Double Cord Research Articles

Vickers Hardness Variation on the Part and Welding Cord Subjected to Plastic Deformation

By performing Vickers identifications in the area of the weld bead and the areas adjacent to it, the degree of plastic deformation can be assessed, highlighting the different hardness in the case of welding and the base material. During this work, welded specimens were made in the central area with a double V-shaped cord. One of the specimens was loading until breaking, noting that the rupture occurred in an area further away from the welding area. Another 13 specimens were required at varying degrees of deformation. Stresses above the elastic limit create differences in the plastic deformation of the areas of the weld bead and those in its vicinity. Due to the fact that the base material and the material of the weld bead have different elastic characteristics, much more pronounced plastic deformations occur in the base material compared to the weld bead. It was found that the base material suffered significantly greater plastic deformation than the weld bead. Significant differences in hardness occur in the area of the weld bead relative to the area of the base material.

Fetal-maternal incompatibility in the Rh system. Rh isoimmunization associated with hereditary spherocytosis: case presentation and review of the literature.

Next to A and B antigens, agglutinogen D exhibits the highest immunogenicity. Following the transfusion of D-positive red blood cells (RBCs), almost 80% of D-negative recipients develop anti-D antibodies (Abs). Subsequently, anti-D immunization further promotes the synthesis of Abs towards other blood group antigens in or outside the Rh system. The D antigen is also involved in 95% of cases of hemolytic disease of the newborn. Transfusions, hemotherapy, grafts, and obstetric history (abortions, ectopic pregnancy, births) are all risk factors for Rh isoimmunization. In the case of ABO compatibility between mother and fetus, Rh-positive fetal RBCs that have reached the maternal bloodstream are not destroyed by group agglutinins, and Rh antigenic sites are not hidden by the maternal immune system. But a Rh-negative mother with a homozygous Rh-positive husband will certainly have a Rh-positive fetus. As it has an irreversible evolution, the Rh isoimmunization once installed cannot be influenced in the sense of decreasing the Ab titer, therefore, injectable globulin has no effect. A particular case was that of a newborn with Rh system incompatibility associated with hereditary spherocytosis The clinical balance at birth reflects the severe jaundice of the female newborn of 3140 g, gestational age 38∕39 weeks, extracted by lower-segment transverse Caesarean section, with a double loop nuchal cord, Apgar score 8. Because the jaundice was severe and atypical (face and upper chest), we considered the possibility of coexistence of hemolytic disease of the newborn by Rh blood group incompatibility associated with hereditary spherocytosis, as it turned out to be true and mentioned. Changes in genes encoding proteins in the structure of the RBC membrane have amplified hemolysis induced by maternal-fetal isoimmunization in the Rh system. Massive hemolysis accentuated by congenital spherocytosis, confirmed later, imposed blood transfusion and dynamic monitoring.

Unrelated Cord Blood Transplantation in Children, Adolescents, and Young Adults with Acute Leukemia or Myelodysplastic Syndrome: A Retrospective Comparative Study from the French Society for Bone Marrow Transplantation and Cellular Therapy Between Real-World Data and Previously Reported Results of a Randomized Clinical Trial

We previously reported results of a French randomized clinical trial (RCT) comparing the risk of transplantation failure (including transplant-related mortality [TRM], engraftment failure, and autologous recovery) in single and double unrelated cord blood (UCB) transplantation in children and young adults with hematologic malignancies. We concluded that single-UCB transplantation with an adequate cell dose is the standard of care, leading to a 70% two-year overall survival (OS). It remains unclear, however, whether RCT participants have better outcomes than comparable patients not treated in the setting of a clinical trial. We compared the characteristics and outcomes of RCT participants (n=137) to a Francophone population-based registry of patients (real-world [RW] group) fulfilling the eligibility criteria used in our RCT and transplanted with 1 or 2 UCB units after a myeloablative conditioning (MAC) regimen between March 2015 (end of inclusion in the RCT) and February 2019 (n=141). The primary endpoint was the 2-year cumulative incidence (CI) of transplantation strategy failure as defined in our RCT. The 2 groups were comparable in terms of age, disease distribution, hematologic status at transplantation, follow-up, and HLA compatibility. Patients in the RW group were more likely to be transplanted with a single-unit UCB (87.9% versus 49.6%, P< .001) and to receive a radiation-free regimen (39.0% versus 60.6%, P< .001). The 2-year CI of transplantation strategy failure, TRM, and the 2-year probability of OS were similar between the 2 groups, although the relapse risk was higher in the RW group (31.2% ± 7.7% versus 20.4% ± 6.8%, P= .01), resulting in a significantly lower disease-free survival (DFS) (59.2% ± 8.4% versus 69.3% ± 8.0%, P= .047). This difference remained statistically significant only in the group of patients with acute lymphoid leukemia (ALL) who did not receive the conditioning regimen recommended by the RCT (fludarabine 75 mg/m2, total body irradiation 12 Gy, cyclophosphamide 120 mg/kg). The results of our RCT appear to be reproducible in real-world conditions, provided that the same cord blood selection criteria and conditioning regimen are used.

Transference, transformations, constitution and resistance in psychoanalytic group work

The author presents the possibility of doing therapeutic work with the technique of psychoanalytic psychodrama in a group of "antisocial" adolescent girls. He analyses, in particular, a specific type of transference in the group, which he calls "topical transference", which gives the group a dreamlike dimension. In this way, it is possible to bring out the double umbilical cord of the dream that operates in groups. This double umbilical cord is at the origin of resistance in group work, but above all in institutions. Recognition of this specificity allows fruitful work with groups within institutions. The author analyses the device of traditional care from group theorisations. He compares their differences in the treatment of unconscious conflicts. Through analysing the ways of approaching the Oedipal complex in groups, he demonstrates that the two main modes of transference described earlier are found in the exteriority/confidentiality dynamic. They establish inverse figure/background relations in the psychoanalytic group devices and classical psychoanalytic treatment.

Impact of Center Experience with Donor Type on Outcomes: A Secondary Analysis, Blood and Marrow Transplant Clinical Trials Network 1101

We previously reported the results of Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1101, a randomized comparison of hematopoietic cell transplantation (HCT) performed with double umbilical cord blood units (dUCB) or with haploidentical bone marrow (haplo-BMT) with post-transplantation cyclophosphamide (PTCy) in the nonmyeloablative setting. Those results showed similar progression-free survival in the 2 treatment groups but lower nonrelapse mortality and better overall survival in the haplo-BM arm. In this secondary analysis, we sought to investigate whether transplantation center's previous experience with haplo-BM and/or dUCB HCT had an impact on outcomes. All patients randomized in BMT CTN 1101 were included. Center experience was assigned based on the number of transplantations with each platform performed in the year before initiation of the study according to the Center for International Blood and Marrow Transplant Research. Centers were then classified as a dUCB center (>10 dUCB HCTs; n=117 patients, 10 centers), a haplo-BM center (>10 haplo-BM HCTs and ≤10 dUCB HCTs; n=110 patients, 2 centers), or other center (≤10 haplo and ≤10 dUCB HCTs; n=140 patients, 21 centers). After adjusting for age, Karnofsky Performance Status, and Disease Risk Index, we found that haplo-BM centers had lower overall mortality with this donor type compared with dUCB centers (hazard ratio [HR], 2.56; 95% confidence interval [CI], 1.44 to 4.56). In contrast, there were no differences in overall mortality between haplo-BM and dUCB in centers that were experienced with dUCB HCT (HR, 1.02; 95% CI, .59 to 1.79) or had limited to no experience with either dUCB or haplo-BM HCT (HR, 1.36; 95% CI, .83 to 2.21). The higher risk of treatment failure and overall mortality in dUCB HCT in haplo BM-experienced centers was driven by a significantly higher risk of relapse (HR, 1.78; 95% CI, 1.07 to 2.97). With the exception of worse outcomes among dUCB HCT recipients in haplo-BM centers, transplantation center experience in the year before initiation of BMT CTN 1101 had a limited impact on the outcomes of this randomized clinical trial.

Review/Perspective On the Diagnosis and Surgical Management of Spinal Arachnoid Cysts.

Background: Spinal arachnoid cysts (SAC) are typically congenital, spontaneous, traumatic (i.e., including iatrogenic/surgical), or inflammatory in origin. In descending order, they occur in the thoracic, lumbar, and cervical spine, and originate from focal entrapment of the arachnoid membrane. Arachnoid cysts represent 1–2% of all cystic spinal masses/tumors. The majority are extradural arachnoid cysts (EDAC) while 10% of all arachnoid cysts are intradural (IDAC) including subarachnoid, or extra-arachnoidal/subdural. Only rarely are they intramedullary in location. The clinical symptoms/signs of IDAC/EDAC include; intracranial hypotension (i.e., due to continued cerebrospinal fluid drainage), radiculopathy, and/or myelopathy.Methods: Magnetic Resonance Images (MR) and Myelo-Computed Tomography (Myelo-CT) studies classically document the predominant dorsal location of IDAC/EDAC. They also show their extent and severity contributing to root, cord, and/or cauda equina compression. In the cervical/thoracic spine, MR/Myelo-CT studies classically show the “double cord” or “windsock” signs, while the “fake arachnoiditis sign” may be seen in the lumbar spine. The latter sign signals the presence of a circumferential extra-arachnoidal-subdural cyst that centrally “traps” the cauda equina. Note, that this resembles and is often misinterpreted as adhesive archnoiditis.Results: Patients with significant SAC-related neurological deficits typically warrant early surgery. That surgery includes; partial/total resection/fenestration of cyst walls, and occlusion of communicating fistulas with or without accompanying shunts.Conclusion: It is critical to recognize the clinical (i.e., intracranial hypotension, radiculopathy, and/or myelopathy) and radiographic MR/Myelo-CT signs (i.e., “double cord,” “windsock signs”, or “fake arachnoiditis sign”) of IDAC, EDAC, or intramedullary spinal arachnoid cysts to appropriately offer treatment. For those with significant neurological deficits, early surgery (i.e. optimally 0-< 24 hours after the onset of symptoms/signs consisting of laminectomies, partial/total cyst resection/fenestration, and ligation/occlusion of the subarachnoid-cyst fistula with or without shunt placement), is essential to avoid significant permanent neurological sequelae.

Retinopathy associated with severe thrombocytopenia

In January, 2019, a 37-year-old, White man presented to Saint-Etienne University Hospital (France) with relapsed Hodgkin lymphoma. A PET-CT scan showed hypermetabolic adenomegaly above and below the diaphragm, without visceral or bone involvement. Two cycles of intravenous chemotherapy (gemcitabine 800 mg/m2, vinorelbine 15 mg/m2, and pegylated liposomal doxorubicin 10 mg/m2 on days 1 and 8 every 21 days) resulted in a complete metabolic response in March, 2019. Consolidation consisted of double umbilical cord blood transplantation (dUCBT; total nucleated cells 15·4 × 107 cells per kg and 19·1 × 107 cells per kg for each cord, CD34+ cells 6·5 × 105 cells per kg and 7·9 × 105 cells per kg) after an intravenous conditioning regimen (thiotepa 5·0 mg/kg, busulfan 3·2 mg/kg, fludarabine 40 mg/m2, thymoglobulin 5·0 mg/kg).

Double cord vertebral body tethering (VBT) for flexible lumbar curves combined with posterior spinal fusion (PSF) for rigid thoracic curves in skeletally immature patients with adolescent idiopathic scoliosis (AIS)

Double cord vertebral body tethering (VBT) for flexible lumbar curves combined with posterior spinal fusion (PSF) for rigid thoracic curves in skeletally immature patients with adolescent idiopathic scoliosis (AIS)

Durable outcomes of double cord blood transplantation in adults with acute lymphoblastic leukemia: high-risk features for early and long-term mortality.

Background:Cord blood transplantation (CBT) has been reported as an acceptable option with comparable outcomes to conventional donors in adults with acute lymphoblastic leukemia (ALL). We aimed to analyze the long-term CBT outcomes and risk factors for early and long-term mortalities.Methods:Between 2006 and 2020, 112 patients (median age: 35 years; 62 Ph-negative ALL and 50 Ph-positive ALL) were treated with double CBT. Conditioning regimen consisted of total body irradiation (12 Gy) plus cytarabine (9.0 g/m2) plus fludarabine (150 mg/ m2), and graft-versus-host disease (GVHD) prophylaxis was attempted by administering tacrolimus plus mycophenolate mofetil.Results:The median time for neutrophil and platelet recovery was 25 days (range: 5–59 days) and 34 days (range: 7–185 days), respectively. The cumulative incidence of acute GVHD at 1 year was 43.8%, and the incidence of acute GVHD with grades III–IV was 8.9%. The overall cumulative incidence of chronic GVHD was 22.0%, and the incidence of moderate to severe chronic GVHD was 8.5%. After a median follow-up of 60.1 months (range: 5.7–181.3 months), the 5-year cumulative incidence of relapse (CIR) and nonrelapse mortality (NRM) were 15.9% and 28.5% (9.7% and 27.2% for CR1), respectively, and the 5-year overall survival (OS) was 57.9% (66.5% for CR1). In multivariate analysis of 88 patients receiving double CBT in CR1, delayed CR1 was related to high CIR, and age older than 40 years was associated with high NRM and early mortality. Unexpectedly, Ph-positive ALL with MRD had a higher NRM and early mortality than Ph-negative ALL and Ph-positive ALL without MRD subgroups, possibly due to delayed neutrophil and platelet recovery.Conclusion:Our data suggest that double CBT for adult ALL in CR1 has a greater benefit in younger patients and in patients with Ph-positive ALL without MRD or Ph-negative ALL.

Impact of Center Experience with Donor Type and Treatment Platform on Outcomes: A Secondary Analysis BMT CTN 1101

BACKGROUND: Our group recently reported on the results of Blood and Marrow Transplant (BMT) Clinical Trials Network (CTN) 1101 a randomized comparison between double umbilical cord blood (dUCB) and haploidentical bone marrow (haplo) with post-transplant cyclophosphamide (ptCy) in the nonmyeloablative setting that showed similar progression free survival (PFS) between the two treatment groups, but lower non-relapse mortality (NRM) and better of overall survival (OS) in the haplo arm. In this secondary analysis we sought to investigate if transplant center experience with haplo and or cord blood HCT had an impact on outcomes.PATIENTS AND METHODS: All patient randomized in BMT CTN 1101 were included. In order to determine the transplant center experience with either haplo or dUCB we queried the Center for International Blood and Marrow Transplant Research (CIBMTR) for number of transplants with each platform in the year prior to initiation of the study. Centers were then grouped as dUCB center (> 10 dUCB, n=117, 10 centers), Haplo center (>10 haplo and ≤10 dUCB, n=110, 2 centers), and ≤10 haplo and ≤10 dUCB HCTs (other center, n=140, 21 centers). Further analysis considered the alternative cut-off for haplo (> 5 vs ≤ 5) experience, and considered the outcomes based on the donor experience vs. others (e.g. dUCB > 10 vs. ≤ 10; haplo > 5 vs. ≤ 5).RESULTS: The effect of center experience on HCT outcomes shown in Figure, below . After adjusting for age, Karnofsky performance score and, disease risk index we found that there was no difference in outcomes between haplo and dUCB for centers that were experienced with dUCB or had limited to no experience with either dUCB or haplo. In contrast, in centers that were primarily experienced with haplo had better outcomes with this donor type, as compared to dUCB. The higher risk of treatment failure (relapse or death) and overall mortality in dUCB in haplo experienced centers was driven by significantly higher risk of relapse. We then considered the transplant experience with each of the donor types separately. In transplant centers that had performed > 10 dUCB, there were similar outcomes for recipients of both dUCB and haplo. Similarly, centers that had ≤ 5 haplo HCTs had no difference in outcomes between donor types suggesting an overlap with centers that had performed > 10 dUCB HCTs. Overall mortality was higher among dUCB recipients in centers that had performed ≤ 10 dUCB. Notably, the hazard ratio of non-relapse mortality favored haplo in all four donor experience type of transplant center, albeit not statistically significant.CONCLUSION: Except for dUCB recipients in centers with < 10 dUCB/year had worse overall mortality, primarily driven by relapse, the transplant center experience in the year prior to the initiation of BMT CTN 1101 had limited impact on the outcomes of this randomized clinical trial. [Display omitted] DisclosuresBrunstein: NANT: Research Funding; FATE: Research Funding; GamidaCell: Research Funding; BlueRock: Research Funding; AlloVir: Consultancy. Costa: Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria. Cutler: Deciphera: Consultancy; Cimeio: Consultancy; Editas: Consultancy; Kadmon: Consultancy; Pfizer: Consultancy; Mallinckrodt: Consultancy; CareDx: Consultancy; Incyte: Consultancy; Omeros: Consultancy; Syndax: Consultancy; Mesoblast: Consultancy; Jazz: Consultancy. Horowitz: Sobi: Research Funding; Regeneron: Research Funding; Orca Biosystems: Research Funding; Tscan: Research Funding; Xenikos: Research Funding; Miltenyi Biotech: Research Funding; Stemcyte: Research Funding; Medac: Research Funding; Vor Biopharma: Research Funding; Kite/Gilead: Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; Kiadis: Research Funding; Seattle Genetics: Research Funding; Mesoblast: Research Funding; GlaxoSmithKline: Research Funding; Sanofi: Research Funding; Pfizer, Inc: Research Funding; Omeros: Research Funding; Magenta: Consultancy, Research Funding; Jazz Pharmaceuticals: Research Funding; Vertex: Research Funding; Genentech: Research Funding; Takeda: Research Funding; Novartis: Research Funding; Shire: Research Funding; Gamida Cell: Research Funding; Daiicho Sankyo: Research Funding; CSL Behring: Research Funding; Chimerix: Research Funding; Bristol-Myers Squibb: Research Funding; bluebird bio: Research Funding; Astellas: Research Funding; Amgen: Research Funding; Allovir: Consultancy; Actinium: Research Funding. Horwitz: Gamida Cell: Research Funding. McGuirk: Novartis: Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; EcoR1 Capital: Consultancy; Pluristem Therapeutics: Research Funding; Novartis: Research Funding; Bellicum Pharmaceuticals: Research Funding; Astelllas Pharma: Research Funding; Gamida Cell: Research Funding; Fresenius Biotech: Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau. Rezvani: US Department of Justice: Consultancy; Kaleido: Other: One-time scientific advisory board; Nohla Therapeutics: Other: One-time scientific advisory board; Pharmacyclics-Abbvie: Research Funding. Rybka: Spark Therapeutics: Consultancy; Merck: Consultancy. Vasu: Kiadis, Inc.: Research Funding; Boehringer Ingelheim: Other: Travel support; Seattle Genetics: Other: travel support; Omeros, Inc.: Membership on an entity's Board of Directors or advisory committees.

Racial Disparities in Access to Alternative Donor Allografts Persist in the Era of “Donors for All”

Racial Disparities in Access to Alternative Donor Allografts Persist in the Era of “Donors for All”

Clinical Outcomes of Patients with Newly Diagnosed Myelodysplastic Syndrome with MLL Aberrations

IntroductionMixed lineage leukemias (MLL) are an extremely aggressive subset of leukemias that are inherently resistant to several therapies. MLL aberrations (deletion KMT2A and MLL rearrangements) are extremely rare in myelodysplastic syndrome (MDS) and little is known regarding their clinical course or outcomes. The aim of the study is to determine the natural course of the disease in our patient population.MethodsA retrospective cytogenetic database search of patients presenting to a tertiary cancer center from January 2005 to February 2021 with the diagnosis of MDS and CMML with presence of MLL aberrations was conducted. Deletion KMT2A was defined as deletion of 11q23 on cytogenetic studies. Patients who had received prior therapy with hypomethylating agents (HMAs), cytarabine-based regimens, or intensive chemotherapy were excluded. The International Working Group 2006 criteria was used for response assessment. Progression-free survival (PFS) was calculated from date of diagnosis to date of progression from MDS to AML. Overall survival (OS) was determined from the date of diagnosis to the date of death or last follow-up visit.ResultsBetween January 2005 to February 2021, 3369 patients (pts) with the diagnosis of MDS (n=2761) and CMML (n=608) were identified. Of these, 30 pts had MLL aberrations with 18 pts with MLL rearrangements (MLL r) and 12 pts with deletion 11q23 (del-KMT2A). Baseline characteristics are present in Table 1.Among 18 pts with MLL r MDS, 6 pts did not undergo any therapy at our institution. Of the remaining 12, 9 (75%) pts received HMA based therapy, 1 (8%) patient (pt) proceeded to allogeneic stem cell transplant(allo-HSCT) and 2 (17%) pts received intensive chemotherapy (idarubicin, fludarabine and cytarabine). Of the 9 pts who received HMA therapy, 5 (56%) pts had transformation to AML, 2 (22%) pts achieved CR and underwent allo-HSCT, 1 (11%) pt had persistent disease and 1 (11%) developed concurrent metastatic sarcoma and stopped treatment. Out of the 2 (22%) pts who underwent allo-HSCT, 1 pt received maintenance HMA post-transplant but relapsed with transformation to AML after 9 months, and the other was lost to follow up. 1 (11%) pt who had persistent disease received intensive chemotherapy and went into CR and subsequently underwent double umbilical cord transplant and continues to remain in CR. The 2 (17%) pts who received intensive chemotherapy frontline both went into CR, but one developed concurrent malignancy and stopped treatment. The other pt was transitioned to HMA therapy but relapsed with transformation to AML. The 1 patient who received frontline allo-HSCT relapsed with transformation to AML after 5 months. The overall median follow-up duration was 24 months with a median OS of 10 months (Figure 1) and a median PFS of 3.5 months(Figure 2).12 pts with del-KMT2A were identified, out of which 2 pts did not receive treatment. Of the remaining 10 pts, 8 (80%) received HMA based therapy and 2 (20%) pts received investigational treatments. Of the 8 pts who received HMA therapy, 1 (12.5%) achieved CR and remains in CR, 4 (50%) pts had no response, 2 (25%) had hematological improvement (HI) but one died of other causes and the other elected to stop treatment, 1 (12.5%) pt had transformation to AML. Of the 4 pts with no response, 2 pts elected to stop treatment, with 1 developing concurrent malignancy. Of the remaining 2 pts, 1 pt was placed on an investigational agent and had progression to AML and the other was placed on lenalidomide and then an investigational agent, but ultimately pursued hospice. Of the 2 pts on investigational agents both had persistent disease and one patient died and the other elected to stop treatment due to concurrent illness. The overall median follow-up duration was 154 months with a median OS of 16 months (Figure 1) and median PFS of 8 months (Figure 2). Clinical course is presented in Table 2.ConclusionPrognosis of patients with MLL alterations and MDS is very poor. MLL r MDS had worse outcomes with rapid transformation to AML compared to del-KMT2A. New therapies are needed for this group of patients. [Display omitted] DisclosuresIssa: Syndax Pharmaceuticals: Research Funding; Novartis: Consultancy, Research Funding; Kura Oncology: Consultancy, Research Funding. Sasaki: Novartis: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Kantarjian: Novartis: Honoraria, Research Funding; Immunogen: Research Funding; Aptitude Health: Honoraria; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; Jazz: Research Funding; Astellas Health: Honoraria; Astra Zeneca: Honoraria; Ipsen Pharmaceuticals: Honoraria; KAHR Medical Ltd: Honoraria; NOVA Research: Honoraria; Precision Biosciences: Honoraria; BMS: Research Funding; AbbVie: Honoraria, Research Funding; Taiho Pharmaceutical Canada: Honoraria.

Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation in Secondary Central Nervous System Lymphoma

Introduction:Aggressive non-Hodgkin's lymphoma (aNHL) with secondary central nervous system (sCNS) involvement has a poor prognosis. Studies have reported a response to induction treatment as low as 35%, leaving less than half of patients eligible for autologous stem cell transplant (ASCT). Outcomes of patients in these clinical scenarios are dismal and treatment is ill-defined. Small case series suggest chimeric antigen receptor (CAR)-T cell therapy may play a role in the management of relapsed/refractory (R/R) B-cell lymphoma (BCL) with sCNS involvement, but follow-up is limited and response duration is uncertain. Allogeneic hematopoietic stem cell transplant (alloHCT) offers a durable remission for a subset of patients with R/R systemic aNHL primarily mediated through a graft versus lymphoma (GVL) effect, but it is unclear if GVL properties include the immune-privileged CNS. The present study aims to describe outcomes of a cohort of patients with R/R aggressive B- and T-cell NHL with sCNS involvement who underwent alloHCT at a single academic institution.Methods:This is a retrospective analysis that includes all patients with R/R aNHL with sCNS involvement who underwent alloHCT at the University of California, Los Angeles from 2005-2020. The UCLA Institutional Board Review approved this study. Relevant clinical data was extracted from medical records. Hematopoietic cell transplantation comorbidity index (HCT-CI) and time to neutrophil and platelet engraftment were measured according to Center for International Blood and Marrow Transplant Research criteria.Results:Ten patients were included (3 females, 7 males). Histologic subtypes included anaplastic BCL (1), mantle cell lymphoma (1), blastic natural killer-cell lymphoma (1), peripheral T-cell lymphoma, not otherwise specified (1), primary mediastinal BCL (1), and diffuse large B-cell lymphoma (DLBCL) (non-germinal center=3, germinal center-like=2). Two DLBCL patients had histologic transformed lymphoma (follicular lymphoma =1, chronic lymphocytic lymphoma = 1). Four patients had sCNS involvement at the time of initial diagnosis or during frontline treatment; the remaining 6 patients developed sCNS lymphoma at relapse. sCNS lymphoma was identified in the parenchymal (n=4), leptomeningeal (n=3), or both (n=3) compartments.The median age at the time of alloHCT was 49.5 (range 28-68), and 1 patient was ˃ 60. At the time of alloHCT, 1 patient had residual disease in the CNS and the remaining 9 patients were in a complete remission. Eight patients received ˃ 3 prior lines of therapy, and 3 patients failed prior ASCT. HCT-CI scores were 0 (n=1), 1 (n=2), 2 (n=3), 3 (n=1), and unknown (n = 3). Donor types included 10/10 matched related (3), 10/10 matched unrelated (4), 9/10 mismatched related (1), and double umbilical cord blood (2). Graft source was peripheral blood in 8 patients and cord blood in 2 patients. Conditioning regimens included myeloablative, reduced intensity and non-myeloablative in 6, 3 and 1 patient(s), respectively. Six patients received total body irradiation-containing conditioning. The average time to neutrophil engraftment was 18 days (range 11-29), and the average time to platelet engraftment was 26.5 days (range 18-59). One patient had primary graft failure.Of the 6 patients with day 100 disease reassessment (CR at time of alloHCT=5, PR in CNS at time of alloHCT=1), all were in CR. With a median follow-up of 341 days, 2 patients relapsed (CNS=1 and systemic = 1), and 6 patients died. Cause of death included infection (n=3), lymphoma (n=1), primary graft failure (n=1), and organizing pneumonia (n=1). Six patients developed acute graft versus host disease (GVHD) (grade 1-2, n=1; grade 3, n=5), and 4 patients developed chronic GVHD (score 1-2, n= 2; score 3, n=2). The median overall and progression-free survival for the entire cohort was 341 days (range 23-4825) and 268.5 days (range 23-4825), respectively.Conclusions:AlloHCT in patients with R/R aNHL with sCNS involvement is feasible and may provide a durable response in a subset of patients. Four patients remained alive and free of disease one year post-alloHCT and one patient converted from a PR to a CR in the CNS 100 days post-alloHCT, suggesting effective donor immune surveillance within the CNS. Transplant-related morbidity and mortality limits the widespread application of this therapeutic modality and less toxic approaches are urgently needed. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Haploidentical Versus Cord Blood Stem Cell Transplantation As the Second Transplant for Relapsed Acute Myeloid Leukemia Patients after the First Stem Cell Transplantation

Haploidentical Versus Cord Blood Stem Cell Transplantation As the Second Transplant for Relapsed Acute Myeloid Leukemia Patients after the First Stem Cell Transplantation

Primary graft failure, but not relapse, may be identified by early chimerism following double cord blood unit transplantation

AbstractUmbilical cord blood transplantation (UCBT) has increased access to potentially curative therapy for patients with life-threatening disorders of the bone marrow and immune system. The introduction of reduced intensity conditioning (RIC) regimens and double umbilical cord unit infusions (DUCBT) has broadened the applicability of UCBT to more frail or larger recipients. The kinetics of chimerism after RIC DUCBT and their clinical utility are poorly understood. The RIC CBT trial reported here sought to prospectively evaluate the role of lineage-specific chimerism after DUCBT in adult patients with hematologic malignancies in the United Kingdom. Fifty-eight patients with a median age of 52 years were recruited, with overall and progression-free survivals of 59% (95% confidence interval [CI], 45%-71%) and 52% (95% CI, 39%-64%), respectively, at 2 years. Nonrelapse mortality was 4% (95% CI, 1%-13%) at day 100, and the relapse rate was 31% (95% CI, 21%-45%) at 1 year. Peripheral blood lineage-specific chimerism was feasible from day 7 after transplant onward. Five patterns of chimerism were observed including (1) complete single unit dominance (39 patients), (2) sustained donor-donor mixed chimerism (3 patients), (3) sustained donor-recipient mixed chimerism (5 patients), (4) dominance reversion (1 patient), and (5) primary graft failure (4 patients). The RIC CBT trial enabled adult patients with high-risk hematologic malignancies to safely access UCBT in the United Kingdom and provided novel insights into the kinetics of donor and recipient chimerism after RIC DUCBT that are clinically relevant. This trial was registered at https://www.clinicaltrialsregister.eu/ctr-search/trial/2004-003845-41/GB as #NCT00959231 and EudraCT 2004-003845-41.

Influence of Total Body Irradiation Dose Rate on Idiopathic Pneumonia Syndrome in Pediatric Patients With Acute Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation

<h3>Purpose/Objective(s)</h3> To evaluate the relationship between total body irradiation (TBI) and other factors in the development of idiopathic pneumonia syndrome (IPS) in pediatric patients undergoing allogeneic hematopoietic cell transplantation (HCT) for acute leukemia. <h3>Materials/Methods</h3> Between 2006-2019, 121 pediatric patients with acute leukemia (84 lymphoblastic, 37 myeloid), ranging in age from 1 to 21 years (median 12), underwent allogeneic HCT at a single institution with matched sibling (n = 33), single unrelated cord blood (sUCB; n = 57), or double unrelated cord blood (dUCB; n = 31) donor. Pretransplantation conditioning included cyclophosphamide (100-120 mg/kg) with (n = 89) or without fludarabine (75 mg/m²) (n = 32). TBI was delivered in 8 b.i.d. fractions of 1.65 Gy over 4 days via opposed lateral beams of 6, 18, or 25 MV prescribed to midplane at umbilicus, with the patient in a semi-recumbent position, and without lung shielding. Aluminum lung compensator was utilized if predicted mid-lung point dose was ≥3% higher than prescription dose (n = 28). Dose rate was specified at 9-20 cGy/min and depended on linear accelerator availability. Patients were stratified by receipt of high-dose-rate (HDR; > 15 cGy/min; 36%) or low-dose-rate (LDR; ≤15 cGy/min; 64%) delivery. IPS was defined as pulmonary injury based on clinical symptoms, radiographic evidence, or pulmonary function testing within 100 days of HCT in the absence of concurrent infection. The association between treatment factors and IPS was examined. <h3>Results</h3> Overall, IPS developed in 22 (18%) patients from day 6 to 83 (median 20) after HCT. On univariate analysis, factors associated with IPS included donor type (matched sibling 12%, sUCB 12%, dUCB 35%, <i>P</i> < 0.01), HDR TBI (35% vs 9% for LDR, <i>P</i> < 0.01), and lower beam energy (35% for 6 MV and 15% for 18/25 MV, <i>P</i> = 0.04). The finding of beam energy significance is likely the result of the 6 MV cohort having a greater dose rate (median 16 cGy/min) than the 18/25 MV cohort (11 cGy/min). On competing risk regression analysis, the pre-specified factors of dose rate, beam energy, lung compensator, age, HCT comorbidity index, and donor type were included in the model. All factors except age (hazard ratio [HR] 1.09, <i>P</i> = 0.20) and lung compensator (HR 1.8, <i>P</i> = 0.17) showed an independent statistically significant association with IPS. Kaplan-Meier estimated 1-year survival was 73% for the entire cohort. Time-dependent effect of IPS did not show an association with overall survival (HR 1.2, <i>P</i> = 0.76). <h3>Conclusion</h3> TBI dose rate is an important variable in the risk of pulmonary toxicity in children treated with allogeneic HCT. TBI dose rates ≤15 cGy/min reduced the risk of posttransplantation IPS and should be strongly considered as an easily implemented parameter in pre-transplantation TBI-based conditioning.

Engraftment of Double Cord Blood Transplantation after Nonmyeloablative Conditioning with Escalated Total Body Irradiation Dosing to Facilitate Engraftment in Immunocompetent Patients

To improve accrual to a randomized clinical trial of double unrelated cord blood (dUCB) versus HLA-haploidentical bone marrow (haplo-BM) transplantation, patients with less previous therapy and potentially greater immunocompetence were enrolled. To reduce the risk of graft rejection, patients randomized to receive dUCB received a higher dose of total body irradiation (TBI) (300 cGy versus 200 cGy). In this study, we investigated whether the inclusion of recipients of 300 cGy TBI influenced the trial outcomes. This was a secondary analysis of dUCB recipients, 161 who received TBI 200 cGy and 18 who received TBI 300 cGy. Fine and Gray regression was used to evaluate the effect of TBI dose on relapse and nonrelapse mortality (NRM). Cox regression was used for evaluation of neutrophil engraftment and overall survival. Patient characteristics were similar in the 2 TBI dose subgroups. The probability of neutrophil engraftment was 100% for patients who received TBI 300 cGy versus 91% (95% confidence interval, 86% to 95%) for those who received TBI 200 cGy (P=.64), which was similar after regression analysis adjusting for age, total infused nucleated cell dose, HLA matching to the patient, and comorbidity score. We also investigated whether the lower survival probability and higher cumulative incidence of NRM observed in the dUCB arm of BMT CTN 1101 could be influenced by the TBI 300 cGy patient subset. There was no significant difference in the 1-year incidences of NRM and relapse or in 1-year survival, even after adjustment in multivariate analysis. Patients in BMT CTN 1101 who received TBI 300 cGy and 200 cGy had similar engraftment and early mortality. We conclude that inclusion of a modified regimen for dUCB transplantation had no demonstrable influence on this large randomized trial.

First Application Of The EBMT Risk Score In Double Umbilical Cord Blood Transplantation For Hematological Malignancies: Significant Impact On Different Outcomes

The European Group for Blood and Marrow Transplantation (EBMT) risk score provides a simple tool to assess chances and risks of hematopoietic stem cell transplantation (HSCT) for an individual patient from related and unrelated donors. To our knowledge, this score has never been applied in double umbilical cord blood transplantation (dUCBT). We recently published results of 136 patients who underwent dUCBT reported to the SFGM-TC registry from 23 centers between 2005 and 2007 (Labussiere et al., Exp. Hem. 2013). After having recorded the full data on CB units including HLA and sex, we decided to test the validity of the EBMT risk score and check its application in dUCBT. There were 88 males and 48 females with a median age of 41 years (range: 18 – 66), 76 patients with acute leukemias (42 AML, 27 ALL, 5 secondary AL and 2 Biphenotypic AL), 8 with chronic leukemias (5 lymphoid and 3 myeloid), 10 with myelodysplasic syndormes, 24 with Hodgkin and non Hodgkin lymphomas, 13 with multiple myelomas and 5 with other myeloproliferative diseases. Median interval between diagnosis and transplantation was 20.5 months (range: 3-385). At time of allogeneic transplantation, 41 patients were in first complete remission (CR1), 40 in ≥CR2 and 55 less than CR. Forty-six patients received myeloablative and 90 reduced intensity conditioning regimens. The EBMT risk score uses the 5 pre-transplant factors: age of the patient, disease status, time from diagnosis to transplant, kind of donor (related/unrelated), and donor-recipient sex combination with 0 to 1 or 2 points (pts) for each factor. Age was categorized as <20 years (0 pt; n= 6), 20 to 40 years (1 pt; n= 59) and >40 years (2 pts; n=71). For disease status we distinguished patients in CR1 at transplantation, (0 pt; n=41) from patients in CR >1 (1 pt; n=40) and patients not in CR (2 pts; n=55). Time from diagnosis to transplant was categorized into ≤12 months (0 pt; n=26) and >12 months (1pt; n=110). The adaptation of the new risk score concerned HLA and sex matching. Complete information concerning HLA typing was obtained from the database of the national network of cord blood banks on behalf of Eurocord. HLA typing was evaluated across 3 loci: HLA-A, -B and -DRB1; it was based on antigenic level for HLA-A and HLA-B, and on allelic level for HLA-DRB1. HLA matching showed patients with at least 4/6 HLA matching on HLA-A, -B and DRB1 without any mismatch on DRB1 alleles between the recipient and each UCB unit and the 2 units together (0 pt; n=77); patients with at least 4/6 HLA matching on HLA-A and -B between the recipient and each unit but without complete matching on DRB1 or with less than 4/6 HLA matching between the 2 units (1 pt; n=51), and finally patients with more than 2 mismatches on the three loci (2 pts; n=8). Donor-recipient sex combination separated all others (0 pt; n=73) from the male recipient with one female and one male cord blood unit (1pt; n=45) and male recipient with two female cord blood units (2 pts; n=18). Hence, we found 5 patients (4%) in score 1, 12 (9%) in score 2, 23 (17%) in score 3, 26 (19%) in score 4, 30 (22%) in score 5, 26 (19%) in score 6, 11 (8%) in score 7 and 3 (2%) in score 8. We pooled patients with scores 1-2; 3-4 and 5-8 as their outcomes were found to be similar. After a median follow-up of 49.5 months, the 3 years probabilities of overall and progression-free survivals for the whole population were 41% and 35% respectively. with a two-year cumulative relapse incidence of 28% (24.0 – 31.8). Interestingly patients with score 1-2 showed better overall survival rates than those with score 3-4 and 5-8 with a 3 years probability of 77%, 42% and 32% respectively (p=0.002); this was associated with a 3 years relapse incidence of 19%, 35% and 55% respectively (p=0.021), while the 3 years transplant related mortality (TRM) was 6%, 39% and 36% respectively (score 1-2 versus all others, p=0.02), Figure 1. [Display omitted] In conclusion, we found that the EBMT risk score can perfectly be applied to double UBCT with a significant impact on different outcomes; its use enables a better selection of patients who will benefit the more from this treatment strategy. Disclosures:No relevant conflicts of interest to declare.

Haploidentical Hematopoietic Stem Cell Transplantation With Reduced Intensity Conditioning, T-Cell Replete Grafts and Post-Transplant Cyclophosphamide In Pediatrics

Hematopoietic stem cell transplants (HSCT) may be curative in the treatment of many hematological diseases. However, most patients do not have an HLA- matched sibling donor and an unrelated donor search may be a long process, during which the patients' disease may relapse or progress. Haploidentical transplants with in vitro T-cell depletion have been used in Pediatrics. However, it requires specialized laboratory infra-structure to manipulate the graft, increases the chances of graft failure and relapse. In vivo T-cell depletion can be achieved with the use of post-transplant cyclophosphamide, as reported by the Johns Hopkins and other groups. The results in adults are very promising and comparable to unrelated double cord blood transplants. Children, however, have not been included in any of the reported protocols. Our objective is to report the institutional experience with five consecutive children who received Haploidentical HSCT with reduced intensity conditioning, T-cell replete grafts and post transplant cyclophosphamide. MethodsChildren with clear indication to be treated with HSCT and no HLA-matched related or unrelated donor available were offered compassionate haploidentical transplants. Conditioning comprised cyclophosphamide 14.5 mg/kg/day on days -6 and -5, fludarabine 30 mg/m2/day for five consecutive days starting on day -6, and 2Gy total body irradiation given in a single fraction on day -1. Bone marrow was harvested from donors and infused into recipients on day 0. The target nucleated cell dose was 5 x10(8) mononuclear marrow cells/kg (i.e., peripheral blood count was substracted from the marrow cell count). There was no graft manipulation. GVHD prophylaxis consisted of cyclophosphamide 50 mg/kg IV on days +3 and +4 with 140% Mesna divided on hours 0, 4, 8 and 12 after each dose, Mycophenolate mofetil 15 mg/kg po every 8 hours (maximum 3 g/day) from day +5 to day +35, and tacrolimus from day + 5 to day +180 to keep levels between 5 and 10ng/ml. Prophylactic antimicrobial therapy was started on day +1 and included fluconazole and acyclovir. ResultsFive children with AML and T-ALL (three in CR2; one induction failure and one 4th relapse) were offered haploidentical transplants as the first HSCT. They had a median age of 10 years (4-16) and weight 41 kg (14-67), 2 girls. One graft was a peripheral blood stem cell collection per physician preference. The median total nucleated cell count was 12x10(8)/kg (10-27) with 10x10(6) CD34/kg (5-15). Mucositis was mild in three patients and none of them had sinusoidal obstruction syndrome. All patients engrafted after a median 14 days (13-17) but one of them, in 4th relapse of acute promyelocytic leukemia (APL), rejected the graft. Two of four evaluable patients had mild acute graft versus host disease (GVHD), and one mild chronic GVHD. The patient with APL died of two graft rejections on day+125, one T-ALL relapsed on day+180 and three children are disease-free with excellent clinical status one month to 1.7 years after transplant. We conclude that haploidentical HSCT with post-transplant cyclophosphamide is feasible to treat children without an available matched related or unrelated donor and should be prospectively studied. Disclosures:No relevant conflicts of interest to declare.

Prognostic Factors of Patients Undergoing an Allogeneic Stem Cell Transplant Admitted to an Intensive Care Unit

Introduction Patients who have received an allogeneic stem cell transplant (allo-HSCT) and require acute care in the intensive care unit (ICU) are unlike other patients requiring ICU care. The use of current ICU-based prognostic indices (APACHE II, SAPS II, and SOFA) have not shown to be useful for patients who have received an allo-HSCT. In order to better understand this patient population, we retrospectively analyzed patient, disease and hospital specific factors to determine if there were any risks that had significant prognostic value. Methods Data was collected from 413 patients undergoing allogeneic stem cell transplant at a single center from 2007-2013. Of the patients analyzed, 52 patients required ICU support during their HSCT admission. Of these patients the median age at time of transplantation was 59 (range: 26-75) with 52% male and 48% female. The indications for HSCT were: AML (42%), NHL (12%), ALL (10%), MM (10%), MDS (12%), CLL (10%), CML (2%), HD (2%) and AA (2%). The HSCT donor types were: matched-unrelated (56%), double cord (12%), matched-related (33%), and syngeneic. For these patients we reviewed and analyzed several variables, including age, performance status, HCT-CI, DRI, neutrophil engraftment status. The low range for HCT-CI was defined as 0-1 (52%), the moderate-high range 2+ (48%). Median time to neutrophil engraftment was 15 days (9-36 days). Results Our multivariate analysis revealed that HCT-CI and timing of ICU admission (pre or post-engraftment) where significant prognostic factors. Allo-HSCT patients requiring ICU support with a low HCT-CI score had a significantly better 1 year overall survival in comparison to similar patients with moderate to high HCT-CI scores (p=0.04). We also found that allo-HSCT patients requiring ICU support after neutrophil engraftment (>15 days) had a worse 1 year overall survival compared to HSCT patients requiring ICU prior to neutrophil engraftment (p= 0.04). Conclusion There is a great need for more specific prognostic factors for allo-HSCT patients requiring ICU support. Our findings demonstrate the potential utility of the HCT-CI and timing of ICU admission in the outcomes of HSCT patients admitted to the ICU. Based on these findings we plan to explore these factors in a larger prospective study. Download : Download high-res image (49KB) Download : Download full-size image Figure . Disclosures No relevant conflicts of interest to declare.