Intensive Chemotherapy In Patients Research Articles

Study of the intestinal microbiota composition and the effect of treatment with intensive chemotherapy in patients recovered from acute leukemia

A dataset comprising metagenomes of outpatients (n = 28) with acute leukemia (AL) and healthy controls (n = 14) was analysed to investigate the associations between gut microbiota composition and metabolic activity and AL. According to the results obtained, no significant differences in the microbial diversity between AL outpatients and healthy controls were found. However, significant differences in the abundance of specific microbial clades of healthy controls and AL outpatients were found. We found some differences at taxa level. The relative abundance of Enterobacteriaceae, Prevotellaceae and Rikenellaceae was increased in AL outpatients, while Bacteirodaceae, Bifidobacteriaceae and Lachnospiraceae was decreased. Interestingly, the abundances of several taxa including Bacteroides and Faecalibacterium species showed variations based on recovery time from the last cycle of chemotherapy. Functional annotation of metagenome-assembled genomes (MAGs) revealed the presence of functional domains corresponding to therapeutic enzymes including l-asparaginase in a wide range of genera including Prevotella, Ruminococcus, Faecalibacterium, Alistipes, Akkermansia. Metabolic network modelling revealed potential symbiotic relationships between Veillonella parvula and Levyella massiliensis and several species found in the microbiota of AL outpatients. These results may contribute to develop strategies for the recovery of microbiota composition profiles in the treatment of patients with AL.

Comparing the Efficacy and Safety of Venetoclax Combined with Decitabine Versus Conventional Chemotherapy As Induction Therapy for Young Adults with Newly Diagnosed Acute Myeloid Leukemia - Interim Analysis of a Multicenter, Randomized, Phase 2b Trial

Introduction: Venetoclax in combination with hypomethylating agents (HMAs) is a first-line induction regimen recommended by NCCN guidelines for older or unfit AML patients. In a phase 2 study (NCT04752527) from our group, venetoclax plus decitabine (VEN-DAC) resulted in a 93% of response rate in young adult patients with newly diagnosed (ND) ELN adverse-risk AML. Currently, there is a lack of data on the VEN-DAC regimen in ND young adults with favorable or intermediate risk AML who are fit for intensive chemotherapy. There are also no studies directly comparing the VEN-DAC regimen with intensive chemotherapy in patients with ND AML. Here, we report the results of an interim analysis of a multicenter, randomized, phase 2b trial (NCT05177731) , which explored the efficacy and safety of VEN-DAC versus intensive chemotherapy (idarubicin and cytarabine) in ND AML patients. Methods: Adult patients with newly diagnosed AML aged between 18 and 59 years were enrolled. The diagnosis was made according to the WHO 2016 criteria. Risk stratification was performed according to the 2017 ELN recommendations. Eligible patients were randomized in a 1:1 ratio to the VEN-DAC group (decitabine 20mg/m 2 on days 1-5 and venetoclax at an escalated dose of 100mg, 200mg and 400mg by day 28) or the IA-12 group (idarubicin 12mg/m 2 on days 1-3 and cytarabine 100mg/m 2 on days 1-7). Patients who did not respond to the treatment were allowed to receive another cycle of the original induction regimen. Intermediate-dose cytarabine (2g/m 2, q12h, days 1-3) were applied as consolidation therapy. The primary endpoint was the composite complete remission (CRc, including complete remission, CR and complete remission with incomplete hematologic recovery, CRi). The secondary endpoints included measurable residual disease (MRD) negative remission (defined as <1×10 -3 by flow cytometry), event-free survival (EFS) , overall survival (OS) and adverse events. Results: Since March, 2022, a total of 163 patients with AML were screened and 116 patients were randomized. Sixty patients received the VEN-DAC regimen and 55 patients received the IA-12 regimen. There were no differences in baseline characteristics between the two groups of patients (Table 1). Bythe cut-off date of July 11, 2023, a total of 102 patients have been evaluated, 55 in the VEN-DAC group and 47 in the IA-12 group. The overall CRc rate in the VEN-DAC group was 85.5%, which was comparable to that of the IA-12 group (78.7%, P=0.37). The MRD-negative CR rate in the VEN-DAC group was 67.3%, which was much higher than that in the IA-12 group (53.2%) ( P=0.147). According to univariate analysis, efficacy of the VEN-DAC regimen did not differ from that of the IA-12 regimen with respect to sex, age, initial bone marrow blast count, genetic risk category, and major molecular markers (Figure 1A). Notably, the CRc rate and MRD-negative CR rate were significantly higher in the VEN-DAC group than in the IA-12 group for intermediate-risk and adverse-risk patients, especially those with adverse risk ( P=0.031 for CRc, P=0.029 for MRD-negative CR) (Figure 1A). At median follow-ups of 7.8 months (range, 0.9-16.6), the EFS and OS were not reached in both groups. The median time for platelets to recovery to 20×10 9/L or above in the VEN-DAC group was 12 days after induction in the VEN-DAC group, which was shorter than that in the IA-12 group (21 days) ( P<0.01). In addition, patients in the VEN-DAC group required fewer platelet (5 U vs 7 U, P<0.01) and red blood cell infusions (3 U vs 5 U, P=0.023) during induction as compared with that in the IA-12 group. In addition, the incidence of grade 3 or higher febrile neutropenia (41.8% vs. 83.0%), infection (27.3% vs. 72.3%) and sepsis (5.5% vs. 31.9%) were all significantly lower in the VEN-DAC group than in the IA-12 group ( P<0.01) (Figure 1B). Conclusion: In newly diagnosed young AML patients, venetoclax in combination with decitabine as an induction regimen had comparable efficacy and a higher safety profile compared to IA-12 regimen. In particular, patients with adverse-risk AML showed higher and deeper remission rate in the venetoclax plus decitabine group as compared with the IA-12 group.

Venetoclax and Azacitidine for Molecular Relapse during First Line Intensive Chemotherapy in Patients with NPM1 Mutated or Core Binding Factor (CBF) AML. a Study from the Dataml Registry

Introduction: Molecular follow-up (FU) for AML patients (pts) with NPM1 mutation, RUNX1::RUNX1T1 or CBFB::MYH11 fusion transcripts has been established over the last ten years. Real-time quantitative PCR (qPCR) is the gold standard for the evaluation of measurable residual disease (MRD) in pts undergoing intensive chemotherapy (IC). Failure to achieve a deep molecular response is a strong predictive factor of relapse and survival and may guide post remission therapy (Ivey A, NEJM 2016). Moreover, the ELN MRD working party recommended a schedule for molecular FU and recently established a definition of molecular relapse (Heuser M, Blood 2021). However, there is no therapeutic consensus for pts with molecular relapse before overt clinical relapse. Frontline allogeneic hematopoietic cell transplantation (alloHCT), salvage IC or even waiting for morphological relapse in order to screen molecular characteristics of the relapsing disease or propose a clinical trial, may be discussed with pts. Venetoclax with azacitidine (VEN/AZA) was recently approved in unfit AML pts and demonstrated a particular efficacy in NPM1-mutated AML. In this study, we thought to describe the safety and efficacy of VEN/AZA in pts with NPM1 mutated or CBF AML in molecular relapse after first line IC. Methods: Pts of the DATAML registry with the following criteria were included in this study : AML with NPM1 mutation, RUNX1::RUNX1T1 or CBFB::MYH11 transcripts, first line IC, morphological complete remission (CR), no alloHCT in first line, regular monitoring of MRD by qPCR in bone marrow (BM) and/or blood, molecular relapse defined according to ELN2021 guidelines on two successive samples, at least one cycle of VEN/AZA. Pts with molecular relapse followed by morphological relapse before VEN/AZA or those who relapsed after alloHCT were not included. Treatment: First line IC was cytarabine 200 mg/m² d1-7 with idarubicin 9mg/m²/d1-5 or daunorubicin 90mg/m²/d1-3 in pts 18-60y or cytarabine 100 mg/m² d1-7 with idarubicin 8mg/m²/d1-5 and lomustine 200 mg/m²/d1 in pts > 60y. Post remission therapy was intermediate or high dose cytarabine or mini-consolidations according to age and performance status. Midostaurin was added in FLT3-mutated pts. At time of molecular relapse, pts received off label venetoclax 400 mg/d (d1-14, d1-21 or d1-28 according to centers) with no ramp-up and azacitidine 75 mg/m²/d subcutaneously (d1-5, d8-9). Antifungal/antibiotic prophylaxis and G-CSF use were not systematically recommended. Results: Twenty-two pts treated with VEN/AZAfrom 21/09/2020 to30/03/2023 were included. Their characteristics at diagnosis were: female (n= 14), median age 55y (range 27-71), de novo AML (n=21), median WBC (68 giga/L, range 2.32-339.7), NPM1 mutation (n=20), CBFB::MYH11 (n=2), FLT3 mutation (n=13). All pts achieved first CR after one cycle of induction chemotherapy. Pts received a median of three consolidation cycles. All but three pts had negative MRD or low level MRD (LL-MRD) in blood and/or BM at the end of consolidation. The median time between CR1 and molecular relapse was 9.5 months (range, 1-50). The median time between molecular relapse and first VEN/AZA cycle was 51 days. During first cycle of VEN/AZA, 12, 5 and 5 pts received 14, 21 or 28 days venetoclax, respectively; 19 were treated as out-pts, 4 received posaconazole and GCSF was used in 11 pts. 12 and 3 pts had grade 3-4 neutropenia or febrile neutropenia (FN), respectively. Only 3 pts (14%) were hospitalized for FN. The median number of VEN/AZA cycles was 2 (range 1-12). After C1+/-C2, 10 (45%) and 11 pts (55%) had undetectable or LL MRD in blood, respectively (Fig1). 20 pts were bridged to alloHCT in morphological CR after a median of 2 cycles (range, 1-4). Only one pt had a molecular progression before transplantation after 2 cycles. Two pts died, one had a molecular relapse after 7 cycles and progress rapidly to frank relapse, the other one died of post-transplant complication while in CR with undetectable MRD. All other pts remained in CR at date of last news. With a median FU from D1C1 of 13.5 months, median OS wat not reached and 1y-OS was 86% (Fig2). Conclusion: In the setting of molecular relapse, VEN/AZA is safe, prevent overt relapse, and induce a high rate of molecular response before alloHCT. Molecular relapse becomes a major therapeutic challenge. Clinical trial endpoints should include the treatment of molecular relapse as an event for RFS and EFS estimation.

Association between Molecular Profile and Outcome after Intensive Chemotherapy in Patients > 60 Years with Adverse Cytogenetic Risk and/or Secondary Acute Myeloid Leukemia - a Filo Study

Background: Recognizing the prognostic importance of genetic characteristics rather than clinical history, secondary acute myeloid leukemia (AML), i.e., arising from prior cytotoxic therapy and/or an antecedent hematologic disorder (AHD), is now considered a diagnostic qualifier rather than a separate disease entity (Döhner, Blood 2022). To assess the relationship between clinical history and/or adverse cytogenetics and outcome, we report herein the molecular profile of AML patients >60 years with secondary AML and/or adverse cytogenetics included in a multicentric prospective trial. Methods: Fit patients >60 years with secondary AML and/or adverse cytogenetics according to the European LeukemiaNet, included in the Rev-5-Aza trial (NCT01301820), received induction therapy with lomustine 200 mg/m 2 day 1, idarubicin 8 mg/m 2 days 1-5, and cytarabine 100 mg/m 2 days 1-7. Patients in complete remission (CR) after one induction cycle received consolidation therapy with 12 cycles of alternating azacitidine 75 mg/m 2 days 1-7 and lenalidomide 10 mg days 1-21 every 28 days (Hunault-Berger M, Blood Cancer J 2017). Mutational profile was determined by targeted sequencing of complete coding regions, including splice sites, of 77 genes recurrently mutated in myeloid malignancies using custom SureSelect QXT capture system (Agilent, Santa Clara, CA, USA) on NextSeq500 platform (Illumina, San Diego, CA, USA). As a validation cohort, we determined the molecular profile of 73 patients with adverse cytogenetic risk and/or secondary AML in first CR after the same induction therapy but who received standard chemotherapy consolidation with 6 cycles of idarubicin 8 mg/m 2 day 1 and cytarabine 50 mg/m 2/12 hours days 1-5. Results: Between March 2011 and February 2013, 117 fit patients >60 years included in the Rev-5-Aza trial received induction therapy with 56% reaching first CR and four patients undergoing allogeneic hematopoietic cell transplantation. The molecular profile could be established in 97 of these patients (83%; median age 70 years, interquartile range (IQR): 65-73; therapy-related AML, 32%; AHD, 46%; adverse cytogenetic risk, 70%). Secondary-type mutations were the most frequently observed (49%; ASXL1, 12%; BCOR, 16%; EZH2, 2%; RUNX1, 18%; SF3B1, 8%; SRSF2, 14%; STAG2, 10%; U2AF1, 8%; and ZRSR2, 0%) followed by TP53 mutations (44% of patients). Patients with TP53 mutations were more likely to have adverse risk cytogenetics (95%) in comparison to patients with secondary-type mutations (64%). No clinical or biological characteristic was associated with the achievement of CR (secondary-type mutations, 51%, TP53 mutation, 49%). Clinical history was not associated with overall survival (OS) as patients with therapy-related AML had the same outcome as other patients (hazard ratio [HR]=1.04, P=0.9) and patients with AHD had a more favorable outcome (HR=0.57, P=0.02). On the other hand, adverse cytogenetics was associated with decreased OS (HR=3.32, P<0.001). Whereas TP53 mutations were associated with decreased OS (HR=3.71, P<0.001), secondary-type mutations were not (HR=0.64, P=0.049; Figure A). After multivariable analysis, both complex karyotype (CK; HR=0.006, P=0.006) and TP53 mutations (HR=2.12, P=0.03) were independently associated with OS. Considering both CK and TP53 mutations identified three groups of patients with differential OS (median 1.57 vs. 0.91 vs. 0.45 years, P<0.001; Figure B). Similar results were observed in the validation cohort. Patients in first CR from both cohorts were then compared to identify molecular subgroups for which a lenalidomide/azacitidine consolidation was associated with improved OS in comparison to standard chemotherapy. No molecular subgroup had increased OS with lenalimomide/azaciditine consolidation while standard chemotherapy was associated with improved outcomes in patients with adverse risk cytogenetics. Conclusion: Together, these data suggest that the clinical history contains limited prognostic value compared to genetics, supporting the most recent approach to use cytogenetic and molecular data to assess disease risk. In this patient population, complex karyotype and TP53 mutations, rather than secondary-type mutations, were associated with outcome. Figure. (A) Overall survival according to secondary-type and TP53 mutations status. (B) Overall survival according to complex karyotype (CK) and T P53 mutation status.

Real-World Outcomes Using Front-Line Midostaurine in Combination with Intensive Chemotherapy for Patients Aged ≥ 60 Years Old with FLT3 Mutated Acute Myeloid Leukemia

BACKGROUND: The prognosis of patients with acute myeloid leukemia (AML) varies depending on the presence of mutations in the FLT3 tyrosine kinase. Internal tandem duplications (ITD) and mutations in the tyrosine kinase domain (TKD) result in continuous activation of FLT3, leading to uncontrolled blast proliferation. Since the publication of the clinical trial CALGB 10603 (RATIFY), it has been established that adding midostaurine to intensive chemotherapy improves the overall survival (OS) of patients with mutated FLT3. However, it is worth noting that this study only included patients 18-59 years old. Subsequently, a phase II clinical trial (AMLSG 16-10 trial) conducted a subgroup analysis suggesting that midostaurine may also benefit to patients between 60 and 70 years of age. Nevertheless, these findings have not been studied in real-world clinical practice. METHODS : This is multicentric non-interventional retrospective real-world study including patients ≥60 years of age with newly diagnosed FLT3-mutated AML treated with intensive chemotherapy and midostaurine (50 mg orally twice daily, d8-22) between 1st 2017 and July, 30 th 2021 from the French Innovate Leukemia Organization (FILO) and the Programa Español de Tratamientos en Hematología (PETHEMA). The primary objective was to evaluate the efficacy of midostaurine in combination with intensive chemotherapy in patients over 60 years old. We assessed the rate of complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) after induction therapy, OS and event-free Survival (EFS). RESULTS: A total of 191 patients (FILO Group 122 (63.9%); PETHEMA Group 69 (36.1%)), aged between 60 and 77 years, were enrolled in the study. The patients had a median age of 67.8 years (range 60.1; 77.6). Among them, 134 (70.2%) were aged less than 70 years, while 57 (29.8%) were aged 70 years or older. 159 (83.3%) had a performance status (ECOG) of 1 or lower, while 24 (12.6%) had an ECOG of 2 or higher. 151 (79.1%) had de novo acute myeloid leukemia (AML), and 40 (20.9%) had secondary AML at diagnosis. The median white blood cell count at diagnosis was 26.5 x 10^9/L [5.99; 107]. The median percentage of blasts in the bone marrow at diagnosis was 76% [55; 88.5]. The frequency of FLT3-ITD mutation was 154 (80.6%), FLT3-TKD mutation was 44 (23%), and double mutations were observed in 7 (3.7%) patients. The median FLT3 ITD/wt ratio was 57% [22.5 - 78]. 119 (62.3%) were NPM1 muted. Regarding the intensive chemotherapy schedule in induction, 162 (84.8%) patients were treated with idarubicin-based regimens, 18 (9.4%) with daunorubicin-based regimens, and 8 (4.2%) with CPX-351. After induction, 150 (78.5%) of the patients achieved complete remission/complete remission with incomplete hematologic recovery (CR/CRi). Of those patients, 96 (64%) proceeded to intensive chemotherapy schedule in consolidation, with 83 (86.5%) of them receiving midostaurine. In contrast, 32 (21.3%) received non-intensive chemotherapy consolidation, with 27 (84.4%) receiving midostaurine. Additionally, 37 (24.7%) of the patients who achieved CR/CRi after induction underwent a hematopoietic-cell transplantation (HCT), with 33 (89.2%) undergoing allogeneic HCT and 4 (12.1%) undergoing autologous HCT. The median follow-up of the patients was 32 months. OS for the entire population was 23 months with a 2-years OS of 49.1% (95%CI: 41.5-56.7). Median EFS for the entire population was 11.1 months with a 2-years EFS of 37.1%. (95%CI: 29.6-44.5). For patients undergoing allogeneic HCT after achieving CR/CRi following induction, the median OS was not reached, with a 2-year OS of 69% (95% CI: 54.6-88.3). In contrast, for patients who achieved CR/CRi after induction but did not undergo allogeneic HCT, the OS was 32.6 months with a 2-year OS of 50.2% (95% CI: 48.4-68.2). CONCLUSIONS: This real-life study suggests that the addition of midostaurine to intensive chemotherapy regimens in elderly patients could result in acceptable CRc, OS and EFS. In order to establish the benefit of midostaurin, we will compare these results with a historical control cohort.

Maintenance therapy with a combination of azacitidine, danazol, and thalidomide after intensive chemotherapy in patients with acute myeloid leukemia

ABSTRACTObjectiveThis study aimed to evaluate the efficacy of azacitidine (AZA) combined with danazol (DNZ) and thalidomide (THD) maintenance therapy after intensive chemotherapy (IC) in patients with acute myeloid leukemia (AML).Methodswe retrospectively analyzed the clinical data of 11 patients treated with AZA combined with DNZ and THD as maintenance therapy after IC at the Baiyun Hospital were between February 2017 and March 2021. The patients' clinical features, relapse-free survival (RFS), and overall survival (OS) were analyzed.ResultsEleven cases fulfilled the AML criteria per the 2016 World Health Organization classification. Of the 11 patients, five were females, and six were males, with a median age of 45 years (range, 23-65 years). Ten patients were in the first complete remission (CR1), and one patient was in the second complete remission (CR2). All patients received AZA combined with DNZ and THD maintenance therapy after IC. The median number of AZA cycles received was 7 (6-12). Until June 2022, the median follow-up period was 37 (14-63) months; one patient had a relapse, and three died. RFS at 1 year and 3 years was 100% and 71.1%, respectively, and OS at 3 years was 100%.ConclusionAZA combined with DNZ and THD maintenance therapy is effective for patients with AML who are ineligible for allogeneic hematopoietic stem cell transplantation. Further studies with large sample sizes and randomized are needed to verify these findings.

Invasive Fungal Infection Mimicking Infarctions in a Child with Acute Lymphoblastic Leukemia

Invasive fungal infection is a major cause of morbidity and mortality after intensive chemotherapy in patients with leukemia who present with febrile neutropenia. The most common sites of involvement are the lungs, sinonasal region, and disseminated blood stream infection. Visceral organ involvement is usually seen in the form of fungal abscesses, with parenchymal infarcts being less common. We report an unusual case of invasive fungal infection presenting with extensive liver infarction, global renal infarction, and multiple brain lesions in a 4-year-old boy with acute lymphoblastic leukemia on induction chemotherapy.

Gemtuzumab Ozogamicin Plus Intensive Chemotherapy for Patients with NPM1-Mutated Acute Myeloid Leukemia

Gemtuzumab Ozogamicin Plus Intensive Chemotherapy for Patients with NPM1-Mutated Acute Myeloid Leukemia

Risk-adapted local therapy and intensive chemotherapy in patients with high-risk rhabdomyosarcoma.

10031 Background: Outcomes for patients with metastatic RMS remain poor. Dose escalation of radiation may reduce risk of local failure, and maintenance therapy has prolonged survival in intermediate risk patients. We investigated a multimodal chemotherapeutic regimen with risk adapted local therapy and the addition of maintenance therapy following intensive chemotherapy to improve the outcome for patients with high-risk RMS. Methods: We conducted a phase 2 multi-center trial for patients with newly diagnosed high-risk (stage 4) RMS. Patients received 54 weeks of chemotherapy (vincristine/irinotecan, interval compressed vincristine/doxorubicin/cyclophosphamide and ifosfamide/etoposide, and vincristine/dactinomycin/cyclophosphamide) followed by 4 cycles of anti-angiogenic maintenance therapy (bevacizumab, sorafenib, cyclophosphamide). Primary tumor local control consisted of surgery and photon/proton radiation therapy (RT) dependent on the degree of resection (negative margin – no RT, positive margin – 36 GyRBE, unresected ≤5cm – 50.4 GyRBE, unresected > 5cm – 59.4 GyRBE). RT was administered at Week 4 or 20 based on size/location, and to radiographically visible (non-CR) sites of metastatic disease at end of treatment. Results: Thirty-nine eligible patients with high-risk RMS (64% FOXO1 fusion positive, 74% with nodal disease, 67% Oberlin score > 1) were enrolled. Two of 13 patients with Oberlin score ≤ 1 were FOXO1 fusion positive whereas 23 of 26 patients with Oberlin score > 1 were fusion positive. Seventeen patients received maintenance therapy as planned (progression, n = 12; received alternate maintenance regimen, n = 4; other, n = 6) with a median of 4 cycles (range 1-4). Common toxicities of maintenance included palmar-plantar erythrodysesthesia (n = 9), rash (n = 7), and cystitis (n = 6). At a median follow-up of 43.5 months for survivors, 3-year EFS was 29.5% (95% CI 15.4-45.1%). Fusion positive status significantly predicted EFS (negative, 60.6% vs. positive, 9.6%, p = 0.019), whereas low Oberlin score approached significance for EFS (≤1, 56.6% vs. > 1, 16.4%, p = 0.064). The cumulative incidence of local failure was 17.5% (95% CI 6.9-32.2%). Twenty-one patients achieved CR of all metastatic sites and did not receive metastatic site RT. Of those, 7 experienced disease recurrence in a pre-existing metastatic soft tissue site. Among 4 patients who received metastatic site RT at the end of treatment, one patient experienced disease recurrence in a pre-existing metastatic site. Conclusions: The addition of maintenance therapy to intensive chemotherapy and risk adapted radiotherapy did not improve EFS in this population. Consolidative radiation should be considered for soft tissue metastatic sites regardless of radiographic response. Clinical trial information: NCT01871766.

Prediction of survival with intensive chemotherapy in acute myeloid leukemia.

Progress with intensive chemotherapy and supportive care measures has improved survival in newly diagnosed acute myeloid leukemia (AML). Predicting outcome helps in treatment decision making. We analyzed survival as the treatment endpoint in 3728 patients with newly diagnosed AML treated with intensive chemotherapy from 1980 to 2021. We divided the total study group (3:1 basis) into a training (n=2790) and a validation group (n=938). The associations between survival and 27 characteristics were investigated. In the training cohort, the multivariate analysis identified 12 consistent adverse prognostic variables independently associated with worse survival: older age, therapy-related myeloid neoplasm, worse performance status, cardiac comorbidity, leukocytosis, anemia, thrombocytopenia, elevated creatinine and lactate dehydrogenase, cytogenetic abnormalities, and the presence of infection at diagnosis except fever of unknown origin. We categorized patients into four prognostic groups, favorable (7%), intermediate (43%), poor (39%), and very poor (11%) with estimated 5-year survival rates of 69%, 36%, 13%, and 3% respectively (p < .001). The predictive model was validated in an independent cohort. In a subset of patients with molecular mutation profiles, adding the mutation profiles after accounting for the effects of previous factors identified NPM1 (favorable), PTPN11, and TP53 (both unfavorable) mutations as molecular prognostic factors. The new proposed predictive model for survival with intensive chemotherapy in patients with AML is robust and can be used to advise patients regarding their prognosis, to modify therapy in remission (e.g., proposing allogeneic stem cell transplantation in first remission), and to compare outcome and benefits on future investigational therapies.

ELN 2017 classification significantly impacts the risk of early death in acute myeloid leukemia patients receiving intensive induction chemotherapy.

Early mortality remains a challenging therapeutic facet of the initial induction phase of intensive chemotherapy in patients with acute myeloid leukemia (AML). The impact of standard molecular evaluation and risk category of the European LeukemiaNet (ELN) 2017 classification model on early mortality has not been rigorously evaluated thus far. We reviewed the medical records of 320 consecutive adult patients with newly diagnosed AML treated with intensive induction chemotherapy in our center from 2007 to 2021. The median age was 56years; 33 patients (10%) died during induction. Patient age, white blood cell count, hemoglobin level, platelet level, creatinine, uric acid, lactate dehydrogenase serum levels, and FLT3-ITD and CEBPA mutational status did not significantly impact early mortality. NPM1mut patients had a lower likelihood of early death compared to NPM1wt (5% versus 13%; p = 0.023) whereas patients with high-risk cytogenetic studies experienced higher rates of induction mortality compared with intermediate and favorable risk patients (20% versus 8 and 7%, respectively; p = 0.049). Adverse risk ELN 2017 was significantly more likely to die during induction compared with intermediate and favorable risk patients (20% versus 10 and 4%, respectively; p = 0.001). Patients treated in 2007-2011 experienced a significantly higher rate of induction death compared with patients in 2012-2021 (17% versus 8%; p = 0.039). Multivariate analysis confirmed adverse ELN 2017 [odds ratio (OR), 6.7; 95% confidence interval (CI), 1.74-25.3; p = 0.006) and treatment timeframe (OR, 0.35; 95% CI, 0.14-0.85; p = 0.019) as pivotal predictors of early mortality. ELN 2017 is a robust prognosticator of early mortality in intensively treated AML patients.

A national Danish proof of concept on feasibility and safety of home -based intensive chemotherapy in patients with acute myeloid leukemia

Technological advances have made it possible to offer home-based chemotherapy to patients without health care professionals being present. Prior studies on effects of home-based treatment lack inclusion of patients with hematologic malignancies. We present data from a multicenter single-arm feasibility and safety study of home-based intensive chemotherapy in patients with newly diagnosed acute myeloid leukemia and their quality of life and psychological wellbeing. This national study included patients from six sites in Denmark who received intensive chemotherapy on programmed CADD Solis infusion pumps through a central venous catheter and were also managed as outpatients during treatment-induced pancytopenia. Data are presented from 104 patients, receiving 272 treatments with 1.096 (mean 4.57, SD 3.0) home infusion days out of 1.644 treatment days (67 %). Sixty-two of 168 (36.9 %) reinduction and consolidation treatment cycles ensuing pancytopenia phases were solely handled in the outpatient clinic. Patients reported high satisfaction with home-based treatment, which had a positive influence on their ability to be involved in their treatment and be socially and physically active. No unexpected events occurred during the intervention. Overall, patients improved in all quality of life outcomes over time. Home-based intensive chemotherapy treatment was feasible and safe in this population.ClinicalTrials.gov identifier: NCT04904211.

Updated Survival and Response Analyses from a Phase 1 Study of Ivosidenib or Enasidenib Combined with Induction and Consolidation Chemotherapy in Patients with Newly Diagnosed AML with an IDH1 or IDH2 Mutation

Updated Survival and Response Analyses from a Phase 1 Study of Ivosidenib or Enasidenib Combined with Induction and Consolidation Chemotherapy in Patients with Newly Diagnosed AML with an IDH1 or IDH2 Mutation

ELN 2017 Classification Significantly Impacts on the Risk of Early Death in Acute Myeloid Leukemia Patients Receiving Intensive Induction Chemotherapy

Background. Early mortality remains a challenging therapeutic facet of the initial induction phase of intensive chemotherapy in patients with acute myeloid leukemia (AML). The impact of standard molecular evaluation and risk category of the European LeukemiaNet (ELN) 2017 classification model on early mortality have not been rigorously evaluated thus far.Aim. Evaluate the impact of standard clinical, laboratory, cytogenetic, and molecular parameters on the likelihood of early death following induction chemotherapy in a cohort of uniformly treated AML patients receiving standard intensive induction chemotherapy.Methods. We reviewed the medical records of 320 consecutive adult patients with newly diagnosed AML treated with intensive induction chemotherapy in our center from 2007 to 2021. The Kaplan-Meier method was used to determine overall survival and the log-rank test was used to compare differences between groups. All tests were two-sided and a p-value < 0.05 was considered statistically significant.Results. From October 2007 to January 2021, 320 adult patients with AML were treated with standard anthracycline and cytarabine-based intensive induction chemotherapy . Median age was 56 years (range, 18 to 92); 33 patients (10%) died during induction. As outlined in table 1, patient age, white blood cell count, hemoglobin level, platelet level, creatinine, uric acid, lactate dehydrogenase serum levels, FLT3-ITD and CEBPA mutational status did not significantly impact on early mortality. NPM1 mut patients had a lower likelihood of early death compared to NPM1 wt (5% versus 13%; p=0.023) whereas patients with high-risk cytogenetic studies experienced higher rates of induction mortality compared with intermediate and favorable risk patients (20% versus 8% and 7%, respectively; p=0.049). Adverse risk ELN 2017 were significantly more likely to die during induction compared with intermediate and favorable risk patients (20% versus 10% and 4%, respectively; p=0.001). Patients treated in 2007-2011 experienced a significantly higher rate of induction death compared with patients in 2012-2021 (17% versus 8%; p=0.039). Multivariate analysis confirmed adverse ELN 2017 [odds ratio (OR), 6.7; 95% confidence interval (CI), 1.77-25.3; p=0.005) and treatment timeframe (OR, 0.36; 95% CI, 0.15-0.87; p=0.023) as pivotal predictors of early mortality.Conclusion. Our data underscore the tight association of the ELN 2017 risk model with early induction mortality in AML patients receiving intensive induction chemotherapy. With the introduction of novel agents as well as innovative regimens combining these agents, it is becoming clear that better prognostic tools are needed at the provider level to navigate the rapidly changing therapeutic landscape seen in current management of AML patients. Our findings further underpin the importance of integrated prognostication models and their profound implications on the immediate peri-induction setting in AML patients. [Display omitted] DisclosuresAvigdor: Gilead: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS: Research Funding; Janssen: Research Funding; Takeda: Consultancy, Honoraria.

Palliative care and coping in patients with acute myeloid leukemia: Mediation analysis of data from a randomized clinical trial.

It has been shown previously that integrated palliative care for patients with acute myeloid leukemia (AML) during intensive chemotherapy leads to improvements in quality of life (QOL) and mood. Coping has been shown to mediate palliative care interventions in advanced cancer; the mechanisms by which improvements occur among patients with AML remain unexplained. The authors conducted a secondary analysis of data from a multisite randomized trial of integrated palliative and oncology care (IPC; n = 86) versus usual care (n = 74) for hospitalized patients with AML undergoing intensive chemotherapy. IPC patients met with palliative care at least twice weekly during their initial and subsequent hospitalizations. Patients completed the Functional Assessment of Cancer Therapy-Leukemia, the Hospital Anxiety and Depression Scale, and the Brief Coping Orientation to Problems Experienced Inventory to assess QOL, mood, and coping at the baseline and at weeks 2, 4, 12, and 24. Linear regression models were used to assess the effect of IPC on coping. Causal mediation regression models were used to examine whether changes in coping mediated intervention effects on patient-reported outcomes at week 2. One hundred sixty eligible patients (68.1%) were enrolled. Those randomized to IPC reported improvements in approach-oriented coping (P < .01) and reductions in avoidant coping (P < .05). These changes in coping mediated the intervention effects on QOL (95% CI, 2.14-13.63), depression (95% CI, -2.05 to -0.27), and anxiety symptoms (95% CI, -1.25 to -0.04). Changes in approach-oriented and avoidant coping accounted for 78% of the total palliative care intervention effect on QOL, for 66% of the effect on depression, and for 35% of the effect on anxiety symptoms. Palliative care integrated during intensive chemotherapy for patients with AML facilitates coping strategy use. Improvement in coping skills accounts for a substantial proportion of the effect from a palliative care intervention on patient-reported outcomes.

Impact of Oral Voriconazole As Prophylaxis during Intensive Chemotherapy for Adult Patients with Acute Myeloid Leukemia: A Retrospective Cohort Study Using Japanese Administrative Database

BackgroundPrevention of invasive fungal infections (IFIs) during chemotherapy is an important issue for patients with hematologic malignancies. Although preventive effects of antifungal drugs on hematological stem cell transplantation (HSCT) has been reported, the appropriate approach for prophylaxis of IFIs during intensive chemotherapy for patients with acute myeloid leukemia (AML) has been still unclear. To solve this issue, we analyzed the Diagnosis Procedure Combination/Per-Diem Payment System (DPC/PDPS) database instituted by the Ministry of Health, Labour and Welfare of Japan as a payment system for medical services, which contains a large nationwide inpatient administrative data. The objective of this study is to investigate the effectiveness of oral voriconazole (VRCZ) as prophylaxis of IFIs in adult AML patients undergoing intensive chemotherapy.MethodsThis is a retrospective cohort study analyzing data of which were extracted from the DPC database collected from July 2010 to June 2015. The prophylactic usage of oral antifungal drugs is defined as administration of these drugs for more than 3 consecutive days prescribed within 3 days after the onset of chemotherapy. The selection criteria were as follows: patients diagnosed as AML, aged 18 years or older, conducted intensive chemotherapy under aseptic management, and administrated either of oral fluconazole (FLCZ), itraconazole (ITCZ) or VRCZ for the prophylactic usage defined as above. The data for HSCT were excluded. The main analyses were conducted in these 2 groups: the group of patients administrated oral VRCZ, and the other oral azoles (FLCZ or ITCZ). Primary outcome was the intravenous antifungal drug usage within 30 days after the onset of chemotherapy. Subgroup analyses were performed in the following categories: 1) VRCZ group vs FLCZ group/VRCZ group vs ITCZ group; 2) Age < 65/ Age ≥ 65. Secondary outcomes were 1) length of hospital stay, and 2) in-hospital mortality. The log-transformed values were used for analyses of length of hospital stay because its distribution was right-skewed. Panel instrumental variable (IV) method was carried out to address unobserved time-invariant characteristics of individuals, time-variant factors, and the endogeneity due to the unmeasured bias.ResultsA total of 63,197 inpatient data of 923 hospitals for AML patients aged 18 years or older were screened. Finally, 10,083 data of 413 hospitals, including 655 in VRCZ group, 4,445 in FLCZ group, and 4,983 in ITCZ group, were met to the selection criteria. The result of panel IV approach showed that prophylactic administration of oral VRCZ was significantly associated with the reduction of intravenous antifungal drug usage within 30 days after the onset of chemotherapy compared to the other azoles (RD −0.13, 95%CI −0.22 to −0.03, p = 0.012). It was also associated with the shortening the log-transformed value of length of hospital stay compared to the other oral azoles (RD −0.11, 95%CI −0.23 to −0.00, p = 0.043), but not with in-hospital mortality (RD 0.02, 95%CI −0.04 to 0.08, p = 0.513). In the subgroup analyses, prophylactic administration of oral VRCZ was significantly associated with the reduction of intravenous antifungal drug usage compared with FLCZ (RD −0.18, 95%CI −0.28 to −0.08, p < 0.001), but not with ITCZ (RD −0.07, 95%CI −0.16 to 0.34, p = 0.150). When the data was analyzed by age groups, it was significantly associated with the reduction of intravenous antifungal drug usage in patients under the age of 65 (RD −0.18, 95%CI −0.35 to −0.02, p = 0.033), but not in patients aged 65 years or older (RD −0.09, 95%CI −0.22 to 0.04, p = 0.196) compared to the other azoles.ConclusionsBy analyzing the large nationwide database, the present results revealed that the prophylactic administration of oral VRCZ would be effective for reducing the intravenous antifungal drug usage and shortening of hospital stay, which might contribute to reduction of IFIs and improvement of quality of life especially for young AML patients receiving the intensive chemotherapy. DisclosuresYoshida:Bristol-Myers Squibb: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; ONO PHARMACEUTICAL CO., LTD.: Honoraria; Nippon Kayaku Co.,Ltd.: Honoraria.

Response-Adapted Sequential Treatment with Azacitidine and Intensive Chemotherapy in Patients > 60 Years Old with Newly Diagnosed AML: Results of the RAS-Azic Trial of the East German Study Group (OSHO)

▪Age >60 years (y) is independently associated with poorer outcomes in AML. An increasing incidence of s-AML and t-AML as well as age-related genetic abnormalities increase the likelihood of resistance to treatment. After intensive chemotherapy (IC), complete remission (CR/CRi) rates of 48-51% and a day (d) 90 mortality of 19-27% are reported (Niederwieser et al, ASH 2016). In pts >65y, azacitidine (AZA), a hypomethylating agenet, yields CR/CRi rates of 27.8% and a one-year survival (OS) of 46.5% (Dombret et al, Blood 2015). In the RAS-AZIC (DRKS00004519) study, a multicenter, investigator-initiated, combined phase I/II trial, AZA was integrated with IC in an individualized response-based approach in pts >60y with newly diagnosed AML. The rationale was a treatment sequence with a low probability of toxicity and a high probability of efficacy. Outcomes are presented. Patients and methods: In the phase I part, upfront AZA (75 mg/m2/day s.c) for 7 d followed by IC (Mitoxantrone 10 mg/m2/day d 1-3 and cytarabine 1g/m2/BID d1,3,5,7) on d17 was declared admissible through a 3+3 design (n=9). Between June, 2014 and May, 2016, 103 pts received priming with AZA followed by IC or AZA in phase II (Fig. 1) based on bone marrow (BM) blasts d15 (<45 vs >45%) and CR/CRi d56, previousely identified as predictors for long-term response to AZA in AML (Al-Ali et al, Leuk Lymph 2012). AZA maintenance was offered to pts in remission until relapse or allogeneic HCT. Primary objective was d90 response (OR) [CR/CRi/PR] in the 109 pts who received the maximal tolerated priming dose of AZA. Safety, d90 mortality, OS, EFS; RFS were further end points. Protocol treatment was considered non-inferior to standard IC if, on an intention-to-treat basis, an OR >61% was reached. Adverse events (AEs) were reported according to the NCI CTCAE 4.03. All pts gave written informed consent. Results: Median age was 70 (61-85) y. A median of 6 comorbidities/patient were reported [hypertension, n=55 (50%); cardiac disorders, n=47 (43%); diabetes mellitus, n=26 (24%); history of non-myeloid neoplasia, n=22 (20%)]. Median baseline BM blasts and WBC were 50% and 4.3 (range 0.4-153)x109/L respectively. Type of AML was de novo AML (63.3%), s-AML (23.9%), and t-AML (12.8%). Genetic risk according to the 2010 ELN stratification was high in 28%, int-I and II each in 23.4%, favorable in 14%; and not evaluable in 11.2%. All pts received first-line AZA, 90% and 78% of pts received protocol assigned treatment based on d15 BM blasts and d56 response respectively [AZA1+AZA2, n=24 (22%); AZA1+AZA2+IC1, n=30 (27.5); AZA1+ IC1, n=35 (32.2%); AZA1+ IC1+IC2, n=9 (8.3%)]. Hematologic and non-hematologic AEs lead to a postponement of response-adapted IC1 in 5.4% and 8% of pts respectively. Overall, infections were the most frequent non-hematologic AE [> grade 2 in 26.5%, 21%, and 53.5% of pts under AZA1, AZA2, and IC respectively]. Day 90 OR and mortality were 63.3% [CR/CRi 56.9%; PR 6.4%] and 10% respectively. OR was 73%, 80%, 52%, and 50% in favorable, int-I, int-II, and high-risk genetics respectively (p=0.07). One-year OS, EFS, and RFS were 63.8% (95% CI, 55% to 73%), 46% (95% CI, 36% to 55%), and 50% (95% CI, 38% to 62%) respectively. Age, baseline BM blasts, WBC, type of AML, FLT3/NPM1 mutational status,and d15 blasts <45%/>45% had no impact on OR and OS. In pts >75y, OS was 69% compared to 59.3% in pts < 64y (p=0.4). OS and EFS were associated with d90 OR. After a median follow-up of 19.7 months (m), median survival and EFS times for responders were 23.2 and 15.8 vs. 6.7 and 4.7m for non-responders respectively (p<000). High risk genetics were associated with a poorer OS [median survival times were not reached for favorable and int-I; 15.3 and 11.4m in int-II and high risk respectively] (p=0.002). Similar associations were found for EFS (p=0.002) and RFS (p=0.005) (Fig. 2). Conclusion: With a response-adapted approach in elderly patients with AML, favorable outcomes with low toxicity are possible even in patients >70 years. The well-known negative impact of pretreatment variables such as increasing age or type of AML on outcome could, at least partly, be ameliorated with treatment. The results of this trial emphasize that age alone should not be the determinant of treatment decisions. [Display omitted] DisclosuresJaekel:Celgene: Other: Travel support. Maschmeyer:Boehringer-Ingelheim: Honoraria; AstraZeneca: Honoraria; Astellas: Honoraria; Janssen-Cilag: Honoraria; Basilea: Honoraria; Bristol-Meyers Squibb: Honoraria; Celgene: Honoraria; Merck-Serono: Honoraria; Pfizer: Honoraria, Travel support; Gilead: Honoraria; Amgen: Honoraria; Bristol-Meyers Squibb: Other: Travel support. Al-Ali:Gilead: Consultancy, Honoraria; Alexion: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding.

Prevention of Dysbiosis Complications with Autologous Fecal Microbiota Transplantation (auto-FMT) in Acute Myeloid Leukemia (AML) Patients Undergoing Intensive Treatment (ODYSSEE study): First Results of a Prospective Multicenter Trial

Introduction. There is a growing body of evidence highlighting the possible interactions between the microbiota and cancer. However, little is known about the consequence on the microbiota of the intensive chemotherapy in patients with AML. Indeed, intensive treatments of AML are known to negatively impact gut microbiota composition; it is measured by a deep shutdown of diversity indices (eg. Simpson), also called dysbiosis. Decrease in microbiota diversity may impact the immune system and may have consequences on the outcome of AML patients. Therefore, development of strategies to manipulate the gut microbiota may minimize treatment-related complications and potentially improve outcomes. With this background, we developed a single arm prospective phase I/II multicenter trial (ClinicalTrials.gov Identifier: NCT02928523) aiming to evaluate use of auto-FMT in AML patients treated with intensive chemotherapy and antibiotics.Patients and methods. For this purpose, at the time of admission and AML diagnosis, patients were requested to donate stools that were screened according to standard recommendations. If deemed appropriate according to protocol criteria, stools were conditioned, processed with a patented diluent, and stored frozen until transplantation performed after recovery from aplasia and before the second course of chemotherapy. The auto-FMT inoculum was administered as an enema, and was prepared for each individual patient according to standardized and reproducible processes developed by the sponsor of the trial. The primary endpoint was the recovery of microbiota diversity and correction of dysbiosis after auto-FMT. The microbiome diversity and richness were measured at baseline (prior to induction chemotherapy), after induction chemotherapy, and around 10 days post-auto-FMT. Microbiome restoration was assessed at the genus and species level, on the basis of metagenomic results obtained for the 3 sequential samples. Illumina TruSeq Nano Prep kit was used for sequence-library preparation and samples were sequenced on HiSeq 2500 2x125bp, 40 million reads/sample. Secondary objectives included monitoring of the immune system, safety and feasibility of auto-FMT, and a set of parameters exploring the impact of auto-FMT on different patient-related outcomes (clinical status and recovery).Results. At time of this planned intermediate analysis, 35 AML patients eligible for intensive induction chemotherapy (intermediate and unfavorable karyotype) with a median age of 53 (range, 23-67) years were screened. The current interim results concern the 9 patients who fulfilled all criteria for inclusion and were able to proceed to auto-FMT after intensive induction therapy (“3+7” induction or equivalent). Prior to the start of induction chemotherapy, the mean baseline Simpson index (measured at genus level) was 0.836 (95%CI, 0.755-0.987). At the end of induction chemotherapy, a highly significant decrease of -0.519 ([-0.677, -0.361], p<.001) was observed, highlighting the deleterious impact on the gut microbiome of intensive chemotherapy and the multiple antibiotics received during induction. Per protocol, these patients were able to receive an auto-FMT prior to receiving their subsequent consolidation chemotherapy. Auto-FMT was well tolerated, only one serious adverse event was reported: a case of E. Coli infection which resolved after appropriate antibiotherapy. After auto-FMT, the Simpson index returned back to baseline level (difference=0.023 ([-0.135, 0.181], p=0.776), and virtually identical results were obtained when Simpson was measured at species level. The ongoing immunomonitoring of these 9 patients suggested data correlated with the dysbiosis correction.Conclusions. This first multicenter prospective trial reached its primary endpoint in all analyzed cases thus far, and established the capacity of auto-FMT to correct dysbiosis and restore a normal microbiota in AML patients receiving intensive induction chemotherapy and wide-spectrum antibiotics. Correlations with clinical and immune parameters that may influence AML outcome are currently being analyzed and will be presented. The apparent modulation of the immune system through microbiota restoration is a promising venture in the treatment of AML patients warranting further investigations. (The trial was funded by MaaT Pharma whose product was tested in this protocol). DisclosuresMohty:Sanofi: Honoraria, Speakers Bureau. Recher:Celgene, Sunesis, Amgen, Novartis: Research Funding; Novartis, Celgene, Jazz, Sunesis, Amgen: Consultancy. Plantamura:Maat Pharma: Employment. Lehert:Maat Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Doré:Maat Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Intensive Chemotherapy Is Not Recommended for Patients with AML or High-Risk MDS Aged over 60 Years with Complex Karyotype Anomalies.

Background: Intensive chemotherapy for patients with MDS or AML aged over 60 years still is a matter of debate. Although there are some patients with long-term survival after intensive chemotherapy, it is discussed controversially how to treat old patients with AML or high-risk MDS.Methods: Between 1991 and 2003, 158 patients with MDS or AML underwent intensive chemotherapy with either Ida-Ara-C or TAD, followed by a second course of Ida-Ara-C or TAD, and followed by 2 years maintenance chemotherapy at our institution. Patients were either followed up until relapse, death or to July, 31.th.2004. Median time of follow up was 14 months.Results: Median age at diagnosis was 67 years (60–78). There were 92 males and 66 females. In 101 patients, initial karyotype was available. 51 patients had a normal karyotype and in 50 patients an abnormal karyotype could be detected, 26 of whom had a complex karyotype.94 patients (60%) entered complete remission (CR), 7 patients achieved partial remission (PR), 41 patients failed to respond (26%), and 16 patients succumbed within 4 weeks after the beginning of the induction therapy (10%). Patients with a normal or non-complex karyotype entered CR in 72%, whereas only 34% of patients with complex karyotype achieved CR (p=0.001). 86 (54%) patients received a consolidation therapy with another course of Ida-Ara-C or TAD. 20 patients received at least three courses of maintenance chemotherapy.Median survival of the entire group was 15 months. At the time of analysis, only 19 patients were still alive. Patients with normal karyotype had a median survival of 19 months, as compared to 5 months in patients with abnormal karyotype (p<0.00005). Patients with a complex karyotype had a median survival of 4 months only (p=0.00005).Two years after the beginning of the treatment, only 27% of the patients were still alive. A very small group of patients (n=9) achieved long-lasting remission of more than 3 years. 20 patients died in CR due to infectious complications during the consolidation chemotherapy or due to causes not related to the disease. The initial karyotype and entering CR after induction chemotherapy could be identified as the only prognostic parameters for predicting survival within in entire group. In a multivariate analysis, initial karyotype was the only independent predictive parameter.Conclusions: Intensive chemotherapy is not recommended for patients with AML or high-risk MDS aged over 60 years with complex karyotype anomalies, because of a very poor prognosis, due to low CR rates and early relapses. Alternative treatment strategies, like deacetylating agents or demethylating agents should be performed for those patients.

Ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed AML: a phase 1 study

Ivosidenib (AG-120) and enasidenib (AG-221) are targeted oral inhibitors of the mutant isocitrate dehydrogenase (mIDH) 1 and 2 enzymes, respectively. Given their effectiveness as single agents in mIDH1/2 relapsed or refractory acute myeloid leukemia (AML), this phase 1 study evaluated the safety and efficacy of ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed mIDH1/2 AML. Ivosidenib 500 mg once daily and enasidenib 100 mg once daily were well tolerated in this setting, with safety profiles generally consistent with those of induction and consolidation chemotherapy alone. The frequency of IDH differentiation syndrome was low, as expected given the concurrent administration of cytotoxic chemotherapy. In patients receiving ivosidenib, the frequency and grades of QT interval prolongation were similar to those observed with ivosidenib monotherapy. Increases in total bilirubin were more frequently observed in patients treated with enasidenib, consistent with this inhibitor's known potential to inhibit UGT1A1, but did not appear to have significant clinical consequences. In patients receiving ivosidenib (n = 60) or enasidenib (n = 91), end-of-induction complete remission (CR) rates were 55% and 47%, respectively, and CR/CR with incomplete neutrophil or platelet recovery (CR/CRi/CRp) rates were 72% and 63%, respectively. In patients with a best overall response of CR/CRi/CRp, 16/41 (39%) receiving ivosidenib had IDH1 mutation clearance and 15/64 (23%) receiving enasidenib had IDH2 mutation clearance by digital polymerase chain reaction; furthermore, 16/20 (80%) and 10/16 (63%), respectively, became negative for measurable residual disease by multiparameter flow cytometry. This trial was registered at www.clinicaltrials.gov as #NCT02632708.