Intensive Induction Research Articles

A retrospective study of the prognostic value of early induction of S-1 postoperative adjuvant therapy for pancreatic cancer.

689 Background: The usefulness of oral S-1 administration as adjuvant therapy (AC) after pancreatic cancer surgery has been demonstrated (1). Our study also suggested the importance of maintaining relative dose intensity or postoperative early induction (2). In a large Japanese data set, a comparison of induction before and after the postoperative 10 weeks showed a worse prognosis in the group which started 10 weeks after surgery (3). However, the number of patients of which early induction is possible are gradually increasing with recent improvements of surgical outcomes. In the present study, we retrospectively evaluated the survival benefit of AC which was started within 2 weeks after surgery. Methods: 129 patients with invasive pancreatic cancer who underwent radical surgery from January 2018 to May 2023 were enrolled in this retrospective study. The patients were divided into the following groups: 46 (36%) underwent induction within 2 weeks, 56 (43%) within 3-6 weeks, 13 (10%) after 7 weeks, and 14 (10%) without AC (4 with low renal function, 4 with deteriorating physical condition after surgery, 4 with not desired, and 2 with comorbid disease treatment). The background of each group was as follows (Described in the following order; induction within 2 weeks after surgery: 3-6 weeks: after 7 weeks: without AC), age 71: 71: 71: 78 (n.s.), pancreatic head cases 52: 68: 69: 50% (n.s.), BR cases 35: 23: 8: 21% (n.s.), NAC performed 86: 38: 15: 29% (p < 0.001), preoperative CEA ≥ 5.0ng/ml 24: 23: 8: 21% (n.s.), preoperative CA19-9 ≥ 37U/ml 48: 52: 54: 64% (n.s.), PV/SMV reconstruction 20: 16: 31: 14% (n.s.), postoperative complications (Clavien Dindo ≤3) 0: 16: 31: 43% (p < 0.001), Pathological stage 2 or higher 83: 65: 77: 79% (n.s.). Results: The need for reduction of S-1 dosage was 87: 89: 92% of the patients (n.s.), and the 6-month completion rate was 70: 71: 61% (n.s.). Median overall survival duration in each group was as follows: not reached: 49.5: 35.5: 48.6 months, and 1-year postoperative recurrence-free survival was 73: 66: 45: 71%, median recurrence free survival time was 34.0: 20.8: 10.3: 12.1 months, and induction within 2 weeks after surgery group significantly improved the recurrence-free survival in comparison with the group of after 7 weeks (p < 0.05). No significant factors were detected in multivariate analysis. Conclusions: These results suggest that early induction of AC as a result of improvement of surgical outcomes would contribute to postoperative recurrence-free survivals. 1. Uesaka et al, Lancet, 2016. 2. Matsushima et al. Anticancer Res, 2022. 3. Tomimaru et al, J Gastroenterol, 2023.

XPO1/Exportin-1 in Acute Myelogenous Leukemia; Biology and Therapeutic Targeting

Exportin 1 is responsible for the export of hundreds of proteins, several RNA species and ribosomal components from the nucleus to the cytoplasm. Several transported proteins are important for regulation of cell proliferation and survival both in normal and malignant cells. We review the biological importance and the possibility of therapeutic targeting of Exportin 1 in acute myeloid leukemia (AML). Exportin 1 levels can be increased in human primary AML cells, and even exportin inhibition as monotherapy seems to have an antileukemic effect. The results from Phase I/II studies also suggest that exportin inhibition can be combined with conventional chemotherapy, including intensive induction and consolidation therapy possibly followed by allogeneic stem cell transplantation as well as AML-stabilizing therapy in elderly/unfit patients with hypomethylating agents. However, the risk of severe toxicity needs to be further evaluated; hematological toxicity is common together with constitutional side effects, electrolyte disturbances, and gastrointestinal toxicity. A recent randomized study of intensive chemotherapy with and without the Exportin inhibitor selinexor in elderly patients showed reduced survival in the selinexor arm; this was due to a high frequency of relapse and severe infections during neutropenia. Experimental studies suggest that Exportin 1 inhibition can be combined with other forms of targeted therapy. Thus, Exportin 1 inhibition should still be regarded as a promising strategy for AML treatment, but future studies should focus on the risk of toxicity when combined with conventional chemotherapy, especially in elderly/unfit patients, combinations with targeted therapies, identification of patient subsets (AML is a heterogeneous disease) with high susceptibility, and the possible use of less toxic next-generation Exportin 1 inhibitors.

Pre-phase treatment with rituximab and high-dose methotrexate to re-evaluate eligibility for intensive induction treatment of frail patients with central nervous system lymphoma.

Not available.

New Combination Regimens vs. Fludarabine, Cytarabine, and Idarubicin in the Treatment of Intermediate- or Low-Risk Nucleophosmin-1-Mutated Acute Myeloid Leukemia: A Retrospective Analysis from 7 Italian Centers

Background: Nucleophosmin-1 (NPM1) mutation accounts for 30% of acute myeloid leukemia (AML) cases and defines either low- or intermediate-risk AML, depending on FLT3-ITD mutation. New combination regimens (NCRs), adding midostaurin and gemtuzumab ozogamicin (GO) to the 3 + 7 scheme, are commonly used, though there are no data that compare NCRs with intensive induction chemotherapy. Methods: To evaluate the efficacy and safety of NCRs and FLAI in NPM1+ AML, we retrospectively analyzed 125 patients treated with FLAI (n = 53) or NCRs (n = 72) at seven Italian Centers. Results: The median age was 61 years and 51/125 (41%) were FLT3-ITD+. The complete remission (CR) rate was 77%, slightly better with NCRs (83% vs. 68%; p = 0.054). NCRs yielded a superior median overall survival (OS) (not reached (NR) vs. 27.3 months; p = 0.002), though the median event-free survival (EFS) was similar (NR vs. 20.5 months; p = 0.07). In low-risk AML, CR was higher in NCRs (94% vs. 72%, p = 0.02), as were median OS (NR vs. 41.6 months; p = 0.0002) and EFS (NR vs. 17.8 months; p = 0.0085). In intermediate-risk AML (FLT3-ITD+), there were no differences in CR (60% vs. 71%; p = 0.5), OS (p = 0.27), or EFS (p = 0.86); only allogeneic transplantation improved OS (NR vs. 13.4 months; p = 0.005), regardless of induction regimen. The safety profile was similar, except for delayed platelet recovery with FLAI (22 vs. 18 days; p = 0.0024) and higher-grade II–IV gastrointestinal toxicity with NCRs (43% vs. 18.8%; p = 0.0066). Conclusions: Our data suggest the superiority of NCRs over FLAI in low-risk patients, while all outcomes were comparable in intermediate-risk patients, a setting in which only transplants positively impacted on survival.

Clinical decision support tool-guided, selective intensive induction strategy of ustekinumab in patients with Crohn's disease: A multicenter cohort study.

We aimed to evaluate the effectiveness and safety of clinical decision support tool (CDST)-guided initial selective intensive induction therapy (IIT) for patients with Crohn's disease (CD) who were treated with ustekinumab (UST) and to identify those most likely to benefit from IIT. Patients with active CD were included in this multicenter retrospective study and were categorized as low-, intermediate-, and high-probability responders according to the UST-CDST. IIT was defined as intensive induction by two or three initial doses of weight-based intravenous UST administration. Patients treated with standard therapy (ST) served as controls. The primary end-point was corticosteroid-free clinical remission (CFCR) at Week 24. Secondary end-points included clinical remission, clinical response, endoscopic remission, endoscopic response, and C-reactive protein (CRP) normalization at Week 24. Propensity score adjustments was conducted to ensure comparability. A total of 296 patients were included. At Week 24, IIT was associated with higher rates of CFCR (72.3% vs 43.0%, p < 0.001), clinical remission (77.3% vs 47.1%, p < 0.001), clinical response (78.1% vs 60.1%, p = 0.001), endoscopic remission (26.1% vs 9.9%, p = 0.024), and endoscopic response (58.6% vs 36.9%, p = 0.018) in low-intermediate-probability responders compared with ST. CRP normalization was comparable between groups. No significant differences were found in any end-points in high-probability responders. No serious adverse events were observed. The efficacy of IIT was superior to that of ST in patients with predicted poor response to UST, which may be regarded as a novel strategy for stratifying patients at baseline.

Response to intensive induction chemotherapy after failure of frontline azacitidine and venetoclax in acute myeloid leukemia.

Response to intensive induction chemotherapy after failure of frontline azacitidine and venetoclax in acute myeloid leukemia.

EE282 Budget Impact Analysis of Ivosidenib in Combination With Azacitidine for the Treatment of Previously Untreated mIDH1 Positive Acute Myeloid Leukaemia (AML) Patients, Ineligible for Intensive Induction Chemotherapy in Greece

EE282 Budget Impact Analysis of Ivosidenib in Combination With Azacitidine for the Treatment of Previously Untreated mIDH1 Positive Acute Myeloid Leukaemia (AML) Patients, Ineligible for Intensive Induction Chemotherapy in Greece

Central nervous system relapse after allogeneic HCT in FLT3-mutated AML

Central nervous system (CNS) relapse in acute myeloid leukemia (AML) is rare, but prognostically extremely unfavorable and associated with very high mortality rates. Aim of our single-center study was to define risk factors for CNS relapse in patients with FLT3-mutated AML after allogeneic hematopoietic cell transplantation (HCT) and to determine the impact of pre-emptive or salvage therapy with FLT3-inhibitors (FLT3i) on occurrence of CNS relapse and overall prognosis. We analyzed 39 FLT3-mutated AML patients who were treated with intensive induction therapy and consecutively underwent HCT at our institution. We observed that the remission status before HCT was strongly associated with relapse probability. Notably, FLT3-mutated AML showed a high propensity for CNS relapse with a cumulative incidence of 50% (95% confidence interval [CI], 16–77) at 2 years in non-responders pre-HCT compared to 0% in responders (cause-specific hazard ratio, 24.5, 95% CI, 2.9-206.2; p = 0.003). This was not abrogated by pre-emptive or salvage therapy with FLT3i in first relapse. Targeted therapies prior to transplant, use of intrathecal chemoprophylaxis or closer monitoring may be considered in patients with FLT3-mutated AML with active disease prior to HCT in order to prevent CNS relapse.

Lack of Benefit of Autologous Hematopoietic Cell Transplantation (auto-HCT) in Mantle Cell Lymphoma (MCL) Patients (pts) in First Complete Remission (CR) with Undetectable Minimal Residual Disease (uMRD): Initial Report from the ECOG-ACRIN EA4151 Phase 3 Randomized Trial

Background:MCL is a B-cell non-Hodgkin lymphoma for which auto-HCT is often employed in first CR, based on non-randomized phase 2 trials, and a randomized trial (Dreyling et al, Blood 2005) conducted before the advent of more effective induction and maintenance regimens. The TRIANGLE trial (Dreyling et al, Lancet 2024) suggested that auto-HCT may not add benefit to more effective induction and maintenance regimens containing high-dose cytarabine, rituximab and BTK inhibitors. E4151 explored whether auto-HCT benefits pts achieving deep first remission, as measured by a highly sensitive immunoglobulin high throughput sequencing minimal residual disease (MRD) assay.Methods:EA4151 is a four arm trial conducted through the U.S. National Clinical Trials Network (NCTN) and Blood and Marrow Transplant Clinical Trials Network (BMT-CTN). Pts with MCL between the ages of 18 and 70 and in first remission were eligible. After induction, pts underwent PET/CT, bone marrow biopsy, and the clonoSEQ® MRD assay from peripheral blood. Pts in CR with uMRD at 1 in 10-6 sensitivity (uMRD6) were randomized 1:1 to Arm A (auto-HCT + 3 years of maintenance rituximab [MR]) or Arm B (3 years of MR alone), stratified by MIPI-c score and intensive vs non-intensive induction. Pts with either MRD-positive (MRD+) CR or MRD-indeterminate CR (Arm C and Arm D, respsectively) both received auto-HCT + 3 years of MR. Pts who were MRD+ pre-transplant had MRD repeated at day 100. Primary endpoint was to compare overall survival (OS) in Arms A and B, with secondary endpoints including progression-free survival (PFS). Primary analysis population included all randomized pts. As some pts refused their assigned treatment (N=65 [25.3%] for arm A and N=2 [0.8%] for arm B), a “treated as assigned” analysis was also performed. Stratified logrank test was used to compare survival distributions. P-values are two-sided.Results:From Aug 2017 to July 2024, 650 pts were assigned to a treatment arm with 257, 259, 49, and 85 pts enrolled on Arms A, B, C, and D, respectively. Pts were 79% male and 92% white race. Median age was 60 years (range 27-70). MIPI-c was low/low-intermediate (LI) in 63% and high/ high-intermediate (HI) in 37%. Induction was intensive (defined as high-dose cytarabine-containing) in 73% and non-intensive in 27%. A BTK inhibitor was given during induction in 7.2% of pts, and during maintenance in 0.3% of pts.The third pre-planned interim analysis was based on data as of 7/15/24, with median follow up of 2.7 years. The futility boundary was an OS hazard ratio (HR) of 0.984 for Arm A vs B. The estimated OS HR for Arm A vs B in all randomized (n=516) and pts treated as assigned (n=375) were 1.11 (CI 0.71-1.74, p=0.66) and 1.00 (CI 0.58-1.74, p=0.99), respectively and crossed the futility boundary. The 3 year (yr) OS for Arms A and B were 82.1% and 82.7% in all randomized pts, and 86.2% and 84.8% in pts treated as assigned. The estimated PFS HR for Arm A vs B in all randomized and pts treated as assigned were 1.05 (CI 0.71-1.56, p=0.79) and 0.95 (CI 0.59-1.54, p=0.84), respectively. The 3 yr PFS for Arms A and B were 76.6% and 77.4% in all randomized pts, and 81.5% and 80.4% in pts treated as assigned.For Arm C, 3 yr OS and PFS were 81.9% (CI 69.6-96.4%) and 76.9% (CI 64.4-91.7%), respectively. For Arm D, 3 yr OS and PFS were 85.1% (CI 76.0%-95.4%) and 73.4% (62.7-85.9%), respectively. For the MIPI-c low/LI group, 3 yr OS was 84.6% vs 85.7% for Arm A vs B (p=0.96), while in the MIPI-c high/HI group, 3 yr OS was 77.4% vs 77.6% for Arm A vs B (p=0.71). For the intensive induction group, 3 yr OS was 83.0% vs 86.2% for Arm A vs B (p=0.30), while in the non-intensive induction group, 3 yr OS was 79.5% vs 72.8% for Arm A vs B (p=0.48).Exploratory analysis of MRD+ pts (Arm C) showed that pts who converted to uMRD6 post auto-HCT (n=17) had 3 yr OS of 100% and PFS of 100%, whereas those who remained MRD+ (n=13) post auto-HCT had 3 yr OS of 63.6% and PFS of 48.8%. Causes of death (COD) in Arm A were 4.7% lymphoma, 5.1% COVID-19, and 5.0% other/unknown. COD in Arm B were 3.5% lymphoma, 6.6% COVID-19, and 4.6% other/unknown. In Sept 2024, the DSMC recommended termination of accrual and release of trial findings based on these results.Conclusion:In this interim analysis, in the era of highly effective induction and maintenance regimens, MCL pts in first CR with uMRD6 did not benefit from consolidative auto-HCT. Pts who remain MRD+ after induction may benefit from auto-HCT. Longer follow-up will be important to confirm these findings.

Outcomes with intensive treatment for acute myeloid leukemia: an analysis of two decades of data from the HARMONY Alliance.

Since 2017, targeted therapies combined with conventional intensive chemotherapy have started to improve outcome of patients with acute myeloid leukemia (AML). However, even before these innovations outcomes with intensive chemotherapy have improved, which has not yet been extensively studied. Thus, we used a large pan-European multicenter dataset of the HARMONY Alliance to evaluate treatment-time dependent outcomes over two decades. In 5359 AML patients, we compared the impact of intensive induction therapy on outcome over four consecutive 5-year calendar periods from 1997 to 2016. During that time, the 5- year survival of AML patients improved significantly, also across different genetic risk groups. In particular, the 60-day mortality rate has dropped from 13.0% to 4.7% over time. The independent effect of calendar periods on outcome was confirmed in multivariate models. Improvements were documented both for patients.

Comparison of FLAG-Idarubicin to FLAG-Idarubicin Plus Venetoclax for Treatment of Newly Diagnosed AML in Patients Eligible for Intensive Induction. Analysis of 200 Consecutive Patients Treated at a Single Center

Comparison of FLAG-Idarubicin to FLAG-Idarubicin Plus Venetoclax for Treatment of Newly Diagnosed AML in Patients Eligible for Intensive Induction. Analysis of 200 Consecutive Patients Treated at a Single Center

Prognostic Impact of PTPN11 mutations in Acute Myeloid Leukemia

Background: The classification of acute myeloid leukemia (AML) is being refined as knowledge of associated genetic alterations increases. The role of the protein tyrosine phosphatase non-receptor type 11 (PTPN11) oncogene is well-established in Noonan syndrome and juvenile myelomonocytic leukemia, although less is known about its implications in adult AML. PTPN11 is involved in RAS/MAPK signaling pathway regulation. In this study, we sought to characterize the co-mutational landscape and outcomes of PTPN11 mutations in patients with AML. Methods: We retrospectively analyzed a database of 645 patients aged &amp;gt; 18 years with AML treated at our institution from 2014 to 2024. The PTPN11wild-type cohort was selected to match age, ECOG score, and Charlson Comorbidity Index (CCI) score median and range of the PTPN11mut cohort. Data was collected on molecular and cytogenetic profiles, European Leukemia Net (ELN) risk, response after induction therapy, and survival. Composite complete response (CCR) was defined as complete response, CR with incomplete hematologic recovery, or CR with partial hematologic recovery. Median relapse-free survival (mRFS) and overall survival (mOS) were compared using the Kaplan Meier method. RFS included patients who had primary refractory disease. Categorical variables were compared using Fisher's exact test. Continuous variables were compared using the unpaired t test. Results: PTPN11 mutations were detected in 35 patients with newly diagnosed AML. Those who received intensive induction had a median age of 62 (range, 24-74), median ECOG score of 1 (range, 0-2), and median CCI score of 4 (range, 2-11). The PTPN11mut non-intensive cohort had a median age of 78 (range, 70-85), ECOG of 2 (range, 1-3), and CCI of 7 (range, 5-12). Within a matched cohort of 216 patients with PTPN11wild-type, both the intensive and non-intensive groups had similar characteristics to their PTPN11mut counterpart . Co-occurring mutations in NPM1 were significantly enriched in the PTPN11mut cohort compared to PTPN11wild-type (46% v. 25%, p=0.015). There were no significant differences in cytogenetic profiles. The frequency of patients in each ELN genetic risk category was similar between the two cohorts. The mOS was 11.2 months in the PTPN11mut cohort and 15.3 months in the PTPN11wild-type cohort (HR=1.31, p=0.236). There were no significant survival differences between PTPN11mut and PTPN11wild-type when stratified by induction treatment intensity. The mOS of the PTPN11mut cohort was significantly shorter than that of the PTPN11wild-type favorable risk group (mOS=not reached [NR], HR=2.42, p=0.006) and PTPN11wild-type intermediate risk group (mOS=23.8 months, HR=1.90, p=0.033) but similar to mOS of the PTPN11wild-type adverse risk group (mOS=12.7 months, HR 0.94, p=0.80). Patients with PTPN11mut favorable risk AML had significantly worse mRFS (6.5 v. 22.8 months, HR 2.24, p=0.041) and shorter mOS than those with PTPN11wild-type favorable risk disease (21 months v. NR, HR 2.11, p=0.166), although the latter did not reach significance. Of note, all patients in the PTPN11mut favorable risk group had NPM1 co-mutations. PTPN11mut intermediate risk patients also had shorter mOS than PTPN11wild-type intermediate risk patients (12.3 v. 23.8 months, HR 2.35, p=0.065), trending toward significance. There was no difference in mOS between PTPN11mut adverse risk and PTPN11wild-type adverse risk (9.5 v. 10.5 months, HR 1.17, p=0.594). PTPN11mut with NPM1wild-type (not stratified by ELN risk) had a mOS of 11.1 months, similar to that of PTPN11mut with NPM1mut (12.3 months, HR 0.64, p=0.336). Conclusions: While PTPN11 mutations frequently co-occur with NPM1 mutations, they are also associated with higher risk mutations. PTPN11mut is associated with shorter OS and earlier relapse in ELN favorable risk AML compared to favorable risk with PTPN11wild-type, despite co-occurring NPM1 mutations. These patients should be considered for stem cell transplant in first remission. Co-occurring NPM1mut alone does not improve the OS of PTPN11mut. The OS of PTPN11mut AML more closely resembles that of ELN adverse risk AML. Overall, PTPN11 mutations are associated with poor prognosis. Larger studies are warranted to support the incorporation of PTPN11 into the ELN criteria for higher risk AML.

De-escalated Induction Therapy and Thiotepa/Busulfan-based Autologous Stem Cell Transplantation for Primary Central Nervous System Lymphoma

BackgroundThiotepa-based autologous stem cell transplantation (ASCT) improves survival in primary central nervous system lymphoma (PCNSL), but > 30% of patients are unable to undergo ASCT following commonly used intensive induction regimens. MethodsThis retrospective population-based study included consecutive patients ≥ 18 years old with PCNSL who were intended for ASCT in Alberta, Canada between 2011 and 2022. A reduced-intensity induction protocol was further abbreviated in 2018 to decrease toxicity and expediate ASCT by incorporating rituximab, procarbazine, and only 2 doses of high-dose methotrexate and 1 cycle of high-dose cytarabine before consolidation with thiotepa-busulfan conditioning. Progression-free survival (PFS) and overall survival (OS) were determined using the Kaplan–Meier method. ResultsAmong 71 patients with median age 58 years (range 26-72), ASCT was completed in 56 (79%), with the transplantation rate among patients > 60 years old increasing by 30% following the abbreviation of induction therapy. With median follow-up time 3.9 years, 4-year PFS and OS were 69% (95% CI 56%-79%) and 80% (95% CI 67%-88%) for all patients and 75% (95% CI 57%-86%) and 85% (95% CI 68%-93%) for ASCT recipients, respectively. There was 1 death due to treatment-related mortality during induction and none after ASCT, including among 17 transplanted patients > 60 years old. ConclusionAn abbreviated induction regimen followed by thiotepa-busulfan-based ASCT achieves high transplantation rates with low risks of relapse and treatment-related mortality, thereby providing an effective treatment strategy for PCNSL.

Translational Research on Azacitidine Post-Remission Therapy of Acute Myeloid Leukemia in Elderly Patients (QOL-ONE Trans-2).

The achievement of complete remission (CR) is crucial for acute myeloid leukemia (AML) patients undertaking curative therapy, but relapse often occurs within months, highlighting the need for strategies to prolong disease-free survival (DFS). Our phase III study compared the efficacy and safety of azacitidine (AZA) to best supportive care (BSC) in elderly AML patients who achieved CR following intensive induction and consolidation therapy. This ancillary study (QOL-ONE Trans-2) evaluated biological changes in bone marrow using Next-Generation Sequencing (NGS). We analyzed baseline, randomization, and 6-month post-remission samples from 24 patients (median age of 71 and 12 males). High-throughput NGS targeted 350 myeloid malignancy-related genes, considering variants with a variant allele frequency ≥ 4%. At diagnosis, all patients had 5 to 17 (median = 10) mutations, with DNMT3A (42%), NPM1 (33%), and TET2 (33%) being most frequent. FANCA mutations in four patients were linked to a higher relapse risk (HR = 4.96, p = 0.02) for DFS at both 2 and 5 years. Further HLA-specific NGS analyses are ongoing to confirm these results and their therapeutic implications.

Ivosidenib (Tibsovo)

We recommend that Tibsovo in combination with azacitidine be reimbursed by public drug plans for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) with an IDH1 R132 mutation who are not eligible to receive intensive induction chemotherapy, if certain conditions are met. Tibsovo in combination with azacitidine should only be covered to treat adult patients with newly diagnosed AML with an IDH1 R132 mutation who are considered ineligible for standard intensive induction chemotherapy and are aged at least 75 years; have an Eastern Cooperative Oncology Group (ECOG) performance status of 2; have severe organ dysfunction in the heart, lungs, kidneys, or liver; and/or have any other comorbidity judged to be incompatible with intensive induction chemotherapy. Tibsovo in combination with azacitidine should only be reimbursed if prescribed by clinicians with expertise in managing patients with AML in a specialized hematology or oncology clinic, and the treatment should be supervised and delivered in institutions with expertise in systemic therapy delivery. The total drug cost of ivosidenib plus azacitidine should not exceed that of venetoclax plus azacitidine. Lastly, it must be feasible to test patients for IDH1 R132

Chromothripsis in myeloid malignancies.

Chromothripsis refers to massive genomic rearrangements developed during a catastrophic event. In total acute myeloid leukemia (AML), the incidence of chromothripsis ranges from 0 to 6.6%, in cases of complex karyotype AML, the incidence of chromothripsis ranges from 27.3 to 100%, whereas in cases of AML with TP53 mutations, the incidence ranges from 11.1 to 90%. For other types of malignancies, the incidence of chromothripsis also varies, from 0 to 10.5% in myelodysplastic syndrome to up to 61.5% in cases of myelodysplastic syndrome with TP53 mutations.Chromothripsis is typically associated with complex karyotypes and TP53 mutations, and monosomal karyotypes are associated with the condition. ERG amplifications are frequently noted in cases of chromothripsis, whereas MYC amplifications are not. Moreover, FLT3 and NPM1 mutations are negatively associated with chromothripsis. Chromothripsis typically occurs in older patients with AML with low leukocyte counts and bone marrow blast counts. Rare cases of patients with chromothripsis who received intensive induction chemotherapy revealed low response rates and poor overall prognosis. Signal pathways in chromothripsis typically involve copy number gain and upregulation of oncogene gene sets that promote cancer growth and a concomitant copy number loss and downregulation of gene sets associated with tumor suppression functions.Patients with chromothripsis showed a trend of lower complete remission rate and worse overall survival in myeloid malignancy. Large-scale studies are required to further elucidate the causes and treatments of the condition.

Genomic characterization of AML with aberrations of chromosome 7: a multinational cohort of 519 patients

BackgroundDeletions and partial losses of chromosome 7 (chr7) are frequent in acute myeloid leukemia (AML) and are linked to dismal outcome. However, the genomic landscape and prognostic impact of concomitant genetic aberrations remain incompletely understood.MethodsTo discover genetic lesions in adult AML patients with aberrations of chromosome 7 [abn(7)], 60 paired diagnostic/remission samples were investigated by whole-exome sequencing in the exploration cohort. Subsequently, a gene panel including 66 genes and a SNP backbone for copy-number variation detection was designed and applied to the remaining samples of the validation cohort. In total, 519 patients were investigated, of which 415 received intensive induction treatment, typically containing a combination of cytarabine and anthracyclines.ResultsIn the exploration cohort, the most frequently mutated gene was TP53 (33%), followed by epigenetic regulators (DNMT3A, KMT2C, IDH2) and signaling genes (NRAS, PTPN11). Thirty percent of 519 patients harbored ≥ 1 mutation in genes located in commonly deleted regions of chr7—most frequently affecting KMT2C (16%) and EZH2 (10%). KMT2C mutations were often subclonal and enriched in patients with del(7q), de novo or core-binding factor AML (45%). Cancer cell fraction analysis and reconstruction of mutation acquisition identified TP53 mutations as mainly disease-initiating events, while del(7q) or −7 appeared as subclonal events in one-third of cases. Multivariable analysis identified five genetic lesions with significant prognostic impact in intensively treated AML patients with abn(7). Mutations in TP53 and PTPN11 (11%) showed the strongest association with worse overall survival (OS, TP53: hazard ratio [HR], 2.53 [95% CI 1.66–3.86]; P < 0.001; PTPN11: HR, 2.24 [95% CI 1.56–3.22]; P < 0.001) and relapse-free survival (RFS, TP53: HR, 2.3 [95% CI 1.25–4.26]; P = 0.008; PTPN11: HR, 2.32 [95% CI 1.33–4.04]; P = 0.003). By contrast, IDH2-mutated patients (9%) displayed prolonged OS (HR, 0.51 [95% CI 0.30–0.88]; P = 0.0015) and durable responses (RFS: HR, 0.5 [95% CI 0.26–0.96]; P = 0.036).ConclusionThis work unraveled formerly underestimated genetic lesions and provides a comprehensive overview of the spectrum of recurrent gene mutations and their clinical relevance in AML with abn(7). KMT2C mutations are among the most frequent gene mutations in this heterogeneous AML subgroup and warrant further functional investigation.

Patients with TP53-Mutated Acute Myeloid Leukemia Receiving Intensive Induction Therapy Have Superior Outcomes Due to a Higher Rate of Salvage Therapy: A Single Institution, Retrospective Study.

TP53 mutations (TP53m) define the most treatment-refractory acute myeloid leukemia (AML) subtype. Optimal treatment approaches have not been established in this setting. We reviewed our institutional experience to identify therapy sequencing, treatment response, and survival patterns in these patients. This study was a single-center, retrospective cohort analysis. Our cohort includes 86 TP53m and 337 TP53 wild-type (TP53wt) adult AML patients. TP53m AML patients presented with lower bone marrow and peripheral blasts; none presented with hyperleukocytosis. Patients who received intensive treatment up front demonstrated superior overall survival (OS) over those receiving first-line non-intensive therapy (2-year OS 22% versus 7%; p = 0.02). However, the complete remission (CR) rates among the first-line intensive and non-intensive therapy groups were comparable (21.9% and 29.4%, respectively, p = 0.49). The improved OS is therefore attributed to superior cumulative CR in the intensive group. First-line intensively treated patients were more likely to receive and respond to salvage, leading to a cumulative CR rate of 65.7% (versus 29.4%, p = 0.003). Achieving CR at any point is strongly associated with superior survival outcomes with 2-year OS of 31% versus 0% for those not achieving CR ever (p < 0.01). We find that TP53m AML rarely presents with oncological emergencies, suggesting that clinical trial enrollment is feasible in this group. Additionally, in our cohort, intensive induction therapies lead to superior survival outcomes attributed to successful salvage therapy. These data suggest that strategic therapy sequencing and salvage therapy may be important in optimizing outcomes for TP53m AML patients.

Care Patterns and Barriers to Outpatient Care for Adults With AML Following Intensive Chemotherapy at NCCN Member Institutions.

Prolonged hospitalization following intensive (re)induction chemotherapy for acute myeloid leukemia (AML), while standard, is costly and resource intense, limits inpatient bed capacity, and negatively impacts quality of life. Early hospital discharge (EHD) following completion of chemotherapy has proven safe as an alternative at select institutions, but is not widely implemented. From February 2023 through May 2023, the NCCN Best Practices Committee conducted a survey evaluating AML hospitalization patterns, care models, and barriers to EHD at its 33 member institutions. A total of 30 (91%) institutions completed the survey; two-thirds treat >100 patients with AML annually and 45% treat more than half of these with intensive chemotherapy. In the (re)induction setting, 80% of institutions keep patients hospitalized until blood count recovery, whereas 20% aim to discharge patients after completion of chemotherapy if medically stable and logistically feasible. The predominant reasons for the perceived need for ongoing hospitalization were high risk of infection, treatment toxicities, and lack of nearby/accessible housing. There was no significant association between ability to practice EHD and annual AML volume or treatment intensity patterns (P=.60 and P=.11, respectively). In contrast, in the postremission setting, 87% of centers support patients following chemotherapy in the outpatient setting unless toxicities arise requiring readmission. Survey responses showed that 80% of centers were interested in exploring EHD after (re)induction but noted significant barriers, including accessible housing (71%), transportation (50%), high toxicity/infection rate (50%), high transfusion burden (50%), and limited bed availability for rehospitalization (50%). Hospitalization and care patterns following intensive AML therapy vary widely across major US cancer institutions. Although only 20% of surveyed centers practice EHD following intensive (re)induction chemotherapy, 87% do so following postremission therapy. Given the interest in exploring the EHD approach given potential advantages of EHD for both patients and health care systems, strategies to address identified medical and logistical barriers should be explored.

Real-World Treatment Patterns and Clinical Outcomes in Unfit AML Patients: Results of Current Retrospective Study in Romania

Aim: The incidence of acute myeloid leukemia (AML) increases along with the aging population and its prognosis worsens with increasing age. Limited data is available on the real-world survival, clinical outcomes, and treatment patterns in Romanian AML patients unfit for intensive chemotherapy. Given the rapidly changing AML treatment landscape, this retrospective chart review aimed to understand historical AML treatment pathways, their associated outcomes, and the economic impact. Material and methods. Adult patients across Romania with primary or secondary AML, ineligible for intensive induction chemotherapy, for whom the first-line systemic therapy (FLST) or best supportive care (BSC) was initiated between January 2015 and December 2018 were evaluated. The outcomes assessed included overall survival (OS), progression-free survival (PFS), response rates and healthcare resource utilization (HRU). Results. Of the 98 patients included, 85.7% received FLST and 14.3% received BSC as first-line therapy. The median OS was 10.0 months in those who received a hypomethylating agent as FLST and 3.4 months in the BSC group. Median PFS was 8.0, 6.4, and 3.4 for hypomethylating agents and low-dose cytarabine as FLST, and BSC, respectively. During the first line therapy the best response was stable disease and was achieved in 20.2% of the FLST patients and 14.3% of the BSC patients. HRU was generally numerically higher in patients with FLST as compared to the ones who received BSC as first-line therapy. Conclusion. The survival and outcomes of unfit AML patients in Romania remain poor highlighting the unmet need for effective treatment options in this population.