Daratumumab, carfilzomib, lenalidomide, and dexamethasone with tandem transplant for high-risk newly diagnosed myeloma.

ABSTRACT: High-risk (HR) cytogenetics are associated with poor outcomes in newly diagnosed multiple myeloma (NDMM), and dedicated studies should address this difficult-to-treat population. The phase 2 study 2018-04 from the Intergroupe Francophone du Myelome evaluated feasibility of an intensive strategy with quadruplet induction and consolidation plus tandem transplant in HR transplant-eligible (TE) NDMM. HR cytogenetics were defined by presence of del(17p), t(4;14), and/or t(14;16). Treatment consisted of daratumumab-carfilzomib-lenalidomide-dexamethasone (D-KRd) induction, autologous stem cell transplantation (ASCT), D-KRd consolidation, second ASCT, and daratumumab-lenalidomide maintenance. The primary end point was feasibility. Fifty patients with previously untreated NDMM were included. Median age was 57. Del(17p), t(4;14), and t(14;16) were found in 40%, 52%, and 20% of patients, respectively. At data cutoff, the study met the primary end point with 36 patients completing second transplant. Twenty patients discontinued the study due to stem cell collection failure (n = 8), disease progression (n = 7), adverse event (n = 4), or consent withdrawal (n = 1). Grade 3 to 4 D-KRd induction/consolidation-related adverse events (>5% of patients) were neutropenia (39%), anemia (12%), thrombocytopenia (7%), and infection (6%). The overall response rate was 100% for patients completing second transplant, including 81% complete response. Premaintenance minimal residual disease (MRD) negativity rate (10-6) was 94%. After a median follow-up of 33 months, the 30-month progression-free survival (PFS) and overall survival were 80% and 91%, respectively. In conclusion, D-KRd with tandem transplant is feasible in patients with HR TE-NDMM and resulted in high response rates and PFS. This trial was registered at www.clinicaltrials.gov as #NCT03606577.

Impact of the practice of touch-massage® by a nurse on the anxiety of patients with hematological disorders hospitalized in a sterile environment, a randomized, controlled study.

CONTEXT: In addition to curative care, supportive care is beneficial in managing the anxiety symptoms common in patients in sterile hematology unit. We hypothesize that personal massage can help the patient, particularly in this isolated setting where physical contact is extremely limited. The main objective of this study was to show that anxiety could be reduced after a touch-massage® performed by a nurse trained in this therapy. METHODS: A single-center, randomized, unblinded controlled study in the sterile hematology unit of a French university hospital, validated by an ethics committee. The patients, aged between 18 and 65 years old, and suffering from a serious and progressive hematological pathology, were hospitalized in sterile hematology unit for a minimum of three weeks, patients were randomized into either a group receiving 15-minute touch-massage® sessions or a control group receiving an equivalent amount of quiet time once a week for three weeks. In the treated group, anxiety was assessed before and after each touch-massage® session, using the State-Trait Anxiety Inventory questionnaire with subscale state (STAI-State). In the control group, anxiety was assessed before and after a 15-minute quiet period. For each patient, the difference in the STAI-State score before and after each session (or period) was calculated, the primary endpoint was based on the average of these three differences. Each patient completed the Rosenberg Self-Esteem Questionnaire before the first session and after the last session. RESULTS: Sixty-two patients were randomized. Touch-massage® significantly decreased patient anxiety: a mean decrease in STAI-State scale score of 10.6 [7.65-13.54] was obtained for the massage group (p ≤ 0.001) compared with the control group. The improvement in self-esteem score was not significant. CONCLUSION: This study provides convincing evidence for integrating touch-massage® in the treatment of patients in sterile hematology unit. TRIAL REGISTRATION: NCT02343965.

Tocilizumab in combination with a standard induction chemotherapy in acute myeloid leukaemia patients (TOCILAM study): a single-centre, single-arm, phase 1 trial.

Background: In acute myeloid leukaemia (AML), interleukin-6 (IL-6) promotes chemo-resistance and its levels correlate with poor prognosis. IL-6 blockade may represent a promising therapeutic strategy. We aimed to test, tocilizumab, an anti-IL-6 receptor (R) monoclonal antibody in combination with standard intensive AML induction chemotherapy. Methods: This investigator-initiated single-centre phase 1 trial was conducted at Nantes University Hospital in France. According to a continual reassessment method, three escalating doses were tested of intravenous (IV) tocilizumab (4, 6, and 8 mg/kg) administered at day (d) 8 of a standard AML induction chemotherapy (IV idarubicine 8 mg/m2 d1 to d5 + IV cytarabine 100 mg/m2 d1 to d7). All adults (aged ≥ 18 years) with an Eastern Cooperative Oncology Group performance status of 0-2 and with a newly diagnosed (excluding patients with a favourable risk according to ELN-2017 classification if <60 year-old) or a relapsed/refractory AML were eligible. The primary objective was to determine the maximum tolerated dose of tocilizumab to administrate with a standard intensive AML induction. Safety outcomes were continuously monitored for at each participant contact. This trial is registered with ClinicalTrials.gov, NCT04547062. Findings: Between Dec 29, 2020 and Dec 1, 2022, 12 patients were enrolled, of whom 75% had an ELN-2017 high-risk profile, and were treated with tocilizumab- two patients at 4 mg/kg, two at 6 mg/kg and eight at 8 mg/kg of tocilizumab. No dose-limiting toxicity related to tocilizumab was documented. There were nine serious adverse events, none of which were related to tocilizumab, and there was no treatment-related deaths. MTD was thus not reached. Two deaths occurred during induction. In the remaining ten evaluable patients, nine responded to treatment. Interpretation: The combination of tocilizumab with standard AML intensive induction appears to be safe and resulting responses are encouraging. A dose of 8 mg/kg of tocilizumab given at day 8 of induction could be used for further phase 2/3 studies. Funding: The Leucémie Espoir Atlantique Famille (LEAF)-"Tous avec Fabien" association.

Hematopoietic stem cell transplantation for acute lymphoblastic leukemia: why do adolescents and young adults outcomes differ from those of children? A retrospective study on behalf of the Francophone Society of Stem Cell Transplantation and Cellular Therapy (SFGM-TC).

PURPOSE: In the acute lymphoblastic leukemia (ALL) landscape, adolescents and young adults (AYA) often present high-risk diseases and increased chemotherapy-related toxicity. Studies analyzing the outcomes of AYA after hematopoietic stem cell transplantation (HSCT) are scarce. Our study aimed to compare the outcomes of children and AYA with ALL after HSCT and to determine the factors influencing potential differences. METHOD: 891 patients, from the SFGM-TC registry, aged between 1 and 25 years who received HSCT between 2005 and 2012 were included. The outcomes of AYA were compared to the ones of their younger counterparts. RESULTS: Five-year OS and GRFS were lower in AYA: 53.1% versus 64% and 36% versus 47% (p = 0.0012 and p = 0.007, respectively). WhileCIR was similar in both groups, 5 year-treatment related mortality was higher in AYA: 19% versus 13% (p = 0.04). The lower GRFS in AYA was mainly explained by a higher chronic graft versus host disease (cGvHD) incidence: 32% versus 19% (p < 0.001). Use of peripheral blood stem cells and use of anti-thymoglobulin appeared to be the main factors impacting cGvHD occurrence in AYA. CONCLUSION: AYA have worse outcomes than children after HSCT for ALL because of a greater risk of TRM due to cGvHD. HSCT practices should be questioned in this population.

Prophylactic or Preemptive Low-Dose Azacitidine and Donor Lymphocyte Infusion to Prevent Disease Relapse following Allogeneic Transplantation in Patients with High-Risk Acute Myelogenous Leukemia or Myelodysplastic Syndrome.

Because of the persistently high rates of relapse of patients with high-risk acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) following allogeneic hematopoietic stem cell transplantation (allo-HSCT), post-transplantation maintenance therapy has been proposed. We previously initiated a Phase II trial in which epigenetic therapy was combined with immunotherapy in an attempt to reduce disease relapse. In that study, low-dose azacitidine (AZA) and escalating doses of donor lymphocyte infusion (DLI) were given as post-allo-HSCT maintenance treatment. In the present study, we retrospectively analyze a larger cohort of patients receiving post-transplantation maintenance therapy and provide updates on some patients of the earlier study. The objectives of the present study were to analyze the cumulative incidence of relapse (CIR), overall survival (OS), and progression-free survival (PFS) and the incidence of acute and chronic graft-versus-host disease (GVHD) of patients with high-risk AML or MDS receiving post-transplantation maintenance treatment with AZA with or without DLI. We retrospectively analyzed 77 patients (54 with AML, 23 with MDS) considered at high risk based on either their genomic or clinical status at transplantation. Following allogeneic transplantation, they received at least 1 cycle of prophylactic or preemptive low-dose AZA with or without escalating doses of DLI to prevent disease relapse. Almost one-half of the patients (47%) were able to receive the full 12 cycles of scheduled AZA, and a majority (79%) received at least 1 DLI. With a median follow-up of 24 months, 19 patients (25%; 16 with AML, 3 with MDS) relapsed, at a median of 9.8 months (range, 4 to 58.6 months), giving a 22% CIR at 24 months. OS and PFS at 24 months were 70.8% and 68.3%, respectively. The cumulative incidences of grade II-IV acute GVHD and chronic GVHD were 27.4% and 45%, respectively. Only a minority of patients (11%) required delayed administration of AZA. These findings confirm that AZA-DLI maintenance is both tolerable and effective in reducing the risk of post-transplantation relapse.

A Prospective Study of Association of Micronutrients Deficiencies during Pregnancy and Neonatal Outcome among Women after Bariatric Surgery.

Little is known about the association of micronutrients deficiencies during pregnancy and neonatal outcome among women after Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG). We present a prospective study of 87 consecutive women with a history of RYGB (n = 37) or SG (n = 50) who underwent complete and regular clinical and biological nutritional assessments during pregnancy. Data on maternal characteristics, biological nutritional parameters, antenatal management, and perinatal outcome were collected. The objective was to evaluate serum levels of micronutrients at the second trimester, and to assess the association between micronutrients deficiencies and neonatal outcome. After RYGB, maternal age (34.3 ± 4.9 vs. 31.1 ± 4.6 years; p = 0.003) and pregnancy timing after surgery (64.5 ± 47.0 vs. 38.1 ± 28.1 months; p = 0.002) were significantly higher, and pre-pregnancy BMI was significantly lower (29.8 ± 5.6 vs. 32.9 ± 7.1 kg/m2; p = 0.03). Maternal and neonatal outcomes were similar. Additional supplementations after blood tests were similar in groups. Zinc, selenium, vitamins A1, B1, B6, C, and E levels were not different depending on the type of surgery. Zinc deficiency (7/87) was significantly more frequent after RYGP (18.9% vs. 0%; p = 0.02) and selenium deficiency (15/87) was similar in groups (21.6% after RYGB and 14.0% after SG; p = 0.36). The mean birth weight was significantly lower in selenium deficiency cases (3137 ± 550 vs. 3535 ± 737 g; p = 0.04). Selenium deficiency was negatively correlated with birth weight (r = -0.23; p = 0.03) and with birth weight z-score (r = -0.26; p = 0.01), but not correlated after adjustment for the procedure. The levels of micronutrients surveillance along pregnancy in women with a history of bariatric surgery is necessary to decrease the risk of inadequate fetal growth in the patients.

A Novel Absorbable Stapler Provides Patient-Reported Outcomes and Cost-Effectiveness Noninferior to Subcuticular Skin Closure: A Prospective, Single-Blind, Randomized Clinical Trial.

BACKGROUND: Deep dermal suturing is critical for scar quality outcomes. The authors evaluated a new, fast medical device for dermal suturing, with the hypothesis of noninferiority with regard to clinical scar and cost-effectiveness. METHODS: A prospective, patient-blind, randomized, multicenter noninferiority study in 26 French hospitals was conducted. Patients were randomized 1:1 to suturing with conventional thread or a semiautomatic stapler. The Patient Scar Assessment Scale was rated at 3 months for primary endpoint effectiveness. Secondary endpoints were cost-effectiveness of the two suturing methods, prevalence of complications, suturing/operating time, Observer Scar Assessment Scale and Patient Scar Assessment Scale score, scar aesthetic quality 18 months after surgery, and occupational exposure to blood during surgery. RESULTS: Six hundred sixty-four patients were enrolled, 660 were randomized, and 649 constituted the full analysis (stapler arm, n = 324; needle arm, n = 325). Primary endpoint Patient Scar Assessment Scale score in the stapler arm was not inferior to that in the needle arm at 3 months or after 18 months. The mean operating time was 180 minutes in the stapler arm and 179 minutes in the needle arm (p = not significant). The mean suturing time was significantly lower in the stapler arm (p < 0.001). There were seven occupational exposures to blood in the needle arm and one in the stapler arm. The two arms did not differ significantly in terms of complications (p = 0.41). The additional cost of using the device was &OV0556;51.57 for the complete-case population. CONCLUSION: Wound healing outcome was no worse than with conventional suturing using a semiautomatic stapler and associated with less occupational exposure to blood. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, I.

Impact of fecal microbiota transplantation on chronic recurrent pouchitis in ulcerative colitis with ileo-anal anastomosis: study protocol for a prospective, multicenter, double-blind, randomized, controlled trial.

BACKGROUND: Almost 15% of patients with ulcerative colitis (UC) will require a proctocolectomy with ileal pouch-anal anastomosis (IPAA) as a result of fulminant colitis, dysplasia, cancer, or medical refractory diseases. Around 50% will experience pouchitis, an idiopathic inflammatory condition involving the ileal reservoir, responsible for digestive symptoms, deterioration in quality of life, and disability. Though the majority of initial cases of pouchitis are easily managed with a short course of antibiotics, in about 10% of cases, inflammation of the pouch becomes chronic with very few treatments available. Previous studies have suggested that manipulating the composition of intestinal flora through antibiotics, probiotics, and prebiotics achieved significant results for treating acute episodes of UC-associated pouchitis. However, there is currently no established effective treatment for chronic antibiotic-dependent pouchitis. Fecal microbiota transplantation (FMT) is a novel therapy involving the transfer of normal intestinal flora from a healthy donor to a patient with a medical condition potentially caused by the disrupted homeostasis of intestinal microbiota or dysbiosis. METHODS: Our project aims to compare the delay of relapse of chronic recurrent pouchitis after FMT versus sham transplantation. Forty-two patients with active recurrent pouchitis after having undergone an IPAA for UC will be enrolled at 12 French centers. The patients who respond to antibiotherapy will be randomized at a ratio of 1:1 to receive either FMT or sham transplantation. DISCUSSION: On April 30, 2014, the World Health Organization published an alarming report on antibiotic resistance. Finding an alternative medical treatment to antibiotics in order to prevent relapses of pouchitis is therefore becoming increasingly important given the risk posed by multiresistant bacteria. Moreover, if the results of this study are conclusive, FMT, which is less expensive than biologics, could become a routine treatment in the future. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03524352. Registered on 14 May 2018.

Are corticosteroid injections needed after needling and lavage of calcific tendinitis? Randomised, double-blind, non-inferiority trial.

OBJECTIVE: Steroid injections are common after an ultrasound-guided puncture and lavage (UGPL) of calcific tendonitis of the rotator cuff. However, steroids may prevent calcification resorption and negatively affect tendon healing. Our study was designed to determine whether saline solution was non-inferior to steroids in the prevention of acute pain reactions in the week following UGPL. METHODS: This was a randomised, double-blinded, controlled non-inferiority trial with 12-month follow-up. We included 132 patients (66 in each group) with symptomatic calcification measuring more than 5 mm. Patients received 1 mL of saline or steroid (methylprednisolone 40 mg) in the subacromial bursa at the end of UGPL. Primary outcome was the maximal pain during the week following the procedure with a prespecified non-inferiority margin of 10 mm (0-100 visual analogue scale). Secondary outcomes included pain at rest and during activity, function (disabilities of the arm, shoulder and hand score) and radiological evolution of the calcification over the 12-month follow-up. RESULTS: The estimated mean difference in the first week's maximal pain between these two groups was 11.76 (95% CI 3.78 to 19.75). Steroids significantly improved VAS pain at rest and during activities, as well as function at 7 days and 6 weeks. They did not change the rate of calcification resorption, which occurred in 83% and 74% of patients at 12 months in the saline and steroid groups. CONCLUSION: Non-inferiority of saline when compared with steroids could not be established. However, steroid injection improved pain in the 6 weeks following the procedure, and function in the 3 months after, with no significant effect on calcification resorption. TRIAL REGISTRATION NUMBER: NTC02403856.

Impact of stem cell graft on early viral infections and immune reconstitution after allogeneic transplantation in adults.

BACKGROUND: Viral infections are well-known complications after allogeneic stem cell transplant (allo-SCT). OBJECTIVES: We compared prospectively incidences of DNAemia and active infections (AI) for five opportunistic viruses (Human Herpesvirus 6 (HHV-6), Epstein-Barr virus (EBV), BK polyomavirus (BKPyV), Cytomegalovirus (CMV) and Adenovirus (ADV)) and kinetics of immune reconstitution (IR) in adults receiving either double umbilical cord blood (dUCB group) or unrelated peripheral blood stem cell (uPBSC group) allo-SCT after a reduced-intensity conditioning (RIC) regimen. STUDY DESIGN: Whole blood samples were collected at transplant, every 15days during the first 3 months and at 4, 5 and 6 months post-transplant. RESULTS: Sixty-five patients were enrolled (uPBSC n=34; dUCB n=31). Incidences of HHV-6 and BKPyV DNAemia were significantly higher for dUCB (97% vs 23.5% and 58% vs 32%, respectively) while EBV DNAemia was more frequently detected in uPBSC (71% vs 26%). The incidence of CMV DNAemia was similar between both groups. ADV AI developed only in dUCB. HHV-6 AI were also higher in dUCB (84% vs 21%). In multivariate analysis, dUCB graft was the only independent factor associated with HHV-6 DNAemia (OR: 19.0; 95%CI: 5.2-69.1; p<0.0001) while EBV DNAemia were significantly associated with uPBSC (OR: 29.9; 95%CI: 5.68-158; p <0.0001). dUCB graft was also the only factor associated with HHV-6 AI. Finally, higher counts and faster recoveries of B lymphocytes (p<0.0001) and monocytes (p=0.0007) were observed in the dUCB group. CONCLUSION: We demonstrate a strong correlation between sources of graft and patterns of viral DNAemia and AI and IR after RIC allo-SCT.

VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial.

The Intergroupe Francophone du Myélome conducted a randomized trial to compare bortezomib-thalidomide-dexamethasone (VTD) with bortezomib-cyclophosphamide-dexamethasone (VCD) as induction before high-dose therapy and autologous stem cell transplantation (ASCT) in patients with newly diagnosed multiple myeloma. Overall, a total of 340 patients were centrally randomly assigned to receive VTD or VCD. After 4 cycles, on an intent-to-treat basis, 66.3% of the patients in the VTD arm achieved at least a very good partial response (primary end point) vs 56.2% in the VCD arm (P = .05). In addition, the overall response rate was significantly higher in the VTD arm (92.3% vs 83.4% in the VCD arm; P = .01). Hematologic toxicity was higher in the VCD arm, with significantly increased rates of grade 3 and 4 anemia, thrombocytopenia, and neutropenia. On the other hand, the rate of peripheral neuropathy (PN) was significantly higher in the VTD arm. With the exception of hematologic adverse events and PN, other grade 3 or 4 toxicities were rare, with no significant differences between the VTD and VCD arms. Our data support the preferential use of VTD rather than VCD in preparation for ASCT. This trial was registered at www.clinicaltrials.gov as #NCT01564537 and at EudraCT as #2013-003174-27.

Screening of esophageal varices by esophageal capsule endoscopy: results of a French multicenter prospective study.

BACKGROUND AND STUDY AIM: Esophageal video capsule endoscopy (ECE) is a new technique that allows examination of the esophagus using a noninvasive approach. The aim of this study was to compare ECE with esophagogastroduodenoscopy (EGD) for the diagnosis of esophageal varices in patients with cirrhosis. PATIENTS AND METHODS: A total of 330 patients with cirrhosis and with no known esophageal varices were prospectively enrolled. Patients underwent ECE first, followed by EGD (gold standard). The endoscopists who performed EGD were blind to the ECE result. Patient satisfaction was assessed using a visual analog scale (maximum score 100). RESULTS: A total of 30 patients were excluded from the analysis because they did not undergo any endoscopic examinations. Patients (mean age 56 years; 216 male) had mainly alcoholic (45 %) or viral (27 %) cirrhosis. The diagnostic indices of ECE to diagnose and correctly stage esophageal varices were: sensitivity 76 % and 64 %, specificity 91 % and 93 %, positive predictive value 88 % and 88 %, and negative predictive value 81 % and 78 %, respectively. ECE patient satisfaction scored significantly higher than EGD (87 ±â€Š22 vs. 58 ±â€Š35; P < 0.0001). CONCLUSIONS: ECE was well tolerated and safe in patients with liver cirrhosis and suspicion of portal hypertension. The sensitivity of ECE is not currently sufficient to replace EGD as a first exploration in these patients. However, due to its excellent specificity and positive predictive value, ECE may have a role in cases of refusal or contraindication to EGD. ECE might also improve compliance to endoscopic follow-up and aid important therapeutic decision making in the prophylaxis of bleeding. TRIAL REGISTRATION: EudraCT (ID RCB 2009-A00532-55) and ClinicalTrials.gov (NCT00941421).

Phase 1/2 study of carfilzomib plus melphalan and prednisone in patients aged over 65 years with newly diagnosed multiple myeloma.

This phase 1/2 dose-escalation study investigated the combination of carfilzomib with melphalan and prednisone (CMP) in patients aged >65 years with newly diagnosed multiple myeloma (MM). Melphalan and prednisone were administered orally on days 1 to 4; carfilzomib was IV administered on days 1, 2, 8, 9, 22, 23, 29, and 30 of a 42-day cycle. Patients received up to 9 cycles of CMP. In the phase 1 dose-escalation portion, the primary objectives were to determine the incidence of dose-limiting toxicities during the first cycle of CMP treatment to define the maximal tolerated dose (MTD) of carfilzomib. In the phase 2 portion, the primary objective was to evaluate the overall response rate (ORR) of CMP. In the phase 1 portion of the study, 24 patients received CMP at carfilzomib dosing levels of 20 mg/m(2), 27 mg/m(2), 36 mg/m(2), and 45 mg/m(2). The MTD was established as 36 mg/m(2). In the phase 2 portion of the study, 44 patients were enrolled at the MTD. Among 50 efficacy-evaluable patients treated at the MTD, the ORR was 90%. The projected 3-year overall survival rate was 80%. The combination of CMP was observed to be effective in elderly patients with newly diagnosed MM. This trial was registered at www.clinicaltrials.gov as #NCT01279694 (Eudract identifier 2010-019462-92).

Risk factors for hepatocellular carcinoma in Caucasian patients with non-viral cirrhosis: the importance of prior obesity.

BACKGROUND & AIMS: In patients with cirrhosis, the risk of hepatocellular carcinoma (HCC) depends upon age, gender and the etiology of liver disease. Few studies are available in Caucasian patients with alcoholic or metabolic cirrhosis without viral hepatitis. METHODS: Cross-sectional clinical data from 905 HCV- and HBV-negative Caucasian patients with alcoholic or metabolic cirrhosis were prospectively collected in four French centres. The risk factors for HCC were identified by logistic regression analysis in the whole population and in a nested case-control study. RESULTS: The etiology of cirrhosis was alcoholic (48%), metabolic (7%) or mixed (45%). Patients were predominantly male (80%), mean age 62 years old and 31% had HCC. Mean body mass index (BMI) was 27 ± 5 and 30% were obese at inclusion. The maximum BMI reached throughout life was 31 ± 6 and 63% had been obese. Ninety percent of the population had daily alcohol consumption, 73% were smokers. Hepatocellular carcinoma was independently related to male gender (P < 0.0001), older age (P < 0.0001), past obesity (P = 0.007), diabetes (P = 0.037), abnormal levels of transaminases (P < 0.0001) and tobacco consumption (P = 0.007). The case-control study (200 HCC cases matched with 400 non-HCC cases for gender, age and Child-Pugh score) confirmed past obesity, tobacco and abnormal levels of transaminases. CONCLUSIONS: Beside diabetes, male gender and age, a past history of obesity, but not an existing overweight, as well as exposure to tobacco and elevated transaminases were three risk factors which could improve the strategy for HCC screening in Caucasian cirrhotic patients without hepatitis B or C.

Comparison of outcomes after two standards-of-care reduced-intensity conditioning regimens and two different graft sources for allogeneic stem cell transplantation in adults with hematologic diseases: a single-center analysis.

Recent advances in allogeneic stem cell transplantation (allo-HSCT) have included the advent of reduced-intensity conditioning (RIC) regimens to decrease the toxicity of myeloablative allo-SCT and the use of double umbilical cord blood (dUCB) units as a graft source in adults lacking a suitable donor. The FB2A2 regimen (fludarabine 30 mg/kg/day for 5-6 days + i.v. busulfan 3.6 mg/kg/day for 2 days + rabbit antithymocyte globulin 2.5 mg/kg/day for 2 days) supported by peripheral blood stem cells (PBSCs) and the TCF regimen (fludarabine 200 mg/m² for 5 days + cyclophosphamide 50 mg/kg for 1 day + low-dose [2 Gy] total body irradiation) supported by dUCB units are currently the most widely used RIC regimens in many centers and could be considered standard of care in adults eligible for an RIC allo-SCT. Here we compared, retrospectively, the outcomes of adults patients who received the FB2A2-PBSC RIC regimen (n = 52; median age, 59 years; median follow-up, 19 months) and those who received the dUCB-TCF RIC regimen (n = 39; median age, 56 years; median follow-up, 20 months) for allo-SCT between January 2007 and November 2010. There were no significant between-group differences in patient and disease characteristics. Cumulative incidences of engraftment, acute grade II-IV and chronic graft-versus-host disease were similar in the 2 groups. The median time to platelet recovery, incidence of early death (before day +100), and 2-year nonrelapse mortality were significantly higher in the dUCB-TCF group (38 days versus 0 days [P <.0001]; 20.5% versus 4% [P = .05], and 26.5% versus 6% [P = .02], respectively). The groups did not differ in terms of 2-year overall survival (62% for FB2A2-PBSC versus 61% for dUCB-TCF), disease-free survival (59% versus 50.5%), or relapse incidence (35.5% versus 23%). In multivariate analysis, the presence of a lymphoid disorder was associated with a significantly higher 2-year overall survival (hazard ratio, 0.42; 95% confidence interval, 0.20-0.87; P = .02), whereas patients receiving a FB2A2-PBSC allo-SCT had a significantly lower 2-year nonrelapse mortality (hazard ratio, 0.24; 95% confidence interval, 0.1-0.7; P = .01). There were no factors associated with higher 2-year disease-free survival or lower relapse incidence. This study suggests that the dUCB-TCF regimen provides a valid alternative in adults lacking a suitable donor and eligible for RIC allo-SCT. Prospective and randomized studies are warranted to establish the definitive role of dUCB RIC allo-SCT in adults. In addition, strategies for decreasing nonrelapse mortality after dUCB RIC allo-SCT are urgently needed.

Prognostic impact of immune status and hematopoietic recovery before and after fludarabine, IV busulfan, and antithymocyte globulins (FB2 regimen) reduced-intensity conditioning regimen (RIC) allogeneic stem cell transplantation (allo-SCT).

This retrospective analysis aimed to assess hematopoietic and immune recovery in a cohort of 53 patients [males: n = 33; median age: 59 yr (range: 22-70)] who received a FB2 (fludarabine 120-150 mg/m² + IV busulfan 6.4 mg/kg + antithymocyte globulin thymoglobulin 5 mg/kg) reduced-intensity conditioning (RIC) allo-stem cells transplantations (SCT). With a median follow-up of 19 months (range: 2-53), the 2-yr overall survival, disease-free survival (DFS), relapse incidence, and non-relapse mortality were 63%, 59.5%, 35%, and 6%, respectively. In univariate analysis, the factors correlated with a significantly higher 2-yr OS and DFS were a higher total circulating lymphocytes count at transplant (>730/mm(3) ; OS: 81% vs. 43%, P = 0.02; DFS: 73% vs. 45.5%, P = 0.03) and a higher recovery of leukocytes (>5300/mm(3) ) (2-yr OS: 81% vs. 44%, P = 0.007; 2-yr DFS: 72% vs. 46%, P = 0.08), neutrophils (>3200/mm(3) ) (2-yr OS: 76% vs. 50%, P = 0.03; 2-yr DFS: 67% vs. 52.0%, P = 0.1), and monocytes (>590/mm(3) ; 2-yr OS: 80% vs. 45%, P = 0.004; 2-yr DFS: 76% vs. 42%, P = 0.01) at day +30 post-transplant. In multivariate analysis, the only independent factors associated with a significantly higher OS and DFS were a better immune status at transplant (lymphocytes count >730/mm(3) ) and a higher monocytes count (>590/mm(3) ) at day +30 post-transplant. These results suggest that immune status and hematopoietic recovery before and after FB2 RIC allo-SCT can be significant predictors of outcome. This paves the way for future studies aiming to closely monitor the kinetics of immune recovery after RIC allo-SCT and to evaluate the impact of growth factors and other immunostimulatory cytokines in the setting of RIC allo-SCT.

Characterization of various blood and graft sources: a prospective series.

BACKGROUND: Studies comparing cell components of blood and graft sources are very scarce. We present here a thorough study examining the cellular content of various sources of blood and cell therapy products. STUDY DESIGN AND METHODS: We have prospectively compared by fluorescence-activated cell sorting analyses the cellular composition of three blood sources on the one hand--peripheral blood (PB; n = 10) versus granulocyte-colony-stimulating factor (G-CSF)-mobilized PB (GCSF-PB, n = 10) versus cord blood (CB, n = 10)--and of three graft sources on the other hand--unmanipulated bone marrow (uBM, n = 5) versus leukapheresis product (LP, n = 10) versus thawed CB graft (n = 7). RESULTS: All median absolute numbers of cell subsets were found significantly higher in GCSF-PB and LP, except for monocytoid dendritic cells (mDCs) in CB and uBM. The most impressive results were the median quantities of memory T and B lymphocytes but also of plasmacytoid DCs (pDCs) contained in LP compared to thawed CB graft, with ratios of 375, 318, and 247, respectively. The proportions of naive and CD4+/CD8- T cells, transitional B cells, and CD5+ and naive B lymphocytes were found significantly higher in CB samples while the proportions of mDCs and pDCs were found significantly lower. CONCLUSION: Our study shows strong differences in terms of quantitative and qualitative cellular composition between several blood or graft sources, possibly explaining the differences observed in terms of outcomes after transplant.

HHV-6 cell receptor CD46 expression on various cell subsets of six blood and graft sources: a prospective series.

BACKGROUND: Cord Blood (CB) are increasingly used as an alternative stem cells source in adults for allogeneic Stem Cell Transplantation (allo-SCT). The risk of human herpesvirus (HHV-6) reactivation is significantly higher after CB transplant vs unrelated peripheral blood stem cells (PBSC) allo-SCT. Higher HHV-6 cell receptor CD46 expression on progenitor cells in CB may explain this difference. OBJECTIVES: To prospectively compare the HHV-6 cell receptor CD46 expression on various cell subsets of three freshly harvested blood sources on one hand and of three graft sources on the other hand. STUDY DESIGN: 52 samples were used for the purpose of this study. They were issued from peripheral blood (PB, n = 10), G-CSF mobilised PB (GCSF-PB, n = 10), cord blood (CB, n = 10), unmanipulated bone marrow (uBM, n = 5), leukapheresis product (LP, n = 10) and thawed CB graft (n = 7). CD46 expression was assessed by FACS analysis on total lymphocytes, monocytes, NK cells, T and B cells subsets, plasmacytoid (pDCs) dendritic cells and stem cells. RESULTS: As all cell subsets were found CD46 positive, CD46 mean fluorescence intensity (MFI) was then considered for comparison between the three blood sources and the three graft sources. The most impressive result observed was that HHV-6 cell receptor CD46 expression was significantly reduced in almost all cell components of thawed CB graft compared to other graft sources. CONCLUSIONS: This original study shows strong differences in term of quantitative CD46 expression between several blood and grafts samples. Our results suggest that other factors than the qualitative CD46 expression play a role in the higher HHV-6 reactivation observed after CB transplant in adults.