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Since 1980's, the established/standard treatment of acute myeloid leukemia (AML) is cytarabine infusion with anthracycline (7 + 3 regimen). We compared the 7 + 3 regimen in older secondary/high-risk AML patients from a clinical trial with a matched population from the Swedish AML Registry treated with an increased cytarabine dose in induction and consolidation as recommended in the Swedish National Guidelines since 2005. After successful propensity score matching, 104 patients per group were included. The primary outcome was overall survival (OS), and standard dosed patients had a median OS of 6.4 versus 10.7 months with increased dose intensity (hazard ratio: 0.69, p  = 0.012), with 5-year OS of 8.7% and 18.1%, and remission rates of 36% and 60%, respectively ( p  < 0.001). Median OS after allogeneic hematopoietic cell transplantation (in 27.9% per group) was 10.4 and 20.7 months, respectively. We conclude that the more intensive cytarabine schedule seems to provide improved outcomes inthe investigated AML patient group.

Background: Decitabine (DAC), a DNA methyltransferase inhibitor, has shown efficacy combined with chemotherapy for relapsed or refractory (R/R) acute myeloid leukemia (AML) in adults, but less is known about its efficacy in children. Accordingly, we conducted a study which involved a priming regimen consisting of DAC with cladribine, cytarabine, and granulocyte-stimulating factor (DAC-CLAG) and compared the efficacy and safety of this regimen with CLAG alone., Methods: A total of 39 R/R AML children who received the CLAG or DAC-CLAG regimen in Shanghai Children's Hospital were retrospectively enrolled in this non-randomized study. These regimens were studied sequentially over time. Twenty-two patients received CLAG from 2015, while 17 patients were administered epigenetic priming with DAC before CLAG from 2020. Patients were subsequently bridged to stem cell transplantation (SCT) or consolidation chemotherapy. Complete remission (CR) and adverse effects were analyzed by Fisher's exact test, and survival was analyzed by the Kaplan-Meier method., Results: DAC-CLAG conferred a numerically higher CR compared to CLAG (70.59% vs 63.64%; P = 0.740). High CR rates occurred in patients with good cytogenetics (P = 0.029) and prior induction without cladribine (P = 0.099). The 1-year event-free survival (EFS) was 64.71% ± 11.59% and 63.31% ± 10.35% in the DAC-CLAG and CLAG group (P = 0.595), and 1-year overall survival (OS) was 81.45% ± 9.72% and 77.01% ± 9.04%, respectively (P = 0.265). The 1-year OS and EFS after SCT were higher in the DAC-CLAG than in the CLAG cohort (100% vs 92.31% ± 7.39%, P = 0.072; 92.31% ± 7.39% vs 85.71% ± 9.35%, P = 0.158). Univariate analysis revealed that a good prognosis included good cytogenetics (P = 0.002), non-complex karyotype (P = 0.056), CR on reinduction (P < 0.0001), and bridging to SCT (P = 0.0007). Use of a hypomethylating agent (P = 0.049) and bridging to SCT (P = 0.011) were independent prognostic factors. Grade 3/4 hematologic toxicity and infection were the main adverse events., Conclusions: DAC prior to the CLAG regimen improved remission in pediatric R/R AML, and was feasible and well tolerated. CLAG ± DAC as a salvage therapy prior to SCT induced improved survival., (© 2024. The Author(s).)

Background: Recent advances in the treatment of acute promyelocytic leukemia (APML) have seen unprecedented improvements in patient outcomes. However, such rapid growth in understanding often leads to uncertainty regarding superiority among candidate treatment regimens, especially when further scrutinized from an epidemiological perspective., Aims: The aim of this systematic review with epidemiological analysis was to identify and compare commonly utilized protocols for standard-risk APML with a particular focus on complete remission (CR), overall/disease-free survival (DFS), and reported adverse events., Methods and Results: Medline, Scopus, and CINAHL were interrogated to identify studies utilizing all-trans retinoic acid (ATRA) in addition to arsenic trioxide (ATO) and/or anthracyclines such as idarubicin (IDA) in the treatment of de-novo APML. After collation of studies, an epidemiological analysis was subsequently performed to compare protocols with regards to outcomes of interest using number needed to benefit (NNB) and number needed to harm (NNH) measures. Seventeen articles, describing 12 distinct trials, were included in the analysis. These trials made use of three unique protocols; CR rates were 94%-100% for ATO/ATRA regimens, 95%-96% for ATO/ATRA/anthracycline regimens, and 89%-94% for ATRA/anthracycline regimens. Epidemiological analysis demonstrated NNB for CR was 9.09 (ATO/ATRA vs. ATRA/IDA) and 20.00 (ATO/ATRA vs. ATO/ATRA/IDA), NNH for neutropenia was -3.45 (ATO/ATRA vs. ATRA/IDA), and NNH for infection was -3.13 (ATO/ATRA vs. ATRA/IDA) and -1.89 (ATO/ATRA vs. ATO/ATRA/IDA)., Conclusion: The ATO/ATRA regimen is superior to chemotherapy-containing protocols at inducing remission and promoting survival in patients with APML. The regimen is better tolerated than the proposed alternatives with fewer adverse events. Future research opportunities include quantifying APML epidemiology and pursuing oral arsenic as an option for simplification of therapeutic protocols., (© 2024 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Background: With local recurrence of rectal cancer continuing to decrease, distant recurrence is becoming a major concern, especially for patients with low- and intermediate-risk stage II/III rectal cancer. Therefore, a new treatment strategy is warranted for these patients. This single-arm phase II trial aimed to assess the effect of neoadjuvant chemotherapy (NCT) in low- and intermediate-risk stage II/III rectal cancer and explore candidate radiological and clinical parameters for early prediction of tumour response after two cycles of CAPOX., Methods: Patients with mid-low stage II/III rectal cancer with low and intermediate risk were examined. The primary outcome was defined as a clinicopathological response by integrating tumour longitudinal length reduction (TLLR) on MRI into pathological tumour regression grade (TRG). After completing NCT, patients with TRG0-2 and TRG3 with a TLLR rate greater than 30 per cent were considered to be responders. Secondary outcomes included pathological complete response (pCR), adverse events and local and distant recurrence., Results: This study enrolled 61 eligible patients. No patient was converted to neoadjuvant chemoradiotherapy owing to tumour progression. The clinicopathological response and pCR rates were 78.7 and 21.3 per cent respectively. After two cycles of CAPOX, TLLR, TRG on MRI, and mucosal lesion regression grade on endoscopy had potential discriminative ability (area under the curve greater than 0.7) for predicting both clinicopathological and pathological response., Conclusion: NCT alone achieves good tumour response rates in patients with low- and intermediate-risk stage II/III rectal cancer, and predicting tumour response to NCT is feasible at an early treatment phase., Registration Number: NCT03666442 (http://www.clinicaltrials.gov)., (© The Author(s) 2021. Published by Oxford University Press on behalf of BJS Society Ltd.)

Introduction: While most patients with mantle cell lymphoma (MCL) receive therapy shortly after diagnosis, a subset of patients with indolent-behaving disease can safely defer treatment. In this subgroup, we evaluated the importance of treatment intensity in patients with MCL who defer initial therapy., Methods: Out of 1134 patients with MCL from 12 academic centers, we analyzed 219 patients who initiated therapy at least 90 days after diagnosis. Patients who received induction with high-dose cytarabine and/or autologous stem cell transplantation (ASCT) in first remission were considered to have received intensive therapy (n = 88) while all other approaches were non-intensive (n = 131)., Results: There was no difference in progression-free (PFS; P = .224) or overall survival (OS; P = .167) in deferred patients who received non-intensive vs. intensive therapy. Additionally, univariate and multivariate Cox proportional hazards models were performed for PFS and OS. Treatment at an academic center (HR 0.43, P = .015) was associated with improved OS in both univariate and multivariate models, while intensity of treatment was not associated with improved OS in either model., Conclusions: These results indicate that intensified initial treatment is not associated with improved survival after deferring initial therapy, although prospective studies are needed to determine which of these patients with MCL may benefit from intensive therapy., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Elderly and/or unfit patients with acute myeloid leukemia have historically been challenging to manage as they were ineligible for what was considered standard of care treatment with induction chemotherapy. The emergence of venetoclax with hypomethylating agents or low-dose cytarabine has substantially improved outcomes in the frontline setting with manageable toxicity. However, this regimen can be challenging to deliver given its differences from standard intensive chemotherapy. In this review, we summarize the landmark trials that established venetoclax-based combinations as a new standard of care for patients with acute myeloid leukemia not suitable for intense chemotherapy, provide practical clinical pearls for managing patients on these therapies, and offer a brief overview of modifications to these regimens under development to improve their efficacy and/or applicability.

Aims: This study aimed to investigate the clinical value of 125 I radioactive particle implantation combined with regional arterial chemotherapy perfusion in the treatment of pancreatic cancer., Subjects and Methods: The clinical data of 23 patients with pancreatic cancer were retrospectively analyzed, and the patients were divided into two groups. In the observation group, 11 patients were injected with radioactive particles in combination with regional arterial chemotherapy. In the control group, 12 patients were treated with simple regional arterial perfusion chemotherapy. Curative effect, pain relief, survival period, and adverse reactions were compared between the two groups., Results: The proportion of patients was significantly higher in the observation group (complete remission + partial remission) (72.73%) than in the control group (41.67%). The 6-month and 9-month survival rates in the experimental group were 91.7% and 50%, respectively, while those in the control group were 63.6% and 18.2%, respectively, with significantly statistical difference. The 12-month survival rate in the experimental group was 16.7% and was significantly higher than that in the control group (8.3%). The experimental group should greater improvement in pain symptoms than the control group, and there was no statistical difference between the two groups except in complications of 125 I radioactive particle implantation., Conclusions: We conclude that 125 I radioactive particle implantation combined with regional arterial perfusion chemotherapy is an effective and comprehensive treatment for advanced pancreatic cancer., Competing Interests: None

Rationale: B-lymphoblastic lymphoma (B-LBL) with BCR/ABL mutation (Ph+ B-LBL) is a rare type of cancer in both childhood and adults. Its clinical manifestations are similar to those of other types lymphoma. However, the targeted therapy can substantially improve the outcome of Ph+ B-LBL., Patient Concerns: A 19-year-old male with blood type O, Rh+ was admitted into our hospital on August 14, 2018, due to a recurrent fever and hypocytosis for 6 months., Diagnoses: Routine blood exam showed pancytopenia. Bone marrow sample flow cytometry (FCM) exam showed abnormal cells were 2.27% of the nucleated cells, and was classified as the abnormal early B-lineage lymphoblastic cells. FISH testing showed the BCR/ABL positive cells were 13.6%. Karyotype analysis showed the 46, XY, t(9;22)(q34;q11). Molecular analysis of BCR/ABL mutation on ABL kinase showed that BCR/ABL T315I mutation. Patient was diagnosed with B-LBL with BCR/ABL mutation (Ph+ B-LBL)., Interventions: The patient was given chemotherapy with VDPI regimen (Vinorelbine, daunorubicin, prednisone, imatinib)., Outcomes: The patient achieved complete remission after 2 courses' treatment, followed by one course of clarithromycin regimen and another two courses of VDPI regimen. Patient remains in complete remission as of March 10, 2021., Lessons: In B-LBL, a BCR/ABL mutation can happen in some of these patients. It is important to guide the pathologist to perform appropriate gene mutation detection, in addition to routine Immunohistochemistry test, to ensure an accurate diagnosis and use the targeted agent for treatment. According to the literature and our results, it seems that intensive chemotherapy plus TKI regimen is effective in inducing complete remission, and allo-SCT should be used as a long-term strategy., Competing Interests: This study was funded by the Joint Research Project of the Science and Technology Department of Henan Province, China (LHGJ20190039, SBGJ20202076, Grant Recipient: JY). National Natural Science Foundation of China (U1804192, Grant Recipient: YL). The funding bodies did not participate in study design, in data collection, analysis, and interpretation, and in writing the manuscript. The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Extranodal natural killer/T cell lymphoma (ENKTL) is a rare type of mature T and NK neoplasm. It is more prevalent in Asia and Latin America where the Epstein-Barr virus is endemic and has been linked to the disease. Most studies have emerged from those 2 regions to evaluate best management options. There are no standards of care in the management owing to the lack of unified approach depending on the treatment region and availability of different therapy options. Several reviews have focused on the outcome of the different chemotherapy combinations. There are no systematic reviews of the toxicity of those regimens despite the fact that many of them incorporate the use of asparaginase and/or radiation in combination with chemotherapy. We have found that although integration of asparaginase and/or radiation have led to improved outcome, it was done at the expense of increased toxicity. The most recent studies are showing promising outcomes while decreasing toxicity., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Acute megakaryoblastic leukemia (AMKL) is a biologically heterogeneous subtype of acute myeloid leukemia that originates from megakaryocytes. Patients with AMKL with non-Down syndrome (DS) had a poorer prognosis. However, clear prognostic indicators and treatment recommendations for this subgroup remain controversial., Patients and Methods: Herein, we performed a retrospective study on 40 patients (age ≤ 18 years) with non-Down syndrome AMKL at our institution. We assessed the effect of different prognostic factors, such as their cytogenetic abnormalities, early treatment response, and the role of hematopoietic stem cell transplantation (HSCT) as post-remission treatment on the outcomes., Results: The complete remission (CR) rate of the patients was 57.9% and 81.1%, respectively, at the end of induction therapy 1 and 2. The overall survival (OS) and event-free survival rates at 2 years were 41% ± 13% and 41% ± 10%, respectively. An analysis of the cytogenetic features showed that patients with +21 or hyperdiploid (> 50 chromosomes) had significantly better OS than those in other cytogenetic subgroups (P log-rank  = .048 and P log-rank  = .040, respectively). Besides cytogenetics, an excellent early treatment response (CR and minimal residual disease < 1% after induction therapy 1) also provided a significant survival benefit in univariate analysis in our study. However, multivariate analysis indicated that allogeneic HSCT was the only independent prognostic marker (relative risk, 11.192; 95% confidence interval, 2.045-61.241; P = .005 for OS and relative risk, 5.400; 95% confidence interval, 1.635-17.832; P = .006 for event-free survival, respectively)., Conclusion: AMKL in patients with non-Down syndrome has a poor outcome. With poor OS but CR rates comparable with other acute myeloid leukemia subtypes, allogenic HSCT may be a better option for post-remission therapy than conventional chemotherapy, especially for those having a poor response to induction therapy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: No standard guideline has been established for the treatment of plasmablastic lymphoma (PBL) and prognosis remains extremely poor, given that patients relapse early after chemotherapy and show resistance to commonly used cytostatic drugs., Patient Concerns: We present the case of a 52-year-old HIV-negative man who presented with a mass at the left sternoclavicular joint. He had no significant comorbidities and no latent immunosuppression., Diagnosis: The largest lymph node measured was 36 × 19 mm. An excisional biopsy showed diffuse proliferation of large lymphoid cells which were positive for CD38 and CD138, but negative for CD20. He was diagnosed with stage IV PBL with a low IPI., Interventions: The patient was treated with four cycles of induction therapy with bortezomib, epirubicin and dexamethasone. He achieved complete remission. But 3 months after receiving consolidated autologous hematopoietic stem cell transplantation, he relapsed. Allogeneic hematopoietic stem cell transplantation was performed on the patient., Outcomes: The patient achieved remission again and there were no serious complications after allogeneic hematopoietic stem cell transplantation. This patient was followed up once every three months, and to date, he has been disease-free for more than 4 years., Conclusion: The survival of recurrent PBL after autologous hematopoietic stem cell transplantation is very poor. Salvage allogeneic hematopoietic stem cell transplantation may bring long-term survival opportunities for those patients. Further clinical studies are needed to explore the role of allogeneic hematopoietic stem cell transplantation in refractory and recurrent PBL., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Acute lymphoblastic leukemia (ALL) with t(1;19)/TCF3-PBX1 is a common genotype, and its prognosis has significantly improved owing to risk stratification and intensive treatment. This study aimed to determine the outcomes and prognostic factors of patients with TCF3-PBX1 treated with the modified Berlin-Frankfurt-Münster protocol., Patients and Methods: Between 2005 and 2017, a total of 1051 pediatric patients with ALL were enrolled. TCF3-PBX1 was detected by reverse-transcriptase PCR and/or cytogenetic analysis. Clinical characteristics and treatment outcomes were analyzed and compared in patients with TCF3-PBX1 and with other B-precursor ALL (B-ALL)., Results: TCF3-PBX1 was detected in 64 patients with ALL (6.1%), and all were of B-cell lineage. These patients were more likely to express the pre-B-ALL immunophenotype (P < .001), be in the National Cancer Institute high-risk group (P = .030), and exhibit more rapid disease clearance during induction therapy (P < .001) compared to patients with other B-ALL. However, the outcomes of this genotype were not better than those of other patients with intermediate risk. At a median (range) follow-up of 60.6 (0.8-184.5) months, the estimated 5-year overall survival was 85.2 ± 4.6% versus 88.2 ± 1.8% (P = .500) and 5-year event-free survival was 76.8 ± 5.5% versus 83.0 ± 2.0% (P = .210) for patients with TCF3-PBX1 and those with other B-ALL. After adjusting for other risk factors, reemergent minimal residual disease (MRD) was the most significant poor prognostic indicator for patients with TCF3-PBX1., Conclusion: The overall outcome of patients with TCF3-PBX1 was intermediate at our institution. Sequential MRD measurement is important for this genotype. Thus, more efforts should be made to eradicate reemergent MRD to improve prognosis., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Classical Hodgkin lymphoma (cHL) is a curable malignancy, with a complete remission rate of approximately 90%. However, relapse remains a significant cause of mortality. Prognostic factors are useful in guiding therapy. This is a large, single-institution study defining the clinicopathologic features, prognostic factors, and treatment outcomes of patients with cHL., Patients and Methods: We reviewed 727 patients with cHL treated at H. Lee Moffitt Cancer Center and Research Institute from 1990 to 2017. Data on demographics, laboratory studies, and disease statuses were collected from the institutional database and electronic medical records. Statistical analyses, overall survival (OS), progression-free survival (PFS), and multivariate analyses were performed., Results: The median age was 35 years. Fifty-four percent of patients were men; 45.6% had advanced stage disease; 82% were treated with ABVD (doxorubicin hydrochloride [adriamycin], bleomycin sulfate, vincristine, and dacarbazine) as frontline therapy; and 70% achieved complete response. The median PFS after first-line treatment was 16.8 years. The median OS of patients with early stage and advanced stage cHL was 19 and 12.9 years, respectively. Poor prognostic factors for OS included older age, advanced stage disease, presence of B symptoms, and a higher International Prognostic Score., Conclusion: Despite high cure rates, cHL accounted for the cause of death in 47% of patients who died during follow-up. Prognostic factors, such as age, stage at diagnosis, International Prognostic Score, and B symptoms, are helpful to guide treatment. Outcomes observed in this study are comparable with those reported in previously published studies., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Legacy data show that ∼40% of children with acute lymphoblastic leukemia (ALL) were cured with limited antimetabolite-based chemotherapy regimens. However, identifying patients with very-low-risk (VLR) ALL remains imprecise. Patients selected based on a combination of presenting features and a minimal residual disease (MRD) level <0.01% on day 19 of induction therapy had excellent outcomes with low-intensity treatment. We investigated the impact of MRD levels between 0.001% and <0.01% early in remission induction on the outcome of VLR ALL treated with a low-intensity regimen. Between October of 2011 and September of 2015, 200 consecutive patients with B-precursor ALL with favorable clinicopathologic features and MRD levels <0.01%, as assessed by flow cytometry in the bone marrow on day 19 and at the end of induction therapy, received reduced-intensity therapy. The 5-year event-free survival was 89.5% (± 2.2% standard error [SE]), and the overall survival was 95.5% (± 1.5% SE). The 5-year cumulative incidence of relapse (CIR) was 7% (95% confidence interval, 4-11%). MRD levels were between 0.001% and <0.01% on day 19 in 29 patients. These patients had a 5-year CIR that was significantly higher than that of patients with undetectable residual leukemia (17.2% ± 7.2% vs 5.3% ± 1.7%, respectively; P = .02). Our study shows that children with VLR ALL can be treated successfully with decreased-intensity therapy, and it suggests that the classification criteria for VLR can be further refined by using a more sensitive MRD assay., (© 2021 by The American Society of Hematology.)

Inotuzumab ozogamicin (InO), an anti-CD22 monoclonal antibody conjugated to calicheamicin, is approved in Europe and the United States for treatment of adults with relapsed or refractory acute lymphoblastic leukemia (ALL). Population analyses were performed to evaluate the relationship between InO exposure and efficacy and safety end points in patients with ALL. The probability of achieving complete remission/complete remission with incomplete hematologic recovery (CR/CRi) and minimal residual disease (MRD)-negativity for InO relative to chemotherapy was also investigated. Data from study 1010 (NCT01363297) and INO-VATE (NCT01564784) were pooled for exposure-response (InO, n = 234) and treatment-response (InO, n = 234; chemotherapy, n = 143) analyses. The analyses demonstrated that InO exposure was significantly correlated with achieving CR/CRi and MRD-negativity, as well as with hepatic event adjudication board-reported veno-occlusive disease/sinusoidal obstruction. Patients with ALL treated with InO had significantly greater odds of achieving CR/CRi (7-times higher) and MRD-negativity (13-times higher) than those receiving chemotherapy., (© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Purpose: Alvocidib is a cyclin-dependent kinase 9 inhibitor leading to downregulation of the antiapoptotic BCL-2 family member, MCL-1. Alvocidib has shown clinical activity in a timed sequential regimen with cytarabine and mitoxantrone in relapsed/refractory and newly diagnosed acute myeloid leukemia (AML) but has not been studied in combination with traditional 7+3 induction therapy., Patients and Methods: A multiinstitutional phase I dose-escalation study of alvocidib on days 1-3 followed by 7+3 (cytarabine 100 mg/m 2 /day i.v. infusion days 5-12 and daunorubicin 60 mg/m 2 i.v. days 5-7) was performed in newly diagnosed AML ≤65 years. Core-binding factor AML was excluded., Results: There was no MTD on this study; the recommended phase II dose of alvocidib was 30 mg/m 2 i.v. over 30 minutes followed by 60 mg/m 2 i.v. infusion over 4 hours. There was one dose-limiting toxicity of cytokine release syndrome. The most common grade ≥3 nonhematologic toxicities were diarrhea (44%) and tumor lysis syndrome (34%). Overall, 69% (22/32) of patients achieved complete remission (CR). In an exploratory cohort, eight of nine (89%) patients in complete remission had no measurable residual disease, as determined by a centralized flow cytometric assay. Clinical activity was seen in patients with secondary AML, AML with myelodysplastic syndrome-related changes, and a genomic signature of secondary AML (50%, 50%, and 92% CR rates, respectively)., Conclusions: Alvocidib can be safely administered prior to 7+3 induction with encouraging clinical activity. These findings warrant further investigation of alvocidib combinations in newly diagnosed AML. This study was registered at clinicaltrials.gov identifier NCT03298984., (©2020 American Association for Cancer Research.)

Background: Primary lymphomas involving the female genital tract are rare, and those arising from cervix are extremely uncommon. They are often misdiagnosed because of their rarity., Methods and Cases: The treatment and clinical outcomes of the four cases treated at our institution were compared with the previously published studies. Written informed consent was taken. We highlight four cases of primary diffuse large B-cell lymphoma of cervix treated at our institution with immunochemotherapy and radiotherapy. The mean age was 50 years (range, 39-62 years). Three patients had stage I disease while one had stage II disease. All the patients were in complete remission following treatment with immunochemotherapy and radiation therapy. The average disease free survival was 20 months (range, 8-43 months). None of the patients had any local or systemic relapse., Conclusion: These cases highlight the physicians to be aware of this entity as their management, natural history and prognosis is completely different from squamous carcinomas of the cervix. Surgery should not be attempted in these patients. Immunochemotherapy and radiotherapy results in favorable clinical outcomes., (© 2020 Wiley Periodicals LLC.)

Purpose: We sought to improve upon frontline bendamustine/rituximab (BR) induction therapy followed by rituximab maintenance in untreated high-risk follicular lymphoma (FL)., Patients and Methods: Patients were randomized to BR induction followed by 2-year rituximab maintenance (BR-R), BR with bortezomib and rituximab maintenance (BVR-R), or BR followed by lenalidomide (1 year) with rituximab maintenance (BR-LR). Dual primary objectives were complete remission (CR) rate and 1-year disease-free survival (DFS); 289 patients enrolled (NCT01216683)., Results: For induction, 92%, 87%, and 86% of patients randomized to BR-R, BVR-R, or BR-LR received six cycles, respectively. CR rate with BR versus BVR induction was 62% versus 75%, respectively ( P = 0.04). One-year DFS rates with BR-R versus BR-LR were 85% versus 67%, respectively ( P = 0.0009). This was due to an imbalance in CR rates post-BR induction and discontinuation due to adverse events (AEs). The most common grade 3-4 AEs for BVR versus BR were neutropenia and sensory neuropathy (12% vs <1%); 83% of the latter occurred with intravenous bortezomib. The most common grade 3-4 AEs related to LR versus rituximab maintenance were neutropenia 66% versus 21%, respectively ( P < 0.0001), and febrile neutropenia 10% versus 2%, respectively ( P = 0.05). The overall treatment-related mortality was 1.4%. With 5-year median follow-up, 3-year PFS rates for BR-R, BVR-R, and BR-LR were 77%, 82%, and 76%, respectively ( P = 0.36) with OS rates of 87%, 90%, and 84%, respectively ( P = 0.79). For prognostication, CR rate and POD-24 were associated with survival., Conclusions: Altogether, neither bortezomib added to BR induction nor lenalidomide added to rituximab maintenance immediately post-BR induction is recommended in untreated FL., (©2020 American Association for Cancer Research.)

Aim: The KEYNOTE-659 study evaluated the efficacy and safety of pembrolizumab in combination with chemotherapy as the first-line treatment in Japanese patients with advanced gastric/gastroesophageal junction (G/GEJ) cancer. In this paper, we report results from cohort 1 (S-1 plus oxaliplatin [SOX] with pembrolizumab)., Methods: This was a non-randomised, multicentre, open-label phase IIb study in patients with advanced programmed death-ligand 1 (PD-L1)-positive, human epidermal growth factor receptor 2-negative G/GEJ tumours. The primary endpoint was the objective response rate (ORR) assessed by blinded independent central review (BICR). Secondary endpoints were duration of response (DOR), disease control rate (DCR), time to response (TTR), progression-free survival (PFS), overall survival (OS) and safety. Exploratory analyses were performed based on the PD-L1 combined positive score (CPS) status., Results: Fifty-four patients were evaluated. The median follow-up was 10.1 months. ORR and DCR by BICR were 72.2% (95% confidence interval [CI] 58.4-83.5) and 96.3% (95% CI 87.3-99.5), respectively. Median DOR, TTR, PFS and OS were as follows: not reached, 1.5 months, 9.4 months and not reached. The ORR was 73.9% in patients with CPS ≥1 to <10 and 71.0% in those with CPS ≥10. Grade ≥3 treatment-related adverse events (TRAEs) were reported by 57.4% of patients. The most common grade ≥3 TRAEs were decreased platelet count (14.8%), decreased neutrophil count (13.0%), colitis (5.6%) and adrenal insufficiency (5.6%)., Conclusions: SOX with pembrolizumab showed encouraging efficacy and a manageable safety profile for the first-line treatment of advanced G/GEJ cancer., Trial Registration: NCT03382600/JapicCTI-183829., Competing Interests: Conflict of interest statement Y. Negoro, M. Tsuda, S Shiratori, S.R. Han and T. Oshima, declare no conflicts of interest. A. Kawazoe reports grants and personal fees from Taiho Pharmaceutical and Ono Pharmaceutical and grants from Sumitomo Dainippon Pharma and MSD, outside the submitted work. N. Machida reports personal fees from Taiho Pharmaceutical and MSD, during the conduct of the study. K. Yamaguchi reports grants and personal fees from Taiho, grants from MSD, during the conduct of the study; grants and personal fees from Chugai Pharm, personal fees from Takeda, personal fees from Merck Serono, personal fees from Bayer, grants and personal fees from Daiichi-Sankyo, grants and personal fees from Ono Pharm, grants and personal fees from Lilly Japan, grants from Gilliad, grants from Dainippon Sumitomo, grants from Boehringer Ingelheim, personal fees from Bristol and grants from Sanofi, outside the submitted work. H. Yasui reports personal fees from Taiho Pharmaceutical and Yakult Honsha and grants from MSD, during the conduct of the study; personal fees from Chugai Pharmaceutical, Bristol-Myers Squibb Japan and Eli Lilly Japan; grants and personal fees from Daiichi Sankyo and grants from Ono Pharmaceutical, outside the submitted work. M. Azuma reports grants and personal fees from Taiho Pharmaceutical during the conduct of the study and grants and personal fees from Ono Pharmaceutical, outside the submitted work. K. Amagai reports grants from MSD, during the conduct of the study; grants from MSD, Taiho Pharmaceutical, Bayer, Hisamitsu and Daiichi Sankyo, outside the submitted work. H. Hara reports grants from Japan Agency for Medical Research and Development (AMED) during the conduct of the study; grants from AstraZeneca, Sumitomo Dainippon Pharma, Merck Serono, Eisai, LSK BioPharma, Incyte, Pfizer, Boehringer-Ingelheim and BeiGene; grants and personal fees from Daiichi Sankyo, MSD, Taiho Pharmaceutical, Chugai Pharmaceutical, Ono Pharmaceutical and BMS and personal fees from Eli Lilly, Yakult Honsha, Sanofi and Takeda Pharmaceutical, outside the submitted work. H. Baba reports grants, personal fees and non-financial support from Taiho Pharmaceutical, during the conduct of the study; grants, personal fees and non-financial support from Ono Pharmaceutical and Eli Lilly Japan; grants and personal fees from Takeda Pharmaceutical and Chugai Pharmaceutical; grants and non-financial support from Merck Serono, Yakult Honsha and Johnson & Johnson and grants from Shionogi & Co, Covidien Japan, Takeda Pharmaceutical, Shin Nippon Biomedical Laboratories, Novartis and Toyama Chemical, outside the submitted work. H. Hosaka reports grants from Taiho Pharmaceutical, Ono Pharmaceutical and Bristol-Myers Squibb, outside the submitted work. H. Kawakami reports personal fees from Bristol-Myers Squibb, Eli Lilly, Taiho Pharmaceutical, Ono Pharmaceutical, Takeda Pharmaceutical, MSD, AstraZeneca, Bayer and Yakult Honsha; grants and personal fees from Chugai Pharmaceutical, Daiichi Sankyo and grants from Eisai, outside the submitted work. Y. Omuro reports grants from MSD, during the conduct of the study and grants from Ono Pharmaceutical, Five Prime, Daiichi Sankyo, Astellas and BeiGene, outside the submitted work. T. Esaki reports grants from Astellas, MSD, Sumitomo Dainippon Pharma, Nihon Kayaku, Novartis and Pfizer; grants and personal fees from Daiichi-Sankyo, Ono Pharmaceutical, Merck Serono, Taiho Pharmaceutical, Eli Lilly, Bayer, Bristol-Myers Squibb; personal fees from Takeda Pharmaceutical, Kyowa Kirin, Chugai Pharmaceutical, Eisai and Sanofi, outside the submitted work. K. Yoshida reports grants and personal fees from Taiho Pharmaceutical and MSD, during the conduct of the study; grants and personal fees from Asahi Kasei Pharma, Chugai Pharmaceutical, Covidien Japan, Daiichi Sankyo, Eisai, Eli Lilly Japan, Johnson & Johnson, Merck Serono, Nippon Kayaku, Novartis, Ono Pharmaceutical, Otsuka Pharmaceutical, Sanofi, Tsumura and Yakult Honsha; grants from Abbott, AbbVie, Astellas, Biogen Japan, Celgene, GlaxoSmithKline, KCI, Kyowa Kirin, Meiji Seika Pharma and Toray Medical and personal fees from AstraZeneca, Bristol-Myers Squibb, Denka, EA Pharma, Olympus, Pfizer, Sanwa Kagaku Kenkyusho, SBI Pharma, Takeda Pharmaceutical, Teijin Pharmaceutical and TERUMO, outside the submitted work. T. Nishina reports grants and personal fees from Taiho Pharmaceutical, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol-Myers Squibb and Eli Lilly and grants from Daiichi Sankyo, MSD and Sumitomo Dainippon Pharma, outside the submitted work. Y. Komatsu reports grants and personal fees from Taiho Pharmaceutical, during the conduct of the study; grants and personal fees from Eli Lilly Japan K.K., Taiho Pharmaceutical, Chugai Pharmaceutical, Takeda Pharmaceutical, Bayer Yakuhin, Ltd., Bristol-Myers Squibb, Sanofi S.A., Merck Biopharma, Ono Pharmaceutical, MSD K.K., Yakult Honsha, Otsuka Pharmaceutical; grants from National Cancer Center Hospital, NanoCarrier, Baxter International Inc., Clinical Co., Ltd., Quintiles and IMS Health, Sysmex Corporation, Mediscience Planning Inc., Sumitomo Dainippon Pharma, Kyowa Kirin, Asahi Kasei Pharma Corporation and Nippon Zoki Pharmaceutical, outside the submitted work. K. Shitara reports grants and personal fees from Astellas Pharma, Eli Lilly, Ono Pharmaceutical and MSD; personal fees from Bristol-Myers Squibb, Takeda Pharmaceutical, Pfizer, Novartis, AbbVie and Yakult Honsha; grants from Sumitomo Dainippon Pharma, Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharmaceutical and MediScience, outside the submitted work., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To compare the outcome of induction-remission in acute lymphoblastic leukaemia patients treated according to two different guidelines., Methods: The descriptive retrospective cohort study was conducted at The Children's Hospital Lahore, Pakistan, and comprised clinical information sheets of acute lymphoblastic leukaemia patients from September 2014 to August 2015. Data regarding demographics, risk categorisation, rapid early response and induction-remission assessment was collected separately for Group 1 patients treated with Lahore protocol and Group 2 patients using United Kingdom acute lymphoblastic leukaemia-2011 interim guidelines. Data was analysed using SPSS version 20.0., Results: Of the 98 patients who had a median age of 6.4 years (interquartile range: 1.5-16 years), 48(49%) were in Group 1 and 50(51%) in Group 2. There were 14(29%) patients with standard risk in Group 1 while 34(71%) were high-risk. The corresponding numbers in Group 2 were 30(60%) and 20(40%) in Group 2. Rapid early response was noted in 18(37.5%) patients in Group 1 and 11(28%) in Group 2. Remission was achieved in 38(79%) patients in Group 1 and 36(72%) in Group 2. There was significant association of rapid early response with induction-remission in Group 2 (p<0.05) but not in Group 1 (p>0.05)., Conclusions: Induction-remission rate was comparable in the two treatment groups, but significant association of rapid early response with induction-remission was observed only in patients treated using United Kingdom acute lymphoblastic leukaemia-2011 interim guidelines.

It remains unclear whether there is a relationship between therapeutic effects of hypomethylating agents (HMAs) and epigenetic modifier gene mutations (EMMs) in patients with cytogenetically intermediate-risk acute myeloid leukemia (IR-AML). Based on targeted-capture sequencing, we retrospectively analyzed the correlation between EMMs and prognosis in 83 IR-AML patients treated with decitabine in combination with cytarabine, aclarubicin hydrochloride and granulocyte colony-stimulating factor (DCAG, n = 35) or "7 + 3" induction regimens (n = 48). In the multivariate analyses, EMM (+) patients did not show any statistically significant difference in remission rates from EMM (-) patients in the DCAG group (p > 0.05), but achieved inferior complete remission (CR; p = 0.03) and overall remission rates (ORR; p = 0.04) after the first course of standard induction regimens (p < 0.05). In the EMM (-) cohort, the DCAG group showed the tendency of adverse total CR (p = 0.06). Besides, DCAG group with EMMs achieved the best survival outcome independent of baseline characteristics, whereas it was opposite in EMM (+) patients receiving standard induction regimens (p < 0.05). Additionally, in the EMM (+) cohort, the survival rate of isolated DCAG group was statistically similar to that of the combination of standard chemotherapies and allogeneic hematopoietic stem cell transplantation (allo-HSCT) (p > 0.40), whereas patients who received only standard regimens had the worst survival rate (0.0%, p < 0.01). It can be concluded that the EMMs might be regarded as the potentially predictive biomarkers of better response to DCAG in IR-AML patients., (© 2019 UICC.)

Purpose: To evaluate the predictive value of the in vitro chemosensitivity using ATP-TCA method to compare the clinical efficacy of patients with AML., Methods: Bone marrow or peripheral blood samples were collected from 65 patients with AML, and the in vitro chemosensitivity of four drugs (cytarabine/idarubicin/decitabine/aclacinomycin) was measured by an ATP-tumor chemosensitivity assay., Results: Aclacinomycin and cytarabine had the highest chemosensitivity rates (66.7%, 8/12 and 58.5%, 38/65, respectively), while idarubicin and decitabine had rates of 6.5% (3/46) and 0% (0/35), respectively. Complete remission (CR) was achieved in 66.2% (43/65) of patients, and there was a statistically significant correlation between CR and in vitro chemosensitivity for cytarabine (47.7% vs 18.5%, p = 0.002), but not for the anthracyclines (p = 0.950). In addition, three other factors significantly correlated with CR: disease status (p = 0.005), FLT3-ITD/TKD mutation (p = 0.003) and chemotherapy regimens (p = 0.004). Furthermore, multiple logistic regression analysis revealed that the sensitivity of cytarabine was one of the significant risk factors for CR [hazard ratio (HR) = 5.52; 95% confidence interval (CI) = 1.47-20.70; p = 0.011]., Conclusions: The in vitro chemosensitivity as tested by ATP-TCA demonstrated a significant correlation with CR for chemotherapy and can be a useful tool to optimize personalized treatments for patients with AML.

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are characterized by a progressive accumulation of leukemic cells in the peripheral blood, bone marrow, and lymphoid tissues. Treatment of CLL/SLL has evolved significantly in recent years because of the improved understanding of the disease biology and the development of novel targeted therapies. In patients with indications for initiating treatment, the selection of treatment should be based on the disease stage, patient's age and overall fitness (performance status and comorbid conditions), and cytogenetic abnormalities. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with CLL/SLL.

GREEN (NCT01905943) is a nonrandomized, open-label, single-arm, phase 3b study investigating the safety and efficacy of obinutuzumab alone or in combination with chemotherapy in chronic lymphocytic leukemia (CLL). We report the preplanned subgroup analysis of 140 previously untreated, fit CLL patients who received obinutuzumab plus fludarabine and cyclophosphamide (G-FC). The primary endpoint was safety and tolerability. Efficacy was the secondary endpoint. Obinutuzumab 1000 mg was administered intravenously on Day (D)1 (dose split D1‒2), D8 and D15 of Cycle (C)1, and D1 of C2-6 (28-day cycles). Standard intravenous/oral doses of fludarabine and cyclophosphamide were administered on D1-3 of C1-6. Overall, 87.1% of patients experienced grade ≥ 3 adverse events (AEs), including neutropenia (67.1%) and thrombocytopenia (17.1%). Serious AEs were experienced by 42.1% of patients. Rates of grade ≥ 3 infusion-related reactions and infections were 19.3% and 15.7%, respectively. Overall response rate was observed in 90.0%, with 46.4% of patients achieving complete response (CR; including CR with incomplete marrow recovery). Minimal residual disease negativity rates were 64.3% in peripheral blood and 35.7% in bone marrow (intent-to-treat analysis). After a median observation time of 25.6 months, 2 year progression-free survival was 91%. Frontline G-FC represents a promising treatment option for fit patients with CLL.

Background: The objective of this study was to conduct the first systematic evaluation of the long-term economic impact of arsenic trioxide (ATO) plus all-trans retinoic acid (ATRA) for the treatment of patients with newly diagnosed acute promyelocytic leukemia (APL) from the perspective of the Chinese health care system., Methods: On the basis of clinical data from a randomized phase 3 trial, a time-dependent Markov model with 4 health states (complete remission, relapse or treatment failure, post-treatment failure, and death) was used to evaluate the incremental costs per quality-adjusted life-year (QALY) gained from the ATO plus ATRA regimen compared with the ATRA plus chemotherapy (CT) regimen over a 30-year period. All costs were adjusted to 2018 levels based on the Chinese Consumer Price Index. Both costs and health outcomes were discounted by 3% annually. One-way sensitivity analysis and probability sensitivity analysis were performed., Results: Compared with the ATRA plus CT strategy, the ATO plus ATRA strategy was associated with 1.38 additional QALYs gained and $392.05 (estimated in 2018 US dollars) in incremental costs per patient over 30 years. Consequently, the incremental cost-effectiveness ratio was $284.02 per QALY gained, which was far below the Chinese willingness-to-pay threshold of $29,306 per QALY gained. Sensitivity analyses demonstrated the robustness of these results., Conclusions: From the perspective of the Chinese health care system, the ATO plus ATRA strategy is cost-effective for patients with newly diagnosed APL compared with the ATRA plus CT strategy. Therefore, the authors strongly suggest that China's health authorities choose the former strategy for these patients, whether for the elderly or for young people., (© 2019 American Cancer Society.)

Background: Omacetaxine mepesuccinate (OME) has antileukemic effects against acute myeloid leukemia (AML) carrying an internal tandem duplication of Fms-like tyrosine kinase 3 (FLT3-ITD). A phase 2 clinical trial was conducted to evaluate a combination treatment of sorafenib and omacetaxine mepesuccinate (SOME)., Methods: Relapsed or refractory (R/R) or newly diagnosed patients were treated with sorafenib (200-400 mg twice daily) and OME (2 mg daily) for 7 (first course) or 5 days (second course onward) every 21 days until disease progression or allogeneic hematopoietic stem cell transplantation (HSCT). The primary endpoint was composite complete remission, which was defined as complete remission (CR) plus complete remission with incomplete hematologic recovery (CRi). Secondary endpoints were leukemia-free survival (LFS) and overall survival (OS)., Results: Thirty-nine R/R patients and 5 newly diagnosed patients were recruited. Among the R/R patients, 28 achieved CR or CRi. Two patients showed partial remission, and 9 patients did not respond. Among the 5 newly diagnosed patients, 4 achieved CR, and 1 achieved CRi. The median LFS and OS were 5.6 and 10.9 months, respectively. Prior Fms-like tyrosine kinase 3 (FLT3) inhibitor exposure (P = .007), 2 or more inductions (P = .001), and coexisting IDH2 (P = .008) and RUNX1 mutations (P = .003) were associated with lower CR/CRi rates. HSCT consolidation and deep molecular responses (defined as an FLT3-ITD variant allelic frequency [VAF] ≤ 0.1% or a nucleophosmin 1 [NPM1] mutant VAF ≤ 0.01%) were associated with better OS and LFS. Prior FLT3 inhibitor exposure and 2 or more inductions were associated with inferior LFS., Conclusions: SOME was safe and effective for R/R and newly diagnosed FLT3-ITD AML., (© 2019 American Cancer Society.)

Acute undifferentiated leukemia (AUL) is a subtype of acute leukemias of ambiguous lineage. There is no standard treatment approach for AUL, although acute lymphoblastic leukemia-like regimens for induction therapy have been used. Additional data suggest that AUL may be better treated as acute myeloid leukemia (AML), given their similarities in genetic, cytogenetic, and gene expression patterns. Somatic mutations of IDH1 are found in 7% to 14% of patients with AML; however, the patient in this study was the first patient with IDH1-mutated AUL treated with ivosidenib. In this case, a woman aged 39 years was found to have anemia and thrombocytopenia after presenting to her primary care physician with fatigue, weight loss, and persistent infections. During further workup of the cytopenia, she was diagnosed with AUL and received 7+3 (daunorubicin, 60 mg/m2/d intravenously on days 1-3, and cytarabine, 100 mg/m2 24-hour continuous intravenous infusion on days 1-7) due to the presence of the IDH1 mutation. Bone marrow biopsy performed on day 14 of 7+3 showed persistent disease, and ivosidenib was initiated due to severe HLA alloimmunization (panel-reactive antibody, 100%) and significant bleeding complications. The patient achieved a complete morphologic and molecular remission on ivosidenib monotherapy despite critical bleeding complications during induction. Targeted therapy using ivosidenib may represent an encouraging therapeutic option in patients with AUL and IDH1 mutations. Additional evaluation of ivosidenib in this subgroup of patients with AUL is needed.

Objective: This study was conducted with the aim of making the contribution to a decision for treatment and determination of the modalities in patients diagnosed with non-Hodgkın lymphoma which increasingly become widespread in the geriatric population., Materials and Methods: Ninety-one patients aged over 65 years diagnosed with lymphoma and treated in Bezmialem Vakıf University Medical Faculty Hospital and Haseki Training and Research Hospital between 2008 and 2013 were retrospectively evaluated. Finally, 63 patients for whom data could be reached were included in the study., Results: Examining the results, histological diagnoses of our patients were as follows: diffuse large B-cell lymphoma (50.8%), follicular lymphoma (23.8%), marginal zone lymphoma (12.7%), mantle cell lymphoma (4.8%), T-cell lymphoma (4.8%), lymphoplasmacytic lymphoma (1.6%) and small lymphocytic lymphoma (1.6%). Stages at the time of diagnosis were early stage by 33.3% and late stage by 66.7%. Of the patients, 36.5% had a low-intermediate and 63.5% a high-intermediate International Prognostic Index score. According to the Eastern Cooperative Oncology Group scoring, 34.9% of the patients have an Eastern Cooperative Oncology Group score of 2-4. Activities of daily living score of 33.3% patients was under 5. Looking at the responses to treatment, the complete response was found in 50.8%, partial response in 4.8%, stable disease in 1.6% and progressive disease in 9.5% of the patients. The mean follow-up duration of patients was found as 25.2 months and disease-free survival after remission as 20.2 months., Conclusion: We found that we have achieved a complete remission in more than half of our patients (50.8%). Based on this, treatment should aim remission in elderly patients.

Introduction: A phase II study was conducted in patients, unsuited for surgery, with locally advanced squamous cell carcinoma of oral cavity (stage III or IV) and without distant metastasis. The objectives were to evaluate overall response (OR) rate and safety of subjects treated with induction regimen docetaxel and cisplatin, followed by definitive chemoradiotherapy (CRT) in this setting., Methods and Materials: Induction regimen consisted of docetaxel 75mg/m2 and cisplatin 75mg/m2 on day 1; cycles repeated every 21 days for three cycles with supportive G-CSF treatment beginning at first cycle. Definitive CRT consisted of weekly cisplatin 30mg/m2 for four weeks starting concomitantly with 60 Gy/30 fractions of conventional radiotherapy for six weeks. Primary and secondary efficacy criteria were OR rate at three weeks after cycle three and eight weeks after last cycle of CRT respectively., Results: Three centers enrolled 35 patients. Primary efficacy endpoint: OR rate of evaluable patients after induction (n=27) was 88.9% (95% CI:71.9-96.2). Complete response (CR) was not achieved by any patient; partial response (PR) was achieved by 88.9% (24/27). From intent to treat (ITT) analysis OR rate was 68.6% (24/35). Secondary efficacy endpoint: OR rate of evaluable patients after definitive CRT (n=19) was 78.9%(95%CI:56.7-91.5) with CR and PR achieved by 2(10.5%) and 13(68.4%) patients respectively. From ITT analysis CR rate was 5.7% (2/35) and OR rate was 42.9% (15/35). During induction most common hematological toxicity was leukopenia in eight patients, with =Grade 3 leukopenia reported in three patients. During CRT most common adverse events were alopecia, stomatitis and nausea., Conclusion: We observed an ITT response rate of 68.6% with induction regimen docetaxel plus cisplatin, with a manageable safety profile. Hence, further investigation in this setting is warranted.

Purpose: Myelodysplastic syndromes (MDSs) refractory or relapsed after hypomethylating agents (HMAs) remain a therapeutic challenge. The CHG regimen has been demonstrated to be effective in initially treating higher risk MDS. The current study evaluated the efficacy and toxicity of the CHG regimen in patients who were resistant to decitabine., Methods: Patients with higher risk MDS relapsed or refractory to decitabine were enrolled in this study. Each patient received the CHG regimen (cytarabine (25 mg/day, days 1-14) and homoharringtonine (1 mg/day, days 1-14) intravenously with G-CSF (300 μg/day) subcutaneously from day 0 until neutrophil count recovery to 2.0 × 10 9 cells/L). Next gene sequencing with a 31-gene panel was carried out in patients., Results: Thirty-three patients were enrolled, including 12 relapsed and 21 refractory cases. The overall response rate (ORR) was 39.4% (13 of 33), with 9 (27.3%) achieving complete remission (CR), 2 having marrow CR (mCR), and 2 achieving partial remission (PR). The CR rate was higher in patients harboring fewer gene mutations (0-1) (55.6%) than in those with more gene mutations (> 1) (12.5%) (p = 0.021). The median overall survival (OS) of the 33 patients was 7.0 months. Patients who achieved a response had significantly longer survival times than were found in those without a response (21.0 M vs. 4.0 M, p < 0.0001). The regimen was endurable for most of the patients., Conclusions: The CHG priming regimen provided a safe and effective salvage regimen for higher risk MDS patients who were resistant to decitabine. Further studies involving larger samples will be needed. Clinical trial No. ChiCTR-ONC-11001501.

The application of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has revolutionized the treatment of acute promyelocytic leukemia (APL). More than 80-90% of patients are expected to be cured with a combination of ATRA, ATO and/or chemotherapy. In this review, we focus on the remaining obstacles to a cure for all patients with APL. We review the issue of early death and coagulopathy and discuss the particular challenges in the care of patients with high-risk APL and patients with relapsed APL. We also give recommendations and highlight ongoing efforts to improve the persistently high early death rate and the outcomes of high risk and relapsed APL patients.

Background: Immune checkpoint inhibitors (ICI) are active in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). Recent data suggest that exposure to ICI improves response to salvage chemotherapy (SCT) in advanced non-small-cell lung cancer. We evaluated response to chemotherapy in patients who had progressed on ICI in patients with R/M SCCHN., Patients and Methods: A retrospective study was conducted at 4 French centres. Eligibility criteria were patients who progressed after treatment with ICI for R/M SCCHN and received SCT and for whom efficacy data were available between September 2014 and January 2018., Results: Of 232 patients treated with ICI, 82 met eligibility criteria: 84% were male. ICI was given as monotherapy in 45% of patients or as combination in 55%. SCT included taxanes (56.1%), cetuximab in combination with taxanes or platinum (50%), platinum-based regimen (36.6%). The median number of treatment lines before SCT was 2 (range 1-6). The objective response rate (ORR) to SCT was 30%. Three patients (4%) presented complete response and 22 patients (27%) had partial response. Median progression-free survival was 3.6 months and median overall survival was 7.8 months. The age at SCT, initial tumour location, number of prior chemotherapy regimens, type of chemotherapy before ICI, best response to ICI, site of relapse and Eastern Cooperative Oncology Group at SCT were not associated with response to SCT on univariate analysis., Conclusion: In R/M SCCHN, the ORR to SCT was high (30%) suggesting that exposure to ICI may increase tumour sensitivity to chemotherapy., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Fms-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations, common in pediatric acute myeloid leukemia (AML), associate with early relapse and poor prognosis. Past studies have suggested additional cooperative mutations are required for leukemogenesis in FLT3-ITD+ AML. Using RNA sequencing and a next-generation targeted gene panel, we broadly characterize the co-occurring genomic alterations in pediatric cytogenetically normal (CN) FLT3-ITD+ AML to gain a deeper understanding of the clonal patterns and heterogeneity at diagnosis and relapse. We show that chimeric transcripts were present in 21 of 34 (62%) of de novo samples, 2 (6%) of these samples included a rare reoccurring fusion partner BCL11B. At diagnosis, the median number of mutations other than FLT3 per patient was 1 (range 0-3), which involved 8 gene pathways; WT1 and NPM1 mutations were frequently observed (35% and 24%, respectively). Fusion transcripts and high variant allele frequency (VAF) mutants, which included WT1, NPM1, SMARCA2, RAD21, and TYK2, were retained from diagnosis to relapse. We did observe reduction in VAF of simple or single mutation clones, but VAFs were preserved or expanded in more complex clones with multiple mutations. Our data provide the first insight into the genomic complexity of pediatric CN FLT3-ITD+ AML and could help stratify future targeted treatment strategies., (© 2019 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Purpose: Bendamustine and rituximab (BR) has been established as a superior frontline therapy over R-CHOP in the treatment of follicular lymphoma (FL). Yttrium-90 Ibritumomab tiuxetan ( 90 YIT) is an effective consolidation strategy after chemotherapy induction. This prospective, single-arm, multicenter, phase II trial evaluated the response rate, progression-free survival (PFS), and tolerability of BR followed by consolidation with 90 YIT in patients with untreated FL., Patients and Methods: The study included grade 1 to 3a FL patients aged ≥18 years, chemotherapy-naïve, and requiring treatment for stage II-IV disease. Study treatment included an initial rituximab treatment, followed by four cycles of BR. Patients were eligible for consolidation with 90 YIT, 6 to 12 weeks after BR, if they obtained at least a partial response after induction had adequate count recovery and bone marrow infiltration < 25%., Results: Thirty-nine patients were treated. Eighty-two percent had an intermediate or high-risk Follicular Lymphoma International Prognostic Index score, and 6 of 39 (15%) were grade 3a. The response rate was 94.8%, and the complete response(CR)/CR unconfirmed (CRu) rate was 77% in the intention-to-treat analysis. The conversion rate from PR to CR/Cru after 90 YIT was 81%. After median follow-up of 45 months, the PFS was 0.71 (95% confidence interval, 0.57-0.89)., Conclusions: This report demonstrates that four cycles of BR followed by consolidation with 90 YIT achieve high response rates that are durable. In addition, consolidation with 90 YIT results in a high conversion rate of PR to CR/CRu. A short course of BR followed by 90 YIT is a safe and effective regimen for frontline treatment of FL., (©2019 American Association for Cancer Research.)

Background: This multicenter, randomized phase 2 trial evaluated complete responses (CRs), efficacy, and safety with ofatumumab and bendamustine and with ofatumumab, bendamustine, and bortezomib in patients with untreated, high-risk follicular lymphoma (FL)., Methods: Patients with grade 1 to 3a FL and either a Follicular Lymphoma International Prognostic Index (FLIPI) score of 2 with 1 lymph node >6 cm or an FLIPI score of 3 to 5 were randomized to arm A (ofatumumab, bendamustine, and maintenance ofatumumab) or to arm B (ofatumumab, bendamustine, bortezomib, and maintenance ofatumumab and bortezomib)., Results: One hundred twenty-eight patients (66 in arm A and 62 in arm B) received treatment. The median age was 61 years, and 61% had disease >6 cm; 29% had an FLIPI score of 2, and 71% had an FLIPI score of 3 to 5. In arm A, 86% completed induction, and 64% completed maintenance. In arm B, 66% and 52% completed induction and maintenance, respectively. Dose modifications were required in 65% and 89% in arms A and B, respectively. Clinically significant grade 3 to 4 toxicities included neutropenia (A, 36%; B, 31%), nausea/vomiting (A, 0%; B, 8%), diarrhea (A, 5%; B, 11%), and sensory neuropathy (A, 0%; B, 5%). The estimated CR rates were 62% (95% confidence interval [CI], 50%-74%) and 60% (95% CI, 47%-72%) in arms A and B, respectively (P = .68). With a median follow-up of 3.3 years, the estimated 2-year progression-free survival (PFS) and overall survival (OS) rates were 80% and 97%, respectively, for arm A and 76% and 91%, respectively, for arm B., Conclusions: The CR rates, PFS, and OS were not improved with the addition of bortezomib to ofatumumab and bendamustine in patients with high-risk FL. Although grade 3 to 4 toxicities were similar, more patients treated with bortezomib required dose modifications and early discontinuation., (© 2019 American Cancer Society.)

Objective: To assess if the use of a dose-dense regimen of chemotherapy can improve the prognosis in patients with primary gastric diffuse large B-cell lymphoma in early stages (I-II) but associated with worse prognostic factors., Methods: One hundred and eight consecutive patients with primary gastric diffuse large B-cell lymphoma in early stages (I-II) with high serum levels of lactic dehydrogenase and beta 2 microglobulin (more than >2 of normal levels), which were associated with a worse prognostic outcome, were treated with a dose-dense chemotherapy: CHOP with increased doses of cyclophosphamide and doxorubicin, was administered every 14 days (instead of 21 days). The end points of this study were to improve outcome measured from progression-free survival and overall survival and to evaluate acute toxicities., Results: Complete response was achieved in 85 patients (78%). Actuarial curves at five years show that progression-free survival was 82% and overall survival was 85%. Hematological toxicities were severe, but no death-related treatment was observed., Conclusions: We considered that in this setting of patients, the use of a dose-dense regimen could be of benefit because it improves outcome and toxicities were well controlled.

Literature on high-dose chemotherapy followed by autologous stem cell rescue in relapsed retinoblastoma is limited to <150 cases reported so far. We present our experience and the challenges faced in the management of a 7-year-old boy with relapsed isolated extraocular retinoblastoma in the right fibula who received salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell rescue. Electrolyte disturbances, renal tubulopathy, and seizures were the most significant transplant-related morbidity. The child is now 3 years postautograft in remission. Monitoring for second malignant neoplasm and late side effects remain the main challenges in the years to come.

Acute myeloid leukemia (AML) is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths due to leukemias in the United States. Recent advances have resulted in an expansion of treatment options for AML, especially concerning targeted therapies and low-intensity regimens. This portion of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AML focuses on the management of AML and provides recommendations on the workup, diagnostic evaluation and treatment options for younger (age <60 years) and older (age ≥60 years) adult patients.

Background: Disease progression within < 2 years of initial chemoimmunotherapy and patient age > 60 years have been associated with poor overall survival (OS) in follicular lymphoma (FL). No standard treatment exists for these high-risk patients, and the effectiveness of sequential therapies remains unclear., Patients and Methods: We studied the course of FL with first-, second-, and third-line treatment. Using large population-based data, we identified 5234 patients with FL diagnosed in 2000 to 2009. Of these patients, 71% had received second-line therapy < 2 years, and 29% had received no therapy after first-line therapy, with a median OS of < 3 years. Treatment included rituximab, R-CVP (rituximab, cyclophosphamide, vincristine), R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine), R-Other (other rituximab-containing), and other regimens. The Aalen-Johansen estimator and Cox proportional hazards models were used to quantify the outcomes and assess the effects of the clinical and sociodemographic factors., Results: R-CHOP demonstrated the most favorable 5-year OS among first- (71%), second- (55%), and third-line (61%) therapies. First-line R-CHOP improved OS (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.50-0.64) and reduced the mortality risks after first-line (HR, 0.60; 95% CI, 0.47-0.77), second-line (HR, 0.40; 95% CI, 0.29-0.53), and third-line (HR, 0.63; 95% CI, 0.53-0.76) treatments. B-symptoms, being married, and histologic grade 1/2 were associated with the use of earlier second-line therapy. Early progression from second- to third-line therapy was associated with poor OS. The repeated use of R-CHOP or R-CVP as first- and second-line treatment yielded high 2-year mortality rates (R-CHOP + R-CHOP, 17.3%; R-CVP + R-CVP, 21.1%)., Conclusion: Our multistate approach assessed the effect of sequential therapy on the immediate and subsequent treatment-line outcomes. We found that R-CHOP in any line improved OS for patients with high-risk FL., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To evaluate the efficacy and toxicity of VMP regimen applied to the patients with low-risk gestational trophoblastic neoplasia (LR-GTN) treated in Anhui provincial hospital., Materials and Methods: Between 2005 and 2017, 87 patients with low-risk gestational trophoblastic neoplasia received VMP regimen, consisted of vincristine (VCR), methotrexate (MTX) and platinum (cisplatin, carboplatin or nedaplatin), 68 of whom received VMP as their first-line chemotherapy, and 19 methotrexate-failed patients received VMP regimen as their second-line chemotherapy. The staging and scoring system was based on International Federation of Gynecology and Obstetrics (FIGO 2000) criteria. We describe and analyze their baseline characteristics, remission/resistance/recurrence rates, adverse reactions and prognosis., Results: The first-line VMP protocol can achieve an 83.8% remission rate and it tended to develop resistance when the pretreatment β-hCG reaches 7503.5 IU/L, and can achieve complete remission with FAV and EMA-CO as the salvage regimen. Among the 19 methotrexate-failed patients, 2 of whom were yet resistant to VMP regimen, followed by several courses of salvage chemotherapy such as FAV and EMP, and achieved 89.5% remission rate in second-line VMP group. Resistance to this regimen was obviously related with higher pre-treatment HCG whether used as primary or salvage treatment. Severe myelosuppression (grade 3 or 4) was shown in 4 (5.9%) of 68 cases, of which none was grade 4., Conclusion: For patients diagnosed with LR-GTN VMP regimen was a safe and effective treatment with a high rate of remission., (Copyright © 2019. Published by Elsevier B.V.)

Background: Elderly patients with acute myeloid leukemia (AML) have generally had a poor prognosis with unfavorable clinical and biologic disease features. Hypomethylating agents have shown potential for treating medically unfit and elderly patients with AML., Patients and Methods: We compared the outcomes of elderly patients with AML treated with decitabine and intensive chemotherapy (IC)., Results: The data from 107 patients with newly diagnosed AML aged ≥ 65 years were analyzed. The overall response rate was 38.6% and was significantly greater in the IC group than in the decitabine group (65.6% vs. 26.1%; P < .001). With a median follow-up duration of survivors of 14.8 months, the median overall survival (OS) and event-free survival were 12.3 months (95% confidence interval [CI], 10.0-14.7) and 2.0 months (95% CI, 2.0-2.0), respectively, which were not different between the 2 treatment groups. The FLT3-internal tandem duplication mutation (hazard ratio [HR], 2.637; 95% CI, 1.379-5.043; P = .003), complex karyotype (HR, 2.513; 95% CI, 1.258-5.020; P = .009), and peripheral blood blast percentage at diagnosis (HR, 1.983; 95% CI, 1.148-3.422; P = .014) were analyzed as independent prognostic factors for OS. A subgroup analysis for OS showed that IC was superior to decitabine for patients with the FLT3-internal tandem duplication mutation (P = .025) and poor risk cytogenetics, except for -7/del(7q) (P = .005), and decitabine was associated with longer OS for patients with -7/del(7q) (P = .077)., Conclusion: Decitabine showed a similar OS to IC, despite the lower response rate in patients. The clinical outcomes of specific subgroups seemed to differ with different treatment options. Optimal therapeutic approaches for elderly patients with AML should be further examined., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Pancreatic ductal adenocarcinoma (PDAC) exhibits a variety of phenotypes with regard to disease progression and treatment response. This variability complicates clinical decision-making despite the improvement of survival due to the recent introduction of FOLFIRINOX (FFX) and nab-paclitaxel. Questions remain as to the timing and sequence of therapies and the role of radiotherapy for unresectable PDAC. Here we developed a computational analysis platform to investigate the dynamics of growth, metastasis and treatment response to FFX, gemcitabine (GEM), and GEM+nab-paclitaxel. Our approach was informed using data of 1,089 patients treated at the Massachusetts General Hospital and validated using an independent cohort from Osaka Medical College. Our framework establishes a logistic growth pattern of PDAC and defines the Local Advancement Index (LAI), which determines the eventual primary tumor size and predicts the number of metastases. We found that a smaller LAI leads to a larger metastatic burden. Furthermore, our analyses ascertain that i) radiotherapy after induction chemotherapy improves survival in cases receiving induction FFX or with larger LAI, ii) neoadjuvant chemotherapy improves survival in cases with resectable PDAC, and iii) temporary cessations of chemotherapies do not impact overall survival, which supports the feasibility of treatment holidays for patients with FFX-associated adverse effects. Our findings inform clinical decision-making for PDAC patients and allow for the rational design of clinical strategies using FFX, GEM, GEM+nab-paclitaxel, neoadjuvant chemotherapy, and radiation., Competing Interests: The authors have declared that no competing interests exist.

Here we evaluated whether sequential high-dose chemotherapy (sHD) increased the early complete remission (CR) rate in acute myelogenous leukemia (AML) compared with standard-intensity idarubicin-cytarabine-etoposide (ICE) chemotherapy. This study enrolled 574 patients (age, 16-73 years; median, 52 years) who were randomly assigned to ICE (n = 286 evaluable) or sHD (2 weekly 3-day blocks with cytarabine 2 g/m 2 twice a day for 2 days plus idarubicin; n = 286 evaluable). Responsive patients were risk-stratified for a second randomization. Standard-risk patients received autograft or repetitive blood stem cell-supported high-dose courses. High-risk patients (and standard-risk patients not mobilizing stem cells) underwent allotransplantation. CR rates after 2 induction courses were comparable between ICE (80.8%) and sHD (83.6%; P = . 38). sHD yielded a higher single-induction CR rate (69.2% vs 81.5%; P = . 0007) with lower resistance risk ( P < .0001), comparable mortality ( P = . 39), and improved 5-year overall survival (39% vs 49%; P = . 045) and relapse-free survival (36% vs 48%; P = . 028), despite greater hematotoxicity delaying or reducing consolidation blocks. sHD improved the early CR rate in high-risk AML (odds ratio, 0.48; 95% confidence interval [CI], 0.31-0.74; P = . 0008) and in patients aged 60 years and less with de novo AML (odds ratio, 0.46; 95% CI, 0.27-0.78; P = . 003), and also improved overall/relapse-free survival in the latter group (hazard ratio, 0.70; 95% CI, 0.52-0.94; P = . 01), in standard-risk AML, and postallograft (hazard ratio, 0.61; 95% CI, 0.39-0.96; P = . 03). sHD was feasible, effectively achieved rapid CR, and improved outcomes in AML subsets. This study is registered at www.clinicaltrials.gov as #NCT00495287., (© 2019 by The American Society of Hematology.)

Background: Primary central nervous system lymphomas (PCNSLs) are mainly diffuse large B-cell lymphomas (DLBCLs) of the non-germinal center B-cell (non-GCB) subtype. This study aimed to determine the efficacy of rituximab plus lenalidomide (R2) in DLBCL-PCNSL., Patients and Methods: Patients with refractory/relapsed (R/R) DLBCL-PCNSL or primary vitreoretinal lymphoma (PVRL) were included in this prospective phase II study. The induction treatment consisted of eight 28-day cycles of R2 (rituximab 375/m2 i.v. D1; lenalidomide 20 mg/day, D1-21 for cycle 1; and 25 mg/day, D1-21 for the subsequent cycles); in responding patients, the induction treatment was followed by a maintenance phase comprising 12 28-day cycles of lenalidomide alone (10 mg/day, D1-21). The primary end point was the overall response rate (ORR) at the end of induction (P0 = 10%; P1 = 30%)., Results: Fifty patients were included. Forty-five patients (PCNSL, N = 34; PVRL, N = 11) were assessable for response. The ORR at the end of induction was 35.6% (95% CI 21.9-51.2) in assessable patients and 32.0% (95% CI 21.9-51.2) in the intent-to-treat analysis, including 13 complete responses (CR)/unconfirmed CR (uCR; 29%) and 3 partial responses (PR; 7%). The best responses were 18 CR/uCR (40%) and 12 PR (27%) during the induction phase. The maintenance phase was started and completed by 18 and 5 patients, respectively. With a median follow-up of 19.2 months (range 1.5-31), the median progression-free survival (PFS) and overall survival (OS) were 7.8 months (95% CI 3.9-11.3) and 17.7 months (95% CI 12.9 to not reached), respectively. No unexpected toxicity was observed. The peripheral baseline CD4/CD8 ratio impacted PFS [median PFS = 9.5 months (95% CI, 8.1-14.8] for CD4/CD8 ≥ 1.6; median PFS = 2.8 months, [95% CI, 1.1-7.8) for CD4/CD8 < 1.6, P = 0.03)., Conclusions: The R2 regimen showed significant activity in R/R PCNSL and PVRL patients. These results support assessments of the efficacy of R2 combined with methotrexate-based chemotherapy as a first-line treatment of PCNSL., Clinical Trials Number: NCT01956695., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Patients with relapsed/refractory acute myeloid leukemia after hematopoietic stem cell transplantation (HSCT) have a poor prognosis, with a 2-year survival rate of 14%. The optimal treatment for these patients remains unclear. To treat these patients, we designed a new salvage regimen consisting of decitabine, cladribine, cytarabine, and granulocyte-stimulating factor (D-CLAG)., Case Presentation: Here, we describe a case of acute monocytic leukemia with a complex karyotype in a 38-year-old female patient who relapsed after her first HSCT, which was performed using a matched sibling donor. The patient did not respond to standard induction chemotherapy and subsequently achieved complete remission with the D-CLAG regimen. No severe hematological or extramedullary toxicity was observed. Subsequently, the patient received a second D-CLAG regimen as a bridge therapy and directly underwent haploidentical related HSCT. Following HSCT, the marrow showed complete hematologic and cytogenetic remission. Currently, 1 year after transplantation, the patient's general condition remains good., Conclusions: This case suggests that the D-CLAG regimen can be an option for reinduction in relapsed refractory AML patients as a bridge to transplantation. Nevertheless, further research will be required in the future as this report describes only a single case.

Purpose: A delayed-onset effect of clofarabine in the treatment of an adult patient with acute myeloid leukemia (AML) is reported., Summary: A 44-year-old African-American man with pancytopenia was transferred to an academic medical center for evaluation. His medical history included bipolar depression, gynecomastia, and HIV infection (diagnosed 5 years prior) for which he was being treated with atazanavir, emtricitabine-tenofovir, and ritonavir. He was diagnosed with AML with 60% myeloblasts found during bone marrow biopsy. He had primary refractory disease after induction chemotherapy treatment. His disease was refractory to subsequent therapy with high-dose cytarabine and then etoposide and mitoxantrone. The patient then underwent treatment with granulocyte-colony stimulating factor-primed clofarabine and cytarabine (G-CLAC). At blood count recovery, he was diagnosed with refractory disease, with 17% blasts in peripheral blood and was subsequently discharged home on hospice 38 days after G-CLAC and 19 days after the last dose of filgrastim. He arrived at the outpatient clinic 79 days after G-CLAC chemotherapy with significantly improved blood counts. Two weeks later, a bone marrow biopsy confirmed complete remission with incomplete hematologic recovery., Conclusion: A patient with relapsed AML achieved a delayed response to clofarabine at least 38 days after treatment., (© American Society of Health-System Pharmacists 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)