS after the induction regimen was 63.8%, 73.3%, 69.6%, 58.2%, and 38.5% (P=0.084) , respectively. Multivariate analysis demonstrated that male gender (OR=0.4, 95% CI 0.2-0.9, P=0.038 and OR=0.3, 95% CI 0.1-0.8, P=0.015) , SWOG cytogenetic classification into unfavorable or intermediate (OR=0.1, 95% CI 0.1-0.6, P=0.014 and OR=0.1, 95% CI 0.1-0.3, P=0.004) and receiving low-intensity regimen as induction regimen (OR=0.1, 95% CI 0.1-0.3, P=0.003 and OR=0.1, 95%CI 0.1-0.2, P=0.001) were typical adverse factors impacting the first CR and the final CR; PLT<45 × 10(9)/L (OR=0.4, 95%CI 0.2-0.9, P=0.038) and LDH ≥258 U/L (OR=0.3, 95%CI 0.1-0.7, P=0.005) were independent factors for CR. Among the 94 patients with achieving MLFS, 46 cases had allogeneic hematopoietic stem cell transplantation. With a median follow-up period of 18.6 months, the probabilities of relapse-free survival (RFS) and overall survival (OS) at 3 years were 25.4% and 37.3% in patients with transplantation, and in patients with chemotherapy, the probabilities of RFS and OS at 3-year were 58.2% and 64.3%, respectively. At the time of achieving MLFS, multivariate analysis revealed that age ≥46 years (HR=3.4, 95%CI 1.6-7.2, P=0.002 and HR=2.5, 95%CI 1.1-6.0, P=0.037) , peripheral blasts ≥17.5% at diagnosis (HR=2.5, 95%CI 1.2-4.9, P=0.010 and HR=4.1, 95%CI 1.7-9.7, P=0.002) , monosomal karyotypes (HR=4.9, 95%CI 1.2-19.9, P=0.027 and HR=28.3, 95%CI 4.2-189.5, P=0.001) were typical adverse factors influencing RFS and OS. Furthermore, CR after induction chemotherapy (HR=0.4, 95%CI 0.2-0.8, P=0.015) and transplantation (HR=0.4, 95%CI 0.2-0.9, P=0.028) were substantially linked to longer RFS. Conclusion: Post-MDS-AML and post-MPN-AML had lower response rates and poorer prognoses than t-AML and AML with unexplained cytopenia. In adults with male gender, low platelet count, high LDH, and SWOG cytogenetic classification into unfavorable or intermediate at diagnosis, and receiving low-intensity regimen as the induction regimen predicted a low response rate. Age ≥46 years, a higher proportion of peripheral blasts and monosomal karyotype had a negative effect on the overall outcome. Transplantation and CR after induction chemotherapy were greatly linked to longer RFS.

Secondary Neoplasms After Hematopoietic Cell Transplant for Sickle Cell Disease.

To report the incidence and risk factors for secondary neoplasm after transplantation for sickle cell disease. Included are 1,096 transplants for sickle cell disease between 1991 and 2016. There were 22 secondary neoplasms. Types included leukemia/myelodysplastic syndrome (MDS; n = 15) and solid tumor (n = 7). Fine-Gray regression models examined for risk factors for leukemia/MDS and any secondary neoplasm. The 10-year incidence of leukemia/MDS was 1.7% (95% CI, 0.90 to 2.9) and of any secondary neoplasm was 2.4% (95% CI, 1.4 to 3.8). After adjusting for other risk factors, risks for leukemia/MDS (hazard ratio, 22.69; 95% CI, 4.34 to 118.66; P = .0002) or any secondary neoplasm (hazard ratio, 7.78; 95% CI, 2.20 to 27.53; P = .0015) were higher with low-intensity (nonmyeloablative) regimens compared with more intense regimens. All low-intensity regimens included total-body irradiation (TBI 300 or 400 cGy with alemtuzumab, TBI 300 or 400 cGy with cyclophosphamide, TBI 200, 300, or 400 cGy with cyclophosphamide and fludarabine, or TBI 200 cGy with fludarabine). None of the patients receiving myeloablative and only 23% of those receiving reduced-intensity regimens received TBI. Low-intensity regimens rely on tolerance induction and establishment of mixed-donor chimerism. Persistence of host cells exposed to low-dose radiation triggering myeloid malignancy is one plausible etiology. Pre-existing myeloid mutations and prior inflammation may also contribute but could not be studied using our data source. Choosing conditioning regimens likely to result in full-donor chimerism may in part mitigate the higher risk for leukemia/MDS.

Burkitt lymphoma after solid-organ transplant: Treatment and outcomes in the paediatric PTLD collaborative.

Burkitt lymphoma arising in paediatric post-solid-organ transplantation-Burkitt lymphoma (PSOT-BL) is a clinically aggressive malignancy and a rare form of post-transplant lymphoproliferative disorder (PTLD). We evaluated 35 patients diagnosed with PSOT-BL at 14 paediatric medical centres in the United States. Median age at organ transplantation was 2.0 years (range: 0.1-14) and age at PSOT-BL diagnosis was 8.0 years (range: 1-17). All but one patient had late onset of PSOT-BL (≥2 years post-transplant), with a median interval from transplant to PSOT-BL diagnosis of 4.0 years (range: 0.4-12). Heart (n= 18 [51.4%]) and liver (n= 13 [37.1%]) were the most frequently transplanted organs. No patients had loss of graft or treatment-related mortality. A variety of treatment regimens were used, led by intensive Burkitt lymphoma-specific French-American-British/Lymphomes Malins B (FAB/LMB), n= 13 (37.1%), and a low-intensity regimen consisting of cyclophosphamide, prednisone and rituximab (CPR) n= 12 (34.3%). Median follow-up was 6.7 years (range: 0.5-17). Three-year event-free and overall survival were 66.2% and 88.0%, respectively. Outcomes of PSOT-BL patients receiving BL-specific intensive regimens are comparable to reported BL outcomes in immunocompetent children. Multi-institutional collaboration is feasible and provides the basis of prospective data collection to determine the optimal treatment regimen for PSOT-BL.

PTPN11 mutations Confer Adverse Outcomes and Therapy Resistance in Older Patients with Acute Myeloid Leukemia (AML)

Introduction:PTPN11 is a proto-oncogene that encodes tyrosine phosphatase with 2 Src-homology 2 domain (SHP-2), a protein tyrosine phosphatase crucial in regulating the RAS/MAPK pathway and hematopoietic cell development. Germline and somatic PTPN11 mutations are associated with Juvenile Myelomonocytic Leukemia (JMML), with inferior outcomes and higher relapse rates than other JMML subtypes. The clinical significance of PTPN11 mutations in AML remains inconclusive, and there is limited information on how PTPN11 mutations impact AML outcomes. Methods: AML patients (pts) with PTPN11 mutations were identified at New York-Presbyterian/Weill-Cornell Medicine and Vanderbilt University Medical Center. Patients were stratified by age (<60 vs. ≥60 years); log-rank tests were used for survival data and the fisher-exact test was used to compare non-survival data. Results: 83 AML pts with PTPN11 with evaluable data were identified. The median age was 63, (32 female, 51 male). Among 83 pts, 74 pts underwent treatment: 33.78% (25/74) pts achieved complete response (CR) at some point during treatment, with induction CR 25.7% (19/74) and re-induction or Salvage CR 10.9% (6/55). In older patients, 30/49 (61.2%) received low-intensity regimens and 18/49 (36.7%) received high-intensity regimens. Venetoclax/hypomethylating agents (HMA) (n=17) were the most commonly used treatment in the low-intensity group. Only 3/17 pts (17.7%) achieved a CR, which is significantly lower than what would be expected based on historical controls. Amongst pts who received high intensity therapy, (all received either 7+3 or CPX-351) 5/18 (27.7%) achieved CR. Out of 25 younger pts, 21 received high-intensity regimens, (4 received low-intensity regimens). CR was achieved in 9/21 pts (42.9%), which is also significantly lower than what would be expected based on historical controls. Median overall survival (OS) of the entire cohort was 11 months (figure 1). Median OS was significantly worse in older pts vs younger pts (5.5mo vs 25.0 mo, p=<0.0001, figure 1). Older pts had significantly decreased total CR rates (24.5% vs 52%, p=0.0221), fewer initial high-intensity regimen (36.7% vs 84%, p=0.0002), more initial low-intensity regimen (51% vs 16%, p=0.002), lower hematopoietic stem cell transplantation (HSCT) rate (15.79% vs 38.46%, p=.046), and lower HSCT survival rate at the time of censor (22.2% vs 100%, p= <0.0007). In older pts there was no significant difference in median OS as a function of higher vs lower intensity induction regimen (5 months vs 9 months, p=.9475). In pts that underwent HSCT, median OS was significantly longer in younger pts than older pts (16 months vs NR, p=<0.0001, figure 2). At time of censor, 2/9 (22%) of older pts who underwent HSCT were alive compared to 10/10 younger pts (100%). By 2017 ELN risk classification, 16 pts were favorable risk, 20 intermediate, and 47 adverse. Mutational analysis showed co-mutations in DNMT3A 28.9% (24/83), NPM1 27.7% (23/83), RUNX1 22.9% (19/83), ASXL1 15.6% (13/83), NRAS 15.6% (13/83), and TET2 15.6% (13/83). Older pts had significantly increased RUNX1 co-mutations (19 vs 0, p=<0.0001). Conclusion:PTPN11 mutations were associated with significantly worse OS in older pts. Furthermore, PTPN11 mutations correlated with poor response to high-intensity and low-intensity regimens, including Venetoclax/HMA. In particular, the response to Venetoclax/HMA was worse than what would be expected compared to historical controls. For older pts who achieved a CR and underwent HSCT, survival was uniformly poor. Conversely, the majority of younger AML pts with PTPN11 mutations received high-intensity induction regimens and had significantly better survival outcomes with HSCT than the older age group. These findings suggest that younger pts benefit from high-intensity induction regimens and early consideration of HSCT, while in older pts attempts should be made to focus on clinical trials and novel approaches at targeting the aberrant activated signaling pathways in PTPN11 mutated AML. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Prognostic Factors and Outcomes of Adolescent and Adult Burkitt Lymphoma and Leukemiafrom a Low-Middle Income Country: An Experience from Hematology Cancer Consortium

The treatment of BL/L has evolved on the principles of short-course, intensive, non-cross resistant, alternating chemotherapy. These intensive high-dose methotrexate-based treatment regimens (CODOX-M/IVAC, Hyper-CVAD, BFM, LMB) have led to high response rates and cures in a significant proportion of children and young adults. The addition of rituximab has led to overall survival benefit. There is limited data that dose adjusted EPOCH-R provides a low intensity treatment option for patients who may not be able to tolerate high-dose methotrexate-based regimens. Efficacy of these regimens in real-world, more so in an LMIC setting need to be evaluated given the delays in seeking care, higher risk of treatment-related complications including infections and antecedent treatment interruptions. This retrospective multicentric study collected the data from eight-member centers of Hematology Cancer Consortium (www.hemecancer.org) using an electronic database, to analyze the clinical characteristics, treatment patterns, outcomes and prognostic factors in adolescent and adult newly diagnosed Burkitt lymphoma and leukemia diagnosed between 2012-2019 (including HIV positive). Patients who had received more than 2 weeks of chemotherapy or steroids prior to presentation were excluded. The data included demographic details, performance status (ECOG), HIV serology, bone marrow and CNS involvement, stage, treatment type, use of rituximab, response to treatment, and treatment-related mortality as assessed by the investigator of the respective centre. The primary objective was to evaluate event-free survival at 2 years. Secondary objectives were to evaluate the overall survival, impact of the treatment protocol, use of rituximab, stage, age, performance status, CNS involvement, and HIV positive status on the overall and event-free survival. A total of 312 patients were included in this study. Out of these 257 patients received treatment and were analyzed for the outcome and prognostic factors. The treated and untreated cohorts differed in age [ median age 37 years (range-25-49 years) versus 42 years (range-32-51 years); with the untreated cohort being older. Table 1 provides the baseline characteristics of the patients who received treatment. The HIV positive patients (in treated cohort) had higher LDH [median - 967.5 (range, 509- 2355) vs 589 (311-1141), p=0.003). A total of 100 (42%) patients received intensive and high-dose methotrexate-based chemotherapy, 81 (34%) patients received dose-adjusted EPOCH-based treatment whereas 56 (24%) received other low-intensity or palliative chemotherapy. Patients with HIV were largely treated with a dose-adjusted EPOCH-based regimen (25/32 patients). Patients who received a high-dose methotrexate-based regimen were younger than those who received dose-adjusted EPOCH and other lower intensity regimens (Mean age 29 years versus 42.4 and 43.9 years) At the median follow-up of 36.5 months, the 2-year EFS was 61% and 2-year OS was 73%. There was no significant difference in outcomes in HIV-positive and negative patients. On univariate analysis lack of use of rituximab and use of protocols other than high-dose methotrexate and dose-adjusted EPOCH negatively affected EFS and OS. Age had an adverse impact on the OS but not EFS whereas stage 2 or above had a negative impact on EFS. On multivariate analysis use of regimens other than high-dose methotrexate-based and dose-adjusted EPOCH was a negative prognostic factor for both EFS and OS. The HR favored high dose methotrexate and dose-adjusted EPOCH-based regimen for both EFS and OS; HR- 0.42 (95% CI,0.22,0.77) and 0.27(95% CI,0.13-0.59), respectively. Use of rituximab was associated with better OS HR-0.44(95% CI,0.21-0.93) and a trend toward better EFS - HR-0.58 (95%CI, 0.31-1.07). The treatment-related mortality was 11.2% (29/257) and high serum LDH was associated with higher mortality (p=0.003). Treatment of adolescent and adult Burkitt lymphoma and leukemia with intensive regimens (high-dose methotrexate-based) and dose-adjusted EPOCH regimen resulted in similar survival. Dose-adjusted EPOCH-based regimen was preferred in older patients. The use of rituximab in these patients adds to the overall survival benefit. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Low Intensity Salvage Therapy after Failure of Standard (7 +3) Induction Regimen in Acute Myeloid Leukemia (AML). a Single Center Experience from United Arab Emirates

Hypomethylating agent (HMA) and venetoclaxR as salvage therapy for Acute Myeloid Leukemia (AML) failing intensive induction therapy. A single center experience from United Arab Emirates. Introduction: Patients with AML who are younger and fit for therapy are treated with intensive chemotherapy. Complete remissions (CRs) range from 40-80% (Kantarjian, Blood vol. 116,22 (2010): 4422-9). Non-CR patients can be treated with salvage therapy as a bridge to Allogeneic hematopoietic cell transplant (AlloHCT). Salvage regimens have included high dose cytarabine based therapies (FLAG, MEC, HAM) which can be more toxic limiting the use of AlloHCT. Lower intensity and more targeted therapy could decrease toxicity with improved responses. We describe our experience with a low intensity regimen as salvage treatment after failure of intensive induction therapy and bridge to AlloHCT. Methods: This is a retrospective analysis of AML patients treated at Tawam Hospital, UAE from 01/2019 to 06/2022. Patient data was collected from the medical records including: demographics, hemogram at presentation, bone marrow biopsies, karyotyping, treatment and response. Results: Eighty patients were diagnosed with AML during this period. The median age was 45 years (range 16-95 years). Fifty-seven patients received therapy while twenty-three patients refused or were not eligible due to comorbidities and / or performance status. Intensive chemotherapy (infusional cytarabine and idarubicin 7+3 or FLAG) was used for thirty-three patients. The median age was 35 years (range 16 - 63 years). Cytogenetics (Metaphase Karyotyping and FISH): normal, n=7; good risk n=6 (inv 16 or t (8;21), growth failure n=5, poor risk n=10 (Complex = 3, Del 7 = 3, 11q abnormalities = 3, trans 6;9 =1) other n=5. Molecular testing for NPMI, FLT3, IDH1 and IDH2 was not available. Three patients died during induction and are excluded from analysis. Fifteen patients attained CR after 1 cycle of induction (50%). Twelve patients not in CR received outpatient, low intensity salvage therapy with HMA (5 azacitidine 75 mg/m2 daily x 7 days subcutaneously with Venetoclax 100 mg orally daily x 21 days along with antimicrobial prophylaxis with azoles in 28 days cycles). Bone marrow was repeated after the second cycle. The median number of cycles is 3 (range 1-9). Eight (67 %) achieved CR1. There were no treatment related deaths. This is comparable to our report of FLAG salvage therapy (Hassan IB. Int J Hematol. 2018 Oct;108(4):390-401). Four of the eight patients who achieved remission went for AlloHCT while one is awaiting AlloHCT. One patient is unable to go for HCT and is in remission after 9 cycles of therapy. Two patients after achieving CR relapsed and died of disease progression. With a median follow up of 123 days (range 33 -1107 days) five patients are alive and in remission, one has been lost to follow-up while the other six have died from progressive disease and complications. Conclusion. Low Intensity therapy with HMA and Venetoclax is a reasonable and effective alternative to intensive chemotherapy as first line salvage with minimal morbidity and zero treatment related mortality. Treatment was well tolerated and no patients required hospitalization for complications. This regimen is easily administered as an outpatient, serving as a bridge to AlloHCT

The Adverse Effect of Myelodysplasia-Related Mutations in De Novo Acute Myeloid Leukemia Is Associated with Higher Variant Allelic Frequency (VAF): A Proposal for a Numeric Cutoff for Variant Allelic Frequency

Mutations in myelodysplasia-related genes ASXL1, BCOR, EHZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1 and ZRSR2 (MRmut) are class-defining alterations in acute myeloid leukemia (AML) in the latest World Health Organization (WHO, with the exception of RUNX1) and International Consensus Classification (ICC) schemes and indicate adverse-risk per European Leukemia Net (ELN) 2022 guidelines, unless occurring in favorable-risk AML. The lower limit of detection (LOD) for most clinical-grade next generation sequencing (NGS) is ~1-2% variant allelic frequency (VAF); however, data on the prognostic significance of MRmut relative to VAF is lacking. No guidelines that provide a numeric cutoff for VAF are available for utilizing these mutations to classify AML. Our aim was to define a clinically meaningful VAF cutoff for MR mutations in de novo AML. We included patients (pts) with de novo, untreated AML with MRmut treated at our institution between 2017 to 2022. We excluded pts with acute promyelocytic leukemia, core binding factor AML, and other ELN adverse-risk categories (adverse karyotype and/or TP53 mutation). NGS at baseline was performed using a panel of 81 genes recurrently mutated in myeloid neoplasms (LOD ~1-2%). We performed a best fit classifier on individual MRmut to determine optimal VAF cutoffs using event-free survival (EFS) and overall survival (OS) as endpoints. VAF for MRmut involving X-linked genes was adjusted for men. Pts (n=145) included 92 (63%) men and 53 (37%) women with a median age of 68 years (range, 58-75). 85 (59%) pts had diploid karyotype AML, 51 (35%) had other intermediate-risk non-diploid karyotype AML, and 9(6%) had insufficient metaphases for analysis. 34 (23%) pts had ELN favorable-risk and 111(77%) had ENL adverse-risk AML. Pts were treated with low-intensity+venetoclax (VEN) (72/50%), low-intensity (26/18%), high-intensity (22/15%), and high-intensity+VEN (12/17%) regimens. Median follow-up was 26.9 months (range, 13.9 - 40.8). 72 (49%) pts had 1 MRmut; the remaining had 2-4 concurrent MRmut. MRmut had the following frequencies and VAFs: ASXL1 (28%; median VAF: 26%, [range 2-48%]); BCOR (18%; median VAF 37% [3-100%]); EHZH2 (9%; median VAF 7% [1-55%]), RUNX1 (32%; median VAF 47% [1-96%]), SF3B1 (9%; median VAF: 38% [1-55%]), SRSF2 (46%; median VAF: 37% [1-76%]), STAG2 (20%; median VAF: 44% [15-98%]), U2AF1 (12%; median VAF: 33% [2-43%]) and ZRSR2 (2%; median VAF: 94% [93-95%]). 34 (23%) pts had ELN favorable-risk AML including 28 (23%) with mutated NPM1 without FLT3-ITD and 6 (4%) with CEBPA bZIP mutations, respectively; in 12/34 pts NPM1 or CEBPA bZIP mutations were subclonal compared with clonal MR mutation(s). A summary of baseline genetic and treatment data is provided in Fig 1A. The overall composite remission rate (CR+CRi) was 88% (64% and 24%, respectively) Median OS was 30.3 months and estimated 12/24 month OS were 77%/60%. The median EFS was 24.6 months and estimated 12/24 month EFS were 65%/51%. Pts with ELN favorable-risk AML with MRmut had longer OS and EFS compared with the adverse-risk group (median OS 34.9 vs 27.5 months, median EFS 34.9 vs 22.9 months) but the difference was not significant (p=0.60 and 0.30, respectively). The VAF cutoff for MRmut associated with EFS and OS, respectively, was: ASXL1: 21%/21%, BCOR 25%/25% , EHZH2 15%/15%, RUNX1 25%/27%, SF3B1 31%/31%, SRSF2 32%/35%, STAG2 40%/21%, U2AF1 44%/44% and ZRSR2 47/47%.There was no significant difference in OS or EFS between pts with 1 MRmut vs those involving ≥2 MR genes. Pts treated with high-intensity, high intensity+ VEN and low intensity+VEN regimens had longer OS (Fig 1B) and EFS compared with pts treated with low intensity regimens without VEN (OS: not reached, 31.7 months, 31.4 months vs 8.9 months, respectively, p<0.001; EFS: not reached, 31.7 months, 29.6 months vs 3.7 months, respectively, p<0.001). Our data suggest that the poor prognostic effect of MRmut in de novo AML is associated with higher VAF and not a binary presence or absence of MRmut. The minimum VAFs associated with worse outcome for each MRmut ranged from 15-47%. Additional analysis to create predictive models is in progress to determine the optimal VAF cutoff when using MRmut to assign AML to the WHO/ICC MR categories and to ELN adverse-risk group. Importantly, our results suggest that pts with MRmut and non-adverse karyotype have significantly better outcomes when treated with high-intensity and/or venetoclax-based treatment regimens. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Venetoclax Added to Cladribine (CLAD) + Low Dose AraC (LDAC) Alternating with Azacitidine (AZA) Is Highly Active As Frontline Therapy in Older Patients with Newly Diagnosed Acute Myeloid Leukemia in a Phase 2 Study

Background The combination of venetoclax with AZA for patients with newly diagnosed AML who are older or unfit for intensive chemotherapy significantly improves remission rates and survival compared to AZA alone. A low-intensity backbone combining venetoclax with cladribine (CLAD) plus low-dose araC (LDAC) alternating with HMA has demonstrated encouraging results in older patients with newly diagnosed AML (Kadia TM, et al. J Clin Oncol. 2022). Here we report an updated cohort of patients with longer-term follow up treated on the phase 2 clinical trial of venetoclax added to CLAD/LDAC alternating with AZA. Methods This is a phase 2 study (NCT03586609) investigating the combination of venetoclax with CLAD/LDAC alternating with AZA in older (age ≥ 60 years) or patients <60 years that are unfit for intensive chemotherapy with newly diagnosed AML (excluding APL, CBF). The primary objective was composite complete response rate (CRc; CR+CRi); secondary endpoints were overall survival (OS), disease-free survival (DFS), overall response rate (ORR), and toxicity. Induction was with cladribine 5 mg/m2 IV on D1-5 and araC 20mg SQ BID on D1-10. Consolidation/maintenance consisted of 2 courses of cladribine 5 mg/m2 IV on D1-3 and araC 20 mg SQ BID on D1-10 alternating with 2 cycles of AZA 75 mg/m2 on D1-7, for up to 18 courses. Venetoclax 400 mg was added for each course with dose adjustments for concomitant CYP3A inhibitors. Venetoclax was given for 21 days during induction and for 7-14 days for consolidation depending on measurable residual disease (MRD) and tolerability. One cycle was 4 weeks and up to 2 cycles of induction were allowed. Results A total of 93 patients were treated on study with a median age was 68 years (range: 57 - 84); 28 (30%) patients were ≥ 70 yrs and 1 patient <60, unfit for intensive chemotherapy was enrolled. 29 (31%) patients had secondary or therapy related AML. 52 (56%) had diploid cytogenetics with 11 (12%) having adverse cytogenetics at enrollment. By European Leukemia Network (ELN) risk, 24%, 24%, and 53% were favorable, intermediate, and adverse risk, respectively. The most commonly mutated genes were DNMT3A in 28 (30%), NPM1 in 26 (28%), RAS in 23 (25%), TET2 in 22 (24%), and IDH2 in 20 (22%). TP53 was mutated in 8 (9%) patients. Among 93 evaluable patients the CRc rate was 92%. Best response was CR in 72 (78%), CRi in 13 (14%), no response in 5 (5%), and death in 2 (2%) patients. In responding patients with a bone marrow sample evaluable for assessment of MRD by flow cytometry, 71/85 (84%) achieved MRD negativity while on study. Responses were preserved across ELN risk groups with the CRc (CR/CRi) rate of 95% (86%/9%), 95% (82%/14%), and 90% (73%/17%) for patients with ELN favorable, intermediate, and adverse risk, respectively. CRc rate for TP53 mutated disease was 88% (7/8, 86% MRD negative) and for NPM1 mutated disease was 96% (25/26, 100% MRD negative). 35 (41%) responders received a subsequent allogeneic stem cell transplantation (alloSCT). Early mortality was low with two patients (2%) dying within 4 weeks and five patients (5%) dying with in 8 weeks. The most frequent grade 3/4 non-heme adverse events were febrile neutropenia (n=12), infection (n=7), atrial fibrillation (n=2), and allergic reaction (n=2). One patient developed grade 4 tumor lysis syndrome. With a median follow up of 22.8 months, the median duration of response (DOR) is not reached (95% CI: NE - NE months). Estimated 12- and 24-month DOR are 88.4% (95% CI: 81.0 - 96.4%) and 81.0% (95% CI: 71.0 - 92.4%), respectively. Median disease-free survival (DFS) is not yet reached (95% CI: 24.5 - NE months). Estimated 12- and 24-month DFS are 76.0% (95% CI: 66.8 - 86.4%) and 63.4% (95% CI: 52.1 - 77.1%), respectively. Median overall survival (OS) is not yet reached (95% CI: 25.4 - NE months). Estimated 12- and 24-month OS are 75.7% (95% CI: 66.9 - 85.7%) and 68.3% (95% CI: 58.1 - 80.1%), respectively (Figure). Conclusion Venetoclax added to CLAD/LDAC alternating with AZA is a highly effective, lower-intensity regimen which is well tolerated among older patients with newly diagnosed AML, producing high CRc and MRD negative remission rates and is effective in transitioning older adults to alloSCT. The rates of DFS and OS are encouraging. Further study of this non-anthracycline containing regimen is warranted in older patients both fit and unfit for intensive chemotherapy as a safe and effective induction treatment strategy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Venetoclax Plus Decitabine for Young Adults with Newly Diagnosed ELN Adverse-Risk Acute Myeloid Leukemia: Updated Results of a Phase 2 Trial

Background: The young adults with newly diagnosed (ND) ELN adverse-risk acute myeloid leukemia (AML) fit for intensive chemotherapy (IC) have low complete remission (CR) rate and dismal outcomes compared with AML in favorable- and intermediate-risk categories. Venetoclax (VEN) combination with hypomethylating agents is a new standard of care for older and unfit AML patients (pts) and has been demonstrated to improve composite complete remission and overall survival (OS). We previously reported that VEN plus decitabine (DEC) as frontline treatment for young pts with ND ELN adverse-risk AML and demonstrated promising efficacy and safety at median follow-up of 2.7months in a phase 2 trial (Chen et al, ASH 2021). Here we present an updated analysis of efficacy and safety results in the ongoing study. Methods: This multicenter, single-arm, phase 2 trial (NCT04752527) enrolled young pts (aged between 18 and 59) with ND AML, who met the adverse risk group according to 2017 ELN risk stratification screened by fast next-generation sequencing (NGS), multiplex RT-PCR and fluorescence in situ hybridization (FISH) within 72 hours, and were eligible for standard induction chemotherapy. The study design was previously reported (Chen et al, ASH 2021). The primary outcome was composite complete remission (CRc: CR plus CR with incomplete blood count recovery [CRi] and morphologic leukemia free state [MLFS]). Secondary outcomes were OS, event-free survival (EFS) and safety. The data cut-off date was July 31, 2022. Results: Between February 12, 2021 and July 31, 2022, 286 patients aged between 18 and 59 with ND AML underwent screening. 78 pts were classified as ELN adverse-risk category by fast NGS (within 72 hours) together with multiplex RT-PCR and FISH and 42 pts were enrolled, comprising 26 males and 16 females. Median age was 39 years (range, 19-58) (Table 1). As of the cut-off date, 40 pts completed the first cycle of VEN+DEC and 37 pts completed two courses. In cycle 1, 31 (77.5% [95% CI, 61-89]) pts achieved CRc, 8 (20% [95% CI, 10-36]) pts had partial remission and 1 (2.5% [95% CI, 0-15]) had no response. 24 (77.4% [95% CI, 58-90]) of 31 pts achieving CRc had measurable residual disease (MRD) negativity assessed by multiparameter flow cytometry (MFC) with a sensitivity of 10-3-10-4(0.1%-0.01%). Pts with RUNX1 and FLT3-ITD mutations had higher CRc rates of 83.3% and 80%, respectively. Pts harboring TP53 and ASXL1 mutations achieved encouraging CRc rates of 62.5% and 75%, respectively. The CRc rates in pts with 11q23/KMT2A rearrangements and complex karyotype were 66.7% and 88.9%, respectively. The CRc and MRD negativity were achieved in 91.9% (34/37, 95% CI, 77-98) and 82.3% (28/34, 95% CI, 65-93) of the pts after the second course of treatment. 31 (73.8%) of 42 pts received allogeneic hematopoietic stem cell transplantation (HSCT), among them 26 patients achieved complete remission before HSCT, 3 received HSCT after morphologic relapse and 2 with salvaged HSCT. At median follow-up of 10.2 months (range, 0.8-17), the median OS and EFS were not reached (Figure1a, b). Estimated 12-months OS was 92.9% (95% CI, 79-98) and EFS was 71.4% (95% CI, 55-84). Among enrolled pts achieving CRc in cycle 1, median time to blood cell count recovery for absolute neutrophil count (ANC) ≥1000 cells per μL was 30 days (range, 16-NR), and for platelet count ≥50 000 platelets per μL was 20 days (range, 0-NR). Among 40 pts evaluable for safety analysis, the most common non-hematological adverse events were infections with grade 3 or worse neutropenia in 18 (45%) pts and febrile neutropenia in 11 (27.5%) pts. Notable serious adverse events were pneumonia in 5 (12.5%) pts and sepsis in 1 (2.5%). Mortality rates of 30-day and 60-day were 0%. Conclusions: VEN plus DEC was an effective, lower-intensity regimen that was well tolerated for young adults with ND ELN adverse-risk AML, producing high rates of CR and encouraging EFS and OS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Expression of mi-RNAs Involved in the Hematopoietic Niche Microenvironment in Newly Diagnosed AML Patients

Introduction Acute myeloid leukemia (AML) is a genetically heterogeneous disease and the most common type of acute leukemia in adults. Despite the progress made in the last years in AML therapy, induction treatment failure and disease relapse still remain the main challenges in clinical practice. miRNAs are involved in the pathogenesis of AML as well as influence the differentiation and proliferation of normal hematopoietic cells. The expressions of specific miRNAs have been identified as potential biomarkers for predicting prognosis both in solid tumors and hematological malignancies. Methods The expression of 12 miRNAs involved in hematopoiesis and the microenvironment of the hematopoietic niche: miR-15a-5p, miR-34a-5p, miR-125b-5p, miR-139-5p, miR-146-5p, miR-181a-5p, miR-199b-5p, miR-204-5p, miR-218-5p, miR-299-5p, miR-424-3p, miR-452-5p was determined in duplicates using qPCR in bone marrow samples of newly diagnosed AML patients. The miRCURY LNA SYBR® Green PCR Kit (Qiagen) was used to carry out qPCR. miRNAs expression was normalized using the mean expression of all miRNAs in a given sample. The normalization was performed using the formula ∆Ct = Ct(reference) − Ct(miRNA of interest). This approach results in higher values for higher miRNA expression. Differential expression analysis was carried out using a t-test. Cox proportional hazard regression analyses of clinical factors and miRNAs for predicting overall survival in AML patients were performed. Results To the study group we enrolled 45 (23 women and 22 men) newly diagnosed AML adults with the mean age 45.1 ± 12.8 years. Among them, 13.9% patients (pts) had a low-risk, 44.2% intermediate-risk and 41.9% high-risk AML according to EuropeanLeukemiaNet (ELN) 2017 risk stratification (Döhner et al. 2017). In the study group, 16.7% of pts had NPM1 mutation, whereas 30.2% of pts had FLT3-ITD or FLT3-TKD mutation. The majority of patients (88.9%) received intensive treatment: DA-60 (daunorubicin 60mg/m2 + cytarabine 200mg/m2) regimen (50%), followed by DAC (DA-60 + cladribine 5mg/m2) (40%) and DA-90 (daunorubicin 90mg/m2 + cytarabine 100mg/m2) (10%). Azacitidine in standard dose was used as the low-intensity regimen. There were no statistically significant differences in miRNAs expression according to complete remission (CR) achievement. Patients with high-risk AML had higher expression of miR-125b-5p (fold change- FC=2.3, p=0.017) and lower expression of miR-34a-5p (FC=0.3, p=0.029), miR-199b-5p (FC=0.5, p=0.039) and miR-15a-5p (FC=0.6, p=0.043) as compared to low- and intermediate-risk pts. In patients with NPM1 mutation, miR-34a-5p, miR-146a-5p and miR-15a-5p were significantly upregulated, whereas miR-139-5p, miR-424-3p and miR-452-5p were downregulated. FLT-3-mutated patients had significantly lower expression of miR-424-3p (FC=0.2, p=0.019) comparing to FLT-3-unmutated controls. In patients with unfavorable karyotype, upregulation of miR-125b-5p (FC=2.8, p=0.002) and miR-139-5p (FC=3.0, p=0.027) was observed meanwhile lower expression of miR-34a-5p (FC=0.3, p=0.035) in these patients was detected. The median overall survival (OS) in the study cohort was 12.3 months. In univariate Cox regression analysis, hematopoietic cell transplantation-comorbidity index (HCTCI) score >0 (HR 2.86, 95%CI: 1.15-7.12, p=0.024), white blood cell (WBC) count at diagnosis (HR 1.01, 95%CI: 1.00-1.01, p=0.033), and higher expression (>median) of miR-199b-5p (HR 0.31, 95%CI: 0.12-0.81, p=0.027) (Fig.1) were factors influencing the outcome. In multivariate model, higher expression of miR-199-5p (HR 0.27, 95%CI: 0.08-0.91, p=0.036) retained their significant protective effect in the context of established prognostic factors. Conclusions Our preliminary results demonstrate that the expression of miRNAs involved in the microenvironment niche is deregulated in AML patients. The upregulation of miR-199-5p at the diagnosis is associated with longer overall survival of AML patients. Significantly lower expression of miR-199-5p was reported in ELN high-risk group. These data indicate that miR-199-5p may be a potential prognostic factor in AML patients. Larger studies are needed to confirm our observation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Allogeneic Hematopoietic Stem Cell Transplantation in Older Patients with Acute Myeloid Leukemia: Analysis of Outcomes and Contemporary Trends Spanning 10 Years

Background: Allogeneic hematopoietic stem cell transplantation (SCT) is a highly effective consolidation strategy in acute myeloid leukemia (AML). Non-myeloablative and reduced-intensity (NMA/RIC) conditioning regimens have expanded the use of SCT to older patients (pts) (age ≥ 60 years). Age alone no longer appears to be a barrier for successful SCT, with reported 3-year overall survival (OS) rates in the 45-50% range (Maakaron 2022). Methods: We conducted a retrospective study spanning 10 years to evaluate SCT-related outcomes in older AML. All pts ≥ 60 years presenting to our institution with newly-diagnosed (ND) AML were included. Acute promyelocytic leukemia (APL) was excluded. Median OS and relapse-free survival (RFS) were calculated using the Kaplan Meier method. A landmark analysis was performed to evaluate time-to-event endpoints in pts who underwent SCT in first response compared to those who did not. Results: Between 7/19/2012 and 11/17/2021, we identified 1073 pts ≥ 60 years with ND-AML. The median age at diagnosis was 71 years (range 60-94), 622 (58%) were male, 189 (18%) had prior myelodysplastic/myeloproliferative neoplasm, and 220 (21%) had therapy-related AML. ELN 2017 risk was favorable in 215 (20%), intermediate in 234 (22%), and adverse in 538 (50%) pts (86 with data missing). Most pts (84%) were treated with low-intensity (LOW) regimens. Only 16% were treated with intensive (INT) chemotherapy (intermediate or higher dose cytarabine). Venetoclax (VEN) was included in 34% of the regimens. The CR/CRi rate was 60% in the overall cohort. The CR/CRi rate was 74%, 48%, and 72% in pts treated with INT, LOW, and LOW + VEN therapies, respectively. The median OS and RFS were 11.2 and 10.6 months for the full cohort, respectively. The rate of referral to the SCT service was 38% (413/1073) and increased over time (31% in 2012-2013, 52% by 2020-2021). This occurred in parallel to increasing rates of CR/CRi (53% in 2012-2013, 66% by 2020-2021), likely reflecting increased efficacy of VEN-containing regimens in the later years. We identified 198/1073 pts (18%) who underwent SCT at some point during therapy, 152/198 (77%) in first response (CR/CRi/MLFS) after frontline therapy, and 46/198 (23%) following one or more salvage regimens. Of all ND-AML pts, the SCT rate was 37%, 10%, and 22% in pts treated with INT, LOW, and LOW + VEN, respectively. The rate of undergoing SCT increased over time (15% in 2012-2013, 27% by 2020-2021). Clinical/SCT characteristics for the pts who underwent SCT are shown in table 1. The rate of grade 3/4 acute graft-vs-host disease (GVHD) was 11% and 19% of pts experienced chronic GVHD of any grade. Following SCT, 24% of pts experienced relapse of AML and 21% died without disease relapse. The 100-day mortality following SCT was 13%. We then performed a landmark analysis (using median time to SCT [4.3 months] as the landmark) comparing pts undergoing SCT in first response following frontline therapy at our institution (n=139) to responding pts who did not receive SCT in first response and who were alive and without relapse at the landmark (n=353). Both the median OS (31.0 vs 18.9 months, p=0.0208, figure 1) and median RFS (23.2 vs 10.0 months, p<0.0001) were superior in the pts who underwent SCT compared to those who did not. Pts undergoing SCT in first response were younger (median age 66 vs 72 yrs) and had better performance status (PS 2-4 in 10% vs 22%) compared to no-SCT pts. Distribution of ELN risk categories and best response (CR/CRi/MLFS) were similar in the SCT and no-SCT groups. In pts who responded to initial therapy and were referred for SCT, but ultimately did not undergo SCT in first response (n=161), the most common documented reasons for forgoing SCT were social reasons (pt preference, financial/insurance/caregiver issues) in 29%, disease relapse in 29%, being deemed unfit due to comorbidities in 22%, active uncontrolled infections in 11%, and other reasons in 11%. An adequate donor was documented in 66% of these pts. Conclusions: Our results support the use of SCT as a consolidative strategy in older AML pts. Pts who undergo SCT have superior OS and RFS compared to those who do not. However, fewer than 20% of pts undergo the procedure mostly due to inadequate disease control, comorbidities, and a variety of social reasons. Recent trends indicate higher rates of SCT referral and completion as more effective anti-leukemic therapies are allowing a greater proportion of older AML pts to undergo SCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Long-Term Outcomes of Acute Myeloid Leukemia Following Allogeneic Stem-Cell Transplantation after Decitabine and Venetoclax: Subgroup Analysis of a Phase II Trial

Introduction: Venetoclax (VEN)-based lower intensity regimens are the current standard for older/unfit patients with newly diagnosed acute myeloid (AML). Such regimens are increasingly used in the salvage setting as well. Allogeneic stem-cell transplantation (SCT) following VEN-based regimens has been shown to be safe and feasible in pts with AML (Mukherjee et al. J Clin Oncol 2019; Pratz et al. Blood 2019). We herein describe long-term outcomes after SCT following treatment on a prospective clinical trial of 10-day decitabine and venetoclax (DEC10-VEN) for treatment-naïve and previously treated AML (NCT03404193). Methods: In this phase II trial, pts received decitabine 20 mg/m2 for 10 days during induction and 5 days during consolidation. VEN was administered 400 mg daily on D1-28 during cycle 1 but was held on day 21 if bone marrow evaluation showed blasts ≤5%. During subsequent cycles VEN duration could be reduced in pts with myelosuppression. This trial enrolled pts with ECOG PS ≤3 with adequate organ function. Pts with favorable risk cytogenetics were excluded. Pts with newly diagnosed AML were either unfit for intensive therapy, or older than 60 yrs. Pts in relapsed/refractory cohort were ineligible if they had received prior BCL2 inhibitor. Eligible pts with an available donor could proceed to SCT at any time following achievement of response. Response, overall survival (OS) and relapse-free survival were defined per ELN2017. Survival outcomes were not censored at SCT. Data cut-off date was July 26, 2022. Results: Between January 2018 and June 2022 we enrolled 230 pts with AML, high-risk or relapsed/refractory myelodysplastic syndrome or chronic myelomonocytic leukemia, and blastic plasmacytoid dendritic cell neoplasm. Among 201 pts with AML, CR/CRi/MLFS response was achieved in 146 pts (73%) and 40 pts (20%) were able to proceed to SCT; including 21 pts with treatment-naïve AML and 19 pts with either R/R AML or AML following treatment for antecedent hematological disorder (AHD) including MDS-EB (n=2) and CMML (n=1), considered "previously treated AML". The median age of pts undergoing SCT was 66 yrs (range 18-77); 10 pts (25%) were older than 70 yrs, 16 pts (40%) pts had R/R AML, 19 pts (45%) had ELN adverse risk disease and 4 pts had received prior SCT (Table 1). Fourteen pts in each group received additional concomitant therapy with FLT3 inhibitors including gilteritinib and sorafenib (Table 1). All pts proceeding to SCT were in CR/CRi except in the previously treated group where 4 pts had non-CR/CRi responses including MLFS/aplasia. 28 pts (70%) had achieved negative measurable residual disease (MRD) by flow cytometry (sensitivity 0.1-0.01%) prior to proceeding to SCT while 8/40 pts (20%) had persistent MRD. Remaining 4 pts either had inadequate sample or were not evaluated for MRD. Conditioning regimens and donor types are summarized in Table 1. Median no. of cycles of DEC10-VEN administered was 2 (range 1-12) and the median time to SCT was 3.5 mo from start of DEC10-VEN (range 1.1-16.2). The median follow-up duration was 29.1 mo. Among pts with AML who proceeded to SCT, the 100-day post-SCT mortality was 8% (n=3). The median OS for treatment-naïve pts was 35.1 mo and for previously treated pts was 16.7 mo. Median RFS for treatment naïve pts was 23.5 mo and for previously treated pts was 12.9 mo. Landmark analysis of pts achieving CR/CRi/MLFS and alive at 3.5 mo showed that pts with treatment-naïve AML who were eligible to proceed to SCT (n=21) derived significant benefit in OS with median OS 35.1 vs 15.7 mo in pts who did not / were ineligible (n=60) (HR 0.47, 95% CI 0.24, 0.76, p=.01, Fig. 1). Similarly, pts with previously treated AML who proceeded to SCT in CR/CRi/MLFS (n=18) had median OS of 19.3 vs 12.0 mo for pts who could not (n=36) (HR 0.53, 95% CI 0.28, 1.01, p=.07). Both analyses were limited by confounding factors. At data cut-off, 19 pts (48%) are alive, 8 pts (20%) died in remission, and 13 pts (33%) pts died after disease progression (Table 1). Conclusion: In this prospective trial of DEC10-VEN enrolling older/unfit pts with newly diagnosed AML, secondary AML, and younger or older pts with R/R AML, 20% of pts were able to proceed to SCT. DEC10-VEN served as bridge to SCT for responding pts with newly diagnosed as well as previously treated AML, with low 100-day post-SCT mortality. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

AML-396 Venetoclax-Containing Regimens Improve Outcomes of Intensive Treatment and Allogeneic Hematopoietic Stem Cell Transplantation in Patients With Extramedullary Acute Myeloid Leukemia

The optimal treatment strategy for patients with extramedullary acute myeloid leukemia (eAML) is questionable, especially as applied to extramedullary tumor persistence while bone marrow response is achieved. To determine whether venetoclax-containing regimens, intensive treatment, and allogeneic hematopoietic stem cell transplantation (alloHSCT) can improve outcomes in patients with eAML. Overall, 27 patients with verified eAML were included: 14 were male and 13 were female with a median age of 40 years (13-84). Standard ("7+3"), high-intensity ("HiDAC", "FLAG±Ida"), and low-intensity chemotherapy regimens were administered to all patients. Ten patients (37%) received venetoclax with 5-azacytidine (VEN-AZA) because of comorbidities or refractory disease. AlloHSCT was performed in 17 patients (63%). According to the 2017 ELN risk stratification system, 18.5% (5/27) were favorable risk, 25.9% (7/27) were intermediate risk, and 55.6% (15/27) were adverse risk. Patients with favorable genetic alterations achieved bone marrow remission more frequently (100% vs. 44%, P=0.044) but did not have advantages in the rate of complete extramedullary response (75% vs. 68%, P>0.05). Using HiDAC enabled eradication of extramedullary lesions in case of failure of standard and low-intensity regimens (85% vs. 0%, P=0.044) and decreased the rate of early (during the first 12 months) relapse (38% vs. 100%, P=0.019). The overall response rate to VEN-AZA was 70% (7/10). Five patients (50%) achieved complete eradication of extramedullary tumor after venetoclax; among them, 3 still had persistent extramedullary disease after HiDAC. Performing alloHSCT in first complete remission decreased the risk of early relapse (12% vs. 80%, P=0.015) and demonstrated better median overall survival (38.85 vs. 7.57 months, P=0.013) and relapse-free survival (38.85 vs. 3.78 months, P=0.0021) compared to alloHSCT performed in second and subsequent complete remissions. Favorable genetic aberrations do not increase the frequency of extramedullary response. Intensive treatment helps to achieve complete eradication of extramedullary tumor and reduces early relapse rate. Using VEN-AZA is effective among patients with eAML, including patients who were refractory to intensive treatment, and allows complete response achievement before alloHSCT. The best time to perform the alloHSCT among patients with eAML is the first complete remission.

Contemporary outcomes in IDH-mutated acute myeloid leukemia: The impact of co-occurring NPM1 mutations and venetoclax-based treatment.

Isocitrate dehydrogenase 1 or 2 (IDH1 or IDH2) mutations occur frequently in newly diagnosed (ND) acute myeloid leukemia (AML) often with co-occurring NPM1 mutations, which may influence treatment outcomes. Detailed analysis of IDH-mutated AML treated with venetoclax and influence of co-occurring NPM1 mutations remains unclear. This retrospective single-center cohort study evaluated clinical and molecular demographics,response and survival, and impact of co-occurring NPM1 mutations in patients with IDH1 or IDH2-mutated AML. 556 patients with IDH1, IDH2, and/or NPM1 mutated AML were included. Patients with IDH1mut AML (N= 119) were more likely to have older age, sAML, ELN-adverse risk disease, and adverse-risk cytogenetics compared to those with IDH2mut (N= 229) or IDHwt /NPM1mut AML (N= 208). In multivariate analysis, patients with IDH2mut (HR 0.61 [95%CI: 0.43-0.88], p value: .007) or IDHwt /NPM1mut (HR 0.65 [95% CI: 0.45-0.94], p value: .024) AML had a decreased risk of death versus IDH1mut AML. Venetoclax-based lower-intensity regimens partially abrogated the detrimental effect of IDH1mut with similar OS observed between IDH1mut /NPM1wt , IDH2mut /NPM1wt , and IDHwt /NPM1mut AML. With regards to the influence of IDHmut /NPM1mut cases, IC improved survival in IDH2mut /NPM1mut versus IDH2mut /NPM1wt AML (HR: 0.54 [95% CI: 0.2644-1.082], p value: .077), while venetoclax-based therapy improved survival in IDH1mut /NPM1mut versus IDH1mut /NPM1wt AML (HR: 0.094 [95% CI: 0.01-0.74], p value: .0056). Differing outcomes were observed in IDH1mut versus IDH2mut or NPM1mut AML which were influenced by co-occurring NPM1 mutations and partially abrogated with venetoclax-based therapy. Given the differing biology and survival in IDH1mut AML, investigations incorporating molecularly targeted therapies such as IDH inhibitors remain warranted in this subgroup.

MRD in Venetoclax-Based Treatment for AML: Does it Really Matter?

The prognosis of newly diagnosed patients with acute myeloid leukemia is still unfavorable in the majority of cases within the intermediate and mainly adverse genetic risk group but also in a considerable fraction of favorable-risk patients, mainly due to recurrence of disease after complete remission achievement or, less frequently, primary refractoriness. Besides genetic classification at diagnosis, post-treatment prognostic factors include measurable residual disease evaluation in patients in complete remission and in most cases measurable residual disease (MRD) positivity predicts hematologic relapse potentially allowing early therapeutic intervention. Currently, the most commonly used methods for detection of minimal residual disease are multiparameter flow cytometry and quantitative PCR, applicable to around 90% and 50% of patients, respectively. In addition, in > 90% of acute myeloid leukemia (AML) patients, molecular aberrations can be identified by next-generation sequencing, a technology that is widely used in clinical practice for the initial mutational screening at the time of diagnosis but more often, for MRD detection because its flexibility allows almost every mutated gene to be used as an MRD marker. Threshold levels of residual disease and correlation with outcome have been thoroughly studied and established in younger patients treated with intensive induction and consolidation chemotherapy as well as after allogeneic transplantation. Yet, experience on MRD monitoring and interpretation in patients treated with low-intensity regimens, including new agents, is still limited. The updated armamentarium of anti-leukemic agents includes the BCL-2 inhibitor venetoclax, which demonstrated good tolerability, high response rates, and prolonged overall survival when combined with hypomethylating agents or low dose cytarabine in patients considered elderly/”unfit” to tolerate intensive regimens. Although remissions with negative minimal residual disease clearly translated into improved outcomes after intensive treatments, data supporting the same evidence in patients receiving low-intensity venetoclax-based treatments are not still consolidated. We here review and discuss more recent data on the minimal residual disease interpretation and role in AML patients treated with venetoclax-based combinations.

Особливості зміни показників тренувального навантаження в силовому фітнесі в умовах м’язової діяльності різного характеру

The purpose of the work was to study the peculiarities of the change in the indicators value of training load in power fitness under conditions of using different modes of muscular activity in terms of volume and intensity. Materials and methods. The study involved 50 untrained males aged 18-20 years. 2 research groups of 25 people each were formed: control and main. The participants of the control group used the regimen of low-intensity and large-volume loads developed by us. The representatives of the main group used a regimen of high-intensity loads with the use of time indicators of muscular activity of different parameters. Control over changes in the value of training load indicators was carried out using the following methods: determining the development of maximum muscle strength of the studied contingent in control exercises; quantitative assessment of the level of physical activity in power sports. Results and discussion. The obtained results on the dynamics of the average group indicators of the maximum mass of the projectile when performing training exercises among the surveyed contingent, allow us to conclude that under long-term use of high-intensity loads regimen, the maximum power capabilities of the body develop almost 3 times faster compared to the data fixed during the same period of time in the conditions of application of a low-intensity regimen. In turn, despite a significant (about 51.0%) increase in the parameters of the load in the working set among the representatives of the main group during 3 months of the study, due to an increase in body’s strength capabilities by 36.0%, the results found at the end of the study were 6.8% and they were lower compared to the initial data set among the representatives of the control group. It was investigated that the most pronounced increase in the parameters of the load in the working set by 59.3% (p &lt;0.05) compared to the initial data, was recorded among the representatives of the main group when performing the basic exercise "bench press" in the conditions of using the regimen of high-intensity and low-volume load. It is established that the use of the regimen of power loads developed by us in the process of training activity contributes to the accelerated growth in the parameters of the projectile working mass indicator (by more than 30%) among men of the main group in comparison with opponents. At the same time, it was among the representatives of the main group who used the regime of high-intensity and low-volume loads during training, the indicator of the volume of work in a separate set was almost 70% lower compared to the data recorded among the control group. Conclusion. Against the background of increasing intensity parameters and simultaneously reducing the volume of training work, the results obtained may allow to find one of the effective ways to solve the most relevant problem of modern sports activity, namely, to suspend the process of a constant increase of the values of training loads to provide the body of athletes with the necessary, for further pronounced adaptive changes, stress stimulus and it will help reduce the level of injuries in power sports

Low-intensity therapy cures over 40 % of children with rapid Flow-MRD responding ALL: the ALL-MB 2008 trial results

Serious side effects occur during therapy for childhood acute lymphoblastic leukemia (ALL), and survivors can experience long-term consequences. This study aimed at identifying patients who can be successfully treated with low treatment intensity combining clinical parameters and minimal residual disease (MRD) measurements. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. ALL-MB studies used reduced-intensity therapy from the beginning, for standard risk (SR) patients no cyclophosphamide, a very low daunorubicin dose, no high dose of methotrexate, no cranial irradiation. In the ALL-MB 2008 study, 1702 children (49.1 % of all patients) were classified as SR due to favorable initial characteristics. These included 295 patients treated in institutions who took part in a pilot study on MRD measurement using flow cytometry on day 15 and/or at the end of induction (EOI). The most suitable time point for MRD measurement was EOI with threshold 0.1% in 90.5 % of the patients with excellent results: event-free survival of 95 % and overall survival of 97 %, that identified the large proportion of patients (more than 40 % of all ALL patients). The outcome of children with slower MRD response was significantly worse. Initial SR characteristics plus one single MRD measurement at EOI identify more than 40 % of all children with ALL who can be successfully treated with low-intensity regimens as used in the MB protocols.

P581: PHASE II STUDY OF LOWER-INTENSITY FRONTLINE THERAPY FOR NEWLY DIAGNOSED PATIENTS WITH AML WHO ARE UNFIT OR OTHERWISE NOT ELIGIBLE FOR FRONTLINE CLINICAL TRIALS

Background: Pts with newly diagnosed (ND) AML frequently present with abnormal organ function, poor performance status (PS), concurrent active malignancies, and active infections. These factors often preclude these pts from enrollment on frontline clinical trials, since standard eligibility routinely exclude them. Aims: Therefore, we designed a lower-intensity regimen of cladribine plus low-dose cytarabine (LDAC) alternating with decitabine (DAC) with less stringent inclusion criteria in ND pts unfit or otherwise ineligible for existing clinical trials. Methods: Pts >18 years with untreated AML and ineligible for other frontline AML clinical trials were enrolled (NCT01515527). Eligibility criteria included either creatinine ≥2mg/dL; or total bilirubin ≥2 mg/dL; or ECOG PS of 3 or 4; or ineligible for participation in a higher priority protocol. Pts with active concurrent malignancies and ongoing infection related to their AML could be enrolled. Induction was cladribine 5 mg/m2 IV on D1-5, Cytarabine 20 mg SQ twice daily on D 1-10, followed by consolidation with cladribine 5 mg/m2 IV on D1-3, Cytarabine 20 mg SQ twice daily on D 1-10 alternating with decitabine 20 mg/m2 IV, daily on D 1-5. The primary objective was 60-d survival rate. Results: A total of 25 pts have been enrolled. The median age was 73 years (range, 52-82) with 76% of the cohort older than 70 years. Six pts (24%) had concurrent active malignancy, 4 (16%) had baseline creatinine >2mg/dL, and 9 (36%) had PS ≥3. 76% of them were adverse risk per ELN 2017. Baseline characteristics are shown in figure. Among 25 evaluable pts, 17 (68%) achieved a composite complete response (CRc) including 10 (40%) CR and 7 (28%) CR with incomplete count recovery (CRi). Among responders, 6 pts (35%) achieved MRD neg by flow. Of 7 pts with no response, all were ELN adverse risk. Median cycles to response was 1 (range: 1 - 4). 30- and 60 d mortality was 8% and 16%, respectively, including 2 pts (8%) who died due to pseudomonal sepsis on D8, and the other due to pneumonia on D11. At a median follow up of 9.4 months (range, 0.4- 19.9 m),median OS (6-mo OS% - 61 %), and EFS was 8.3 mo each (6-mo RFS% - 56 %) with a 60-d OS and EFS rate of 83% each, with a median RFS of 5.8 mo (2-mo RFS%-66%; 6-mo RFS% - 49 %). In this challenging patient population, this lower-intensity regimen was well tolerated, with an acceptable toxicity profile. Image:Summary/Conclusion: In an unfit patient population with a high comorbidity burden, that were ineligible for other clinical trials, induction therapy with Cladribine plus LDAC was feasible and effective in newly diagnosed pts with AML. The regimen produced high rates of response, encouraging EFS, OS, and low early mortality in a cohort predicted to have a high risk of early death. Treating this pt population on a clinical trial is feasible and can allow pts to achieve remission and move on to effective post-remission therapy.

P506: ACHIEVEMENT OF MEASURABLE RESIDUAL DISEASE CLEARANCE IS A STRONGER PREDICTOR OF PATIENT OUTCOME THAN TREATMENT INTENSITY IN NEWLY DIAGNOSED PATIENTS WITH ACUTE MYELOID LEUKEMIA

Background: Modern therapy for acute myeloid leukemia (AML) can consist of either intensive or low-intensity regimens selected based on patient (pt) age/comorbidities. Measurable residual disease (MRD) has emerged as a strong independent prognostic factor in AML. It is unknown whether pts who achieve similar levels of MRD clearance experience comparable outcomes irrespective of treatment intensity. Aims: To establish the relative prognostic contribution of treatment intensity and MRD status on overall survival (OS) and relapse-free survival (RFS) in newly diagnosed AML pts who have achieved a first response. Methods: We conducted a retrospective chart review to identify non-CBF, non-APL AML pts treated at our institution between 2010 and 2021 with intensive (IA; int/high-dose cytarabine + anthracycline-based, without venetoclax) or low-intensity (Lo + VEN; low-dose cytarabine/hypomethylating agent-based, with venetoclax) regimens who had achieved CR/CRi/MLFS and undergone MRD testing by multiparameter flow cytometry at time of first response. Differences in baseline pt characteristics were evaluated using the Chi-square or Wilcoxon-Mann-Whitney tests for categorical and continuous variables, respectively. The Kaplan-Meier method was used to estimate median OS and RFS, with pts censored at the time of stem cell transplantation (SCT). Multivariate analysis was performed using a Cox proportional hazards model. Results: We identified 635 pts meeting inclusion criteria. Baseline characteristics are shown in Table 1. Compared to the IA-treated pts (n=385), pts treated with Lo + VEN (n=250) were significantly older, more likely to be male, less likely to achieve MRD clearance, and more likely to be classified as adverse risk by ELN 2017. The SCT rate in the Lo + VEN cohort was half that of the IA cohort (25% vs 50%). Median OS was 51m, 24.6m, 15m, and 9.9m in the IA MRD(-), Lo + VEN MRD(-), IA MRD(+), and Lo + VEN MRD(+) groups, respectively. Median RFS was 27.8m, 15.4m, 7.3m, and 5.2m in the IA MRD(-), Lo + VEN MRD(-), IA MRD(+), and Lo + VEN MRD(+) groups, respectively. Pts within the same MRD category (+ or -) had significantly higher OS and numerically higher RFS if treated with IA versus Lo + VEN. When the analysis was restricted to pts aged ≥ 60 years (n=56 in IA, n=239 in Lo + VEN; Fig. A-B), the differences within MRD categories did not reach statistical significance (median OS NR in IA MRD(-) vs 24.6m in Lo + VEN MRD(-), p=0.08; median OS 13m in IA MRD(+) vs 10.6m in Lo + VEN MRD(+), p=0.50; median RFS NR in IA MRD (-) vs 15.4m in Lo + VEN MRD(-), p=0.07; median RFS 25.1m in IA MRD(+) vs 5.3m in Lo + VEN MRD(+), p=0.24). The SCT rate was 29% (87/295) in the age ≥ 60 cohort. Given the confounding effect of unbalanced pt characteristics between the IA and Lo + VEN cohorts, we performed a multivariate analysis on the full population (n=635) taking into consideration the effects of age, treatment intensity, MRD status, and ELN category on OS and RFS (all significant by univariate analysis). In the multivariate analysis for OS, ELN adverse risk was the strongest predictor (HR 2.09, p<0.001), followed by MRD(+) status (HR 1.68, p<0.001), while treatment intensity and age were not significantly predictive. For RFS, ELN adverse risk (HR 2.31, p<0.001) and MRD(+) status (HR 1.98, p<0.001) were also the only two significant predictors. Image:Summary/Conclusion: In newly diagnosed AML patients, MRD status at time of first response and ELN risk are stronger predictors of pt outcome than intensity of therapy received.