First Cycle Of Induction Chemotherapy Research Articles

625. PHASE II TRIAL OF INDUCTION CHEMOTHERAPY FOLLOWED BY CHEMORADIATION AND MINIMALLY INVASIVE SURGERY FOR LOCALLY ADVANCED CARCINOMA OF THE ESOPHAGUS

Abstract Background Most patients with esophageal cancer (EC) present locally advanced disease. Currently, multimodal strategies as neoadjuvant chemoradiotherapy or perioperative chemotherapy are employed, but still have high local and distant failures rates. This study evaluated the results of a phase II protocol with induction chemotherapy (IC) and concurrent chemoradiation (CR) before surgery for locally advanced carcinoma of the esophagus and esophagogastric junction (EGJ). The primary end point was to evaluate pathological complete remission (PCR) rate at surgical specimen. A PCR ≥ 30% was considered promising for further study. Methods Patients with squamous cell carcinoma (SCC) or adenocarcinoma (AC) of the thoracic esophagus and JEG, clinical stage T1b-3, N0-2, M0, PS 0-2, underwent two cycles of IC with carboplatin and paclitaxel followed by CR with the same agents and minimally invasive esophagectomy. At the screening, 14 days after the first cycle of IC and 6-8 weeks after the CR, metabolic responses were accessed by PET-CT and classified according the PERCIST criteria. Results One hundred and twenty-nine patients were accrued from January 2017 to April 2023. Forty-seven patients started the trial and 45 completed the neoadjuvant part of the protocol. Most patients were male (73.3%), the median age of was 55 years and AC was the most prevalent histological subtype (53.3%). Grade 3/4 toxicity during IC were infrequent and included neutropenia (12.5%), anemia (6.2%) and dysphagia (10.4%). Lymphopenia (10.7%) and dysphagia (6.5%) were the most common grade 3/4 toxicity during CR. All cases received the full radiotherapy dose of 45 Gy by IMRT technique. Thirty-seven patients underwent surgery and 31 had minimally invasive MacKeown esophagectomy with complete tumor resection (R0). Sixty-four percent of all included patients completed the neoadjuvant therapy and survived for 30 days after surgery. The most prevalent postoperative complications were anastomotic fistula (29%) and pneumonia (19%). Median hospital stay was 12 (7-56) days. Six patients (19.3%) had major postoperative morbidity (Clavien-Dindo ≥ IIIb), 4 were reoperated and one (3.2%) died during hospitalization. The median number of lymph nodes retrieved was 24. Eleven patients (33.5%) had pathological positive lymph nodes. The overall pathological complete response rate was 25.8%, 41.8% for SCC and 15.8% for AC. The early metabolic evaluation by PERCIST showed that 2 cases (4.4%) had progressive disease (PD), 26 (57.7%) stable disease (SD), 15 (33.3%) partial response (PR) and 2 (4.4%) complete response (CR). All the CR were SCC. The late metabolic response analysis showed that 1 (2.4%) patient had PD, 6 (14.6%) SD, 23 (56%) PR and 11 (27%) CR. On the basis of an intention-to-treat analysis, the median overall survival was 31.4 months, whereas the five-year overall survival was 31.2%. After curative surgery, 12 patients had recurrence disease. Six (19%) patients had recurrences at distant sites, 4 (12.9%) had loco-regional recurrence and 2 (6.4%) had both patterns. Conclusion This intensified neoadjuvant regimen was efficacious and safe in patients with locally advanced EC, but failed to reach the defined efficacy goal for further investigation, especially for AC.

Atypical hemolytic uremic syndrome during induction chemotherapy in neuroblastoma, a rare phenomenon or common congenital predisposition?

Atypical hemolytic uremic syndrome (aHUS) is a complement-mediated thrombotic microangiopathy sometimes associated with germline variants in genes of the complement system. Clinical findings of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury arise due to aberrant complement protein activation in the circulation. A 13-month-old boy with metastatic neuroblastoma (NB) developed aHUS during his first cycle of induction chemotherapy with germline testing revealing a complement factor H(CFH) gene mutation, currently classified as a variant of uncertain significance (VUS). Now he is in disease remission after successful complement blockade therapy, thus highlighting a unique presentation of aHUS in a patient with newly diagnosed NB.

Survival of Metastatic Human Papillomavirus (HPV)-Related Head and Neck Cancer Receiving Platinum-Based Triplet Induction Chemotherapy and Relevance of Circulating Tumor HPV DNA.

Objectives We aimed to examine the effectiveness of platinum-based triplet induction chemotherapy in metastatic squamous cell carcinoma of the head and neck (HNSCC) at diagnosis in terms of tumor human papillomavirus (HPV) status and the clinical relevance of circulating tumor HPV DNA (ctHPVDNA) during induction chemotherapy. Methods Twenty-one patients were included. ctHPVDNA was longitudinally quantified using optimized digital PCR in a subset of patients. Results HPV-related HNSCC patients (N=7) had a significantly better response to induction chemotherapy than HPV-unrelated HNSCC patients (N=14) (complete or partial response rate, 100% vs. 36%, P = 0.007). Following induction chemotherapy, more HPV-related HNSCC patients than HPV-unrelated patients received radiotherapy (86% vs. 36%, P = 0.06). With a median follow-up of 26 months in surviving patients, the two-year overall survival was 86% in HPV-related HNSCC patients and 43% in HPV-unrelated HNSCC patients (P = 0.04). In two patients, ctHPVDNA levels drastically decreased after the first cycle of induction chemotherapy but turned to continuous increase after the second cycle, suggesting the acquisition of drug resistance by the end of the second cycle. Radiographic imaging after induction chemotherapy failed to identify the drug resistance. In one patient, ctHPVDNA decreased gradually but remained detectable after induction chemotherapy despite no radiographic residual disease. ctHPVDNA became undetectable during radiotherapy. Conclusion HPV-related HNSCC patients with distant metastasis at diagnosis should be treated definitively. The ctHPVDNA level reflects real-time disease activity. ctHPVDNA monitoring during induction chemotherapy could help the decision-making of the therapeutic strategy.

Clinical Significance of Minimal Residual Disease in Pediatric Patients with TCF3/PBX1+ B-cell Acute Lymphoblastic Leukemia

To explore the consistency of flow cytometry (FCM) method and polymerase chain reaction (PCR) technique in the detection of minimal residual disease (MRD) at different treatment stages in pediatric patients with TCF3/PBX1+ B-cell acute lymphoblastic leukemia (B-ALL) and the correlations between the detection results and prognosis. The clinical data of 64 newly diagnosed pediatric patients with TCF3/PBX1+ B-ALL admitted to the Department of Pediatrics of Peking University People's Hospital from January 2005 to December 2017 were retrospectively analyzed. FCM and PCR methods were used to monitor the MRD level in bone marrow samples from 64 children during the same period of treatment on d33 and d90 respectively, and the detection results were analyzed. There were 37 males and 27 females in the 64 patients, with a median age of 8 years(range 0.8 to 16 years). The complete remission (CR) rate after the first cycle of induction chemotherapy was 98.4% (62/63), with overall CR rate of 100%. 12 patients experienced recurrence, with a median recurrence time of 16.9 (5.3-46.3) months. The median follow-up time of the 64 patients was 77.2 (1.0-184.8) months , and the 5-year overall survival (OS) rate and event-free survival (EFS) rate were 82.8%±4.7% and 75.0%±5.4%, respectively. On d90, the concordance rate of the MRD results from the two methods was 98.4%, and the related kappa value was 0.792 (P < 0.001), which were significantly higher than those on d33. After induction chemotherapy (d33), the 5-year EFS rate of MRD-FCM- group (79.3%±5.3%) was significantly better than that of MRD-FCM+ group (40.0%±21.9%) (P =0.028), there were no significant differences in the 5-year OS rate and EFS rate between MRD-PCR+ group and MRD-PCR- group, and the 5-year EFS rate of MRD-FCM-/PCR- group (85.4%±5.5%) was significantly better than that of MRD-FCM+/PCR+ group (40.0 %±21.9%) (P =0.026). In children with TCF3/PBX1+ B-ALL, the MRD results detected by FCM and PCR methods show good consistency, especially in consolidation therapy period (d90). The MRD level at the end of induction therapy (d33) is an important factor affecting the long-term prognosis, especially the MRD results detected by FCM method, which is significantly associated with prognosis.

Outcomes of adult patients with type 1 primary refractory acute myeloid leukemia: a single center experience

ABSTRACTAdult patients with newly diagnosed de novo acute myeloid leukemia (AML), who had less than a 50% reduction in blast numbers and with > 15% residual blasts after first cycle of induction chemotherapy, defined as type 1 primary refractory (REF1), have grave prognosis. We retrospectively analyzed the data of 58 patients with REF1 who received salvage treatments with curative intension to evaluate the impact of salvage regimens with regard to response and overall survival (OS). Seventeen patients received intermediate- or high-dose cytarabine (ID/HD Ara-C) based intensive salvage chemotherapy, 36 patients received G-CSF primed less intensive chemotherapy and 5 patients received novel targeted drugs based low intensive therapy. The CR/CRi and MLFS rate was 6/17 and 2/17, 14/36 and 3/36, 3/5 and 0/5, respectively. The median OS for the whole cohort was 20.3 months. Median OS was comparable between the 3 arms. Overall, 42 patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), 14 patients in the intensive arm, 24 patients in the less intensive arm and 4 patients in the low intensive arm. Median survival for allo-HSCT patients was significantly longer than for non-allo-HSCT patients (38.8 months vs. 2.1 months, p < 0.001). In multivariate analysis, achievement of CR/CRi after the salvage regimen were predictive of OS. We conclude that no significant difference in outcome among traditional salvage regimens in patients with REF1. G-CSF primed less intensive chemotherapy could serve as an alternative of ID/HD Ara-C based intensive chemotherapy and allo-HSCT is indispensable for long-term survival.

Interval changes of histogram-derived diffusion indices predict treatment response to induction chemotherapy in head and neck cancer: a feasibility study.

This retrospective study investigated whether the interval change of apparent diffusion coefficient (∆ADC) [baseline and after the first cycle of induction chemotherapy (ICT)] can be used as a valid predictive imaging biomarker of the treatment response to ICT in head and neck cancer (HNC). A total of 19 consecutive patients with HNC who underwent diffusion-weighted magnetic resonance imaging (DWI) at baseline and after the first cycle of ICT were included. Whole-tumor ADC histogram parameters (mean, median, kurtosis, skewness, entropy, minimal, maximum, 25th percentile, and 75th percentile) were obtained. The correlations of ∆ADC histogram parameters, volume, T-stage, N-stage, and age with the treatment response were examined using the Mann-Whitney U test. The predictive value of histogram parameters was examined using receiver operating characteristic (ROC) curves. Responders showed significantly higher values of ∆ADC25 (0.19±0.23) and ∆ADCmin (1.78±2.98) than non-responders (-0.09±0.15 and -0.73±0.36; P=0.035 and 0.009, respectively). When ∆ADC25 and ∆ADCmin were used for predicting the treatment response, the area under the ROC curve was 0.850/0.933 with a sensitivity of 73.3%/80.0% and specificity of 100%/100% (P=0.036 and 0.009, respectively). ∆ADC25 and ∆ADCmin derived from whole-tumor histogram analysis are valuable imaging biomarkers for the early prediction of the ICT response in HNC.

Chemotherapy dose per kilogram lean body mass increased dose-limiting toxicity event in male head and neck cancer with taxane and platinum-based induction therapy

BackgroundThis study aimed to determine whether drug doses per kilogram of lean body mass (LBM) were associated with dose-limiting toxicity (DLT) events in head and neck cancer (HNC) patients.MethodsThis retrospective cohort study included 179 HNC patients who underwent induction chemotherapy (IC) at a medical center from May 1, 2014, to May 31, 2021. HNC patients’ characteristics, tumor factors, IC regimen and dose, laboratory data, and body composition factors, including lean body mass (LBM) and skeletal muscle index (SMI), derived from CT, MRI, or PET scan images and drug dose per kilogram LBM were recorded. Dose-limiting toxicity (DLT) events were regarded as the primary outcome. Multivariate logistic regression was used to establish a novel risk score for DLT events by the abovementioned variables. The above-mentioned risk score was validated in another cohort.ResultsThe overall DLT events during the first cycle of IC for 179 HNC patients was 24%. After stratifying by gender, docetaxel per kilogram LBM > 2.52 mg/kg (adjusted odds ratio [aOR]: 3.18; 95% confidence interval [CI], 1.25–8.09), pre-treatment glutamic pyruvic transaminase (GPT) > 40 U/L (aOR, 2.61; 95% CI, 1.03–6.64), and history of chronic liver diseases (aOR, 3.98; 95% CI, 1.03–15.46) were significant variables in male HNC patients. The DLT events risk was categorized by summation of the above-mentioned risk factors for male HNC patients. Three risk groups were stratified by overall event of 17.6%, 25.8%, and 75%. The above-mentioned risk score had an acceptable discriminatory ability in another validation cohort.ConclusionsAmong male HNC patients treated with IC, docetaxel per kilogram LBM more than 2.52 mg/kg, pre-treatment GPT > 40 U/L, and history of chronic liver disease were significant risk factors for DLT events. Identifying high-risk patients could help physicians prevent severe/fatal complications among HNC patients undergoing IC, especially for the male individuals.

Dynamic trajectory of platelet counts after the first cycle of induction chemotherapy in AML patients

BackgroundPlatelet counts varied over time after induction chemotherapy. We aimed to investigate the different trajectories of platelet counts after the first cycle of induction chemotherapy in patients newly diagnosed with acute myeloid leukemia.Methods and resultsIn total, 149 individuals were included in this study. We identified four distinct trajectories using a group-based trajectory model: low- stability group (n = 27, 18.12%), low-level decrease–medium elevation group (n = 42, 28.19%), low-level decrease–high elevation group (n = 60, 40.27%), and high-level decrease–medium elevation group (n = 20, 13.42%). The baseline characteristics of the high-level decrease–medium elevation group included higher platelet count, lower white blood cell count, lower percentage of bone marrow blasts, and lower rates of complete remission after the first cycle of induction chemotherapy. Compared with the low-stability group, the hazard ratios were 0.32 (95% confidence interval, 0.15–0.68) for the low-level decrease–medium elevation group, 0.31 (95% confidence interval, 0.15–0.63) for the low-level decrease–high elevation group, and 0.35 (95% confidence interval, 0.13–0.89) for the high-level decrease–medium elevation group after adjustment for age and gender by Cox proportional hazard regression. Compared with the low-stability group, the hazard ratios were 0.33 (95% confidence interval, 0.14–0.77) for the low-level decrease–medium elevation group and 0.31 (95% confidence interval, 0.14–0.67) for the low-level decrease–high elevation group after adjustment for age, gender, white blood cell count, and bone marrow blasts. These associations persisted after adjusting for age, gender, white blood cell count, bone marrow blasts, and platelet count.ConclusionThe dynamic trajectory of platelet counts after the first cycle of induction chemotherapy is a significant predictor of all-cause mortality in patients with acute myeloid leukemia. Timely intervention should be considered for the low-stability group. The low-level decrease–medium elevation and low-level decrease-high elevation groups were independent protective factors for all-cause mortality.

Refining Tumor Treatment in Sinonasal Cancer Using Delta Radiomics of Multi-Parametric MRI after the First Cycle of Induction Chemotherapy.

Background: Response to induction chemotherapy (IC) has been predicted in patients with sinonasal cancer using early delta radiomics obtained from T1- and T2-weighted images and apparent diffusion coefficient (ADC) maps, comparing results with early radiological evaluation by RECIST. Methods: Fifty patients were included in the study. For each image (at baseline and after the first IC cycle), 536 radiomic features were extracted as follows: semi-supervised principal component analysis components, explaining 97% of the variance, were used together with a support vector machine (SVM) to develop a radiomic signature. One signature was developed for each sequence (T1-, T2-weighted and ADC). A multiagent decision-making algorithm was used to merge multiple signatures into one score. Results: The area under the curve (AUC) for mono-modality signatures was 0.79 (CI: 0.65–0.88), 0.76 (CI: 0.62–0.87) and 0.93 (CI: 0.75–1) using T1-, T2-weighted and ADC images, respectively. The fuse signature improved the AUC when an ADC-based signature was added. Radiological prediction using RECIST criteria reached an accuracy of 0.78. Conclusions: These results suggest the importance of early delta radiomics and of ADC maps to predict the response to IC in sinonasal cancers.

The Timing and Epidemiology of Enterococcus Faecium and E. Faecalis Bloodstream Infections (BSI) in Patients with Acute Leukemia Receiving Chemotherapy

Enterococcal BSI occurs frequently in patients with acute leukemia and causes significant morbidity and mortality. Daptomycin non-susceptible Enterococcus (DNSE) infection has emerged as a threat that has limited treatment options. However, the timing of enterococcal BSI in relationship to chemotherapy is unknown. In addition, previous studies have focused on the epidemiology of vancomycin-resistant E. faecium (VRE) BSI. The present study investigates the timing of enterococcal BSI in relationship to chemotherapy and the epidemiology of both E. faecium and E. faecalis BSI in patients with acute leukemia. We hypothesize that most BSIs are gut derived, mucosal barrier injury infections that occur in patients who undergo intensive chemotherapy that causes prolonged neutropenia and chemotherapy-induced mucositis leading to febrile neutropenia and antimicrobial-induced gut dysbiosis.We conducted a retrospective cohort study of patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) admitted to Duke University for infusional chemotherapy from 2010-15. BSI was adjudicated by CDC criteria. Appropriate enterococcal therapy was defined as receipt of an antibiotic with in vitro activity against the BSI isolate. BSI clearance was defined by negative follow-up blood cultures obtained within 72 hours after positive blood cultures. Recurrent BSI was defined by positive blood cultures for Enterococcus after BSI clearance. Bivariate analysis was performed using chi-squared test.Three hundred twelve patients were evaluated for this study, 83 of whom had enterococcal BSI during the study period (27%; Table 1). Eight-seven percent had BSI due to E. faecium while 13% had BSI due to E. faecalis . Most were febrile (82%) and neutropenic (96%) on broad-spectrum antimicrobials at the time of BSI. All patients had an indwelling central line and had received intensive chemotherapy prior to BSI. Median time from acute leukemia diagnosis to BSI was 30 days. BSI occurred most frequently during the first cycle of induction chemotherapy (47%), but a combined 52% of BSIs occurred during the 2nd-5rd cycles of induction chemotherapy. Sixty-six percent of BSIs qualified as mucosal barrier injury infections. Only 2 patients had metastatic sites of infection: 1 with empyema and 1 with CNS infection, both due to VRE. In terms of clinical response to therapy, 61% of patients achieved cure, and 10% died with BSI. Twenty-eight percent suffered recurrent BSI, and 29% of these patients had DNSE BSI after previous daptomycin exposure. Fifty-one percent of patients underwent central line removal for BSI. Failure to remove the central line for BSI did not increase risk of recurrent BSI (p=0.38).Enterococcal BSI typically occurs as a mucosal barrier injury infection in febrile neutropenic patients with acute leukemia receiving intensive chemotherapy. Many cases take place during re-induction chemotherapy in patients with relapsed or refractory disease. VRE is the most common infecting pathogen, but E. faecalis is not an insignificant cause of BSI (13%). In addition, some E. faecium isolates maintain ampicillin or vancomycin susceptibility. These results support empiric anti-VRE therapy with daptomycin upon initial suspicion for enterococcal BSI, but this therapy could be switched to ampicillin or vancomycin depending on isolate susceptibility to conserve daptomycin susceptibility. The risk of recurrent enterococcal BSI is notable as is the emergence of DNSE following daptomycin therapy. However, failure to remove the central line does not appear to be associated with recurrent BSI. Future study of changes to the gut enterococcal microbiome over the course of chemotherapy for acute leukemia will be critical in ultimately preventing enterococcal BSI. [Display omitted] DisclosuresSung:Cellective: Research Funding; Novartis: Research Funding; Merck: Research Funding.

Phase II trial of induction chemotherapy plus chemoradiotherapy with aspirin or placebo in high-risk rectal cancer (ICAR).

e16131 Background: Induction chemotherapy (IC) followed by chemoradiation (CRT) is an attractive approach in locally-advanced, high-risk rectal cancer. Additionally, aspirin has shown potential to lower recurrence rate in colorectal cancer, and improve outcomes alongside CRT in rectal cancer, with higher rate of tumor downstaging. Methods: Randomized, double-blind phase 2 trial to evaluate induction treatment with XELOX, followed by capecitabine-based chemoradiotherapy with aspirin or placebo in a high risk population selected by MRI. The aim of this study was to evaluate MRI response after total neoadjuvant treatment with aspirin or placebo. Results: Of the 25 pts who started treatment between January 2018 and March 2019, 4 pts did not complete (1 pt grade 5 diarrhea; 1pt treatment adherence). Median age was 55yo (32.9 - 73.6), 8 pts (32%) were women, and 80% had 3 or more high-risk criteria. 20 pts (80%) showed symptom improvement in the first cycle of IC. Of the 21 patients who finished treatment until interim analysis, 11 pts received aspirin (2 pts had MRI complete response (CR), 3 pts had minor/no response, and 3 pts had progression disease (PD)). 10 pts received placebo (4 MRI CR, 3 pts had minor/no response, and no PD). Conclusions: Aspirin added to chemoradiotherapy was safe but did not improve response to total neoadjuvant treatment. The study was closed due absence of benefit. Clinical trial information: NCT03170115 .

Molecular response and prognosis of pediatric patients with Ph-positive acute lymphoblastic leukemia treated by tyrosine kinase inhibitors with chemotherapy

Objective To explore the molecular response and prognostic factors of pediatric patients with Ph-positive acute lymphoblastic leukemia (Ph+ ALL) treated by tyrosine kinase inhibitors (TKI) with chemotherapy in TKI era. Methods The clinical data of children newly diagnosed with Ph+ ALL admitted at Department of Pediatrics, Peking University People′s Hospital from August 2006 to February 2017 were retrospectively reviewed.The molecular biological characteristics and survival prognosis of the 30 patients who received continuous TKI with chemotherapy from early induction combined and no subsequent transplantation were analyzed. Results The 30 patients with Ph+ ALL had 19 males and 11 females with a median age of 8-year-old (ranging from 2 to 16 years). The complete remission (CR) rate after the first cycle of induction chemotherapy was 96.7% (29/30 cases), with overall CR rate of 100.0%; Before treatment, the mean level of BCR/ABL mRNA in the 30 patients was 73.2% (0.12%-160.60%) and the level declined significantly with the progression of chemotherapy courses, reaching the plateau stage at the 6th month of chemotherapy (Z=-1.922, P>0.05); nine patients had recurrence, with a median recurrence time of 7 months (3.7-58.8 months). Univariate analysis showed that age (P<0.05), the lever of minimal residual disease (MRD) after induction chemotherapy (P<0.01) and the MRD level at the 3th month of induction chemotherapy (P<0.01) affected the recurrence rate.The median follow-up time of 30 patients was 42.6 months (6.4-96.5 months), and the 3-year overall survival (OS) rate and event-free survival (EFS) rate were (78.6±7.8)% and (72.4±8.4)%, respectively; Cox multivariate analysis showed that the initial white blood cell count ≥34.0×109/L (OR=11.955, 95% CI: 1.075-132.899, P<0.05) and BCR/ABL mRNA reduction less than 3 log from baseline [major molecular response (MMR)] at the 3th month of induction chemotherapy (OR=8.563, 95% CI: 1.254-58.478, P<0.05) were independent risk factors affecting the 3-year EFS rate.In addition, the initial white blood cell count ≥34.0×109/L (OR=14.327, 95% CI: 1.843-243.592, P<0.05) was also an independent risk factor affecting the 3-year OS rate. Conclusions The application of TKI can significantly deepen the molecular response of Ph+ ALL in children.In the TKI era, the initial white blood cell count ≥ 34.0×109/L and BCR/ABL mRNA reduction less than 3 log from baseline (MMR) at the 3th month of induction chemotherapy are independent risk factors for the long-term survival of pediatric Ph+ ALL. Key words: Philadelphia chromosome; Acute lymphoblastic leukemia; Child; Tyrosine kinase inhibitor; Mole-cular response

Complete Remission after the First Cycle of Induction Chemotherapy Determines the Clinical Efficacy of Relapse-Preventive Immunotherapy in Acute Myeloid Leukemia

Background: Contemporary studies have identified &amp;gt;1 cycle of induction chemotherapy to induce complete remission (CR) as an independent risk factor for relapse and mortality in younger adults with acute myeloid leukemia (AML; Othus et al., Leukemia 2019). This study aimed at defining the potential impact of previous induction chemotherapy on the clinical benefit of relapse-preventive immunotherapy in AML. Methods: In a previously reported phase 3 trial (Brune et al., Blood 2006; Martner et al., Blood Rev 2013), two hundred and sixty-one patients with AML in first CR (18-84 years, median 55) who were not eligible for allogeneic transplantation were randomly assigned to receive immunotherapy with histamine dihydrochloride and low-dose interleukin-2 (HDC/IL-2) or standard of care (no treatment, control). The HDC component of this regimen aims at countering immunosuppression induced by reactive oxygen species, which are formed by the NOX2 enzyme expressed by normal and malignant myeloid cells. HDC, a NOX2 inhibitor, improves the function and viability of anti-leukemic lymphocytes such as natural killer cells and cytotoxic T cells (Martner et al., J Pathol 2019). The immunotherapy was initiated in CR1 after the completion of chemotherapy with the aim to prevent relapse in the post-consolidation phase. Cycles 1 to 3 comprised 3 weeks on treatment and 3 weeks off treatment. In cycles 4 to 10 the off-treatment periods were extended to 6 weeks. In each cycle, patients in the treatment arm received HDC (Noventia Pharma, Milan, Italy) at 0.5 mg and human recombinant low-dose IL-2 (aldesleukin; 16 400 IU/kg; Chiron Corporation, Emeryville, CA) subcutaneously twice a day. All patients were followed for at least 36 months after random assignment. The median follow-up time was 48 months. Results: The number of previous induction cycles was known in 260 patients, and 203 of these attained CR after 1 induction cycle (78%). Among the 57 remaining patients, forty-seven attained CR after 2 cycles, and 3 (n=7) or 4 (n=3) cycles were required to induce CR in 10 patients. We compared outcomes of patients who had achieved CR1 after 1 vs &amp;gt;1 cycle of induction chemotherapy and observed a non-significant trend towards inferior outcome in control arm patients who had required &amp;gt;1 induction with a similar trend in younger control patients (&amp;lt;60 years old). In the HDC/IL-2 arm, outcome was significantly superior in younger patients who had attained CR1 after 1 vs &amp;gt;1 induction (leukemia-free survival, LFS, P=0.0007, hazard ratio, HR, 1.67-6.77; overall survival, OS, P=0.009, HR 1.30-6.33 in multivariable analyses correcting for potential confounding factors for relapse and death). When comparing outcomes between treatment and control arms within groups of patients who had attained CR1 after 1 cycle of induction chemotherapy, we observed that the LFS of patients in the HDC/IL-2 arm was significantly superior over controls (P=0.01 in multivariable analysis, N=203). In patients who were &amp;lt;60 years old at random assignment (N=130), treatment with HDC/IL-2 entailed significantly improved LFS (P=0.0008 vs control, HR 0.29-0.72) and OS (P=0.01, HR 0.28-0.75). HDC/IL-2 did not improve LFS or OS in patients who had required &amp;gt;1 cycle of induction to attain CR1 (P&amp;gt;0.5 vs control) and was not significantly beneficial in older patients. A test of interaction supported that the effect size of HDC/IL-2 vs control for LFS was more pronounced in younger patients who had attained CR after 1 (HR=0.48) vs &amp;gt;1 (HR=1.33) cycle of induction (P=0.04). Figure 1 shows Kaplan-Meier analyses of outcome, with unadjusted P-values from logrank tests, in the phase 3 trial arms among all patients attaining CR1 after 1 induction (A and B), in corresponding patients &amp;lt;60 years old (C and D) and in all patients who had attained CR1 after &amp;gt;1 cycle of induction (E and F). Conclusions: These findings imply that the efficiency of previous induction chemotherapy independently determines the clinical benefit of relapse-preventive immunotherapy in adult AML patients who are not candidates for allogeneic transplantation. The results may have implications for the selection of patients who are likely to benefit from treatment with HDC/IL-2 and for the design of clinical trials that evaluate relapse-preventive immunotherapy. Figure 1 Disclosures Thorén: Cytovia, New York: Patents &amp; Royalties: Holds patents protecting the use of NOX2 inhibitors in cancer. Martner:Cytovia, New York: Patents &amp; Royalties: Holds patents protecting the use of NOX2 inhibitors in cancer. Hellstrand:Cytovia, New York: Patents &amp; Royalties: Holds patents protecting the use of NOX2 inhibitors in cancer. OffLabel Disclosure: HDC/IL-2 is approved for the prevention of AML relapse within the EU but is not yet approved in the US.

Treatment of Refractory Acute Myeloid Leukemia and High-Grade Myelodysplastic Syndrome: Implications of Further Care at an Academic Center Versus Community Setting

Introduction: Many patients with newly diagnosed acute myeloid leukemia (AML) or myelodysplastic syndrome with 10-19% blasts (MDS-EB2) do not enter complete remission (CR) following initial induction chemotherapy. At an academic referral center, such patients often stay to receive additional treatment, or return to their home communities for further care. For patients and providers alike, the decision about whether to stay or go after initial treatment failure is often fraught. To better inform such decision-making, in this retrospective single-center analysis, we compared covariate-adjusted survival for patients who elected to stay for further treatment at our center and those who returned to their home communities for subsequent care. Methods: We included adults ≥ age 18 years of age with newly-diagnosed AML or MDS-EB2 treated at our institution between January 2012 and May 2018 who failed to enter CR (&lt; 5% morphologic bone marrow blasts) or CR with incomplete hematologic recovery (CRi) after their first cycle of induction chemotherapy. We excluded patients who died before they could begin re-induction therapy. Patients who stayed at our institution for additional treatment are referred to as the "stay" group (n=86); patients who left are considered the "go" group (n=35). Multivariable Cox regression analysis was used to account for other measured covariates possibly influencing survival. Results: The go group was older and had a higher median treatment-related mortality (TRM) score (Table 1), the latter predictive of the probability of death within the first 28 days of initial induction therapy. Forty-seven percent of stay patients received high-intensity re-induction (containing cytarabine at individual doses ≥1g/m2) while 50% received low-intensity treatment (e.g. azacitidine, decitabine, or low-dose cytarabine). Twenty-nine percent of go patients received treatment (mostly low-intensity) in the community setting, while 63% received supportive care only. The stay patients had a median of 2 subsequent hospitalizations (range 0-12) and spent a median of 27 days hospitalized after initial treatment failure (range 0-124). Survival was longer in the stay group compared to the go group (median 8.3 vs. 1.8 months, p&lt;0.001, Figure 1). After accounting for covariates, the risk of death was 5.6-fold higher (95% CI 2.9-10.8, p&lt;0.001) in go patients (Table 2). Median follow-up of patients alive at last contact was 20 months in the stay group and 1 month in the go group; 31/35 go patients have died (Figure 1). Re-induction treatment produced CR or CRi in 41/86 stay patients (48%). Achievement of CR was the covariate most strongly associated with survival in the stay group, with a time-dependent regression model for CR demonstrating a hazard ratio (HR) of 0.32 (95% CI 0.18-0.56, p&lt;0.001); the deleterious effect of adverse cytogenetics on survival (Table 2) likely reflects its association with the inability to achieve CR. Improved survival was incompletely explained by receipt of allogeneic hematopoietic cell transplant (HCT), though there was a trend toward improved survival among the 30 patients (35%) in the stay group who underwent allogeneic HCT (time-dependent HR 0.73, 95% CI 0.41-1.3, p=0.28). Discussion: Patients with refractory AML or MDS-EB2 who elected to stay at our institution for additional therapy after initial treatment failure were more likely to live longer than those who returned to their communities. Those in the go group mostly received supportive care alone. Although the survival benefit among the stay group was modest (median additional survival of 6.5 months), it was similar to the incremental survival benefits associated with several recently approved drugs and was strongly associated with achievement of CR, which occurred in 48% of stay patients. Although our study is limited by the inability to account for unknown covariates, a definitive randomized study is not feasible. There is also a relative lack of information about the go patients once they left our center, although we do know that these patients were much less likely to receive AML/MDS-directed therapy than their stay counterparts. A principal problem in advising patients to stay for additional treatment is our limited ability to predict CR with re-induction therapy. However, our findings suggest that patients with non-adverse cytogenetics and lower TRM scores might preferentially be so advised (Table 2). Disclosures Othus: Celgene: Other: Data Safety and Monitoring Committee; Glycomimetics: Other: Data Safety and Monitoring Committee. Gardner:Abbvie: Speakers Bureau. Halpern:Pfizer Pharmaceuticals: Research Funding; Bayer Pharmaceuticals: Research Funding. Scott:Novartis: Consultancy; Agios: Consultancy; Incyte: Consultancy; Celgene: Consultancy. Becker:The France Foundation: Honoraria; Accordant Health Services/Caremark: Consultancy; AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding. Percival:Pfizer Inc.: Research Funding; Nohla Therapeutics: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees.

Prospective target assessment and multimodal prediction of survival for personalized and risk-adapted treatment strategies in multiple myeloma in the GMMG-MM5 multicenter trial

BackgroundPersonalized and risk-adapted treatment strategies in multiple myeloma prerequisite feasibility of prospective assessment, reporting of targets, and prediction of survival probability in clinical routine. Our aim was first to set up and prospectively test our experimental and analysis strategy to perform advanced molecular diagnostics, i.e., interphase fluorescence in-situ hybridization (iFISH) in ≥ 90% and gene expression profiling (GEP) in ≥ 80% of patients within the first cycle of induction chemotherapy in a phase III trial, seen as prerequisite for target expression-based personalized treatment strategies. Secondly, whether the assessment of risk based on the integration of clinical, cytogenetic, and expression-based parameters (“metascoring”) is possible in this setting and superior to the use of single prognostic factors.MethodsWe prospectively performed plasma cell purification, GEP using DNA-microarrays, and iFISH within our randomized multicenter GMMG-MM5-trial recruiting 604 patients between July 2010 and November 2013. Patient data were analyzed using our published gene expression report (GEP-R): after quality and identity control, integrated risk assessment (HM metascore) and targets were reported in clinical routine as pdf-document.ResultsBone marrow aspirates were obtained from 573/604 patients (95%) and could be CD138-purified in 559/573 (97.6%). Of these, iFISH-analysis was possible in 556 (99.5%), GEP in 458 (82%). Identity control using predictors for sex, light and heavy chain type allowed the exclusion of potential sample interchanges (none occurred). All samples passed quality control. As exemplary targets, IGF1R-expression was reported expressed in 33.1%, AURKA in 43.2% of patients. Risk stratification using an integrated approach, i.e., HM metascore, delineated 10/77/13% of patients as high/medium/low risk, transmitting into significantly different median progression-free survival (PFS) of 15 vs. 39 months vs. not reached (NR; P < 0.001) and median overall survival (OS) of 41 months vs. NR vs. NR (P < 0.001). Five-year PFS and OS-rates were 5/31/54% and 25/68/98%, respectively. Survival prediction by HM metascore (Brier score 0.132, P < 0.001) is superior compared with the current gold standard, i.e., revised ISS score (0.137, P = 0.005).ConclusionsProspective assessment and reporting of targets and risk by GEP-R in clinical routine are feasible in ≥ 80% of patients within the first cycle of induction chemotherapy, simultaneously allowing superior survival prediction.

Clinical efficacy of decitabine in combination with standard-dose cytarabine, aclarubicin hydrochloride, and granulocyte colony-stimulating factor in the treatment of young patients with newly diagnosed acute myeloid leukemia.

Purpose: The chemotherapeutic regimen DCAG (decitabine with cytarabine, aclarubicin hydrochloride, and granulocyte colony-stimulating factor) is effective for elderly patients with acute myeloid leukemia, but recommendations for young patients remain controversial. This study investigated the tolerance and efficacy of DCAG for patients with newly diagnosed acute myeloid leukemia (aged 14–60 years). The clinical features or molecular markers that may predict response to DCAG were identified.Patients and methods: One-hundred sixty-one consecutive patients with newly diagnosed acute myelogenous leukemia received DCAG or standard (idarubicin plus cytarabine, IA) induction chemotherapy (n=64 and 97, respectively).Results: The rates of complete remission after the first cycle, overall survival (OS), and event-free survival (EFS) were comparable. After the second cycle, the complete remission rate of the DCAG group (54.7%) was significantly lower than that of the reference (78.35%, P=0.005). The following were associated with significantly worse OS, and EFS, in the DCAG group: Eastern Cooperative Oncology Group (ECOG) score ≥3 and no response after the second induction therapy; and FLT3-ITD. The multivariate analysis showed the DCAG group with significantly shorter OS associated with ECOG ≥3 and FLT3-ITD. In the DCAG group, after the first cycle of induction chemotherapy the median recovery times of neutrophils and platelets were 15.8 and 13 days.Conclusion: The DCAG and IA groups were similar with regard to complete remission rate after the first cycle, OS, and EFS. The complete remission rate after the second cycle of the DCAG was significantly lower than that of the IA. Grade 4 neutropenia and thrombocytopenia were a major adverse event associated with DCAG.

Neutropenia during the First Cycle of Induction Chemotherapy Is Prognostic for Poor Survival in Locoregionally Advanced Nasopharyngeal Carcinoma: A Real-World Study in an Endemic Area

PurposeThe purpose of this study was to investigate the effect of neutropenia during the first cycle of induction chemotherapy (IC-1) on survival in locoregionally advanced nasopharyngeal carcinoma (LANPC).Materials and MethodsEligible patients (n=545) with LANPC receiving IC+concurrent chemoradiotherapy were included. Based on nadir neutrophil afterIC-1, all patientswere categorized into three groups: no/grade 1-2/grade 3-4 neutropenia. Five-year overall survival (OS) and disease-free survival (DFS) were compared between groups and subgroups stratified by IC regimen. We also explored the occurrence of IC-1–induced myelosuppression events and the minimal value of post-treatment neutrophil-to-lymphocyte ratio (post-NLRmin). Univariate/multivariate analyses were performed to investigate the effect of IC-1–induced neutropenia, timing of neutropenia, number of myelosuppression events, and high post-NLRmin on OS/DFS.ResultsGrade 1-2/grade 3-4 neutropeniawere associatedwith poorer OS/DFS than no neutropenia (all p < 0.05); OS/DFS were not significantly different between patients experiencing grade 1-2 vs. 3-4 neutropenia. Neutropenia had no significant effect on OS/DFS in patients receiving docetaxel–cisplatin–5-fluorouracil (TPF). Grade 1-2 (grade 3-4) neutropenia negatively influenced OS/DFS in patients receiving cisplatin–5-fluorouracil (PF) (PF and docetaxel–cisplatin [TP]; all p < 0.05). Neutropenia, two/three myelosuppression events, and high post-NLRmin (≥ 1.33) was most frequent on days 5-10, second and third week of IC-1, respectively. After adjustment for covariates, IC-1–induced neutropenia, two/three myelosuppression events, and post-NLRmin ≥ 1.33were validated as negative predictors of OS/DFS (all p < 0.05); timing of neutropenia had no significant effect.ConclusionOccurrence of neutropenia, number of myelosuppression events, and high post-NLRmin during PF/TP IC-1 have prognostic value for poor survival in LANPC.

Treatment of patients with poor risk nonseminomatous germ cell tumors at advanced stages

Modern chemotherapy followed by surgery can cure the majority of patients with advanced nonseminomatous germ cell tumors but only half of patients with poor risk according IGCCCG classification. The most challenge is to treat frail patients with highly extensive disease. First cycle of induction chemotherapy associates with high complication rate (severe infections, cytopenia, tumor-lysis syndrome, bleedings, respiratory insufficiency) and mortality. Using of low-dose first cycle (2–3 days of EP regimen) instead of full-dose one can improve poor patient»s status, prevent severe toxicity, allow to start next cycle earlier and does not diminish long-term outcome.

Characteristics of De Novo Acute Myeloid Leukemia Patients in Palestine: Experience of An-Najah National University Hospital

Objective:To describe the characteristics of de novo acute myeloid leukemia (AML) in the Palestinian population.Study design and setting:A retrospective chart review study was conducted at An-Najah National University Hospital (NNUH) during the period of January, 2014 to December, 2016.Methodology:The medical records of AML patients treated at NNUH were reviewed. All patients at least 16 years of age diagnosed with de novo AML and started on induction chemotherapy were included. Descriptive statistics were employed to analyze the data.Results:Out of 88 patients diagnosed with AML during the study period, 64 had de novo AML and were included. Median age at diagnosis was 36 years, with a male to female ratio of 1.13:1. Two thirds of the cases were from the West Bank and the remainder were from Gaza. Major complaints at presentation were fatigue (64.1%), fever (46.9%), respiratory tract infections (39.1%) and bruising (28.1%). Hepatomegaly was present in 23.4% and splenomegaly in 34.4%. At presentation, the median white blood cells (WBC) count, hemoglobin (Hb) concentration and platelet count were 30. 5x109/L, 9.3g/dL, and 39.5 x109/L, respectively. According to the French American British (FAB) classification, M4 was the most common subtype (32.8%) followed by M3 (21.9%). After a single cycle of induction chemotherapy complete remission (CR) was seen in 26 (41.9%) and non-remission (NR) in 17 (27.4%), while 19 patients (30.6%) died during the first admission for induction.Conclusion:The characteristics of de novo AML in Palestinian patients are comparable to published data elsewhere. M4 was the most common subtype. The outcome of the first cycle of induction chemotherapy was slightly inferior to the published data for M3 patients. Further studies are warranted to identify possible causes.

Early Monoclonal Para Protein Reduction and Response in Multiple Myeloma (EMPEROR study)

Introduction. An early and rapid reduction of monoclonal para protein with bortezomib or bortezomib/doxorubicin therapy in relapsed/refractory myeloma has been associated with a longer time to progression1. However there are no studies to look at early monoclonal paraprotein reduction and response to treatment in newly diagnosed myeloma.Our unit looked at retrospective data in a cohort of newly diagnosed myeloma patients from 2010 till 2016 that were treated with regimens containing a novel agent backbone. The study looked at the paraprotein values pre-induction chemotherapy and the response to first cycle of induction chemotherapy. Further data was collected as regards the nadir paraprotein as well as death and follow-up.Methods. Data was collected on the patients with newly diagnosed myeloma including demographics, paraprotein isotype, and baseline paraprotein values. The patient's induction regimen including number of cycles for induction was collected. Paraprotein levels were measured post first cycle of induction as well as the lowest values post-induction were documented. Patients were grouped according to the best response based on International Myeloma Working Group classification2. Survival was calculated using the Kaplan-Meier product limit method with start time (ie landmark) designated as the date of the first measurement of paraprotein after cycle 1. Univariate analysis was performed using Fisher exact test for categorical variables, Wilcoxon rank-sum test for continuous variables, and logrank test for overall survival.Results: 44 patients were included in the study. There were 24 males and 20 females. Median age of patients was 67 years (range 41-85 years). The distribution of paraprotein isotypes were as follows: IgG kappa 13, IgG lambda 12, IgA kappa 5, IgA lambda 5, kappa light chain 7 and lambda light chain 2 patients. The median value of baseline paraprotein pre induction was 35 g/l (range 7-86 g/l) and light chain difference was 2892 mg/l (range 98-14388 mg/l). The distribution of the type of induction chemotherapy received was as follows: VCD 25, CTD 12, MPT 4 and VMP 3. The median percentage reduction in disease marker (paraprotein level or difference between involved and uninvolved light chain) post first cycle was 59% (range 0-100%) (Table 1). No significant difference in percentage reduction of disease marker post first cycle according to novel agent backbone was seen (P = .140, Table 2). Percentage reduction in disease marker was significantly greater for patients with light chain myeloma compared with those with intact paraprotein (P = .001, Table 3). The best response to induction was 2 patients with stable disease, 16 with partial response, 23 with very good partial response (VGPR) and 3 in complete remission (CR)2. Of 21 patients who had 50% or greater reduction of disease marker after first cycle of induction, 15 patients achieved VGPR/CR (71%) and 6 patients had a less than VGPR. Of 15 patients who had less than 50% reduction of paraprotein levels after first cycle, 6 patients had VGPR/CR and 9 patients had less than VGPR. Overall survival at 3 years after date of first cycle of induction was 63%. No difference in survival was noted in patients groups with more than 50% reduction or less than 50% reduction of disease marker after first cycle of induction .Conclusion : For patients with myeloma treated with novel agent containing regimens, an early rapid reduction in disease marker was more common with light chain myeloma compared with myeloma with intact paraprotein. However, no difference in depth of response or survival was observed according to early rapid reduction. These results suggest a difference in disease kinetics based on the type of disease marker in myeloma which may have implications for treatment scheduling. Patients with > 50% reduction in disease marker appeared to be more likely to achieve at least VGPR compared with those with < 50% reduction (odds ratio 3.6, P = .089)