The range of haploidentical transplant protocols in sickle cell disease: all haplos are not created equally.

Kassim AA ，DeBaun MR 《-》

Bone marrow versus peripheral blood allogeneic haematopoietic stem cell transplantation for haematological malignancies in adults.

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is an established treatment option for many malignant and non-malignant haematological disorders. Peripheral blood stem cells represent the main stem cell source in malignant diseases due to faster engraftment and practicability issues compared with bone marrow stem cells. Since the early 2000s, there have been many developments in the clinical field. Allo-HSCT using haploidentical family donors (haplo-HSCT) has emerged as an alternative for people who do not have human leukocyte antigen (HLA)-matched siblings or unrelated donors. In addition, the introduction of new methods and strategies in allo-HSCT, such as the use of post-transplant cyclophosphamide (PT-Cy), better donor selection, the more frequent administration of anti-thymocyte globulins (ATGs), but also improved management of side effects such as graft-versus-host disease (GvHD) and infection, have impacted outcomes after allo-HSCT. In addition, as transplant indications and strategies continue to adapt in line with novel research findings, the effect of the stem cell source on post-transplant outcomes is unclear. For our analysis, we considered peripheral blood stem cells as the standard graft source for adults with haematological malignancies. This is an update of a review first published in 2014. To assess the effect of bone marrow transplantation versus peripheral blood stem cell transplantation in adults with haematological malignancies with regard to overall survival, disease-free survival, incidence of non-relapse or transplant-related mortality, incidence of extensive chronic graft-versus-host disease (GvHD), incidence of acute GvHD grades III to IV, incidence of overall chronic GvHD, and quality of life. For this update we searched CENTRAL, MEDLINE, Embase, and two trials registries on 2 November 2022 with no language restrictions. We included randomised controlled trials (RCTs) comparing bone marrow transplantation (BMT) with peripheral blood stem cell transplantation (PBSCT) in adults (aged ≥ 18 years) with haematological malignancies. Two review authors independently selected studies and extracted data. We evaluated risk of bias using the original Cochrane risk of bias tool (RoB 1), and we evaluated the certainty of the evidence using the GRADE approach. The updated search identified no new studies for inclusion. We found two additional reports relating to a previously included study; they provided new data on quality of life and infection rates after transplantation. As these are clinically relevant outcomes, quality of life was added to the summary of findings table (replacing acute GvHD II to IV), and rate of infection was added to our list of secondary outcomes. We included nine RCTs with a total of 1521 participants. Overall, the risk of bias in the included studies was low. Median participant age across studies ranged from 21 to 45 years, and studies took place in Canada, the USA, New Zealand, Brazil, Australia, Egypt, and across Europe. Bone marrow transplantation (BMT) compared with peripheral blood stem cell transplantation (PBSCT) likely results in little to no difference in overall survival (hazard ratio (HR) for all-cause death 1.07, 95% CI 0.91 to 1.25; 6 studies, 1330 participants; moderate-certainty evidence). There may be little to no difference between BMT and PBSCT in terms of disease-free survival (HR for disease recurrence or all-cause death 1.04, 95% CI 0.89 to 1.21; 6 studies, 1225 participants; low-certainty evidence) and non-relapse or transplant-related mortality (HR 0.98, 95% CI 0.76 to 1.28; 3 studies, 758 participants; low-certainty evidence). BMT compared with PBSCT likely results in lower rates of extensive chronic GvHD (HR 0.69, 95% CI 0.54 to 0.90; 4 studies, 765 participants; moderate-certainty evidence) and overall chronic GvHD (HR 0.72, 95% CI 0.61 to 0.85; 4 studies, 1121 participants; moderate-certainty evidence). BMT compared with PBSCT may reduce the incidence of acute GvHD grades III to IV, although the 95% CI of the HR is also compatible with no effect (HR 0.75, 95% CI 0.55 to 1.02; 3 studies, 925 participants; moderate-certainty evidence). Evidence from two trials that used different quality of life assessment instruments suggests that BMT compared with PBSCT may be associated with higher quality of life five years after transplantation. Moderate-certainty evidence suggests little to no difference in overall survival following allo-HSCT using bone marrow versus peripheral blood stem cells (the current clinical standard stem cell source). Low-certainty evidence suggests little to no difference between the stem cell sources in terms of disease-free survival and non-relapse or transplant-related survival. BMT likely reduces the risk of extensive chronic GvHD and overall chronic GvHD compared with PBSCT. Evidence from two RCTs suggests that BMT compared with PBSCT may result in higher long-term quality of life, possibly due to the lower chronic GvHD incidence. With this update, we aimed to supply the most recent data on the choice of stem cell source for allo-HSCT in adults by including new evidence published up to November 2022. We identified no new ongoing studies and no new RCTs with published results. Further research in this field is warranted.

Kiene S ，Albrecht M ，Theurich S ，Scheid C ，Skoetz N ，Holtick U ... -  《Cochrane Database of Systematic Reviews》

Allogeneic Hematopoietic Cell Transplant For Bone Marrow Failure or Myelodysplastic Syndrome in Dyskeratosis Congenita/Telomere Biology Disorders: Single-Center, Single-Arm, Open-Label Trial of Reduced-Intensity Conditioning Without Radiation.

Dyskeratosis congenita/telomere biology disorders (DC/TBD) often manifest as bone marrow failure (BMF) or myelodysplastic syndrome (MDS). Allogeneic hematopoietic cell transplant (alloHCT) rescues hematologic complications, but radiation and alkylator-based conditioning regimens cause diffuse whole-body toxicity and may expedite DC/TBD-specific non-hematopoietic complications. Optimization of conditioning intensity in DC/TBD to allow for donor hematopoietic cell engraftment with the least amount of toxicity remains a critical goal of the alloHCT field. We report prospectively collected standard alloHCT outcomes from a single-center, single-arm, open-label clinical trial of bone marrow or peripheral blood stem cell alloHCT for DC/TBD-associated BMF or MDS. Conditioning was reduced intensity (RIC), including alemtuzumab 1 mg/kg, fludarabine 200 mg/m2, and cyclophosphamide 50 mg/kg. A previous single-arm, open-label phase II clinical trial for the same patient population conducted at the same center, differing only by inclusion of 200 cGy of total body irradiation (TBI), served as a control cohort. The non-TBI cohort included 10 patients (ages 1.7-65.9 years, median follow-up of 3.9 years) compared with the control TBI cohort, which included 12 patients (ages 2.2-52.2 years, median follow-up of 10.5 years). Baseline characteristics differed only in total CD34+ cells received, with a median of 5.6 (non-TBI) compared with 2.6 (TBI) x 106/kg (P = .02; no difference in total nucleated cells). The cumulative incidence of day +100 grade II-IV acute and 4-year chronic graft-versus-host disease (GvHD) were low at 0% and 10% (non-TBI) and 8% and 17% (TBI), respectively (acute, P = .36; chronic, P = .72). Primary graft failure was absent. Secondary non-neutropenic graft failure occurred in one (non-TBI cohort). The non-TBI cohort demonstrated delayed achievement of full donor chimerism but superior lymphocyte recovery. There was no difference in 4-year overall survival at 80% (non-TBI) and 75% (TBI; P = .78). MDS as an indication for alloHCT was uncommon but overall associated with poor outcomes. There were 3 MDS patients in the non-TBI cohort: 1 relapsed and died at day +387; 1 relapsed at day +500 and is alive 5.5 years later following salvage with a second alloHCT; 1 relapsed at day +1093 and is alive at day +100 after a second alloHCT. There was 1 MDS patient in the TBI cohort who achieved 100% donor myeloid engraftment without relapse but died at day +827 from a bacterial infection in the setting of immune-mediated cytopenia. Elimination of TBI from the RIC regimen for DC/TBD was not associated with significant changes in rates of graft failure, GvHD, and overall survival but was associated with delayed achievement of full donor chimerism and improved lymphocyte reconstitution. For DC/TBD-associated BMF, TBI appears to be dispensable. Optimal approaches to DC/TBD-associated MDS remain unclear. Larger cohorts are needed to better assess the unique contribution of TBI and donor CD34+ cell dose. Longer follow-up is required to assess differences in DC/TBD complications and late effects.

Dimitrov M ，Merkle S ，Cao Q ，Tryon RK ，Vercellotti GM ，Holtan SG ，Kao RL ，Srikanthan M ，Terezakis SA ，Tolar J ，Ebens CL ... -  《-》

Far Posterior Approach for Rib Fracture Fixation: Surgical Technique and Tips.

The present video article describes the far posterior or paraspinal approach to posterior rib fractures. This approach is utilized to optimize visualization intraoperatively in cases of far-posterior rib fractures. This technique is also muscle-sparing, and muscle-sparing posterolateral, axillary, and anterior approaches have been shown to return up to 95% of periscapular strength by 6 months postoperatively1. Like most fractures, the skin incision depends on the fracture position. The vertical incision is made either just medial to a line equidistant between the palpable spinous processes and medial scapular border or directly centered over the fracture line in this region. The incision and superficial dissection must be extended cranially and caudally, approximately 1 or 2 rib levels past the planned levels of instrumentation, in order to allow muscle elevation and soft-tissue retraction. Superficial dissection reveals the trapezius muscle, with its fibers coursing from inferomedial to superolateral caudal to the scapular spine, and generally coursing transversely above this level. The trapezius is split in line with its fibers (or elevated proximally at the caudal-most surface), and the underlying layer will depend on the location of the incision. The rhomboid minor muscle overlies ribs 1 and 2, the rhomboid major muscle overlies ribs 3 to 7, and the latissimus dorsi overlies the remaining rib levels. To avoid muscle transection, the underlying muscle is also split in line with its fibers. Next, the thoracolumbar fascia is encountered and sharply incised, revealing the erector spinae muscles, which comprise the spinalis thoracis, longissimus thoracis, and iliocostalis thoracis muscles. These muscles and their tendons must be sharply elevated from lateral to midline; electrocautery is useful for this because there is a robust blood supply in this region. Medially, while retracting the paraspinal musculature, visualization with this approach can extend to the head and neck of the rib, and even to the spine. Following deep dissection, the fractures are now visualized. During fracture reduction, it is critical to assess reduction of both the costovertebral joint and the costotransverse joint. With fractures closer to the spine, it is recommended to have at least 2 cm between the rib head and tubercle in order to allow 2 plate holes to be positioned on the neck of the rib; if comminution exists and plating onto the transverse process is needed, several screws are required here for stability as well. For appropriate stability if plating onto the spine is not required, a minimum of 3 locking screws on each side of the fracture are recommended. Contouring of the plates to match the curvature of the rib and to allow for proper apposition may be required with posterior rib fractures. Screws must be placed perpendicular to the rib surface. Following operative stabilization of the rib fractures, a layered closure is performed, and a soft dressing is applied. Nonoperative alternatives include non-opioid and opioid medications as well as corticosteroid injections for pain control. Supportive mechanical ventilation and physiotherapy breathing exercises can also be implemented as needed. Operative alternatives include open reduction and internal fixation utilizing conventional locking plates and screws. Rib fractures are often treated nonoperatively when nondisplaced because of the surrounding soft-tissue support2,3. According to Chest Wall Injury Society guidelines, contraindications to surgical fixation of rib fractures include patients requiring ongoing resuscitation; rib fractures involving ribs 1, 2, 11, or 12, which are relative contraindications; severe traumatic brain injury; and acute myocardial infarction. Patient age of <18 years is also a relative contraindication for the operative treatment of rib fractures. The current literature does not recommend surgical fixation in this age group because these fractures typically heal as the patient ages; however, fracture-dislocations may require the use of instrumentation to prevent displacement. Currently, the U.S. Food and Drug Administration does not approve most plating systems for patients <18 years old4. In certain cases, including those with substantial displacement, persistent respiratory distress, pain, or fracture nonunion, stabilization with open reduction and internal fixation may be appropriate5-7. In cases of flail chest injuries, surgery is often indicated6. Flail chest injuries have been noted in the literature to have an incidence of approximately 150 cases per 100,000 injuries and have been shown to carry a mortality rate of up to 33%8,9. Surgical treatment of rib fractures has been shown to be associated with a decreased hospital length of stay and mortality rate in patients with major trauma1. Expected outcomes of this procedure include low complication rates, decreased hospital and intensive care unit length of stay, and reduced mechanical ventilation time10,11. However, as with any procedure, there are also risks involved, including iatrogenic lung injury from long screws or an aortic or inferior vena cava injury with aggressive manipulation of displaced fractured fragments, especially on the left side of the body. During open reduction, there is also a risk of injuring the neurovascular bundle. Tanaka et al. demonstrated a significant reduction in the rate of postoperative pneumonia in their operative group (22%) compared with their nonoperative group (90%)12. Schuette et al. demonstrated a 23% rate of postoperative pneumonia, 0% mortality at 1 year, an average of 6.2 days in the intensive care unit, an average total hospital length of stay of 17.3 days, and an average total ventilator time of 4 days in the operative group10. Prins et al. reported a significantly lower incidence of pneumonia in operative (24%) versus nonoperative patients (47.3%; p = 0.033), as well as a significantly lower 30-day mortality rate (0% versus 17.7%; p = 0.018)3. This procedure utilizes a muscle-sparing technique, which has demonstrated successful results in the literature on the use of the posterolateral, axillary, and anterior approaches, returning up to 95% of periscapular strength, compared with the uninjured shoulder, by 6 months postoperatively1. The use of a muscle-sparing technique with the far-posterior approach represents a topic that requires further study in order to compare the results with the successful results previously shown with other approaches. The ipsilateral extremity can be prepared into the field to allow its intraoperative manipulation in order to achieve scapulothoracic motion and improved subscapular access.For costovertebral fracture-dislocations, the vertical incision line is made just medial to a line equidistant between the palpable spinous processes and medial scapular border.Lateral decubitus positioning can be utilized to allow for simultaneous access to fractures that extend more laterally and warrant a posterolateral approach; however, it is generally more difficult to access the fracture sites near the spine with this approach.This muscle-sparing technique is recommended to optimize postoperative periscapular strength, as previously demonstrated with other approaches.Incision and superficial dissection must be extended cranially and caudally approximately 1 or 2 rib levels past the planned levels of instrumentation in order to allow muscle elevation and soft-tissue retraction.To avoid muscle transection during surgical dissection, the underlying muscle is split in line with its fibers.During deep dissection, it can be difficult to delineate underlying muscles because these muscles have fibers that do not run in line with the trapezius, and some, like the rhomboid major, run nearly perpendicular to it.Electrocautery is useful while elevating the erector spinae muscles and tendons, as there is a robust blood supply in this region.The erector spinae muscle complex is relatively tight and adherent to the underlying ribs, which may make it difficult to achieve adequate visualization; therefore, at least 3 rib levels must be elevated to access a rib for reduction and instrumentation.Although internal rotation deformities are more common in this region, any external displacement of a fracture can lead to a muscle injury that can be utilized for access.During fracture reduction, it is critical to assess reduction of both the costovertebral joint and the costotransverse joint.Special attention must be given to contouring the implants because there are not any commercially available precontoured implants for this region at this time, and plating onto the spine remains an off-label use of any currently available implant.For the more challenging fracture patterns, the use of a right-angled power drill and screwdriver is recommended.Generally, the incision is utilized as previously described to provide access as far medial as the transverse process if needed. However, in cases in which this approach does not allow proper visualization with rib fracture-dislocations involving the posterior ribs or spine, a midline spinal incision can be utilized while working in combination with a spine surgeon.With fractures closer to the spine, it is recommended to have at least 2 cm between the rib head and tubercle in order to allow 2 plate holes to be positioned on the neck of the rib.If comminution exists and plating onto the transverse process is needed, several screws are required for stability.When measuring the length of screws to be placed in the transverse process, preoperative CT scans can be utilized. CT = computed tomographyCWIS = Chest Wall Injury SocietyIVC = inferior vena cava.

Manes TJ ，DeGenova DT ，Taylor BC ，Patel JN ... -  《-》

Biologically Randomized Comparison of Haploidentical Versus Human Leukocyte Antigen-Matched Related Donor Reduced-Intensity Conditioning Hematopoietic Cell Transplantation.

Using haploidentical donors for allogeneic hematopoietic cell transplantation (HCT) broadens transplant accessibility to a growing number of patients with hematologic disorders. Moreover, haploidentical HCT with post-transplant cyclophosphamide (PTCy) has become widespread practice due to accumulating evidence demonstrating favorable rates of survival and graft-versus-host disease (GvHD). Most studies comparing outcomes by donor sources have been confounded by variability in conditioning regimens, graft type (peripheral blood [PB] or bone marrow), and post-transplant GvHD prophylaxis (PTCy or non-PTCy), making it difficult to define the effect of donor source on outcomes. Levine Cancer Institute started a transplant and cellular therapy program in 2014, with both haploidentical and matched related donor (MRD) transplants initially performed using a uniform reduced-intensity conditioning (RIC) regimen, PB grafts, and PTCy-based GvHD prophylaxis. This retrospective observational study was conducted to compare the clinical outcomes associated with RIC haploidentical HCT and MRD HCT in patients receiving identical conditioning regimens, graft types, and supportive care. Our transplant database was queried to evaluate demographic characteristics, clinical features, and outcomes of RIC HCT for consecutive patients with hematologic malignancies who received haploidentical or MRD grafts between March 2014 and December 2017. An MRD was the preferred donor source; when unavailable, a haploidentical donor was used. Sixty-seven patients underwent haploidentical HCT and 25 MRD HCT. Overall, characteristics of transplant recipients were similar for the haploidentical and MRD groups; however, haploidentical donors were younger than MRDs (median 36 yr versus 57 yr, P < .0001). Results of univariable analysis showed similar overall survival (OS) for haploidentical and MRD HCT (hazard ratio [HR], 1.15; 95% CI, 0.61 to 2.15; P = .669). One-year, 1-yr, and 5-yr OS were 80.2%, 54.7%, and 41.2% for haploidentical HCT and 76.0%, 55.7%, and 51.1% for MRD HCT, respectively. With a median follow-up of 81.90 months, results of multivariable analysis revealed that donor source (haploidentical versus MRD) was not significantly associated with OS (HR, 0.97; 95% CI, 0.51 to 1.87; P = .933), relapse-free survival (HR, 0.75; 95% CI, 0.42 to 1.35; P = .337), cumulative incidence of relapse (HR, 0.81; 95% CI, 0.39 to 1.70; P = .579), or non-relapse mortality (HR, 1.12; 95% CI, 0.40 to 3.14; P = .827). Cumulative incidences of acute GvHD (aGvHD) and chronic GvHD (cGvHD) were not significantly different for haploidentical and MRD HCT (grades II to IV aGvHD: HR, 1.78; 95% CI, 0.72 to 4.37; P = .210; grades III to IV aGvHD: HR, 2.84; 95% CI, 0.34 to 23.63; P = .335; cGvHD: HR, 1.00; 95% CI 0.36 to 2.76; P = .995). With care that was homogenous in terms of conditioning regimens, graft type, GvHD prophylaxis, and supportive care, 92 patients who were biologically randomized to either haploidentical HCT or MRD HCT after RIC with PTCy had comparable outcomes.

Grunwald MR ，Sha W ，He J ，Sanikommu S ，Gerber JM ，Ai J ，Knight TG ，Fasan O ，Boseman V ，Kaizen W ，Chojecki A ，Ragon BK ，Symanowski J ，Avalos B ，Copelan E ，Ghosh N ... -  《-》