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Summary Background Daunorubicin and cytarabine are used as standard induction chemotherapy for patients with acute myeloid leukaemia. CPX-351 is a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio. Primary analysis of the phase 3 trial in adults aged 60–75 years with newly diagnosed high-risk or secondary acute myeloid leukaemia provided support for approval of CPX-351 by the US Food and Drug Administration and European Medicines Agency. We describe the prospectively planned final 5-year follow-up results. Methods This randomised, open-label, multicentre, phase 3 trial was done across 39 academic and regional cancer centres in the USA and Canada. Eligible patients were aged 60–75 years and had a pathological diagnosis of acute myeloid leukaemia according to WHO 2008 criteria, no previous induction therapy for acute myeloid leukaemia, and an Eastern Cooperative Oncology Group performance status of 0–2. Patients were randomly assigned 1:1 (stratified by age and acute myeloid leukaemia subtype) to receive up to two induction cycles of CPX-351 (100 units/m2 administered as a 90-min intravenous infusion on days 1, 3, and 5; on days 1 and 3 for the second induction) or standard chemotherapy (cytarabine 100 mg/m2 per day continuous intravenous infusion for 7 days plus intravenous daunorubicin 60 mg/m2 on days 1, 2, and 3 [7+3]; cytarabine for 5 days and daunorubicin on days 1 and 2 for the second induction [5+2]). Patients with complete remission or complete remission with incomplete neutrophil or platelet recovery could receive up to tw cycles of consolidation therapy with CPX-351 (65 units/m2 90-min infusion on days 1 and 3) or chemotherapy (5+2, same dosage as in the second induction cycle). The primary outcome was overall survival analysed in all randomly assigned patients. No additional adverse events were collected with long-term follow-up, except data for deaths. This trial is registered with ClinicalTrials.gov , NCT01696084 , and is complete. Findings Between Dec 20, 2012, and Nov 11, 2014, 309 patients with newly diagnosed high-risk or secondary acute myeloid leukaemia were enrolled and randomly assigned to receive CPX-351 (153 patients) or 7+3 (156 patients). At a median follow-up of 60·91 months (IQR 60·06–62·98) in the CPX-351 group and 59·93 months (59·73–60·50) in the 7+3 group, median overall survival was 9·33 months (95% CI 6·37–11·86) with CPX-351 and 5·95 months (4·99–7·75) with 7+3 (HR 0·70, 95% CI 0·55–0·91). 5-year overall survival was 18% (95% CI 12–25%) in the CPX-351 group and 8% (4–13%) in the 7+3 group. The most common cause of death in both groups was progressive leukaemia (70 [56%] of 124 deaths in the CPX-351 group and 74 [53%] of 140 deaths in the 7+3 group). Six (5%) of 124 deaths in the CPX-351 group and seven (5%) of 140 deaths in the 7+3 group were considered related to study treatment. Interpretation After 5 years of follow-up, the improved overall survival with CPX-351 versus 7+3 was maintained, which supports the previous evidence that CPX-351 can contribute to long-term remission and improved overall survival in patients aged 60–75 years with newly diagnosed high-risk or secondary acute myeloid leukaemia. Funding Jazz Pharmaceuticals.

Context: Mutations in isocitrate dehydrogenase 1 (IDH1) occur in ~3% of patients with MDS and are associated with increased transformation to acute myeloid leukemia (AML). IVO is an oral, potent, targeted inhibitor of the mutant IDH1 (mIDH1) enzyme and is FDA-approved for mIDH1 R/R AML and mIDH1 newly diagnosed AML in patients ≥75 years old or with comorbidities precluding the use of intensive induction chemotherapy. In the first-in-human, phase 1 study of IVO in patients with mIDH1 advanced hematologic malignancies (NCT02074839), 12 patients with R/R MDS, with median age 72.5 years (range 52–78), received IVO 500 mg once daily (QD). All patients received prior MDS treatment. Investigator-assessed ORR (CR + PR + marrow CR, per IWG 2006) was 75% (95% CI 43–95), with median duration of response of 21.4 months (95% CI 2.3–NE). Nine (75%) patients were transfusion-independent for ≥56 days during treatment. No dose-limiting toxicities or adverse events leading to treatment discontinuation were reported among patients with MDS. Based on these encouraging data, the FDA granted Breakthrough Therapy Designation to IVO in mIDH1 MDS; the study was amended to enroll additional patients with mIDH1 R/R MDS. Objective: To evaluate safety, tolerability, clinical activity, and pharmacokinetics/pharmacodynamics of IVO in patients with mIDH1 R/R MDS. Design: A sub-study of the single-arm, open-label, phase 1 dose escalation and expansion study of IVO in mIDH1 advanced hematologic malignancies, evaluating patients with R/R MDS. Patients must have R/R disease after prior standard therapy; high disease burden based on cytopenia and/or transfusion dependence at baseline; an Eastern Cooperative Oncology Group performance status score of 0–2; and be amenable to bone marrow aspirate and/or core biopsy at specified study timepoints. Patients with documented AML are not eligible. IVO 500 mg QD orally on days 1–28 of 28-day cycles. Results: Study is open; enrollment of ~23 patients from the US and France planned. Results not yet available. Conclusions: This sub-study will provide additional insights into safety, tolerability, clinical activity, and pharmacokinetics/pharmacodynamics of treatment with IVO in patients with mIDH1 R/R MDS. Funding: Agios; Servier.

Natural killer (NK) cells are an emerging immunotherapy approach to acute myeloid leukemia (AML); however, the optimal approach to activate NK cells before adoptive transfer remains unclear. Human NK cells that are primed with the CTV-1 leukemia cell line lysate CNDO-109 exhibit enhanced cytotoxicity against NK-cell-resistant cell lines. To translate this finding to the clinic, CNDO-109-activated NK cells (CNDO-109-NK cells) isolated from related human leukocyte antigen complex (HLA)-haploidentical donors were evaluated in a phase 1 dose-escalation trial at doses of 3×10^5 (n=3), 1×10^6 (n=3), and 3×10^6 (n=6) cells/kg in patients with AML in first complete remission (CR1) at high risk for recurrence. Before CNDO-109-NK cell administration, patients were treated with lymphodepleting fludarabine/cyclophosphamide. CNDO-109-NK cells were well tolerated, and no dose-limiting toxicities were observed at the highest tested dose. The median relapse free (RFS) survival by dose level was 105 (3×10^5), 156 (1×10^6), and 337 (3×10^6) days. Two patients remain relapse-free in post-trial follow-up, with RFS durations exceeding 42.5 months. Donor NK cell micro-chimerism was detected on Day 7 in 10 of 12 patients, with 3 patients having evidence of donor cells on day 14 or later. This trial establishes that CNDO-109-NK cells generated from related HLA-haploidentical donors, cryopreserved, and then safely administered to AML patients with transient persistence without exogenous cytokine support. Three durable complete remissions of 32.6 to 47.6+ months were observed, suggesting additional clinical investigation of CNDO-109-NK cells for patients with myeloid malignancies, alone or in combination with additional immunotherapy strategies, is warranted.

Context: IVO is an oral, potent, targeted inhibitor of the mutant IDH1 (mIDH1) enzyme, approved in the US for the treatment of AML with a susceptible IDH1 mutation in adults with newly diagnosed AML ≥75 years of age or having comorbidities precluding intensive induction chemotherapy, and in adults with R/R AML. In a phase 1 dose escalation and expansion study of IVO in mIDH1 advanced hematologic malignancies ( NCT02074839 ), 12 patients with R/R MDS received IVO 500 mg once daily (QD). Median age was 72.5 years (range 52–78). All patients had received prior treatment for MDS, with 3 (25.0%) and 1 (8.3%) having received 2 or ≥3 prior therapies, respectively. Investigator-assessed ORR (CR + PR + marrow CR) per International Working Group 2006 criteria was 75.0% (95% CI 42.8%, 94.5%) with a median duration of 21.4 months (95% CI 2.3, not estimable). Nine patients (75.0%) were transfusion independent for ≥56 days during study treatment. Based on these data, the FDA recently granted a Breakthrough Therapy Designation status for IVO monotherapy in this indication, and the study has been amended to enroll additional mIDH1 R/R MDS patients. Objective: To assess safety, tolerability, clinical activity, pharmacokinetics, and pharmacodynamics of IVO in patients with mIDH1 R/R MDS. Design: This is a sub-study of the phase 1 study of IVO in mIDH1 advanced hematologic malignancies to evaluate patients with mIDH1 R/R MDS. Patients must have R/R disease after treatment with standard agents indicated for MDS and high disease burden based on cytopenia and/or transfusion dependence at baseline. IVO will be administered at a dose of 500 mg QD orally on Days 1–28 of 28-day cycles. Results: The study is open and will enroll ∼23 patients from the US and France; results not yet available. Conclusions: The favorable efficacy and safety of IVO in the small population of patients with mIDH1 R/R MDS in the phase 1 clinical study supports further evaluation in this MDS sub-study. This sub-study will provide additional insights into safety, tolerability, clinical activity, and pharmacokinetics/pharmacodynamics of treatment with IVO in patients with mIDH1 R/R MDS. Funding: Agios.

BACKGROUND: Safe and effective treatments are urgently needed for patients with relapsed or refractory acute myeloid leukaemia. We investigated the efficacy and safety of vosaroxin, a first-in-class anticancer quinolone derivative, plus cytarabine in patients with relapsed or refractory acute myeloid leukaemia. METHODS: This phase 3, double-blind, placebo-controlled trial was undertaken at 101 international sites. Eligible patients with acute myeloid leukaemia were aged 18 years of age or older and had refractory disease or were in first relapse after one or two cycles of previous induction chemotherapy, including at least one cycle of anthracycline (or anthracenedione) plus cytarabine. Patients were randomly assigned 1:1 to vosaroxin (90 mg/m(2) intravenously on days 1 and 4 in a first cycle; 70 mg/m(2) in subsequent cycles) plus cytarabine (1 g/m(2) intravenously on days 1-5) or placebo plus cytarabine through a central interactive voice system with a permuted block procedure stratified by disease status, age, and geographical location. All participants were masked to treatment assignment. The primary efficacy endpoint was overall survival and the primary safety endpoint was 30-day and 60-day all-cause mortality. Efficacy analyses were done by intention to treat; safety analyses included all treated patients. This study is registered with ClinicalTrials.gov, number NCT01191801. FINDINGS: Between Dec 17, 2010, and Sept 25, 2013, 711 patients were randomly assigned to vosaroxin plus cytarabine (n=356) or placebo plus cytarabine (n=355). At the final analysis, median overall survival was 7·5 months (95% CI 6·4-8·5) in the vosaroxin plus cytarabine group and 6·1 months (5·2-7·1) in the placebo plus cytarabine group (hazard ratio 0·87, 95% CI 0·73-1·02; unstratified log-rank p=0·061; stratified p=0·024). A higher proportion of patients achieved complete remission in the vosaroxin plus cytarabine group than in the placebo plus cytarabine group (107 [30%] of 356 patients vs 58 [16%] of 355 patients, p

It is unknown whether clinical characteristics can successfully predict which multiple myeloma (MM) patients would be poor mobilizers with growth factor (GF) alone so they can be assigned to mobilization with chemotherapy + GF or GF + plerixafor. MM patients (N = 477) who underwent autologous mobilization with GF were retrospectively reviewed and assigned into training and validation cohorts. In multiple regression analysis, age, platelet count at time of mobilization, type of GF utilized, and extent of exposure to lenalidomide independently correlated with peripheral blood (PB)-CD34+ and were integrated in a predicting score (PS) for poor mobilizers, defined as PB-CD34+

Introduction Large granular lymphocytosis (LGL) is observed following hematopoietic stem cell transplantation (HSCT) in 0.5-18.4% of patients. The development of LGL has been associated with and attributed to various conditions such as immune system reconstitution, CMV viremia, and graft-versus-host disease. There is literature available that suggests the development of LGL may be associated with improved outcomes, but management varies greatly because of the different theories surrounding this condition. Thus, we aimed to review a cohort of patients from our institution who developed LGL after HSCT in order to further our understanding and guide management recommendations. Methods We performed a single-center retrospective cohort analysis of patients who had a hematopoietic stem cell transplant from April 1, 2015 to June 30, 2018 and developed large granular lymphocytosis up to one year after transplantation. We collected and reviewed various clinical aspects of each patientOs transplant course and the management of large granular lymphocytosis. Results Of the 127 patients who received an allogeneic HSCT in this time period, 13 patients (10%) were diagnosed with large granular lymphocytosis. Patient demographics, transplant information, and LGL management are listed in Table 1. LGL was diagnosed between 57 and 236 days post-transplant. None of the 13 patients developed EBV viremia by PCR after transplant. 7 of 13 (54%) had CMV viremia/reactivation by PCR after transplant but before LGL diagnosis; 3 of 13 (23%) had CMV viremia by PCR after LGL diagnosis; 3 of 13 (23%) did not develop CMV viremia by PCR before or after LGL diagnosis. 4 of 13 (31%) developed chronic GVHD, and 3 of 13 (23%) developed acute GVHD. Of note, 6 of 13 (46%) had post-transplant cyclophosphamide and 2 of 13 (15%) had CD34 selected grafts; therefore, 8 of 13 (62%) had T-cell depleted transplants. All of the patients in this cohort were alive at day 100. 11 patients had a transplant greater than 1 year ago, and all of these patients were alive at the 1-year mark. Conclusions Based upon the results from this study, we cannot definitively attribute the development of LGL after allogeneic HSCT to one etiology. More importantly, all patients were alive at day 100 and 1 year regardless of the management approach, which suggests that this process may be self-limiting. Therefore, we believe a more conservative and supportive approach to management is warranted.

Polyoma virus BK-induced hemorrhagic cystitis is an important cause of morbidity after hematopoietic stem cell transplantation (HSCT). Fluoroquinolones have been shown in vitro to inhibit BK viral replication by direct inhibition of the BK-encoded DNA gyrase. We hypothesized that extended prophylaxis with ciprofloxacin may decrease the incidence of severe (grades 3 and 4) BK virus-associated hemorrhagic cystitis (sBKHC) after HSCT. We retrospectively collected patient and transplant data, as well as incidence of sBKHC, for all consecutive patients undergoing allogeneic HSCT between June 2006 and August 2010 at our institution. Prophylaxis for sBKHC with ciprofloxacin 500 mg orally twice daily from day 0 until day 60 had been instituted in March 2009, delimiting a group receiving ciprofloxacin prophylaxis (CP) or no prophylaxis (NP). We compared the cumulative incidence of sBKHC in CP and NP, including death in absence of sBKHC as a competing risk. Ninety-two consecutive patients were included in the analysis, 44 in CP and 48 in NP. Median age of patients was 50 years (range: 19-70), and 47% received a myeloablative conditioning regimen. The cumulative incidence of sBKHC was significantly reduced in CP (2.6% versus 20.9%, P = .01). Multivariate Cox regression analysis revealed that assignment to CP and concomitant acute graft-versus-host disease (GVHD) were the only factors independently associated with the occurrence of sBKHC. Patients in CP did not experience a higher risk of Clostridium difficile diarrhea and were less likely to develop episodes of bacteremia. Ciprofloxacin prophylaxis appears safe and effective in reducing the incidence of severe BKHC after allogeneic HSCT.

We present the first known case of the monoblastic type of myeloid sarcoma (also known as extramedullary myeloid tumor, chloroma, and granulocytic sarcoma) with diffuse involvement of the gastrointestinal tract. The patient originally presented with diarrhea and crampy abdominal discomfort. Endoscopically, the disease showed a diffuse inflammatory process mimicking a number of benign conditions, such as inflammatory bowel disease and autoimmune enteropathy. Sequential biopsies of the upper and lower gastrointestinal tract showed a diffuse infiltrate of increasingly atypical cells. The disease progressed to systemic involvement, including widespread lymphadenopathy, splenomegaly, and pulmonary deposits; the patient died 13 months after the development of initial symptoms. The immunohistochemical and histologic profiles of this case are diagnostic of the monoblastic type of myeloid sarcoma.

Summary Background Primary gastric non-Hodgkin's lymphoma (PG-NHL) is common in Saudi Arabia. This has prompted the analysis of a large series of patients with PG-NHL having high-grade diffuse large B-cell lymphoma (DLCL) in order to define the clinical features and outcome of this disease. Patients and methods The data of all adult patients in the series with PG-NHL having DLCL histology were retrospectively reviewed. Patients were eligible if they had biopsy-confirmed diagnoses obtained by endoscopy or following laparotomy. Results Over a 16-year period, 185 patients with DLCL PG-NHL were identified and their data were reviewed. Patients had a median age of 54 years. In 53% of them only one initial therapeutic modality was given, while 47% were managed by a multi-modality approach. One hundred forty patients (76%), 19 (10%), and 26 (14%) attained complete remission (CR), partial remission, and no response/progressive disease, respectively. Multivariate analysis showed that poor performance status and advanced stage were negatively associated with the likelihood of attaining CR. Over a median follow-up of 54 months, 118 (64%) of the patients were alive and disease-free, 17 (9%) were alive with evidence of disease, and the remaining 50 (27%) were dead. The projected 5-year and 10-year overall survivals (OS) (±SD) were 68% (±4%) and 61% (±6%), respectively. The Cox proportional hazards model identified the same variables of response as adverse prognostic factors of survival. Using the influence of performance status, and stage, a prognostic index was constructed to recognize three prognostically distinctive risk categories with overall survival proportions of 87%, 61%, and 45%, respectively. The unadjusted International Prognostic Index, however, failed to classify patients into prognostically meaningful risk strata. Of the 140 patients who achieved CR, the median disease-free survival (DFS) was not reached, but the predicted 5- and 10-year DFS were 82% and 75%, respectively. A multivariate analysis identified poor performance status as the only independent prognostic covariate that adversely influenced DFS. Our analysis showed that compared with single-modality management, multi-modality strategy attained significantly higher CR, and advantageous OS and DFS. Conclusions This large series characterized the clinicopathologic features and outcome of patients with DLCL PG-NHL. Performance status, and stage significantly influenced patient outcome. A prognostic index was developed and it identified three prognostically distinctive risk groups; however, prospective validation is warranted.

We recently reported that combinations of 4-hydroperoxycyclophosphamide (4-HC), an analog of activated cyclophosphamide, and cisplatin have cytotoxic synergism in human leukemia cell lines. We now report that the synergism is sequence-dependent: it was only present when the cells were exposed to 4-HC first. To determine whether the synergism observed was associated with a net increase in total cellular cisplatin levels, platinum levels were measured in leukemic cells using flameless atomic absorption spectroscopy

and quantified CagA translocation by Western blot using anti-phosphotyrosine and antiCagA antibodies. Significantly higher levels of CagA were translocated by the 7.13 0310mutant compared to wild-type H. pylori strain 7.13. By utilizing proteomics technology to contrast two closely related H. pylori strains that induce distinct phenotypes, we have shown that HP0310 may function to alter levels of peptidoglycan, thereby affecting the composition of substrates translocated by the cag secretion system. These studies also provide an important foundation for investigating the role of bacterial virulence factors in H. pylori-induced pathologic sequelae, as such results would ultimately allow for generation of a profile of H. pylori proteins to use for screening persons infected with strains most likely to induce severe disease.

the adequacy of current screening interval. Methods: Three hundreds one medical records from the patients who underwent surgical treatment for primary GC at Korea University Ansan Hospital from January 2002 through December 2006 were reviewed retrospectively. After patients were divided into three groups according to the previous history of gastric endoscopy and the motivation for endoscopic examination based on the presence or absence of symptoms: the group I, patients with repeated endoscopy within the last 2 years (before the detection of GC) regardless of symptom (nZ12), the group II, asymptomatic patients without endoscopic screening within the last 2 years (nZ37), and the group III, symptomatic patiens without endoscopy (nZ252), the clinicopathologic characteristics of three groups were compared. Results: The proportion of early gastric cancer and the tumor size among the 3 groups were 75% vs. 68% vs. 41% (pZ0.001) and 2.7 ! 3.6 cm vs. 4.1 ! 2.5 cm vs. 5.2 ! 3.3 cm (p Z 0.012), respectively. GC in the group I and II was characterized by smaller cancer in an earlier stage. However, notable differences among the 3 gropus were not found in age, sex, tumor location and histology. Conclusion: Endoscopic screening for asymptomatic patients is useful for detecting GC at the early stage. Probably, periodic(2 years interval) endoscopy enables early detection of GC at a smaller size regardless of symptom.

The results of therapy with carbenicillin plus trimethoprim-sulfamethoxazole (C-T/S) were compared to those obtained with carbenicillin plus gentamicin (C-G) in a prospective double-blind study of empiric antibiotic therapy in granulocytopenic patients. Patients were stratified into two groups: favorable-prognosis, group 1 (carcinoma, lymphoma, multiple myeloma), or unfavorable-prognosis, group 2 (acute leukemia, bone marrow transplantation), based on anticipated duration of granulocytopenia. Over-all, empiric antibiotic trials were more often successful (P = 0.004) in group 1 (55 of 62 patients or 89 per cent) than in group 2 (42 of 64 patients, 66 per cent). Within group 1, there was a favorable outcome in 30 of 32 (94 per cent) C-T/S trials and in 25 of 30 (83 per cent) C-G trials (P = 0.25); within group 2, there was a favorable outcome in 23 of 30 (77 per cent) C-T/S trials and in 19 of 34 (56 per cent) C-G trials (P = 0.14). Combined results in both groups indicated a higher proportion of favorable outcome in C-T/S trials (53 of 62, 85 per cent) than in C-G trials (44 of 64, 69 per cent). Further analysis (Mantel-Haenszel test) showed the over-all difference in outcome to be significant (P = 0.049), but the general applicability of this result may be limited by the rather low incidence of gram-negative bacterial infections in this study. There was no difference between the treatment regimens in antibiotic toxicity, and serious superinfection occurred only in group 2 patients (21 per cent of trials), equally divided between treatment arms. Initial protocol dosing achieved target plasma levels of trimethoprim (3 to 8 μg/ml) or gentamicin (4 to 10 μg/ml) in 57 of 68 (84 per cent) C-T/S trials compared to 21 of 60 (35 per cent) C-G trials.

The three components of body mass, body cell mass (BCM), extracellular fluid (ECF), and fat + extracellular solids (ECS: bone, tendon, etc) can be quantified using established isotope dilution techniques. With these techniques, total body water (TBW) and ECF are measured using 3H2O and 82Bromine, respectively, as tracers. BCM is calculated from intracellular fluid (ICF) where ICF = TBW - ECF. Fat + ECS is estimated as: body weight - (BCM + ECF). TBW and ECF can be determined by either of two calculation methods, one requiring several timed plasma samples (extrapolation method) and one requiring a single plasma sample and a 4-h urine collection (urine-corrected method). The comparability of the two calculation methods was evaluated in 20 studies in 12 bone marrow transplant recipients. We found that for determination of TBW and ECF there was a very strong linear relationship (r2 greater than 0.98) between the calculation methods. Further comparisons (by t test, 2-sided) indicated that for the determination of ECF, the methods were not significantly (p greater than 0.90) different; however, TBW determined by the urine-corrected method was slightly (0.1 to 6%), but significantly (p less than 0.01) greater than that determined by the extrapolation method. Therefore, relative to the extrapolation method, the urine-corrected method "over-estimates" BCM and "under-estimates" fat + ECS since determination of these compartment sizes depends on measurement of TBW. We currently use serial isotope dilution studies to monitor the body composition changes of patients receiving therapeutic nutritional support.