The outcome of relapsed childhood acute lymphoblastic leukemia after allogeneic hematopoietic stem-cell transplantations: A single-center experience.

In children with high-risk childhood acute leukemia who undergo allogeneic hematopoietic stem-cell transplantation (allo-HSCT), relapse is still the leading cause of treatment failure. The prognosis is poor, yet prospective studies have only limited data on risk factors and outcomes. We aimed to understand the outcomes and prognostic factors for patients with acute lymphoblastic leukemia (ALL) who relapsed following allo-HSCT. We analyzed retrospectively 46 children with childhood acute lymphoblastic leukemia who had relapsed after receiving their first alloHSCT. All these patients received salvage chemotherapy which consisted of fludarabine, cytarabine, and idarubicin before performing a second alloHSCT. The median follow-up of the 46 patients after the first transplantation was 366 days. The median time from first allo-HSCT to relapse was 278.4 ± 238.4 days. Forty-six patients received salvage chemotherapy before the second alloHSCT, and CR was achieved in 32 of 46 patients. However, only 17 (37%) of 46 patients received a second allo-HSCT, and 15 of 46 patients died from disease progression, infections, and bleeding. Twelve patients are still alive after the second allo-HSCT. Two-year overall survival (OS) was 38.9%. Local therapy was given to 10 (21.8%) patients, either as part of systemic therapy or alone. In multivariate analyses, the time of relapse and curative salvage therapy with a second allo-HSCT were identified as significant prognostic factors for OS. Children with leukemia who had relapsed after the first allo-HSCT received salvage chemotherapy. Our statistical analysis showed that the second HSCT could be beneficial for outcomes if patients relapsed beyond 180 days of the first allo-HSCT.

Pharmacokinetics, Safety, and Efficacy of Letermovir for Cytomegalovirus Prophylaxis in Adolescent Hematopoietic Cell Transplantation Recipients.

INTRODUCTION: Letermovir is a cytomegalovirus (CMV) terminase complex inhibitor approved for prophylaxis of CMV infection and disease in adult CMV-seropositive allogeneic hematopoietic cell transplantation (allo-HCT) recipients (R+). We report pharmacokinetics (PK), safety, and efficacy of letermovir in adolescent (12-18 years) allogeneic HCT recipients from an ongoing clinical study. METHODS: In this phase 2b, multicenter, open-label study (NCT03940586), 28 adolescents received 480 mg letermovir [240 mg with cyclosporin A (CsA)] once daily orally or intravenously. Blood was collected for intensive (n = 14) plasma concentrations of letermovir. Intensive PK data were used for dose confirmation. Target exposure range 34,400-100,000 h × ng/mL for pediatric median exposures was based on model-predicted phase 3 population PK simulations in adult HCT recipients. RESULTS: All participants were CMV-seropositive (body weight 28.7-95.0 kg). Of 12 PK-evaluable participants, 8 receiving 480 mg letermovir without CsA and 4 receiving 240 mg letermovir with CsA achieved exposures comparable to the adult exposure range. Exposure above the target but below the adult clinical program maximum was observed in 1 patient. Safety was consistent with previously described safety in adults. The proportion of participants with clinically significant CMV infection through week 24 post-HCT was comparable (24%) to that in the pivotal phase 3 study in adults (37.5%). CONCLUSIONS: Administration of adult letermovir doses in this adolescent cohort resulted in exposures within adult clinical program margins and was associated with safety and efficacy similar to adults. Results support a letermovir dose of 480 mg (240 mg with CsA) in adolescent allo-HCT recipients.

Comparison of posture and muscle stiffness between adolescent boys with haemophilia and age-matched healthy peers: An observational comparative study.

BACKGROUND: Haemophilic arthropathy is likely to influence posture and muscle stiffness in adolescent male haemophilia patients (HP). OBJECTIVE: This study aimed to investigate the possible change in upright standing posture and stiffness of the superficial postural muscles in HP. METHODS: Twenty-two HP aged between 12 and 19 years and twenty-two healthy peers were included in the study. The photogrammetry was used to assess the upright standing posture from sagittal and frontal planes. Also, stiffness of the superficial postural muscles was evaluated using the myotonometry. RESULTS: A significant difference was found in the craniovertebral, lumbar lordosis, knee flexion-valgus, and ankle plantar flexion angles between the groups (p< 0.05). Craniovertebral, knee flexion, and knee valgus angles were lower; whereas lumbar lordosis and ankle plantar flexion angles were higher in HP compared to the healthy peers. Stiffness of the rectus femoris muscle was lower in HP (p< 0.001). CONCLUSION: This study revealed that the ankle, knee, lumbar, and craniovertebral segments' posture angles were changed and the stiffness of the rectus femoris muscle decreased in HP. Postural alterations and reduced rectus femoris stiffness should be considered in management of the musculoskeletal complications of haemophilia.

Immunogenicity, safety, and efficacy of rurioctocog alfa pegol in previously untreated patients with severe hemophilia A: interim results from a phase 3, prospective, multicenter, open-label study.

AIM: To determine the immunogenicity, safety, and efficacy of rurioctocog alfa pegol in previously untreated patients (PUPs) with severe hemophilia A (HA). METHODS: This prospective, phase 3 study (NCT02615691) was conducted in PUPs, or patients with ≤2 exposure days (EDs) prior to screening, aged <6 years with severe HA. The primary endpoint was incidence of factor VIII (FVIII) inhibitor development. This protocol-specified interim analysis was conducted after 50 patients had completed ≥50 EDs without developing FVIII inhibitors or had developed a confirmed inhibitor at any time. RESULTS: Of the enrolled patients, 59/80 (73.8%) received ≥1 dose of rurioctocog alfa pegol; 54 received prophylaxis, and 35 on-demand treatment. Incidence of inhibitor development was 0.19 (10/52). Total annualized bleeding rate (95% CIs) was 3.2 (2.0-5.0) for patients receiving prophylaxis and 3.2 (1.6-6.3) for on-demand treatment. Hemostatic efficacy of most bleedings was rated as 'excellent' or 'good' after 24 hours (122/131 [93.1%]) and at resolution (161/170 [94.7%]). Five patients received ≥1 dose of rurioctocog alfa pegol for immune tolerance induction (ITI) and 1 patient was defined as having ITI success. Thirteen patients experienced 14 treatment-related adverse events, including 10 cases of FVIII inhibitor development. CONCLUSION: This is the first prospective study of rurioctocog alfa pegol for the treatment of PUPs with severe HA. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT02615691).

Umbilical Cord Management in Late Preterm and Term Infants: A Randomized Controlled Trial.

OBJECTIVE: The study aimed to compare the effects of three different methods of umbilical cord management on hematological parameters in term and late-preterm infants. STUDY DESIGN: A randomized controlled trial comparing intact-umbilical cord milking (I-UCM) with cut-umbilical cord milking (C-UCM) and immediate cord clamping (ICC) in neonates born >35 weeks' gestation. RESULTS: A total of 587 infants were evaluated. Of these, 197 were assigned to I-UCM, 190 to C-UCM, and 200 to ICC. Mean hemoglobin and hematocrit levels at 48 hours of age were higher in I-UCM group compared with the ICC group (p = 0.002 and p = 0.010, respectively). CONCLUSION: These findings suggest that I-UCM is more beneficial choice. Further trials are needed to assess the various long- and short-term effects of different cord milking methods. KEY POINTS: · This is the first study comparing these three methods (I-UCM, C-UCM, and ICC) concurrently.. · I-UCM is more beneficial choice.. · Although the terms I-UCM and C-UCM are often used interchangeably, these are different procedures..

Effects of a supervised therapeutic exercise program on musculoskeletal health and gait in patients with haemophilia: A pilot study.

INTRODUCTION: Episodes of bleeding in patients with haemophilia (PwH) are associated with haemophilic arthropathy, limitations in physical performance, reduced quality of life (QoL), and gait disorders. AIM: This non-randomized, controlled, interventional, prospective, single-centre pilot study aimed to assess the effects of an 8-week supervised therapeutic exercise program on musculoskeletal health, gait kinematic parameters (GKP), functional capacity, and QoL in adult PwH. METHODS: Nineteen PwH were allocated to an exercise group (n = 10) or a control group (n = 9). The patients in the exercise group followed an 8-week supervised therapeutic exercise program. The Haemophilia Joint Health Score (HJHS), a two-dimensional video-based gait kinematic analysis (2D-GKA), the 6-min walking test (6MWT), and the Haemophilia Quality of Life Questionnaire for Adults (Haem-A-Qol) were used as the outcome measures at baseline, after the exercise program (at the 8th week), and at the 6th-month follow-up. RESULTS: A significant improvement was observed in the exercise group in the HJHS-Total and Haem-A-Qol Total scores and the 6MWT value after the exercise program. Moreover, the 2D-GKA revealed improvement in most of the GKP (knee extension during the midstance and late swing phases, ankle dorsiflexion during the midstance phase, and ankle plantar flexion during the preswing phase). However, the gain obtained by the exercise program was not maintained at the 6th-month follow-up for the HJHS-Total and Hem-A-QoL-Total scores and GKP. CONCLUSION: The 8-week supervised therapeutic exercise program was successful in achieving improvement in joint health, GKP, functional capacity, and QoL in PwH.

The effects of manual therapy and exercises on pain, muscle strength, joint health, functionality and quality of life in haemophilic arthropathy of the elbow joint: A randomized controlled pilot study.

INTRODUCTION: Effective physiotherapy interventions are required for haemophilic arthropathy (HA) of the elbow due to its biomechanical differences and contribution to upper limb functionality. AIM: To investigate the effects of manual therapy & exercises on bleeding frequency, pain, range of motion (ROM), strength, joint health, functionality and quality of life (QoL) in HA of the elbow. METHODS: Seventeen participants with HA of the elbow were randomized as Manual Therapy & Exercises Group (MTEG = 9) and Home Exercises Group (HEG = 8). Soft tissue mobilization, joint traction (grade I-II) and Mulligan's mobilization with movement as manual therapy, and stretching/strengthening exercises were applied to MTEG, while HEG had only same exercises as home programme. The interventions lasted 3 days/weekly for 5 weeks. Bleeding frequency was evaluated with patients' records; pain with Numeric Pain Scale; ROM with goniometer; strength with digital dynamometer; joint health with HJHS; functionality with Quick-Disability of Arm, Shoulder and Hand questionnaire; and QoL with Oxford Elbow Score. RESULTS: Bleeding frequency and activity pain were decreased, while elbow ROMs and flexor strength were increased in MTEG (P Ë‚ 0.05). Also significantly improvements were seen in joint health, functionality and QoL in MTEG. HEG showed improvements in activity pain, QoL and some ROMs. MTEG had better results in ROMs, joint health and functionality (P Ë‚ 0.05). CONCLUSION: Manual therapy & exercises may be used without causing bleeding and pain to increase the functionality, joint health and QoL, and is superior to home exercise for joint health and functionality. Home exercises may be ameliorated in pain, QoL and some ROMs.

Impact of the HEAD-US Scoring System for Observing the Protective Effect of Prophylaxis in Hemophilia Patients: A Prospective, Multicenter, Observational Study

Objective: This study aimed to observe the preventive effect of prophylactic treatment on joint health in people with hemophilia (PwH) and to investigate the importance of integration of ultrasonographic examination into clinical and radiological evaluation of the joints. Materials and Methods: This national, multicenter, prospective, observational study included male patients aged ≥6 years with the diagnosis of moderate or severe hemophilia A or B from 8 centers across Turkey between January 2017 and March 2019. Patients were followed for 1 year with 5 visits (baseline and 3th, 6th, 9th, and 12th month visits). The Hemophilia Joint Health Score (HJHS) was used for physical examination of joints, the Pettersson scoring system was used for radiological assessment, point-of-care (POC) ultrasonography was used for bilateral examinations of joints, and the Hemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) score was used for evaluation of ultrasonography results. Results: Seventy-three PwH, of whom 62 had hemophilia A and 11 had hemophilia B, were included and 24.7% had target joints at baseline. The HJHS and HEAD-US scores were significantly increased at the 12th month in all patients. These scores were also higher in the hemophilia A subgroup than the hemophilia B subgroup. However, in the childhood group, the increment of scores was not significant. The HEAD-US total score was significantly correlated with both the HJHS total score and Pettersson total score at baseline and at the 12th month. Conclusion: The HEAD-US and HJHS scoring systems are valuable tools during follow-up examinations of PwH and they complement each other. We suggest that POC ultrasonographic evaluation and the HEAD-US scoring system may be integrated into differential diagnosis of bleeding and long-term monitoring for joint health as a routine procedure.

The effects of manual therapy on musculoskeletal system, functional level, joint health and kinesiophobia in young adults with severe haemophilia: A randomized pilot study.

INTRODUCTION: The effects of manual therapy (MT) on joint health and functional level in haemophilic arthropathy (HA) have relatively under-explored. AIM: To investigate the effects of MT in HA of lower limb joints on musculoskeletal system, functional level, Functional Independence Score in Hemophilia (FISH), Hemophilia Joint Health Score (HJHS) and kinesiophobia. METHODS: Seventeen patients were randomized to the control group (CG = 9) and manual therapy group (MTG = 8). The number of haemarthrosis (NoH) was recorded from the diaries. Range of motion (ROM), strength and pain intensity were measured using goniometer, digital dynamometer and visual analogue scale, respectively. Joint health was evaluated with HJHS, functional independence with FISH, and kinesiophobia with Tampa Scale. Functional Reach (FR), Timed Up-Go (TUG) and 5-Times Sit-to-Stand (5*STS) tests were used to evaluate functional level. Home exercises were given to both groups. Additionally, myofascial release techniques and mobilizations were applied to MTG. Interventions were applied 3 d/weekly for 5 weeks. Assessments were performed at baseline and after treatment. RESULTS: ROM, strength, activity pain, HJHS and FISH were improved in MTG (p˂0.05). Ankle NoH, 5*STS and FR were developed in both groups (p˂0.05), but kinesiophobia, TUG and knee NoH were not significant. Although improvements were observed in favour of MTG in HJHS, FR, activity pain and ankle strength/ROM (p˂0.05), no significant difference was found in FISH, kinesiophobia, TUG, 5*STS, resting pain and knee strength. CONCLUSION: Reduction in ankle NoH indicated that both interventions were safe. The use of MT in HA of lower limb joints was an effective physiotherapy approach to improve functional level, joint health and functional independence.