Clinical significance of occult cerebrospinal fluid involvement assessed by flow cytometry in non‐Hodgkin’s lymphoma patients at high risk of central nervous system disease in the rituximab era

Background and aim: Flow cytometry (FCM) analysis of cerebrospinal fluid (CSF) is more sensitive than conventional cytology (CC) for diagnosis of lymphomatous meningeosis, but the clinical significance of occult central nervous system (CNS) disease (positive FCM with negative CC) remains unknown. Patients and methods: CSF samples from 105 patients with newly diagnosed aggressive lymphomas at high risk of CNS involvement were prospectively studied by both CC and FCM, and results were correlated with cumulative incidence of CNS relapse and overall survival (OS). Patients were divided into three groups: 1) patients without CNS involvement (CC?/FCM?; n = 83); 2) individuals with occult CNS disease (FCM+/CC?; n = 15); and 3) cases with CNS disease (CC+/FCM+; n = 7). Results: Six cases showed CNS relapse or progression: two in Group 1 (2.4%), two in Group 2 (13%) and two in Group 3 (28.5%) (Group 2 vs. 1, P = 0.04; Group 3 vs. 1, P < 0.001). Patients from Groups 2 (P = 0.05) and 3 (P < 0.001) also showed a higher cumulative incidence of CNS relapse than those from Group 1. Significant differences were observed in OS between FCM?/CC? and FCM+/CC+ cases (P = 0.02), while patients with occult CNS disease (FCM+/CC?) displayed intermediate OS rates, although differences did not reach statistical significance. Conclusions: The presence of occult CNS involvement at diagnosis in patients with NHL at high risk of CNS disease is associated with a higher probability of CNS relapse.     

High sensitivity of flow cytometry improves detection of occult leptomeningeal disease in acute lymphoblastic leukemia and lymphoblastic lymphoma

Conventional cytology (CC) of cerebrospinal fluid (CSF) fails to demonstrate malignant cells in up to 45 % of patients with acute lymphoblastic leukemia or lymphoblastic lymphoma (ALL/LL) in whom occult leptomeningeal disease is present. Flow cytometry (FCM) is considered more sensitive than CC, but clinical implications of CC negativity/CC positivity are not yet established. CSF samples from 38 adult patients with newly diagnosed ALL/LL were examined. Five (13 %) and nine (24 %) specimens were CC positive-FC positive (FCM^pos/CC^pos) and CC negative-FC positive (CC^neg/FCM^pos), respectively. The remaining 24 (63 %) samples were double negative (CC^neg/FCM^neg) (p?=?0.001). CC^neg/FCM^pos patients showed a significantly shorter overall survival (OS) compared to CC^neg/FCM^neg ones. In multivariate analysis, the status of single FCM positivity was demonstrated to affect independently duration of OS (p?=?0.005). In conclusion, FCM significantly improves detection of leptomeningeal occult localization in ALL/LL and appears to anticipate an adverse outcome. Further prospective studies on larger series are needed to confirm this preliminary observation.     

Carfilzomib,cyclophosphamide and dexamethasone for newly diagnosed,high-risk myeloma patients not eligible for transplant: a pooled analysis of two studies

Despite remarkable advances in the treatment of multiple myeloma (MM) in the last decades, the prognosis of patients harboring highrisk cytogenetic abnormalities remains dismal as compared to that of standard-risk patients. Proteasome inhibitors have been demonstrated to partially ameliorate the prognosis of high-risk patients. We pooled together data from two phase I/II trials on transplant-ineligible patients with MM receiving upfront carfilzomib cyclophosphamide and dexamethasone followed by carfilzomib maintenance. The aim of this analysis was to compare treatment outcomes in patients with standard-risk versus high-risk cytogenetic abnormalities detected by fluorescence in situ hybridization (FISH) analysis. High risk was defined by the presence of at least one chromosomal abnormality, including t(4;14), del17p and t(14;16). Overall, 94 patients were included in the analysis: 57 (61%) in the standard-risk and 37 (39%) in the high-risk group. Median follow-up was 38 months. In standard- risk versus high-risk patients, we observed similar progression-free survival (PFS) (3-year PFS: 52% vs. 43%, respectively; P=0.50), overall survival (OS) (3-year OS: 78% vs. 73%; P=0.38), and overall response rate (88% vs. 95%; P=0.47), with no statistical differences between the two groups. No difference in terms of PFS was observed between patients with or without del17p. Carfilzomib, used both as induction and maintenance agent for transplant-ineligible newly diagnosed MM patients, mitigated the poor prognosis carried by high-risk cytogenetics and resulted in similar PFS and OS as in standard-risk patients. (Registered at clinicaltrials.gov identifiers: {"type":"clinical-trial","attrs":{"text":"NCT01857115","term_id":"NCT01857115"}}NCT01857115 [IST-CAR-561] and {"type":"clinical-trial","attrs":{"text":"NCT01346787","term_id":"NCT01346787"}}NCT01346787 [IST-CAR-506].)     

Allogeneic hematopoietic cell transplantation with non-myeloablative conditioning for patients with hematologic malignancies: improved outcomes over two decades

We have used a non-myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation for the past 20 years. During that period, changes in clinical practice have been aimed at reducing morbidity and mortality from infections, organ toxicity, and graft-versus-host disease. We hypothesized that improvements in clinical practice led to better transplantation outcomes over time. From 1997–2017, 1,720 patients with hematologic malignancies received low-dose total body irradiation ± fludarabine or clofarabine before transplantation from HLAmatched sibling or unrelated donors, followed by mycophenolate mofetil and a calcineurin inhibitor ± sirolimus. We compared outcomes in three cohorts by year of transplantation: 1997–2003 (n=562), 2004–2009 (n =594), and 2010–2017 (n=564). The proportion of patients ≥60 years old increased from 27% in 1997–2003 to 56% in 2010–2017, and with scores from the Hematopoietic Cell Transplantation Comorbidity Index of ≥3 increased from 25% in 1997–2003 to 45% in 2010–2017. Use of unrelated donors increased from 34% in 1997–2003 to 65% in 2010–2017. When outcomes from 2004–2009 and 2010–2017 were compared to 1997–2003, improvements were noted in overall survival (P=0.0001 for 2004–2009 and P≤0.0001 for 2010–2017), progression-free survival (P=0.002 for 2004–2009 and P<0.0001 for 2010–2017), non-relapse mortality (P<0.0001 for 2004– 2009 and P<0.0001 for 2010–2017), and in rates of grades 2–4 acute and chronic graft-versus-host disease. For patients with hematologic malignancies who underwent transplantation with non-myeloablative conditioning, outcomes have improved during the past two decades. Trials reported are registered under clinicaltrials gov. Identifiers: {"type":"clinical-trial","attrs":{"text":"NCT00003145","term_id":"NCT00003145"}}NCT00003145, {"type":"clinical-trial","attrs":{"text":"NCT00003196","term_id":"NCT00003196"}}NCT00003196, 005803, {"type":"clinical-trial","attrs":{"text":"NCT00006251","term_id":"NCT00006251"}}NCT00006251, {"type":"clinical-trial","attrs":{"text":"NCT00014235","term_id":"NCT00014235"}}NCT00014235, {"type":"clinical-trial","attrs":{"text":"NCT00027820","term_id":"NCT00027820"}}NCT00027820, {"type":"clinical-trial","attrs":{"text":"NCT00031655","term_id":"NCT00031655"}}NCT00031655, {"type":"clinical-trial","attrs":{"text":"NCT00036738","term_id":"NCT00036738"}}NCT00036738, {"type":"clinical-trial","attrs":{"text":"NCT00045435","term_id":"NCT00045435"}}NCT00045435, NCT00052546, {"type":"clinical-trial","attrs":{"text":"NCT00060424","term_id":"NCT00060424"}}NCT00060424, {"type":"clinical-trial","attrs":{"text":"NCT00075478","term_id":"NCT00075478"}}NCT00075478, {"type":"clinical-trial","attrs":{"text":"NCT00078858","term_id":"NCT00078858"}}NCT00078858, {"type":"clinical-trial","attrs":{"text":"NCT00089011","term_id":"NCT00089011"}}NCT00089011, {"type":"clinical-trial","attrs":{"text":"NCT00104858","term_id":"NCT00104858"}}NCT00104858, {"type":"clinical-trial","attrs":{"text":"NCT00105001","term_id":"NCT00105001"}}NCT00105001, {"type":"clinical-trial","attrs":{"text":"NCT00110058","term_id":"NCT00110058"}}NCT00110058, {"type":"clinical-trial","attrs":{"text":"NCT00397813","term_id":"NCT00397813"}}NCT00397813, {"type":"clinical-trial","attrs":{"text":"NCT00793572","term_id":"NCT00793572"}}NCT00793572, {"type":"clinical-trial","attrs":{"text":"NCT01231412","term_id":"NCT01231412"}}NCT01231412, {"type":"clinical-trial","attrs":{"text":"NCT01252667","term_id":"NCT01252667"}}NCT01252667, {"type":"clinical-trial","attrs":{"text":"NCT01527045","term_id":"NCT01527045"}}NCT01527045.     

A phase II,single-centre trial of neoadjuvant toripalimab plus chemotherapy in locally advanced esophageal squamous cell carcinoma

BackgroundEsophageal squamous cell carcinoma (ESCC) remains a challenging malignancy with poor prognosis and limited therapeutic methods. However, recent clinical trials of immune checkpoint inhibitors (ICIs) have shown promising results in the treatment of lethal malignancies. The second-line treatment of late-stage ESCC was approved based on the results of KEYNOTE-180, KEYNOTE-181 and ATTRACTION-1, ATTRACTION-3. Combining ICIs with chemotherapy in neoadjuvant therapy may benefit patients with locally advanced, resectable ESCC.MethodsA two-arm phase II trial was launched in July 2019 in Henan Cancer Hospital. The primary outcome measure will be completed within 21 months. The pathological complete response (pCR) rate is the primary endpoint, and the secondary endpoints include overall survival (OS), disease-free survival (DFS), the toxicities of the neoadjuvant toripalimab plus chemotherapy, the relationship between combined positivity score (CPS) of specimen and the treatment response, the relationship between lymphocyte infiltration and the treatment response, the progression-free survival (PFS) rate, and adverse events (AEs). It was assumed that the pCR rate of this trial might be 25%. Therefore, the 30 enrolled patients could reject the hypothesis at 75% (α=0.1).DiscussionThe study will determine the safety and efficacy of neoadjuvant immunochemotherapy for ESCC and provide enough evidence for phase III clinical trials.Trial registrationClinical Trials.gov, {"type":"clinical-trial","attrs":{"text":"NCT03985670","term_id":"NCT03985670"}}NCT03985670, Registered: October 24, 2019, https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S0008Z9D&selectaction=Edit&uid=U0002MIY&ts=2&cx=-i71o4q. Registry name: “Teripalimab Plus Chemotherapy in Local Advanced Esophageal Cancer”.     

Pediatric-inspired chemotherapy incorporating pegaspargase is safe and results in high rates of minimal residual disease negativity in adults up to the age of 60 years with Philadelphia chromosome-negative acute lymphoblastic leukemia

Administration of pediatric-inspired chemotherapy to adults up to age 60 with acute lymphoblastic leukemia (ALL) is challenging in part due to toxicities of asparaginase as well as myelosuppression. We conducted a multi-center phase II clinical trial (clinicaltrials gov. Identifier: {"type":"clinical-trial","attrs":{"text":"NCT01920737","term_id":"NCT01920737"}}NCT01920737) investigating a pediatric-inspired regimen, based on the augmented arm of the Children’s Cancer Group 1882 protocol, incorporating six doses of pegaspargase 2,000 IU/m2, rationally synchronized to avoid overlapping toxicity with other agents. We treated 39 adults aged 20-60 years (median age 38 years) with newly-diagnosed ALL (n=31) or lymphoblastic lymphoma (n=8). Grade 3-4 hyperbilirubinemia occurred frequently and at higher rates in patients aged 40-60 years (n=18) versus 18-39 years (n=21) (44% vs. 10%, P=0.025). However, eight of nine patients rechallenged with pegaspargase did not experience recurrent grade 3-4 hyperbilirubinemia. Grade 3-4 hypertriglyceridemia and hypofibrinogenemia were common (each 59%). Asparaginase activity at 7 days post-infusion reflected levels associated with adequate asparagine depletion, even among those with antibodies to pegaspargase. Complete response (CR)/CR with incomplete hematologic recovery was observed post-induction in 38 of 39 (97%) patients. Among patients with ALL, rates of minimal residual disease negativity by multi-parameter flow cytometry were 33% and 83% following induction phase I and phase II, respectively. Event-free and overall survival at 3 years (67.8% and 76.4%) compare favorably to outcomes observed in other series. These results demonstrate pegaspargase can be administered in the context of intensive multi-agent chemotherapy to adults aged ≤60 years with manageable toxicity. This regimen may serve as an effective backbone into which novel agents may be incorporated in future frontline studies. Trial registration: https://clinicaltrials. gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT01920737","term_id":"NCT01920737"}}NCT01920737     

Cardiovascular adverse events in patients with chronic lymphocytic leukemia receiving acalabrutinib monotherapy: pooled analysis of 762 patients

Cardiovascular (CV) toxicities of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib may limit use of this effective therapy in patients with chronic lymphocytic leukemia (CLL). Acalabrutinib is a second-generation BTK inhibitor with greater BTK selectivity. This analysis characterizes pooled CV adverse events (AE) data in patients with CLL who received acalabrutinib monotherapy in clinical trials (clinicaltrials gov. Identifier: {"type":"clinical-trial","attrs":{"text":"NCT02029443","term_id":"NCT02029443"}}NCT02029443, {"type":"clinical-trial","attrs":{"text":"NCT02475681","term_id":"NCT02475681"}}NCT02475681, {"type":"clinical-trial","attrs":{"text":"NCT02970318","term_id":"NCT02970318"}}NCT02970318 and {"type":"clinical-trial","attrs":{"text":"NCT02337829","term_id":"NCT02337829"}}NCT02337829). Acalabrutinib was given orally at total daily doses of 100–400 mg, later switched to 100 mg twice daily, and continued until disease progression or toxicity. Data from 762 patients (median age: 67 years [range, 32–89]; median follow-up: 25.9 months [range, 0–58.5]) were analyzed. Cardiac AE of any grade were reported in 129 patients (17%; grade ≥3, n=37 [5%]) and led to treatment discontinuation in seven patients (1%). The most common any-grade cardiac AE were atrial fibrillation/flutter (5%), palpitations (3%), and tachycardia (2%). Overall, 91% of patients with cardiac AE had CV risk factors before acalabrutinib treatment. Among 38 patients with atrial fibrillation/flutter events, seven (18%) had prior history of arrhythmia or atrial fibrillation/flutter. Hypertension AE were reported in 67 patients (9%), 43 (64%) of whom had a preexisting history of hypertension; no patients discontinued treatment due to hypertension. No sudden cardiac deaths were reported. Overall, these data demonstrate a low incidence of new-onset cardiac AE with acalabrutinib in patients with CLL. Findings from the head-to-head, randomized trial of ibrutinib and acalabrutinib in patients with high-risk CLL (clinicaltrials gov. Identifier: {"type":"clinical-trial","attrs":{"text":"NCT02477696","term_id":"NCT02477696"}}NCT02477696) prospectively assess differences in CV toxicity between the two agents.     

AG-348 (mitapivat), an allosteric activator of red blood cell pyruvate kinase,increases enzymatic activity,protein stability,and adenosine triphosphate levels over a broad range of PKLR genotypes

Pyruvate kinase (PK) deficiency is a rare hereditary disorder affecting red blood cell (RBC) glycolysis, causing changes in metabolism including a deficiency in adenosine triphosphate (ATP). This affects red cell homeostasis, promoting premature removal of RBC from the circulation. In this study, we characterized and evaluated the effect of AG-348, an allosteric activator of PK that is currently in clinical trials for treatment of PK deficiency, on RBC and erythroid precursors from PK-deficient patients. In 15 patients, ex vivo treatment with AG-348 resulted in increased enzymatic activity in all patients'' cells after 24 hours (h) (mean increase: 1.8-fold; range: 1.2-3.4). ATP levels increased (mean increase: 1.5-fold; range: 1.0-2.2) similar to control cells (mean increase: 1.6-fold; range: 1.4-1.8). Generally, PK thermostability was strongly reduced in PK-deficient RBC. Ex vivo treatment with AG-348 increased residual activity from 1.4- to >10-fold more than residual activity of vehicle-treated samples. Protein analyses suggest that a sufficient level of PK protein is required for cells to respond to AG- 348 treatment ex vivo, as treatment effects were minimal in patient cells with very low or undetectable levels of PK-R. In half of the patients, ex vivo treatment with AG-348 was associated with an increase in RBC deformability. These data support the hypothesis that drug intervention with AG- 348 effectively up-regulates PK enzymatic activity and increases stability in PK-deficient RBC over a broad range of PKLR genotypes. The concomitant increase in ATP levels suggests that glycolytic pathway activity may be restored. AG-348 treatment may represent an attractive way to correct the underlying pathologies of PK deficiency. (AG-348 is currently in clinical trials for the treatment of PK deficiency. Registered at clinicaltrials.gov identifiers: {"type":"clinical-trial","attrs":{"text":"NCT02476916","term_id":"NCT02476916"}}NCT02476916, {"type":"clinical-trial","attrs":{"text":"NCT03853798","term_id":"NCT03853798"}}NCT03853798, {"type":"clinical-trial","attrs":{"text":"NCT03548220","term_id":"NCT03548220"}}NCT03548220, {"type":"clinical-trial","attrs":{"text":"NCT03559699","term_id":"NCT03559699"}}NCT03559699).     

Factors Predictive of Treatment-Emergent Adverse Events of Prucalopride: An Integrated Analysis of Four Randomized,Double-Blind,Placebo-Controlled Trials

Background/AimsThis integrated analysis aimed to identify the factors associated with the most frequently reported treatment-emergent adverse events (TEAEs) in Asian and non-Asian patients with chronic constipation (CC) who receive prucalopride or placebo over 12 weeks.MethodsPooled data from four randomized, double-blind, placebo-controlled, multicenter, phase III studies ({"type":"clinical-trial","attrs":{"text":"NCT00488137","term_id":"NCT00488137"}}NCT00488137, {"type":"clinical-trial","attrs":{"text":"NCT00483886","term_id":"NCT00483886"}}NCT00483886, {"type":"clinical-trial","attrs":{"text":"NCT00485940","term_id":"NCT00485940"}}NCT00485940, and {"type":"clinical-trial","attrs":{"text":"NCT01116206","term_id":"NCT01116206"}}NCT01116206) on patients treated with prucalopride 2 mg or placebo were analyzed. The associations between predictors and TEAEs were evaluated based on a logistic regression model.ResultsOverall, 1,821 patients (Asian, 26.1%; non-Asian, 73.9%) were analyzed. Prucalopride treatment was significantly associated with diarrhea, headache, and nausea (p<0.001), but not with abdominal pain, compared with placebo. Differences in the prevalence of TEAEs between prucalopride and placebo decreased greatly after the first day of treatment. Compared with non-Asians, Asians were more likely to experience diarrhea and less likely to develop abdominal pain, headache, and nausea. Prior laxative use, CC duration, and body weight were not predictive of any of these TEAEs.ConclusionsPrucalopride treatment was positively associated with diarrhea, headache, and nausea. Asian patients tended to have a higher frequency of diarrhea but lower frequencies of headache, abdominal pain, and nausea compared with non-Asians.     

Clofarabine increases the eradication of minimal residual disease of primary B-precursor acute lymphoblastic leukemia compared to high-dose cytarabine without improvement of outcome. Results from the randomized clinical trial 08-09 of the Cooperative Acute Lymphoblastic Leukemia Study Group.

Novel treatment strategies are needed to improve cure for all children with acute lymphoblastic leukemia (ALL). To this end, we investigated the therapeutic potential of clofarabine in primary ALL in trial CoALL 08-09 (clinicaltrials gov. identifier: {"type":"clinical-trial","attrs":{"text":"NCT01228331","term_id":"NCT01228331"}}NCT01228331). The primary study objective was the minimal residual disease (MRD)- based comparative assessment of cytotoxic efficacies of clofarabine 5x40 mg/m² versus high-dose cytarabine (HIDAC) 4x3g/m², both in combination with PEG-ASP 2,500 IU/m² as randomized intervention in early consolidation. The secondary objective was an outcome analysis focused on treatment arm dependence and MRD after randomized intervention. In B-cell precursor (BCP)-ALL, eradication of MRD was more profound after clofarabine compared to cytarabine, with 93 versus 79 of 143 randomized patients per arm reaching MRD-negativity (c² test P=0.03, leftsided P [Fisher’s exact test]=0.04). MRD status of BCP-ALL after randomized intervention maintained its prognostic relevance, with a significant impact on event-free survival (EFS) and relapse rate. However, no difference in outcome regarding EFS and overall survival (OS) between randomized courses was observed (5-year EFS: clofarabine 85.7, SE=4.1 vs. HIDAC 84.8, SE=4.7 [P=0.96]; OS: 95.7, SE=1.9 vs. 92.2, SE=3.2 [P=0.59]), independent of covariates or overall risk strata. Severe toxicities between randomized and subsequent treatment elements were also without significant difference. In conclusion, clofarabine/PEG-ASP is effective and safe, but greater cytotoxic efficacy of clofarabine compared to HIDAC did not translate into improved outcomes indicating a lack of surrogacy of post-intervention MRD at the trial level as opposed to the patient level, which hampers a broader implementation of this regimen in the frontline treatment of ALL.     

Characterization of breakthrough hemolysis events observed in the phase III randomized studies of ravulizumab versus eculizumab in adults with paroxysmal nocturnal hemoglobinuria

Eculizumab is first-line treatment for paroxysmal nocturnal hemoglobinuria (PNH); however, approximately 11-27% of patients may experience breakthrough hemolysis (BTH) on approved doses of eculizumab. Ravulizumab, a new long-acting C5 inhibitor with a four times longer mean half-life than eculizumab, provides immediate, complete, and sustained C5 inhibition over 8-week dosing intervals. In two phase III studies, ravulizumab was non-inferior to eculizumab (Pinf ≤0.0004) for the BTH endpoint; fewer patients experienced BTH with ravulizumab versus eculizumab in both studies (301 [complement inhibitor−naïve patients], 4.0% vs. 10.7%; 302 [patients stabilized on eculizumab at baseline], 0% vs. 5.1%). In the current analysis, patientlevel data were evaluated to assess causes and clinical parameters associated with incidents of BTH reported during the 26-week treatment periods in the ravulizumab phase III PNH studies. Of the five BTH events occurring in ravulizumab-treated patients across the studies, none were temporally associated with suboptimal C5 inhibition (free C5 ≥0.5 mg/mL); four (80%) were temporally associated with complement-amplifying conditions (CAC). Of the 22 events occurring in eculizumab-treated patients, 11 were temporally associated with suboptimal C5 inhibition, including three events also associated with concomitant infection. Six events were associated with CAC only. Five events were unrelated to free C5 elevation or reported CAC. These results suggest that the immediate, complete, and sustained C5 inhibition achieved through weight-based dosing of ravulizumab reduces the risk of BTH by eliminating BTH associated with suboptimal C5 inhibition in patients with PNH. (Registered at clinicaltrials.gov identifiers: Study 301, {"type":"clinical-trial","attrs":{"text":"NCT02946463","term_id":"NCT02946463"}}NCT02946463; Study 302, {"type":"clinical-trial","attrs":{"text":"NCT03056040","term_id":"NCT03056040"}}NCT03056040.)     

Role of antithymocyte globulin in matched sibling donor peripheral blood stem cell transplantation for hematologic malignancies

Background:High incidence of chronic graft-versus-host disease (GVHD) has been a major drawback of matched sibling donor peripheral blood stem cell transplantation (MSD -PBSCT). This study aimed to investigate the safety and efficacy of antithymocyte globulin (ATG) as a standardized part of GVHD prophylaxis in patients receiving MSD -PBSCT.Methods:A total of 72 patients with hematological malignancies receiving MSD -PBSCT who displayed similar baseline characteristics were either given rabbit ATG ( n = 42) or no ATG (n = 30), in addition to cyclosporine, methotrexate, and mycophenolate mofetil as a standard GVHD prophylaxis regimen. Either patients or donors aged ≥40 years were included in the study. Thymoglobulin was administered at a daily dose of 1.5 mg/kg on day −5 and 3.5 mg/kg on day −4 prior to transplant (the total dose was 5 mg/kg)Results:After a median follow-up of 874 days, the 3-year cumulative incidence of chronic GVHD (cGVHD) was 37.3% in the ATG group and 52.1% in the non -ATG group. The 3-year overall and disease-free survival probability were 71.0% and 62.0% (ATG versus non -ATG, P = .262) and 66.7% and 58.4% (ATG versus non -ATG, P = .334). No difference was found in the 2-year cumulative incidence of nonrelapse mortality and relapse between the ATG and non -ATG groups. This significant reduction in the incidence of cGVHD without increased relapse risk and nonrelapse mortality led to a 3-year GVHD-free, relapse-free survival probability of 66.7% and 40.0% in the ATG and non-ATG groups, respectively.Conclusions:These data suggested that rabbit antithymocyte globulin in the current protocol for GVHD prophylaxis was well tolerable and efficacious.The clinical trial was registered on January 1, 2016 (ClinicalTrials.gov Identifier {"type":"clinical-trial","attrs":{"text":"NCT02677181","term_id":"NCT02677181"}}NCT02677181). https://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT02677181","term_id":"NCT02677181"}}NCT02677181.     

Involvement of central nervous system in adult patients with acute myeloid leukemia: Incidence and impact on outcome

Incidence and effect on outcome of central nervous system (CNS) involvement in adult patients with acute myeloid leukemia (AML) is not clearly defined. To address this issue, 103 consecutive adult patients with newly diagnosed AML, regardless of neurologic symptoms, were submitted to a routine explorative lumbar puncture. Cerebrospinal fluid (CSF) samples were collected from 65 males and 38 females. All 103 CSF samples were examined by conventional cytology (CC) whereas 95 (92%) also by flow cytometry (FCM). At diagnosis, 70 patients (68%) were CNS negative (CNS−), whereas 33 (32%) were CNS positive (CNS+). In 11 of 33 (33%), CNS infiltration was documented either by CC or FCM , in 21 (67%) only by FCM. CNS positivity was significantly associated with a M4-M5 phenotype of the underlying AML (P = .0003) and with high levels of lactate dehydrogenase (P = .006). Overall, 80 of 103 (78%) achieved complete remission with no significant differences between CNS+ and CNS− patients. Five-year disease-free survival and overall survival were found to be shorter in CNS+ patients than in those CNS− (18% vs 50%, P = .006 and 19% vs 46%, P = .02, respectively). In multivariate analysis, CNS status and age were found to affect independently overall survival. In conclusion, the incidence of CNS involvement in adult patients with newly diagnosed AML is higher than expected. Regardless of neurologic symptoms, it should always be searched at diagnosis; CSF samples should routinely be investigated by FCM since a certain proportion of CNS involvements might remain undetected if examination is exclusively CC based.     

Molecular response assessment by quantitative real-time polymerase chain reaction after induction therapy in NPM1-mutated patients identifies those at high risk of relapse

Monitoring minimal residual disease is an important way to identify patients with acute myeloid leukemia at high risk of relapse. In this study we investigated the prognostic potential of minimal residual disease monitoring by quantitative real-time polymerase chain reaction analysis of NPM1 mutations in patients treated in the AMLCG 1999, 2004 and 2008 trials. Minimal residual disease was monitored - in aplasia, after induction therapy, after consolidation therapy, and during follow-up - in 588 samples from 158 patients positive for NPM1 mutations A, B and D (with a sensitivity of 10⁻⁶). One hundred and twenty-seven patients (80.4%) achieved complete remission after induction therapy and, of these, 56 patients (44.1%) relapsed. At each checkpoint, minimal residual disease cut-offs were calculated. After induction therapy a cut-off NPM1 mutation ratio of 0.01 was associated with a high hazard ratio of 4.26 and the highest sensitivity of 76% for the prediction of relapse. This was reflected in a cumulative incidence of relapse after 2 years of 77.8% for patients with ratios above the cut-off versus 26.4% for those with ratios below the cut-off. In the favorable subgroup according to European LeukemiaNet, the cut-off after induction therapy also separated the cohort into two prognostic groups with a cumulative incidence of relapse of 76% versus 6% after 2 years. Our data demonstrate that in addition to pre-therapeutic factors, the course of minimal residual disease in an individual is an important prognostic factor and could be included in clinical trials for the guidance of post-remission therapy. The trials from which data were obtained were registered at www.clinicaltrials.gov (#{"type":"clinical-trial","attrs":{"text":"NCT01382147","term_id":"NCT01382147"}}NCT01382147, #{"type":"clinical-trial","attrs":{"text":"NCT00266136","term_id":"NCT00266136"}}NCT00266136) and at the European Leukemia Trial Registry (#LN_AMLINT2004_230).     

A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis

Ruxolitinib, a potent Janus kinase 1/2 inhibitor, resulted in rapid and durable improvements in splenomegaly and disease-related symptoms in the 2 phase III COMFORT studies. In addition, ruxolitinib was associated with prolonged survival compared with placebo (COMFORT-I) and best available therapy (COMFORT-II). We present a pooled analysis of overall survival in the COMFORT studies using an intent-to-treat analysis and an analysis correcting for crossover in the control arms. Overall, 301 patients received ruxolitinib (COMFORT-I, n=155; COMFORT-II, n=146) and 227 patients received placebo (n=154) or best available therapy (n=73). After a median three years of follow up, intent-to-treat analysis showed that patients who received ruxolitinib had prolonged survival compared with patients who received placebo or best available therapy [hazard ratio=0.65; 95% confidence interval (95%CI): 0.46–0.90; P=0.01]; the crossover-corrected hazard ratio was 0.29 (95%CI: 0.13–0.63). Both patients with intermediate-2– or high-risk disease showed prolonged survival, and patients with high-risk disease in the ruxolitinib group had survival similar to that of patients with intermediate-2–risk disease in the control group. The Kaplan-Meier estimate of overall survival at week 144 was 78% in the ruxolitinib arm, 61% in the intent-to-treat control arm, and 31% in the crossover-adjusted control arm. While larger spleen size at baseline was prognostic for shortened survival, reductions in spleen size with ruxolitinib treatment correlated with longer survival. These findings are consistent with previous reports and support that ruxolitinib offers a survival benefit for patients with myelofibrosis compared with conventional therapies. (clinicaltrials.gov identifiers: COMFORT-I, {"type":"clinical-trial","attrs":{"text":"NCT00952289","term_id":"NCT00952289"}}NCT00952289; COMFORT-II, {"type":"clinical-trial","attrs":{"text":"NCT00934544","term_id":"NCT00934544"}}NCT00934544)     

Standardized monitoring of cytomegalovirusspecific immunity can improve risk stratification of recurrent cytomegalovirus reactivation after hematopoietic stem cell transplantation

Recurrence of cytomegalovirus reactivation remains a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation. Monitoring cytomegalovirus-specific cellular immunity using a standardized assay might improve the risk stratification of patients. A prospective multicenter study was conducted in 175 intermediate- and high-risk allogeneic hematopoietic stem cell transplant recipients under preemptive antiviral therapy. Cytomegalovirusspecific cellular immunity was measured using a standardized interferon- γ enzyme-linked immunospot assay (T-Track® CMV). The primary aim was to evaluate the suitability of measuring cytomegalovirus-specific immunity after the end of treatment for a first cytomegalovirus reactivation to predict recurrent reactivation. Forty of 101 (39.6%) patients with a first cytomegalovirus reactivation experienced recurrent reactivations, mainly in the high-risk group (cytomegalovirus-seronegative donor/cytomegalovirus-seropositive recipient). The positive predictive value of T-Track® CMV (patients with a negative test after the first reactivation who experienced at least one recurrent reactivation) was 84.2% in high-risk patients. Kaplan-Meier analysis revealed a higher probability of recurrent cytomegalovirus reactivation in high-risk patients with a negative test after the first reactivation (hazard ratio 2.73; P=0.007). Interestingly, a post-hoc analysis considering T-Track® CMV measurements at day 100 after transplantation, a time point highly relevant for outpatient care, showed a positive predictive value of 90.0% in high-risk patients. Our results indicate that standardized cytomegalovirus-specific cellular immunity monitoring may allow improved risk stratification and management of recurrent cytomegalovirus reactivation after hematopoietic stem cell transplantation. This study was registered at www.clinicaltrials.gov as #{"type":"clinical-trial","attrs":{"text":"NCT02156479","term_id":"NCT02156479"}}NCT02156479.     

Donor lymphocyte count and thymic activity predict lymphocyte recovery and outcomes after matched-sibling hematopoietic stem cell transplant

Delayed immune recovery is a characteristic feature of allogeneic hematopoietic stem cell transplantation in adult recipients. Although recipient thymic T-cell neogenesis contributes to T-cell regeneration after transplantation, thymic recovery in the transplant recipient decreases with increasing age, and is diminished by intensive preconditioning regimens and graft-versus-host disease. In adult recipients, most events that determine transplant success or failure occur during the period when the majority of circulating T cells is derived from the donor’s post thymic T-cell repertoire. As a result, the make-up of the donor lymphocyte compartment may strongly influence immune recovery and transplant outcomes. The aim of this study was to examine donor lymphocyte counts in a series of patients undergoing an allogeneic hematopoietic stem cell transplant to identify the potential contribution of donor regulatory and conventional T lymphocyte populations to immune recovery and transplant outcomes. We examined donor lymphocyte subset counts in relation to post-transplant lymphocyte recovery and transplant events in 220 consecutive myeloablative, T-cell-depleted, HLA-identical sibling hematopoietic stem cell transplant recipients with hematologic malignancies. In a multivariate analysis, absolute numbers of donor CD4⁺ recent thymic emigrants were associated with overall survival (P=0.032). The donors’ absolute lymphocyte count and thymic production of regulatory T cells were both associated with extensive chronic graft-versus-host disease (P=0.002 and P=0.022, respectively). In conclusion, these results identify donor immune characteristics that are associated with lymphocyte recovery, extensive chronic graft-versus-host disease, and survival in the recipient following allogeneic hematopoietic stem cell transplantation. The study reported here was performed using peripheral blood samples drawn from donors and patients enrolled in the ClinicalTrials.gov-registered trials {"type":"clinical-trial","attrs":{"text":"NCT00001623","term_id":"NCT00001623"}}NCT00001623, {"type":"clinical-trial","attrs":{"text":"NCT00001873","term_id":"NCT00001873"}}NCT00001873, {"type":"clinical-trial","attrs":{"text":"NCT00353860","term_id":"NCT00353860"}}NCT00353860, NCT00066300, {"type":"clinical-trial","attrs":{"text":"NCT00079391","term_id":"NCT00079391"}}NCT00079391, and NCT00398346.     

Impact of Training and Municipal Support on Primary Health Care–Based Measurement of Alcohol Consumption in Three Latin American Countries: 5-Month Outcome Results of the Quasi-experimental Randomized SCALA Trial

PurposeWe aimed to test the effects of providing municipal support and training to primary health care providers compared to both training alone and to care as usual on the proportion of adult patients having their alcohol consumption measured.MethodsWe undertook a quasi-experimental study reporting on a 5-month implementation period in 58 primary health care centres from municipal areas within Bogotá (Colombia), Mexico City (Mexico), and Lima (Peru). Within the municipal areas, units were randomized to four arms: (1) care as usual (control); (2) training alone; (3) training and municipal support, designed specifically for the study, using a less intensive clinical and training package; and (4) training and municipal support, designed specifically for the study, using a more intense clinical and training package. The primary outcome was the cumulative proportion of consulting adult patients out of the population registered within the centre whose alcohol consumption was measured (coverage).ResultsThe combination of municipal support and training did not result in higher coverage than training alone (incidence rate ratio (IRR) = 1.0, 95% CI = 0.6 to 0.8). Training alone resulted in higher coverage than no training (IRR = 9.8, 95% CI = 4.1 to 24.7). Coverage did not differ by intensity of the clinical and training package (coefficient = 0.8, 95% CI 0.4 to 1.5).ConclusionsTraining of providers is key to increasing coverage of alcohol measurement amongst primary health care patients. Although municipal support provided no added value, it is too early to conclude this finding, since full implementation was shortened due to COVID-19 restrictions.Trial RegistrationClinical Trials.gov ID: {"type":"clinical-trial","attrs":{"text":"NCT03524599","term_id":"NCT03524599"}}NCT03524599; Registered 15 May 2018; https://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT03524599","term_id":"NCT03524599"}}NCT03524599Supplementary InformationThe online version contains supplementary material available at 10.1007/s11606-020-06503-9.KEY WORDS: primary health care, municipal action, heavy drinking, Institute for Health Care Improvement, implementation, measurement of alcohol consumption, AUDIT-C, brief advice, Colombia, Peru, Mexico     

Hematopoietic recovery and immune reconstitution after axicabtagene ciloleucel in patients with large B-cell lymphoma

Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 may be associated with long-term adverse effects such as cytopenia and immune deficiency. In order to characterize these late events, we analyzed 31 patients with relapsed or refractory large B-cell lymphoma treated with axicabtagene ciloleucel at our institution on two clinical trials, ZUMA-1 (clinicaltrials gov. Identifier: {"type":"clinical-trial","attrs":{"text":"NCT02348216","term_id":"NCT02348216"}}NCT02348216) and ZUMA-9 (clinicaltrials gov. Identifier: {"type":"clinical-trial","attrs":{"text":"NCT03153462","term_id":"NCT03153462"}}NCT03153462). Complete blood counts, lymphocyte subsets, and immunoglobulin levels were measured serially until month 24 or progression. Fifteen (48%) patients had grade 3-4 cytopenia, including anemia (five, 16%), neutropenia (nine, 29%), or thrombocytopenia (13, 42%) at day 30. Cytopenia at day 30 was not significantly associated with later diagnosis of myelodysplasia. Among patients with ongoing remission, grade 3-4 cytopenia was observed in one of nine (11%) at 2 years. While peripheral CD8⁺ T cells recovered early, CD4⁺ T-cell recovery was delayed with a count of <200/mL in three of nine (33%) patients at 1 year and two of seven (29%) at 2 years. Immunoglobulin G levels normalized in five of nine (56%) patients at 2 years. Thirteen (42%) patients developed grade 3-4 infectious complications, including herpes zoster and Pneumocystis jiroveci pneumonia. These results suggest the need for prolonged monitoring and prophylaxis against opportunistic infections in these patients, to improve the longterm safety of axicabtagene ciloleucel therapy.