Initial Induction Chemotherapy Research Articles

Resilience Development Among Adult Patients With DeNovo Acute Leukemia: A Qualitative Study.

This study aimed to explore the development process of psychological resilience among adult patients with de novo acute leukemia. This study utilized a descriptive qualitative approach, employing a purposeful sampling method to select a sample of 15 newly diagnosed patients with acute leukemia (AL) who underwent their initial induction chemotherapy treatment at the Hematology Department of the First Affiliated Hospital of Zhejiang University School of Medicine, China. Semi-structured interviews were conducted with the selected patients. Content analysis methodology was used to analyze, summarize, and extract themes from the collected data. Three categories emerged-namely, (1) negative period, (2) adaptive response phase, and (3) growth transformation period. The negative period occurs during the initial diagnosis and throughout the treatment cycle. However, influenced by both internal and external protective factors, including personal characteristics and social support, individuals enhance their psychological resilience through emotional regulation, mental adjustment, and adaptive strategies vis-à-vis healthcare decision-making and disease management. Overall, psychological resilience development follows an upward spiral trajectory. This study identified that negative emotions and symptom clusters impede the development of patients' psychological resilience. Moreover, it revealed a substantial need for disease-related information among patients. Therefore, healthcare professionals should prioritize addressing the negative emotions of patients, early identification of protective factors, dynamic monitoring of symptom clusters, effective management, and provision of psychological counseling and interventions. Simultaneously, providing personalized, professional, and systematic disease-related information is vital for promoting psychological resilience development.

Role of induction chemotherapy in advanced-stage olfactory neuroblastoma.

To evaluate the treatment outcomes in patients with advanced-stage olfactory neuroblastoma (ONB) who received induction chemotherapy (IC). The clinical data of 38 patients with advanced-stage ONB who received initial IC were retrospectively analyzed. The response was defined using the Response Evaluation Criteria in Solid Tumors version 1.1. Patients with complete remission or partial remission were defined as responders. Seventeen (44.7%) patients responded to IC. The response rate was higher in patients with high Hyams grade tumor (III/IV) compared to those with low-grade tumors (I/II) (60% vs. 22.2%, p=0.038). Overall, the 5-year cancer-specific survival (CSS) rate was 76.0%. Among nonresponders to IC, a significant difference in 5-year CSS rates was observed between surgery with adjuvant radiotherapy (RT) (100%) versus definitive RT or chemoradiotherapy (CRT) (68.6%) (log-rank p=0.006). However, for responders, there was no significant difference in 5-year CSS rates between surgery with adjuvant therapy (75%) and definitive RT or CRT (51.1%) (log-rank p=0.536). When only high-grade tumors were considered among responders, the 5-year CSS rate was significantly higher in patients who received RT or CRT (51.4%) compared to those who underwent surgery with adjuvant therapy (0%) (log-rank p=0.008). In advanced-stage ONB, RT or CRT may be preferable for high-grade tumor responding to IC. Higher response rate and a potential role for induction IC in determining the optimal definitive treatment modality suggest a positive role for advanced-stage high-grade ONB.

Efficacy of Decitabine Combined with Preexcitation Regimen in Treatment of Newly Diagnosed AML Patients Who Did not Respond to Initial Standard Induction Chemotherapy

To investigate the efficacy of decitabine combined with preexcitation regimen in the treatment of newly diagnosed acute myeloid leukemia (AML) patients who have not been relieved by the first standard induction chemotherapy and its influence on the relative content of regulatory T lymphocytes (Tregs). The clinical data of 102 newly diagnosed AML patients (except acute promyelocytic leukemia) who did not relieve after initial standard induction chemotherapy in Shaanxi Provincial People's Hospital from March 2013 to March 2019 were retrospectively analyzed. Fifty-one patients who accepted pre-excitation regimen were divided into regular group, while another 51 patients treated with decitabine combined with pre-excitation regimen were divided into combination group. The efficacy, incidence of toxic and side effects, Core Scale of Quality of Life (QLQ-C30) score before and after treatment, T lymphocyte subsets (CD3+, CD4+, CD4+/CD8+, Tregs) and 3-year overall survival (OS) rate were compared between the two groups. The total effective rate of combination group was 80.39%, which was significantly higher than 62.75% of regular group (P < 0.05). After treatment, the QLQ-C30 score of combination group was 60.27±6.96, which was significantly lower than 65.73±7.96 of regular group (P < 0.001). There was no statistical difference in the incidence of toxic and side effects between the two groups (P >0.05). After treatment, the levels of CD3+, CD4+, CD4+/CD8+ in the combination group were higher than those in the regular group (all P < 0.001), while Treg was lower (P < 0.001). The 3-year OS rate in the combination group was 72.55%, which was significantly higher than 52.94% in the regular group (P < 0.001). Decitabine combined with preexcitation regimen has a significant effect on AML patients who have not been alleviated by standard induction chemotherapy in the first course of treatment. It can reduce anti-tumor immune suppression and improve immune function by regulating the relative content of Tregs, thus prolongs survival time and improves life quality of patients without increasing adverse reactions.

Efficacy and Safety of Maintenance Therapy Using Cetuximab in Patients with Metastatic Colorectal Cancer: Retrospective Study.

Cetuximab (CET) combined with chemotherapy significantly improved the survival in RAS and RAF wild-type metastatic colorectal cancer (mCRC) patients, while clinical evidence was lacking on the use of maintenance therapy (MT). The study aimed to explore the role of maintenance therapy following Cetuximab + chemotherapy and the optimal Cetuximab-based maintenance therapy regimen. We retrospectively reviewed data on the efficacy and safety of CET-based MT in patients with mCRC who achieved diseasecontrolafter induction therapy. Eighty-one patients with mCRC who achieved disease control after CET + chemotherapy induction were enrolled. Overall median progression-free survival (PFS) was 10.5 (95% CI = 8.8-12.2) months and median maintenance/observation PFS (mnPFS) was 6.0 (95% CI = 5.0-7.0) months. Among these 81 patients, 61 patients were prescribed MT (CET alone for 21 patients and CET + chemotherapy for 40 patients). Median PFS and mnPFS in the MT group were significantly longer than those for the non-MT group. Different MT regimens did not affect PFS and mnPFS significantly. Univariate and multivariate analysis demonstrated MT, complete response/partial response during induction therapy, and absence of peritoneal metastasis to be positively associated with longer PFS and mnPFS. Treatment-related adverse events (AEs) were tolerable during MT, and AE-related deaths were not observed. MT with CET or CET + chemotherapy was an appropriate option following initial induction chemotherapy for patients with RAS and RAF wild-type mCRC. This strategy endowed survival benefits and a tolerable safety profile.

Efficacy and safety of mitoxantrone, etoposide, and cytarabine for treatment of relapsed or refractory acute myeloid leukemia

Background/rationaleMost patients with acute myeloid leukemia (AML) develop relapsed or refractory (R/R) disease after receiving initial induction chemotherapy. Salvage chemotherapy followed by allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only curative therapy for R/R AML. Mitoxantrone, etoposide, and cytarabine (MEC) is the current standard of care salvage regimen for R/R AML at Cleveland Clinic. The primary objective was to determine the overall remission rate (ORR: defined as patients achieving complete remission (CR) or complete remission with incomplete hematologic recovery (CRi)) in R/R AML patients who received MEC. MethodsAdult patients with R/R AML treated with MEC between July 1, 2014 and September 30, 2022 were included. ORR and its association with baseline characteristics were determined. Secondary outcomes included overall survival (OS), event-free survival (EFS), relapse-free survival (RFS), and safety. ResultsSixty patients were evaluated. The ORR was 51.7% (33.3% CR and 18.3% CRi). The median time from receipt of MEC to CR/CRi was 7.7 weeks. Patients with bone marrow blasts ≤20% and peripheral blood blasts ≤30% at MEC initiation were more than twice as likely to achieve CR/CRi compared to those with a higher blast burden. The median OS was 6.3 months. Twenty-four (40.0%) patients proceeded to alloHSCT. Twenty-one (35.0%) patients were transferred to the intensive care unit (ICU) during their admission. ConclusionsMEC is an effective salvage regimen for patients with R/R AML, especially among those with low disease burden at initiation. Febrile neutropenia, infections, and severe oral mucositis were common with MEC administration.

Correlation of Serum Oxidative Stress with the Effect of Initial Induction Chemotherapy in Acute Myeloid Leukemia.

Achieving first complete remission with induction chemotherapy (ICT) for acute myeloid leukemia (AML) correlates with patient's prognosis. This study aimed to determine the correlation between oxidative stress and the outcome of ICT in AML patients. A total of 195 AML patients underwent initial ICT at the Longyan First Affiliated Hospital of Fujian Medical University from 06-11-2018 to 12-30-2023. Three weeks after ICT, patients were divided into two groups, CR (complete remission) and PR (partial remission), by detecting blood parameters and bone marrow cells. Serum oxidative stress-related factors, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), total antioxidant capacity (T-AOC), and growth/differentiation factor-15 (GDF15) activities or levels were measured to assess the diagnostic value of these factors as a means of diagnosing the efficacy of ICT in patients. Factors affecting PR after initial ICT were analyzed. Patients in the PR group had higher levels of oxidative stress three weeks after initial ICT. Compared with the CR group, patients in the PR group had elevated levels of MDA and GDF15 and reduced activities of SOD, GSH-Px, and T-AOC. Serum MDA levels (AUC 0.709; 95% CI. 0.618 - 0.781) and the combination of multiple indicators (AUC 0.791; 95% CI. 704 - 0.851) had diagnostic value for the efficacy of AML patients undergoing ICT. Serum MDA and GDF15 exceeding cutoff values were risk factors for PR in AML patients undergoing ICT, as were serum SOD and T-AOC below cutoff values. Preoperative malnutrition was associated with PR in patients. Serum oxidative stress-related factors in AML patients are helpful in detecting the efficacy of ICT. Oxidative stress in response to ICT is useful for characterizing the efficacy in AML patients after ICT.

GWAS Identifies Variants Associated with Minimal Residual Disease after Induction I in Pediatric Patients with Newly Diagnosed Acute Myeloid Leukemia

Acute myeloid leukemia (AML) patients' clinical outcomes are associated with genetic abnormalities present in leukemic blasts. However, the significance of common genetic variants with regards to variation in AML treatment outcome remains elusive. To that end, we conducted a genome wide association study (GWAS) on 400 pediatric patients diagnosed with de novo AML to identify single nucleotide polymorphisms (SNPs) that may be associated with minimal residual disease (MRD) after the initial induction chemotherapy. Integrating our top SNPs from GWAS results with matched AML-derived transcriptomic data, we performed an expression quantitative trait loci (eQTL) analysis to determine which variants may affect the expression of one or more genes. Array-based whole-genome genotyping with imputation was used to investigate SNPs for association with MRD outcome in 2 pediatric AML cohorts: the multi-site AML02 [NCT00136084, n=167] and AML08 [NCT00703820, n=233] trials. Genotype imputation was performed via TOPMED Imputation Server and yielded 6,741,200 SNPs. MRD positivity was defined as 1 or more leukemic cells per 1000 mononuclear bone-marrow cells. Association analysis with adjustment for ancestry was conducted using logistic regression to model MRD positivity with SNP as a predictor. Genome-wide significance level was set at Bonferroni-corrected P&amp;lt;5x10 -8 and a suggestive significance level of P&amp;lt;1x10 -4. For gene expression profiling, the mRNA expression levels for 137 patients were obtained at diagnosis using GeneChip Human Genome U133A array from patients in the AML02 cohort. For eQTL analysis, we evaluated the association of gene expression using a 500kb window surrounding the top SNPs identified in the GWAS using a linear regression model. A total of 92 SNPs reached the suggestive significance level but none passed the genome-wide threshold. Of the 92 SNPs, 10 SNPs were mapped to the Major Histocompatibility Complex, Class II, DP Alpha 1 gene (HLA-DPA1), with 8 of the 10 SNPs associated with an increased risk of MRD positivity. The top SNP in HLA-DPA1 is located in intron 1 with presence of the variant A allele conferring increased MRD positivity (OR=2.17, 95% CI (1.55-3.04), P=6.64x10 -6, Figure 1A). Of note, HLA-DPA1 SNP was not significantly associated with event free survival (EFS; HR: 1.21, 95% CI (0.95-1.56), P=0.13) or overall survival (OS; HR: 1.28, 95% CI (0.96-1.71), P=0.09), however the direction of association was consistent with the GWAS results. HLA-DPA1 is a protein coding gene and plays an integral role in the immune response by presenting peptides derived from extracellular proteins. HLA-DPA1 and several other MHC class II genes have shown to be downregulated in patients diagnosed with AML who experienced a relapse (PMID: 30380364). The eQTL analysis revealed a significant association with presence of the variant A associated with reduced mRNA expression of HLA-DPA1 (P=0.01, Figure 1B). In addition to the cis-eQTL association of our top SNP with HLA-DPA1 expression, significant associations were also observed with neighboring genes: HLA-DOA, HLA-DQA1, HLA-DQB1, and DAXX. Furthermore, when examining transcriptomic data for association with survival outcomes, we observed high HLA-DPA1 gene expression was significantly associated with favorable OS (HR: 0.46, 95%CI (0.23-0.91), P=0.025), though this association had similar direction it was not significant for association with EFS (HR: 0.68, 95% CI (0.39-1.18), P=0.169). Although limited by numbers, this study is one of the largest GWAS conducted in pediatric AML to identify common SNPs associated with MRD status after initial chemotherapy induction using an integrated genomic and transcriptomic validation approach. None of the SNPs reached genome-wide significant levels, however our top results show that genetic variation in several genes of biological relevance to have an impact on an early outcome endpoint. Moreover, we also have shown that our top SNP located in HLA-DPA1 gene is an eQTL and its mRNA expression is significantly associated with OS. Future studies are aimed at integrating other clinical endpoints such as EFS and OS with hope of creating a polygenic risk score to personalize treatment approaches. In addition, validation of these findings in larger cohorts of AML patients are warranted with future analyses to include known prognostic factors such cytogenetically defined risk.

A Phase 2 Study of Lenalidomide in Combination with Mitoxantrone, Etoposide, and Cytarabine (Len plus MEC) in Patients with Relapsed or Refractory Acute Myeloid Leukemia

Background: Outcomes for patients with relapsed or refractory acute myeloid leukemia (R/R AML) remain extremely poor. Response rates with salvage chemotherapy regimens, such as mitoxantrone, etoposide, and Cytarabine (MEC), have been associated with a complete remission rate of around 20-30%. We previously reported a phase I study combining Lenalidomide (Len) with MEC salvage chemotherapy, with encouraging response rates in R/R AML compared to other historical standards (DeAngelo et al. AJH 2018). This led to the current phase 2 study (NCT03118466) of Len combined with MEC in R/R AML to evaluate for the efficacy of this combination. Methods: We conducted a phase 2 study of Len plus MEC in adult patients (≥ 18 yrs) with R/R AML after 1 or more cycles of induction chemotherapy. Patients received Len dosed at 50mg/day on days 1-10, and Mitoxantrone 8mg/m2/d, Etoposide 100mg/m2/d and Cytarabine 1000mg/m2/d on days 4 through 8 of induction (Kohrt et al AJH 2010). Patients who achieved a complete remission (CR), complete remission with incomplete blood count recovery (CRi) or incomplete platelet recovery (CRp) could proceed with consolidation chemotherapy or hematopoietic stem cell transplantation at the discretion of the treating physician. The study followed a Simon two-stage design powered to detect improvement to a 45% response rate. The primary objective was to determine the response rate. Secondary objectives included time to neutrophil and platelet count recovery, treatment related mortality, rates of relapse, and overall survival. Results: A total of 40 patients were enrolled and received study treatment. The median age was 56 years (range, 19-70); 58% of the patients were male. 73% of patients had relapsed after initial therapy (29/40) while 27% had primary refractory AML (11/40) after their initial induction chemotherapy. The median number of prior therapies was 2 (range, 1-4). The majority of patients had adverse ELN 2023 risk (n=22; 55%). Recurrent gene mutations in 5 or more patients included DNMT3A (n=8), TET2 (n=7), NRAS (n=6), IDH2 (n=5), and ASXL1 (n=5); 2 patients harbored TP53 mutations. The most frequent grade 3-4 treatment-related toxicities were febrile neutropenia (n = 30; 75%), platelet count decrease (n = 40; 100%), anemia (n = 18; 45%), neutrophil count decrease (n = 14; 34%), blood bilirubin increase (n=6, 14%), and anorexia (n = 5; 12%). Three patients (8%) died during the study treatment period, all secondary to hepatic failure; no other early deaths occurred. Two of these patients had baseline grade 1 bilirubin elevation (no other patients in the study reported baseline bilirubin elevations). Median follow-up was 21 months. The overall response rate was 50% (20/40) where 19 achieved CR while 1 achieved CRi. Of 20 responders, the median time to neutrophil count recovery was 28 days and to platelet recovery was 34 days. The median time to relapse was 22.6 months. The median overall survival (OS) of the entire cohort was 16 months (Figure 1). Conclusions: Len plus MEC was associated with a high response rate and improved OS in patients with R/R AML as compared to historical controls. The overall safety profile was similar to prior MEC chemotherapy trials but several patients did experience early hepatic toxicity. Overall these data support evaluating high-dose Len combined with MEC for patients with R/R AML in a randomized study.

Impact of rhG-CSF on Clinical Efficacy and Immune Cell Subsets after Initial Induction Chemotherapy in AML.

The impact of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in acute myeloid leukemia (AML) is still controversial. The purpose of this study is to explore the impact of rhG-CSF administration on clinical efficacy and immune cell subsets after initial induction chemotherapy in AML. The clinical efficacy and immune cell subsets were compared in the newly diagnosed patients with AML according to whether rhG-CSF was used after initial induction chemotherapy. Next, rhG-CSF stimulation experi-ments on leukemia cell lines and primary leukemia blasts were performed in vitro. There was no statistical difference between control group and rhG-CSF therapy group in complete remission rate and relapse free survival. The duration of agranulocytosis was significantly shortened in rhG-CSF therapy group compared with control group. The percentage of circulating monocytic myeloid-derived suppressor cells (M-MDSCs) and regulatory T cells (Tregs) were significantly increased after the administration of rhG-CSF. Furthermore, it was found that rhG-CSF did not promote the proliferation of leukemia cell lines and primary leukemia blasts, but increased the proportion of M-MDSCs and Tregs in vitro. Administration of rhG-CSF after initial induction therapy of AML does not affect the clinical remission and relapse rate, but reduces the duration of agranulocytosis and increases the proportion of M-MDSCs and Tregs.

The Relationship between Speed of Platelet Recovery and Its R-squared and Efficacy after First Induction Chemotherapy in Acute Myeloid Leukemia

To calculate the cut-off values of speed of platelet recovery and its R-squared in patients with acute myeloid leukemia (AML) after initial induction chemotherapy, which were used to predict the complete remission (CR) of the first induction chemotherapy, and guide the clinic to choose the next appropriate chemotherapy regimen as soon as possible. A total of 117 patients with newly diagnosed AML in the Second Hospital of Shanxi Medical University were included. Patients were diagnosed by morphology, immunology, cytogenetics, and molecular biology (MICM) classification, and the risk stratification was evaluated in combination with the clinical situations of the patients at the time of admission. The peripheral platelet counts after the first induction chemotherapy were detected and the linear regression equation was used to calculate the recovery speed of platelet counts in 5 consecutive blood cell analysis before discharge. According to the ROC curve, the cut-off value between the recovery speed and the R-squared was calculated, and the cut-off value was used to divide the patients into different groups. The differences between groups were compared by Pearson χ2 test to observe the remission effect of the first induction chemotherapy. ROC curve analysis showed that the cut-off value for predicting the platelet recovery speed and its R-squared of the first induction chemotherapy to achieve remission was 4.059 5×109/(L·d) and 72.7%, the sensitivity was 77% and 63.9%, the specificity was 62.5% and 67.9%, and the Youden index was 0.395 and 0.318, respectively. The patients were divided into different groups and compared according to the above cut-off values, and the results showed statistical differences (P<0.001, P=0.001). The cut-off value of platelet recovery speed and its R-squared after the first induction chemotherapy calculated by peripheral platelet count and ROC curve in AML patients can be used as an index to evaluate the remission. The faster the platelet recovery speed after chemotherapy is, the more likely patients achieve remission. The more stable the platelet recovery tendency is, the more likely patients achieve remission too.

Time to Count Recovery after Post-Remission Chemotherapy in AML Patients

Background Longer time to achieve complete remission (CR) and recover counts after initial induction chemotherapy in acute myeloid leukemia (AML) patients is associated with decreased overall survival (OS) and relapse-free survival. Prolonged time to count recovery is associated with increased risk of infection and bleeding, and can result in delay of planned subsequent therapies including further chemotherapy or allogeneic transplant. While CR with count recovery after induction chemotherapy typically occurs within 4-5 weeks, there is a paucity of data for count recovery after post-remission (also known as consolidation) chemotherapy. We sought to investigate the time to neutrophil and platelet recovery after the first cycle of consolidation chemotherapy and thereby to identify optimal post-remission chemotherapy regimens. Methods We retrospectively identified adults over 18 years with newly diagnosed WHO-defined AML/high grade myeloid neoplasms (>10% blasts) who received high intensity induction chemotherapy (cladribine, cytarabine, mitoxantrone, and G-CSF, also known as CLAG-M or GCLAM) between 5/1/2014 and 12/31/2019. Patients with variations to the CLAG-M backbone such as sorafenib, midostaurin, gemtuzumab ozogamicin, and decitabine were included as well. This study was approved by the local Institutional Review Board. Consolidation treatment was defined as the first cycle of therapy given once patients achieved CR in marrow by standard criteria and divided into 3 main types for analysis: CLAG-M, CLAG-M without mitoxantrone (CLAG or GCLA) and high dose cytarabine (HiDAC). Patients who did not receive post-remission therapy with these regimens (n=23) or had refractory disease/died before consolidation therapy (n=180) were excluded from analysis. Many patients were enrolled on a single-center clinical trial of CLAG-M with dose-escalated mitoxantrone (NCT02044796). The primary endpoint was evaluation of the number of days from the start of consolidation chemotherapy to the day when absolute neutrophil count (ANC) > 1,000/ml (defined as neutrophil recovery) and platelet count > 100,000/ml (defined as platelet recovery). Early death was defined as death within 28 days of receiving consolidation therapy. Results We identified 307 patients who met our inclusion criteria; of these, 207 patients (67%) received CLAG therapy, 60 patients (20%) with CLAG-M and 40 patients (13%) with HiDAC. Compared to HiDAC, the median age of patients who received CLAG or CLAG-M was lower (p=0.013). The majority of patients were treated off study in all groups. The highest proportion of patients treated on study received CLAG therapy (36%, p=0.03). Early death was a rare event overall (1% for CLAG; 2% for CLAG-M and HiDAC), and no significant differences in ELN 2017 risk, performance status, baseline WBC, platelets, creatinine, albumin, or TRM score were identified among the three groups. Median time to neutrophil recovery was 36 days for HiDAC, 37 days for CLAG, and 50.5 days for CLAG-M (Figure 1A). Median time to platelet recovery was 48 days for HiDAC, 52 days for CLAG, and 94 days for CLAG-M. In multivariable cause-specific hazard regression models controlling for age and study enrollment, no differences were noted between CLAG and HiDAC in time to neutrophil recovery (hazard ratio [HR] 1.2, 95% confidence interval [CI] 0.81-1.76), platelet recovery (HR 1.08, 95% CI 0.71-1.64), or both neutrophil and platelet recovery together (HR 1.06, 95% CI 0.69-1.61). When compared to HiDAC, CLAG-M was associated with a trend towards longer time to neutrophil recovery (HR 0.69, 95% CI 0.43-1.09), platelet recovery (HR 0.73, 95% CI 0.44-1.21), and both neutrophil and platelet recovery together (HR 0.68, 95% CI 0.41-1.13). Controlling for age and study enrollment status, CLAG-M was associated with significantly worse 8-year OS compared to HiDAC (p=0.030), but no significant difference was identified between CLAG and HiDAC (p=0.99) (Figure 1B). Conclusions Post-remission therapy with CLAG is another viable alternative to HiDAC with no significant differences in neutrophil recovery, platelet recovery, and OS. Early death was uncommon for all three groups, but a post-remission course of CLAG-M was associated with decreased OS. Future work will examine the effect of particular cytogenetic and molecular markers on count recovery after post-remission courses. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Occurrence of Thrombosis during Intensive Chemotherapy Treatment for Acute Myeloid Leukemia Patients Does Not Impact on Long-Term Survival

Introduction A thrombotic event is seen in 10% of newly diagnosed acute myeloid leukemia (AML) patients and has been shown to be associated with disseminated intravascular coagulation (Libourel et al. Blood. 2016). As of yet, the association of developing thrombosis during intensive chemotherapy with AML risk models such as the Medical Research Council (MRC) cytogenetics-based assessment and the European LeukemiaNet (ELN) 2017 molecular based risk model has not been rigorously evaluated. In addition, there is a paucity of data pertaining to the long-term prognostic impact of thrombosis in AML patients. Aiming to investigate these prognostic facets of thrombosis in AML, we performed an analysis of patients with AML diagnosed with thrombosis during treatment with intensive chemotherapy. Methods For this analysis, we collected data on baseline clinical, laboratory, cytogenetic and molecular characteristics of patients with newly diagnosed AML who were treated with intensive chemotherapy and were diagnosed with venous thrombosis. These data were compared with intensively treated patients who did not experience thrombosis to assess for clinical parameters associated with a higher likelihood of developing thrombosis, and to determine whether overall survival was affected by thrombosis. Results The analyzed cohort consisted of 335 newly diagnosed AML patients diagnosed and treated between 2007 through 2021 at the Sheba Medical Center. Median patient age at diagnosis was 55 years. At the time of data analysis 162 patients were alive (48%). Two hundred and eighty-three patients were classified as de novo AML (85%) and the remainder were categorized as secondary disease (15%). Ninety patients harbored the FLT3-ITD mutation (28%) and 117 patients harbored NPM1 mutations (39%). Of evaluable patients, 7 were found to have biallelic CEBPA mutations (8%). In terms of MRC cytogenetic risk, 35 patients (11%) were classified as favorable risk, 219 (66%) patients as intermediate risk, 58 patients (17%) as adverse risk and 21 patients had technically insufficient cytogenetic studies. Using the ELN 2017 risk stratification model, 132 patients (40%) had favorable risk disease, 122 patients (36%) intermediate risk, and 80 patients (24%) adverse risk disease. Venous thrombosis was seen in 33 patients (9.9%) with 28 patients diagnosed with central catheter related thrombosis and 5 patients with lower extremity deep vein thrombosis. In 23 patients (70%) thrombosis occurred during the initial induction chemotherapy phase, in 5 patients (15%) during the first consolidation treatment phase, in 3 patients (9%) during the second consolidation treatment phase, and in 2 patients (6%) during admission for salvage chemotherapy. Following diagnosis of thrombosis, the central catheter was taken out in 9 patients (28%), and 3 patients (8.8%) experienced a recurrence of thrombosis. At the time of thrombosis diagnosis, 14 patients (42%) were found to have a concurrent blood stream bacterial infection. Nineteen patients (58%) were started on anticoagulation following the diagnosis of thrombosis. In univariate analysis, patient age, initial levels of white blood cells, hemoglobin, platelets, creatinine, uric acid, lactate dehydrogenase, INR, albumin, and liver function tests were not significantly different between patients who developed thrombosis and those who did not. Disease type (de novo versus secondary), FLT3-ITD and NPM1 mutational status, achievement of remission, and ELN 2017 risk category also not did not differ to a significant degree between groups. However, MRC intermediate risk group patients were significantly more likely to experience thrombosis compared to favorable risk and adverse risk patients (12.8% versus 5.7% and 1.7%, respectively; p=0.049). Overall survival was not significantly impacted by the diagnosis of thrombosis with an estimated median overall survival of 3.7 years seen in patients without thrombosis compared with 2.2 years in patients with thrombosis (p=0.47). Leukemia-free survival was also comparable between groups (2.4 years versus 1 year; p=0.15). Conclusion Venous thrombosis is seen mostly during the initial induction phase of AML patients receiving intensive therapy with a tight association with the MRC intermediate risk category, however long-term survival and leukemia related outcomes are not significantly impacted by the diagnosis of thrombosis.

Cytogenetic Profile Of Acute Lymphoblastic Leukaemia Patients And Its Association With Induction Remission Status.

Acute lymphoblastic leukaemia is characterized by the presence of more than or equal to 20% lymphoblast (early lymphoid precursors) in peripheral blood and/or in bone marrow. Lymphoblast can infiltrate different organs and clinically patients can present with fatigue, pallor, fever, bone pain, bleeding or bruises and lymphadenopathy. ALL is the most common type of malignancy in children. To determine the cytogenetic abnormalities in patients of Acute Lymphoblastic Leukaemia as a predictor of response to induction chemotherapy. It was a descriptive cross-sectional study. This study was conducted at the Armed Forces Institute of Pathology, Rawalpindi over a period of six months from June to November 2019. Bone marrow and peripheral blood samples of newly diagnosed 80 patients of all the age groups and either gender, who received one month treatment for ALL,were analyzed for cytogenetic study. Patients who were previously diagnosed with ALL, who presented with relapse and those who required induction treatment outside the trial hospital were excluded. UK ALL 2011 treatment protocol was adopted for patients up to 25 years old and for patients above 25years old UK ALL 2014 treatment protocol as induction chemotherapy was adopted. Evaluation for remission was carried out at the termination of initial induction chemotherapy on day 29 of treatment. A total of 80 patients were enrolled in the study, comprising 36 (45%) females & 44 (55%) males. The median age of paediatric patients was 5years (<19 years) who were 56/80 (70%) in number whereas the median age of adults was 27 years (>19 years) who constituted 24/80 (30%) of the participants. Cytogenetic of 51 (63.75%) patients revealed hyperdiploidy (chromosome number 51-66) whereas 29(36.25%) of the participants had miscellaneous mutations [(Hypodiploidy, t (9; 22), t (1; 19) and t (12; 21)]. On immunophenotyping 51/80 (63.7%) of the leukemias were of B cell origin and 29 (36.25%) of T-cell origin. Patients with hyperdiploidy, t (12;21) ETV6/RUNX1 and t(1;19)TCF3/PBX1 had better prognosis and higher remission rate compared to those with the other mutations like t(9;22)Ph+ and hypodiploid which were associated with poor prognosis. Association of gender with remission was not statistically significant.

Volumes tumoraux avant et après chimiothérapie : de nouveaux facteurs pronostiques dans les carcinomes nasopharyngés

PurposeThe pre- and post-induction chemotherapy tumor volumes of nasopharyngeal carcinomas may be prognostic indicators for adapting the therapeutic strategy. The objective of our study is to assess the prognostic impact of pre- and post-induction chemotherapy volumes in patients treated for locally advanced nasopharyngeal carcinomas. Patients and methodsThis is a retrospective study including 52 patients with locally advanced nasopharyngeal carcinoma treated with 3 courses of induction chemotherapy (TPF) followed by intensity modulated radiotherapy associated with concomitant chemotherapy. ResultsThe median initial and post induction chemotherapy total volumes were 92.3 and 41.5mL, respectively. At 3 years, the LRFS, DMFS, DFS and OS were respectively 85.9%, 63.5%, 56.8% and 67.8%. In multivariate study, the combination of a high initial volume (>100mL) and post-chemotherapy volume (>35mL) was an independent factor for LRFS, DMFS, DFS and OS. The total baseline volume had a better predictive prognostic value for DFS and OS than the TNM classification (8th edition 2017). ConclusionThe prognostic weight of tumor and nodal volumes was greater than the TNM classification (8th edition). The pre- and post-chemotherapy tumor volumes allow selecting a high-risk patients’ subgroup “high initial and post chemotherapy volumes” in which it would be advisable to offer more intensive treatment regimens.

EVOLVE: Evaluating the Safety of De-escalated Head and Neck Irradiation in HPV Positive Oropharynx Cancer in Non/Minimal Smokers.

<h3>Purpose/Objective(s)</h3> HPV mediated oropharynx cancer in minimal smokers is a favorable disease entity but with high treatment related quality of life burden. Single institutional studies in large academic centers have favorable results with aggressive radiotherapy de-escalation after surgery or after complete response to induction chemotherapy. We hypothesize that radiotherapy can be safely de-escalated in the community cancer center setting. <h3>Materials/Methods</h3> Adults with HPV mediated squamous cell carcinoma of the oropharynx with ≤ 10 pack year smoking history T0-T3N0-N2M0 (AJCC8, including unknown primary p16+ minimal smokers) and with negative margins (if surgical arm) were enrolled on this prospective observational study. Initial surgical resection was performed if an R0 resection was anticipated AND if the surgeon would anticipate a good functional outcome post-operatively. Adjuvant radiotherapy was as per Ma <i>et al</i> JCO 2019. Induction chemotherapy with de-escalated radiotherapy to complete responders was undertaken when surgical resection was not deemed optimal. Platinum eligible induction chemotherapy was as per Marur <i>et al</i> JCO 2017. Platinum ineligible induction chemotherapy was as per Chen <i>et al</i> Lancet Oncology 2017. The primary endpoint was cumulative incidence of local/regional recurrence. Secondary endpoints included quality of life as determined by Head and Neck PRO (FACT-H&N, EORTC QLQ-C30 and H&N35), distant metastasis free survival and overall survival. Preliminary report includes 39 patients with at least 3 months follow-up. Planned accrual is 60 patients. <h3>Results</h3> Median follow-up was 18 months (3-45 months). 31/39 (80%) received initial surgery. 8/39 (20%) received initial induction chemotherapy. 1 withdrew during induction. 100% of patients receiving induction therapy had adequate response to qualify for de-escalation. Cumulative incidence of local/regional recurrence was 3% (1/39). Cumulative incidence of distant metastases was 3% (1/39). Both recurrences occurred in the surgical arm. Overall survival is 100%. No patient in the induction arm required salvage neck dissection or recurred. 1/11 (9%) of patients with extranodal extension (ENE) recurred locally/regionally. 1/11 (9%) patients with ENE recurred distantly. ENE status is unknown in the non-surgical arm. There were no recurrences in the 7 patients with N2 disease. No de-escalated patient required treatment related feeding tube placement. Patient reported quality of life was stable to improved at 12 month follow-up. <h3>Conclusion</h3> In a rural community setting, early results of aggressive de-escalation of radiotherapy demonstrate this approach to be both safe and effective with minimal change in patient reported quality of life. In this favorable disease entity, reported de-escalation results from large academic centers are readily translatable to daily community practice.

Effect of Tumor Microenvironment and Angiogenesis on Clinical Outcomes of Primary Central Nervous System Lymphoma.

Primary central nervous system lymphoma (PCNSL) is a rare lymphoma, and the disease course is often aggressive with poor prognosis outcomes. PCNSL undergoes germinal center reactions and impairs B-cell maturation. However, angiogenesis is also involved in the tumorigenesis and progression of PCNSL. This study investigated the effects of the tumor microenvironment and angiogenesis-associated genomic alterations on the outcomes of PCNSL. The analysis also evaluated the influence of treatment modality and timing on PCNSL survival using partial least squares variance-based path modeling (PLS-PM). PLS-PM can be used to evaluate the complex relationship between prognostic variables and disease outcomes with a small sample of measurements and structural models. A total of 19 immunocompetent PCNSL samples were analyzed by exome sequencing. Our results suggest that the timing of radiotherapy and mutations of ROBO1 and KAT2B are potential indicators of PCNSL outcomes and may be affected by baseline characteristics such as age and sex. Our results also showed that patients with no mutations of ROBO1 and KAT2B, SubRT subgroup showed favorable survival outcomes compared with no SubRT subgroup in short-term follow-up. All SubRT patients have received high-dose methotrexate induction chemotherapy in the initial treatment. Therefore, initial induction chemotherapy combined with subsequent radiotherapy might improve survival outcomes in PCNSL patients who have no ROBO1 and KAT2B somatic mutations in short-term follow-up. The overall findings suggest that the tumor microenvironment and angiogenesis-associated genomic alterations and treatment modalities are potential indicators of overall survival and may be affected by the baseline characteristics of PCNSL patients.

Management of suboptimal response to induction chemotherapy in locoregionally advanced nasopharyngeal carcinoma: Re-induction therapy or direct to Radiotherapy?

BackgroundUnsatisfactory tumor response to induction chemotherapy (IC) is an adverse prognostic factor of locoregionally advanced nasopharyngeal carcinoma (LANPC). A re-induction strategy which applies additional cycles of an alternative IC regimen prior to radiotherapy (RT) has been adopted. MethodsA total of 419 LANPC patients who attained suboptimal response (stable disease or disease progression) according to the Response Evaluation in Solid Tumors (RECIST) guideline after initial IC were retrospectively included. They were divided into those who received additional cycles of re-induction regimen prior to RT (re-induction group, n = 87) and those who had no additional chemotherapy (direct to RT group, n = 332). Propensity score matching (PSM) was used to adjust for potential confounders. Tumor response and long-term survival were compared between two groups. ResultsAfter receiving a second IC regimen, 39.1% of the patients in re-induction group attained partial response; however, the tumor control of subsequent RT was not significantly improved when compared with direct to RT group (patients attaining complete response after RT 55.2% vs. 52.5%, P = 0.757). Patients who received re-induction therapy showed worse locoregional relapse-free survival (LRFS) and progression-free survival (PFS) than those proceeded directly to RT (3-year LRFS 75.7% vs. 83.1%, P = 0.005; 3-year PFS 62.4% vs. 68.3%, P = 0.037). The increased hematological toxicities were observed in re-induction group that included grade 3–4 anemia, thrombocytopenia and liver enzyme increase. ConclusionRe-induction therapy decreased LRFS and PFS and increased toxicities among patients who attain suboptimal response to initial IC regimen, as compared with direct to RT strategy.

Predictive factors of acute respiratory events during initial induction chemotherapy in patients with advanced neuroblastoma.

BackgroundAcute respiratory events (ARE) occasionally occur during induction chemotherapy as a complication in patients with advanced neuroblastoma.AimsThe present study aimed to identify the predictive factors of ARE, defined as severe hypoxia, during initial induction chemotherapy in patients with newly diagnosed advanced neuroblastoma.Methods and ResultsThe medical records of 75 consecutive patients in whom stage III or IV neuroblastoma was newly diagnosed between January 2003 and December 2018 at two medical institutions were retrospectively reviewed. The outcome was ARE, which were assessed by measuring oxygen saturation between days 1 and 14 of initial induction chemotherapy. Severe hypoxia was defined as grade 3 or higher according to the Common Terminology Criteria for Adverse Events version 4 (CTCAE v4.0) or decreased oxygen saturation at rest (e.g., pulse oximeter <88% or PaO2 ≤55 mmHg). Possible predictive factors on admission were first screened for using univariate analyses with P = .05, then models of the predictive power of the outcome were evaluated by generating receiver operating characteristic (ROC) curves. Eleven patients (14.7%) had the outcome, including three (4.0%) who required respiratory support in the intensive care unit. The area under the curve of the ROC for the predictive factors screened by univariate analyses was 0.84 (95% confidence interval [CI]: 0.73–0.95) for lactate dehydrogenase (LDH) and 0.90 (95% CI: 0.82–0.98) for the disseminated intravascular coagulation (DIC) score.ConclusionThe LDH value and DIC score on admission may be clinically useful predictors of ARE during initial induction chemotherapy in patients with advanced neuroblastoma.

Drug Holidays and Overall Survival of Patients with Metastatic Colorectal Cancer

Simple SummaryDuring first-line treatment of metastatic colorectal cancer, drug holidays (DHs) are usually adopted to limit toxicity. Literature lacks a formal demonstration that first-line continuous treatment, or maintenance, provides longer overall survival compared to DHs. We retrospectively studied the overall survival impact of DHs, demonstrating that a treatment break after initial induction chemotherapy may be considered in carefully clinically selected patients with metastatic colorectal cancer. Our study should reassure medical oncologists dedicated to colorectal cancer on the use of DHs. Different de-escalation strategies have been proposed to limit the risk of cumulative toxicity and guarantee quality of life during the treatment trajectory of patients with metastatic colorectal cancer (mCRC). Programmed treatment interruptions, defined as drug holidays (DHs), have been implemented in clinical practice. We evaluated the association between DHs and overall survival (OS). This was a retrospective study, conducted at the University Hospital of Udine and the IRCCS CRO of Aviano. We retrieved records of 608 consecutive patients treated for mCRC from 1 January 2005 to 15 March 2017 and evaluated the impact of different de-escalation strategies (maintenance, DHs, or both) on OS through uni- and multivariate Cox regression analyses. We also looked at attrition rates across treatment lines according to the chosen strategy. In our study, 19.24% of patients received maintenance therapy, 16.12% DHs, and 9.87% both, while 32.07% continued full-intensity first-line treatment up to progression or death. In uni- and multivariate analyses first-line continuous treatment and early discontinuation (treatment for less than 3 months) were associated to worse OS compared to non-continuous strategies (HR, 1.68; 95% CI, 1.22–2.32; p = 0.002 and HR,4.89; 95% CI, 3.33–7.19; p < 0.001, respectively). Attrition rates were 22.8%, 20.61%, and 19.64% for maintenance, DHs, or both, respectively. For continuous therapy and for treatment of less than 3 months it was 21.57% and 49%. De-escalation strategies are safe and effective options. DHs after initial induction chemotherapy may be considered in clinically selected patients with metastatic colorectal cancer.

Primary Plasma Cell Leukemia in China: A Retrospective Single Center Study

Background: Primary plasma cell leukemia (PPCL) is a rare and aggressive malignancy, with a peculiar clinical and biological features and very poor prognosis. It differs from secondary PCL (SPCL), a leukemic transformation from a previously diagnosed multiple myeloma (MM). Although a few studies have suggested that use of novel agents and performing autologous stem cell transplantation (ASCT) has prolonged survival time of PPCL patients, the prognosis is still poor compared with MM, and the optimal therapy remains unclear.Materials and methods: 50 patients with PPCL were enrolled in Blood Diseases Hospital, Chinese Academy of Medical Sciences in China from June 1999 to June 2016. We analyzed the clinical and cytogenetic characteristics of these patients, survival analysis was conducted by Kaplan-Meier estimates and compared using the log-rank test.Results: Median age of 50 cases was 58 years (range between 26 and 86 years), 76% patents were less than 60 years old. There were 34 males and 16 females. The most common immunoglobulin type was IgG (42%), 26% of patients had light chain type. Regarding the ISS, 2 (4.0%) patients were stage I, 7(14.0%) were stage II, and 41 (82.0%) were stage III. 44 patients (88%) was diagnosed with anemia, 5(10%)patients were found leukopenia, while 23 (46%) patients with leukocytosis. 38(76.0%) patients had thrombocytopenia at diagnosis. 14 (28%) patients were found with renal dysfunction. 42(84%) patients showed elevated LDH level.39 (78%) patients had high β-2microglobulin levels (> 5.5 mg/L). 20(40.0%) patients had low serum albumin levels (< 3.5 g/dL) . There were 33(66.0%) patients with hypercalcemia. Organomegaly (liver, spleen and etc.) was detected in 25 (50.0%) patients and osteolytic bone lesions were present in 34(68.0%) patients. 8(16.0%) patients were involved in extramedullary disease.Cytogenetic analysis has showed that the most common abnormalities were complex karyotype (58.3%), while 50% patients with hypodiploid were found in 24 cases. FISH analysis showed that 13 patients with del13q, 15 patients with del17p, and 6 patients with t(4;14), while 12 patients with t(11;14). 14 patients were found at least 2 abnormalities of 30 patients.All patients were treated in our hospital, 36 cases were treated with novel agent-based chemotherapy , such as bortezomib, cyclophosphamide, and dexamethasone(BCD), or bortezomib, doxorubicin, and dexamethasone (PAD), or thalidomide, melphalan, and prednisolone (MPT), or thalidomide ,cyclophosphamide, dexamethasone (TCD), or thalidomide and dexamethasone (TD), or bortezomib,dexamethasone,cis-platin,doxorubicin,cyclophosphamide,etoposide (VDPACE).8 patients were treated with conventional chemotherapy including vincristine, doxorubicin, and dexamethasone(VAD), or cyclophosphamide, etoposide, dexamethasone(CED), or melphalan and prednisolone(MP), or M2 regimen. 6patients received hematopoietic stem cell transplantation (HSCT) after initial induction chemotherapy, 4 of them received ASCT, 2 patients with allogeneic stem cell transplantation (allo-SCT).Three patients achieved complete remission (CR), while 6 patients received very good partial remission (VGPR) after novel agent therapy. In the conventional chemotherapy group, only one patient received VGPR, and 3 patients received partial remission (PR). In the HSCT group, there were one with CR, and 2 patients with VGPR. Overall response rates (ORR) were significantly higher in patients with novel agent-based regimens compared with those treated with conventional chemotherapy (72% vs. 50%, P < 0.05). (Table 3)Take the total cohort as a whole, the median PFS and OS were 6 months (95% CI 0-15.67), and 12 months (95% CI 5.08-18.09). In total, 5 (10%) patients died within less than 1 month. The major causes of early mortality were disease progression and infection. The median OS was lower in patients who were initially treated with conventional agents (12 months, 95%CI 0-26.4) compared with those treated with novel agents (24 months, 95% CI 8.9-39.5, P = 0.15), but the difference was not statistically significant. Additionally, patients with complex karyotypes showed a trend with poor survival compared to those with normal one.Conclusion: Plasma cell leukemia has a higher incidence in cytogenetic aberrations. Novel agent-based chemotherapy combined with SCT could deepen the response rate, and improve the survival time. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.