Myeloablative Conditioning Regimen Research Articles

Impact of Anti-CMV IgG Titers and CD34 Count Prior to Hematopoietic Stem Cell Transplantation from Alternative Donors on CMV reactivation.

Cytomegalovirus (CMV) reactivation remains one of the main infectious complications following hematopoietic stem cell transplantation (HSCT). In this study, we explored the role of anti-CMV antibody titers in HSCT from alternative donors and to compare the risk of CMV reactivation between posttransplant cyclophosphamide-based haploidentical HSCT and antithymocyte globulin-based unrelated donor (URD) HSCT. We included 98 CMV-positive patients, 30 undergoing haploidentical HSCT and 68 undergoing URD HSCT. The majority of patients had a malignant disease (84%), received a myeloablative conditioning regimen (78%), and received a bone marrow graft (90%). The median pretransplantation anti-CMV IgG level was 109 U/mL. With median follow-up of 2.2 years, a total of 72 CMV reactivations occurred in 50 patients. There was no difference in CMV reactivation pattern between haploidentical HSCT recipients and URD HSCT recipients. In multivariable analysis until the first event, the incidence of CMV reactivation was higher in patients with anti-CMV IgG levels >100 U/mL (hazard ratio [HR], 2.38; P=.005) and in patients diagnosed with grade II-IV acute graft-versus-host disease (GVHD) (HR, 10.8; P=.003) after day +50 and lower in patients who received higher doses of CD34 cells (HR, .44; P=.006). In multivariable analysis for recurring events, the incidence of CMV reactivation was higher in patients receiving reduced-intensity conditioning (HR, 1.69: P=.04) and in patients with acute GVHD (HR, 1.88; P = .02), and lower in those who received higher doses of CD34 cells (HR, .55; P=.01). In summary, we have shown that pretransplantation anti-CMV IgG titers are correlated with CMV reactivation risk. More studies are needed to assess how this information can be incorporated in HSCT. The use of high-dose cellular grafts, a modifiable risk factor, also protects against CMV reactivation.

Reduced-Intensity versus Myeloablative Conditioning in Cord Blood Transplantation for Acute Myeloid Leukemia (40-60 years) across Highly Mismatched HLA Barriers-On Behalf of Eurocord and the Cellular Therapy & Immunobiology Working Party (CTIWP) of EBMT.

The use of myeloablative conditioning (MAC) in umbilical cord blood transplantation (UCBT) has been associated with high nonrelapse mortality (NRM) in patients aged >40 years, especially those having a high HLA disparity, thus limiting wider applications. We hypothesized that the NRM advantage of reduced-intensity conditioning (RIC) and higher graft-versus-leukemia effect associated with greater HLA disparities would expand its use for patients (aged 40 to 60 years) without compromising efficacy and compared outcomes between RIC and MAC regimens. In total, 288 patients aged 40 to 60 years, with de novo acute myeloid leukemia, receiving UCBT with at least 2 HLA mismatches with RIC (n=166) or MAC (n=122) regimens were included. As compared to RIC, the MAC cohort included relatively younger patients, having received more single UCBT, with lower total nucleated cell counts and more in vivo T cell depletion. Median time to neutrophil engraftment, infections (bacterial, viral, and fungal), and grade II to IV acute and chronic graft-versus-host disease were similar in both groups. In the multivariate analysis, overall survival (hazard ratio [HR], 0.98; P=.9), NRM (HR, 0.68; P=.2), and relapse (HR, 1.24; P=.5) were not different between RIC and MAC. Refractory disease was associated with worse survival. Outcomes of UBCT for patients aged 40 to 60 years having ≥2 HLA mismatches are comparable after the RIC or MAC regimen.

Allogeneic Stem Cell Transplantation for Patients with Lower-Risk Myelodysplastic Syndrome.

The indication for allogeneic stem cell transplantation (SCT) in patients with lower-risk myelodysplastic syndrome (MDS) is controversial. Here we report 60 patients with a low risk (n=32) or intermediate risk (n=28) classification according to the revised International Prognostic Scoring System (IPSS-R) who underwent allogeneic SCT with a reduced-intensity conditioning (n=45) or myeloablative conditioning (n=15) regimen from an HLA-identical sibling (n=9), a matched unrelated donor (n=36), or a mismatched unrelated donor (n=15). The rates of grade II-IV and grade III-IV acute graft-versus-host disease were 32% and 7%, respectively, resulting in a transplantation-related mortality (TRM) of 17% at 3 years. The cumulative incidence of relapse at 5 years was only 7%, resulting in a 5-year disease-free survival of 72% and overall survival (OS) of 79%. Transplantation from a fully matched donor resulted in significantly improved OS at 5 years (91% versus 70%). Allogeneic SCT in lower-risk MDS (IPSS-R low or intermediate risk) from an HLA-matched donor resulted in excellent OS with a low risk of relapse.

Allogeneic Stem Cell Transplantation in Relapsed/Refractory Multiple Myeloma Treatment: Is It Still Relevant? (Running Title: The Role of Salvage alloSCT in MM).

Background: Despite offering an attractive option, the role of allogeneic stem cell transplantation (alloSCT) for treatment of multiple myeloma (MM) remains unclear. Methods: Recognizing the paucity of data in the Asian population, we retrospectively evaluated the outcomes of 24 patients (median age 52) undergoing alloSCT between April 2003 and November 2017. Results: The median time from diagnosis to alloSCT was 39.4 months. The majority of the patients (70.8%) underwent alloSCT followed by reduced intensity conditioning regimens after a median of five lines of therapy. Among 24 patients, 15 patients (62.5%) had a high-risk MM feature. The two-year relapse-free survival (RFS) and overall survival (OS) of the total patients were 29.2 ± 9.3% and 44.3 ± 10.3%, respectively. Patients who were treated with less chemotherapy lines (<5) before alloSCT had a prolonged RFS and OS. All patients (seven patients) who received a myeloablative conditioning regimen had high-risk features, but two out of seven patients showed long-term survival without lasting sequelae. Nine patients (37.5%) experienced non-relapse mortality (NRM) within one year after alloSCT (the one-year cumulative incidence of NRM was 38.3 ± 10.1%). Conclusion: AlloSCT can still be implemented as effective salvage option in the treatment of relapsed/refractory high-risk MM. The optimal timing of alloSCT remains to be determined.

Optimizing Preparative Regimen for Umbilical Cord Blood Transplantation in Adult Acute Leukemia Patients: Acute Lymphoblastic Leukemia Requires Myeloablative Conditioning but Not Acute Myeloid Leukemia.

Cord blood transplantation (CBT) is a valuable alternative to bone marrow transplantation in adults without readily available donors. We conducted this study to investigate the feasibility of CBT for adult patients with acute leukemia with regards to impact of different conditioning and graft-versus-host disease (GVHD) prophylaxis regimens on clinical outcomes. From 16 centers in Korea, 41 acute myeloid leukemia (AML) and 29 ALL (acute lymphoblastic leukemia) patients undergoing CBT were enrolled. For AML patients, the neutrophil engraftment was observed in 87.5% of reduced intensity conditioning (RIC) and 72.0% of myeloablative conditioning (MAC) (p = 0.242). The median RFS was 5 months and OS 7 months. Conditioning regimen did not affect relapse free survival (RFS) or overall survival (OS). GVHD prophylaxis using calcineurin inhibitors (CNI) plus methotrexate was associated with better RFS compared to CNI plus ATG (p = 0.032). For ALL patients, neutrophil engraftment was observed in 55.6% of RIC and 90.0% of MAC (p = 0.034). The median RFS was 5 months and OS 19 months. MAC regimens, especially total body irradiation (TBI)-based regimen, were associated with both longer RFS and OS compared to other conditioning regimens. In conclusion, individualized conditioning regimens will add value in terms of enhancing safety and efficacy of CBT.

Haploidentical Hematopoietic Stem Cell Transplantation for XIAP Deficiency: a Single-Center Report.

X-linked inhibitor of apoptosis (XIAP) deficiency caused by mutations in the XIAP/BIRC4 gene is a rare inherited primary immunodeficiency also known as X-linked lymphoproliferative syndrome type 2 (XLP2). Hematopoietic stem cell transplantation (HSCT) is currently the only curative strategy available. However, few studies of haploidentical HSCT have been published regarding the outcomes in patients with this syndrome. We evaluated the XIAP gene analysis and clinical characteristics of four Chinese patients with XIAP who underwent haploidentical HSCT. The mutations in the two of four patients had not yet been reported in the literature. All of the patients had recurrent hemophagocytic lymphohistiocytosis but did not have a good matched donor and underwent haploidentical HSCT at BCH in China between September 2016 and December 2018. All four patients received antithymocyte globulin with fludarabine-based regimens. Two patients underwent reduced intensity conditioning (RIC), and the other two received modified myeloablative conditioning (MAC) regimens. Three of the four patients survived. Three patients experienced complications with mixed chimerism. One of the four patients who underwent RIC had early graft loss and then developed grade IV acute graft-versus-host disease (GVHD) after donor lymphocyte infusion with bone marrow. The two patients who received MAC survived with no or mild GVHD, even though one of them developed hepatic veno-occlusive disease in the early stage of transplantation. Haploidentical HSCT may be a treatment option for patients with XIAP deficiency who lack a good matched donor. More studies are needed to determine whether modified MAC with reduced toxicity is more suitable for haploidentical transplantation.

Low Nonrelapse Mortality after HLA-Matched Related 2-Step Hematopoietic Stem Cell Transplantation Using Cyclophosphamide for Graft-versus-Host Disease Prophylaxis and the Potential Impact of Non- Cyclophosphamide-Exposed T Cells on Outcomes.

The use of cyclophosphamide (CY) for bidirectional tolerization of recipient and donor T cells is associated with reduced rates of graft-versus-host disease (GVHD) and nonrelapse mortality (NRM) after HLA-matched hematopoietic stem cell transplantation (HSCT). However, recurrent disease remains the primary barrier to long-term survival. We extended our 2-step approach to HLA-matched related HSCT using a radiation-based myeloablative conditioning regimen combined with a high dose of T cells in an attempt to reduce relapse rates while maintaining the beneficial effects of CY tolerization. After conditioning, patients received their grafts in 2 components: (1) a fixed dose of 2×108/kg T cells, followed 2 days later by CY, and (2) a CD34-selected graft containing a small residual amount of non-CY-exposed T cells, at a median dose of 2.98×103/kg. Forty-six patients with hematologic malignancies were treated. Despite the myeloablative conditioning regimen and use of high T cell doses, the cumulative incidences of grade II-IV acute GVHD, chronic GVHD, and NRM at 1 year and 5 years were very low, at 13%, 9%, and 4.3%, respectively. This contributed to a high overall survival of 89.1% at 1 year and 65.8% at 5 years. Relapse was the primary cause of mortality, with a cumulative incidence of 23.9% at 1 year and 45.7% at 5 years. In a post hoc analysis, relapse rates were significantly lower in patients receiving greater than versus those receiving less than the group median of non-CY-exposed residual T cells in the CD34 product (19.3% versus 58.1%; P=.009), without a concomitant increase in NRM. In its current form, this 2-step regimen was highly tolerable, but strategies to reduce relapse, potentially the addition of T cells not exposed to CY, are needed.

An evaluation of the efficacy of allogeneic hematopoietic stem cell transplantation in patients with mucopolysaccharidosis type I (Hurler syndrome): the experience of the R.M. Gorbacheva Research Institute for Pediatric Oncology, Hematology and Transplantation

Mucopolysaccharidosis type I (MPS IH; Hurler syndrome) is a hereditary storage disease caused by a deficiency of the lysosomal enzyme alpha-L-iduronidase. Enzyme replacement therapy may extend the lifespan of affected patients by 6–12 years but the only currently available radical treatment option is allogeneic hematopoietic stem cell transplantation (allo-HSCT). Objectives: We aim to evaluate the influence of conditioning regimens of various intensities and “graft versus host” disease (GvHD) prophylaxis with anti-thymocyte globulin and post-transplant Cyclophosphamide (PTCy) on overall (OS) and event-free (EFS) survival, the incidence of GvHD, the normalization of alpha-L-iduronidase and glycosaminoglycan (GAG) levels over time as well as cardiovascular and cognitive recovery following allo-HSCT. The study was approved by the Independent Ethics Committee and the Scientific Council of the I.P. Pavlov First Saint Petersburg State Medical University. We included 28 patients with MPS IH who had received allo-HSCT at the clinic at the R.М. Gorbacheva Memorial Institute of Children Oncology, Haematology and Transplantation. The five-year OS was 89%, the EFS – 57%. The use of myeloablative conditioning regimens and allo-HSCT within 12 months of diagnosis improve EFS in affected patients. The cumulative incidence of grade II–IV acute GvHD and grade III–IV acute GvHD was 43% and 18% respectively. The use of PTCy results in a significantly lower incidence of this complication (69% vs 33%, p = 0.013). After allo-HSCT, normal alpha-L-iduronidase levels and urinary GAG excretion were achieved in cases where graft function was normal. Allo-HSCT is an effective treatment for patients with MPS IH. Myeloablative conditioning regimens are the preferred treatment modality for this group of patients but in cases of comorbidities or poor physical status at the time of allo-HSCT, conditioning regimens with reduced intensity may be opted for instead. PTCy may be used for GVHD prevention in patients with MPS IH without increasing the risk of cardiac toxicity.

Factors of bacteriuria in children and young adults following hematopoietic stem cell transplantation

Presence of bacteriuria and urinary microbiota composition is an important index of immunocompromised conditions. These parameters are scarcely studied in patients undergoing hematopoietic stem cell transplantation (HSCT). The aim of this work was to evaluate detection rates of cultured aerobic microbiota from urine samples taken by clinical indications before HSCT and within 4 months after the treatment. The study was approved by the Independent Ethics Committee and the Scientific Council of the I.P. Pavlov First Saint Petersburg State Medical University. We evaluated results of bacterial cultures from 734 urine specimens taken in 50 patients with oncohematological and inborn diseases at the age ranging from 1 to 21 years who were subjected to allogeneic HSCT. The analysis was performed for 3 age groups: 1–5, 6–14, and 15–21 years old. The bacterial cultures proved to be positive with 37.6% of urine samples. The following microbes were revealed at highest rates: K. pneumoniae, 95/734 (12.9%); E. faecalis, 90/734 (12.3%); E. coli, 65/734 (8.9%); E. faecium, 50/734 (6.8%). The bacteriuria rates have shown distinct time dependence, with significantly decreased K. pneumoniae and E. coli detection at earliest terms (1st month) after myeloablative conditioning, which could be explained by effective antibacterial prophylaxis over the time of conditioning and in early posttransplant period. We have shown that the frequency of positive tests for K. pneumoniae и E. coli in these samples were different for distinct age groups, i.e., the positivity rates were significantly higher in youngest children (up to 5 years old) as compared with older age groups, being sufficiently increased 2–3 months after HSCT which may be an index of antibiotic resistance as well as a risk factor for infectious complications of other organs. We have also shown a highly significant increase in K. pneumoniae и E. coli positivity rates when using myeloablative conditioning regimen before HSCT. The immunotoxic effects of cytostatic therapy in HSCT deserve further studies, including biodiversity analysis of urinary microbiota by means of new-generation DNA sequencing. These results may serve as a basis for rational antibacterial therapy in HSCT.

An overview of thrombotic complications of old and new anticancer drugs

Thrombosis is a common complication of cancer with a mean prevalence of 15%. Most commonly, this presents as venous thromboembolism; however, other manifestations such as arterial thrombosis or thrombotic microangiopathy may occur. Cancer itself is not only associated with risk factors for thrombotic complications, including intrinsic biological effect of malignant cells, accompanying operations, or the presence of indwellingvascular catheters, but there is also an additional risk caused by anticancer agents including chemotherapy and immunotherapy. In most cases the underlying pathogenetic factor that contributes to the thrombotic risk associated with chemotherapy is endothelial cell injury (or loss of protection of endothelial integrity, for example by vascular endothelial growth factor inhibition). In addition, individual anticancer agents may have specific prothrombotic effects. As in recent years more intense anticancer drugs are administered, such as in myeloablative conditioning regimens preceding stem cell transplantation, thrombosis and in particular thrombotic microangiopathy are a more frequent complication in anticancer treatment.

Progressive substitution of posttransplant cyclophosphamide with bendamustine: A phase I study in haploidentical bone marrow transplantation.

We have initiated a single center phase I study in patients with hematologic malignancies progressively substituting day +4 posttransplant cyclophosphamide (PT‐CY) with bendamustine (PT‐BEN) following myeloablative conditioning (MAC) and T‐cell replete haploidentical bone marrow transplantation (haplo‐BMT). We report herein our interim analysis of our first three cohorts PT‐CY (mg/kg)/PT‐BEN (mg/m2): 40/20, 20/60, and 0/90. All patients have tolerated PT‐CY/BEN well with no dose limiting toxicities. Compared to contemporaneous controls undergoing haplo‐BMT with the same MAC regimens but only PT‐CY, we have observed earlier trilineage engraftment (P = .002 neutrophils, P = .014 platelets) and a lower incidence of cytomegalovirus reactivation (P = .016) in the PT‐CY/BEN cohorts. After substituting day +4 PT‐CY with PT‐BEN, the registered trial (www.clinicaltrials.gov; NCT02996773) is proceeding to replace day +3 PT‐CY with PT‐BEN with a view to identifying further evidence on the potential advantages of PT‐BEN.

Less Is More: Superior Graft-versus-Host Disease-Free/Relapse-Free Survival with Reduced-Intensity Conditioning and Dual T Cell Depletion in Acute Myelogenous Leukemia.

In this study, we compared the outcomes of patients with acute myelogenous leukemia (AML) in complete remission treated with myeloablative conditioning (MAC) and those treated with reduced-intensity conditioning (RIC) before allogeneic hematopoietic stem cell transplantation (allo-HCT). In addition, we explored the efficacy of dual T cell depletion using anti-thymocyte globulin (ATG) and post-transplantation cyclophosphamide (PTCy) for the prevention of graft-versus-host disease (GVHD) in patients undergoing RIC allo-HCT. Our study cohort comprised 356 adults with AML in complete remission who underwent allo-HCT between 2013 and 2018. One hundred eleven patients (31.2%) received a MAC regimen, and 245 (68.8%) received an RIC regimen. One hundred seventy-one of the patients who received an RIC regimen (68.4%) received ATG, PTCy, and cyclosporine (ATG-PTCY-CsA) for GVHD prophylaxis in accordance with our institutional protocol. Data were collected retrospectively and updated in July 2019. With a median follow-up of 14.5 months (range, 0 to 76 months), 161 patients (45.2%) died, and 66 (18.5%) relapsed. Two-year overall survival (OS), relapse-free survival (RFS), and GVHD-free/RFS (GRFS) were 55%, 52.6%, and 35%, respectively. The intensity of the conditioning regimen, with or without ATG-PTCY-CsA, did not have a significant impact on OS and RFS. However, RIC in combination with ATG-PTCY-CsA was associated with a significantly lower cumulative incidence of acute GVHD and chronic GVHD. The use of RIC with ATG-PTCy-CsA was a significant predictor for higher GRFS secondary to the reduction of clinically relevant GVHD (P= .0001). In patients with AML, RIC allografts and dual T cell modulation with ATG and PTCy led to superior GRFS. The use of this GVHD prophylaxis strategy, along with mitigation of conditioning toxicity using RIC, may result in better long-term quality of life for allo-HCT recipients.

Matched Family versus Alternative Donor Hematopoietic Stem Cell Transplantation for Patients with Thalassemia Major: Experience from a Tertiary Referral Center in South India.

Hematopoietic stem cell transplantation (HSCT) is the only curative option available for patients with thalassemia major in India with increasing access to alternate donor transplantation for patients with no matched family donor. We aimed to analyze the impact of family and alternate donor HSCT on morbidity and mortality post-HSCT. We conducted a retrospective study in the department between July 2007 and December 2018 where all children who underwent HSCT for thalassemia major were included. A total of 264 children were included with a median age of 6 years (male/female, 1.4:1). The graft source was matched related donor (MRD) (76%; parent 15%, sibling 85%) and matched unrelated donor (MUD) (22%). All children received a myeloablative conditioning regimen with treosulfan/thiotepa/fludarabine in 93% and busulfan/cyclophosphamide in 7%. The source of stem cells was peripheral blood in 61%, bone marrow in 38%, and umbilical cord blood in 3%. The incidence of bacteremia was 14% versus 25% in MRD versus MUD groups. There was a higher incidence of posterior reversible encephalopathy syndrome (PRES) in the MUD group (10% versus 3%). Engraftment occurred in 97% with a higher trend toward mixed chimerism in the MRD group (12% versus 2%). When indicated, whole-blood donor lymphocyte infusion was used to ensure complete chimerism in children in the MRD group. A statistically significant difference was found in the incidence of graft versus host disease (GVHD), both acute and chronic between the MUD versus MRD groups, 60% versus 20% and 41% versus 17%, respectively (P=.001). Similarly, immune cytopenia and cytomegalovirus reactivation were also significantly higher in the MUD group, 27% versus 1.4% and 25% versus 2%, respectively (P=.001). Thalassemia-free survival in our cohort was 96%, 94%, and 84% with a median follow-up of 65 months in the matched sibling donor, matched family donor, and MUD groups, respectively. Overall survival of 95% and 90% with a median follow-up of 65 months was noted in those who underwent transplantation less than and greater than 7 years of age, respectively. MUD transplantation for patients with thalassemia major involves specific challenges such as PRES and unusual manifestations of GVHD such as immune cytopenia. Early interventions to optimize supportive care and measures to reduce GVHD are required to ensure survival rates of over 90%.

Effect of KIR/HLA receptor-ligand mode on prognosis of single unrelated cord blood transplantation in patients with hematological malignancies

目的探讨自然杀伤细胞免疫球蛋白样受体（KIR）与人类白细胞抗原（HLA）受配体模式对血液病患者单份非血缘脐血移植（sUCBT）预后的影响。方法回顾性分析2012年7月至2018年6月270例接受sUCBT的血液病患者。移植前脐血及患者均进行HLA12个位点高分辨配型，选择移植物（脐血）的KIR均同时表达2DL1和2DL2/2DL3抑制性基因，根据患者KIR配体情况分为缺失组（C1/C1或C2/C2）和无缺失组（C1/C2）。结果270例血液病患者中男146例（54.1％），女124例（45.9％），中位年龄13（1～62）岁；缺失组174例（64.4％），无缺失组96例（35.6％）。全部患者均采用不含抗胸腺细胞球蛋白（ATG）清髓性预处理方案。缺失组、无缺失组粒细胞植入率均为98.9％（172/174、95/96），中位植入时间分别为16（10～41）d、17（11～33）d（P＝0.705）；血小板植入率分别为88.5％（154/174）、87.5％（84/96），中位植入时间分别为35（11～113）d、38.5（13～96）d（P＝0.317）；缺失组、无缺失组Ⅱ～Ⅳ级急性GVHD发生率分别为38.7％（95％CI 31.4％～45.9％）、50.0％（95％CI 39.6％～59.6％）（P＝0.075），多因素分析显示KIR配体缺失是影响Ⅱ～Ⅳ度急性GVHD发生的独立保护性因素（P＝0.036）。移植后3年累积复发率分别为17.7％（95％CI 11.7％～24.9％）、22.7％（95％CI14.4％～32.2％）（P＝0.288）。中位随访时间742（335～2 512）d，缺失组、无缺失组3年总生存率分别为72.1％（95％CI 64.1％～78.6％）、60.5％（95％CI 47.9％～69.2％）（χ2＝3.629，P＝0.079），3年无病生存率分别为64.9％（95％CI 56.2％～72.3％）、55.4％（95％CI 44.4％～65.0％）（χ2＝3.027，P＝0.082），移植后180 d 非复发死亡率分别为12.1％（95％CI 7.7％～17.4％）、16.7％（95％CI 10.0％～24.8％）（P＝0.328）。结论在不含ATG清髓性预处理sUCBT血液病治疗体系中，缺失抑制性KIR配体患者移植后急性GVHD发生率更低。

T Cell Depleted Haploidentical Hematopoietic Stem Cell Transplantation for Patients with Familial Hemophagocytic Lymphohistiocytosis Who Do Not Have Matched Family Donors: Experience in Oman.

Familial hemophagocytic lymphohistiocytosis (FHLH) is a potentially fatal disorder of immune regulation. Management includes chemotherapy followed by hematopoietic stem cell transplantation (HSCT). T cell depleted (TCD)-haploidentical HSCT could be an option for those patients who do not have HLA matching family donor. The objective of this study was to report on the outcome of TCD-haploidentical HSCT in patients with FHLH who underwent transplantation at Sultan Qaboos University Hospital (SQUH). This is a retrospective report on 12 patients with FHLH who received TCD- haploidentical HSCT at SQUH between August 2010 and December 2018. Epidemiologic characteristics and details on the transplantation procedures and complications were collected from patients' electronic records. Twelve patients with FHLH received TCD-haploidentical HSCT after a myeloablative conditioning regimen composed of treosulfan/thiotepa/fludarabine/anti-thymocyte globulin and rituximab. The mean age at transplantation was 11.67 ± 8 months. All patients had Perforin gene mutations, except 1 patient who had an UNC-13D mutation. Most patients received TCRαβ+/CD19+ depleted grafts for faster immune reconstitution. Seven patients (58.3%) have been cured with a mean follow-up duration of 3.44 years. Four patients died of multiorgan failure secondary to gram-negative sepsis. One patient had primary graft failure, and 2 patients had mild graft-versus-host disease. Two patients had Pneumocystis carinii pneumonia, 2 had adenoviremia, and 9 patients had cytomegalovirus (CMV) viremia. Among patients with CMV viremia, 2 had evidence of disease (retinitis, enteritis). All patients with CMV viremia were treated successfully with foscarnet pre-engraftment and ganciclovir postengraftment, respectively. TCD-haploidentical HSCT could be a viable option for patients with FHLH who do not have HLA matching family donors. Infectious complications are the leading cause of death in that setting. CMV viremia was the most frequently encountered infectious complication.

Successful umbilical cord blood transplantation in children with leukocyte adhesion deficiency type I.

This study aims to investigate the efficacy and safety of umbilical cord blood transplantation (UCBT) without serotherapy for treating children with leukocyte adhesion deficiency type I (LAD-I). Clinical characteristics and data of five children with LAD-I who underwent UCBT at our hospital between September 2016 and September 2018 were retrospectively analyzed. Five (two boys and three girls) patients with LAD-I were included. The median age at UCBT was 9 months (range, 8 to 32 months). The same myeloablative conditioning regimen was administered for each patient and included busulfan, fludarabine, and cyclophosphamide. HLA matching of patients and umbilical cord blood was 8/10 to 10/10. The median dose of total nucleated cells (TNC) infused was 10.2×107/kg (range, 4.5×107 to 20.6×107/kg) and the median dose of CD34+ cells was 3.2×105/kg (range, 1.9×105 to 5.7×105/kg). The median time of neutrophil engraftment was 20 days (range, 13 to 28 days). The median time of platelet engraftment was 36 days (range, 32 to 56 days). All patients received complete donor chimerism (CDC). Four of the five patients developed grade II-IV acute graft-versus-host disease (GvHD). The median follow-up time after transplantation was 19 months (range, 8 to 38 months). Four of the patients survived and achieved complete clinical remission. The other patient died of bronchiolitis obliterans 8 months after UCBT. UCBT is an effective treatment method for LAD-I patients. Also, severe LAD-I patients should undergo stem cell transplantation as early as possible.

Goal-Oriented Monitoring of Cyclosporine Is Effective for Graft-versus-Host Disease Prevention after Hematopoietic Stem Cell Transplantation in Sickle Cell Disease and Thalassemia Major.

Graft-versus-host disease (GVHD) is an important challenge and a major cause of morbidity and mortality in children after hematopoietic stem cell transplant (HSCT). Herein we report our institution's experience of goal-oriented Bayesian monitoring for cyclosporine (CsA) used alone as GVHD prophylaxis during the post-transplant period in pediatric patients with thalassemia major (TM) or sickle cell anemia (SCA) undergoing HLA-matched HSCT. We also studied evolution of chimerism. Twenty-six consecutive patients (SCA, 14; TM, 12) underwent matched sibling donor (MSD) HSCT from 2004 to 2014. All patients received a myeloablative conditioning regimen. GVHD prophylaxis consisted of 20 mg/kg antithymocyte globulin in the conditioning regimens and then CsA alone in the post-transplant period. Target CsA trough blood concentration (TBC) was 150 ± 20 ng/mL. At last follow-up, all patients were alive and free of disease, even in cases of mixed chimerism. Engraftment occurred in all patients. No patient developed grades II to IV acute GVHD, 4 patients developed acute grade I skin GVHD, and only 1 presented with chronic pulmonary GVHD. A better control of GVHD and immunosuppression by a strict monitoring of CsA TBC as described herein is promising and could play a crucial role. Further investigations are required, but this study opens new perspectives to improve survival and safety of HSCT from alternative donors in TM and SCA to levels compatible with that obtained with MSDs.

Outcomes of allogeneic stem cell transplantation for patients with t(6:9) AML- A strong case for allogeneic stem cell transplantation in first complete remission.

Outcomes of allogeneic stem cell transplantation for patients with t(6:9) AML- A strong case for allogeneic stem cell transplantation in first complete remission.

Influence of Germline Genetics on Tacrolimus Pharmacokinetics and Pharmacodynamics in Allogeneic Hematopoietic Stem Cell Transplant Patients.

Tacrolimus exhibits high inter-patient pharmacokinetics (PK) variability, as well as a narrow therapeutic index, and therefore requires therapeutic drug monitoring. Germline mutations in cytochrome P450 isoforms 4 and 5 genes (CYP3A4/5) and the ATP-binding cassette B1 gene (ABCB1) may contribute to interindividual tacrolimus PK variability, which may impact clinical outcomes among allogeneic hematopoietic stem cell transplantation (HSCT) patients. In this study, 252 adult patients who received tacrolimus for acute graft versus host disease (aGVHD) prophylaxis after allogeneic HSCT were genotyped to evaluate if germline genetic variants associated with tacrolimus PK and pharmacodynamic (PD) variability. Significant associations were detected between germline variants in CYP3A4/5 and ABCB1 and PK endpoints (e.g., median steady-state tacrolimus concentrations and time to goal tacrolimus concentration). However, significant associations were not observed between CYP3A4/5 or ABCB1 germline variants and PD endpoints (e.g., aGVHD and treatment-emergent nephrotoxicity). Decreased age and CYP3A5*1/*1 genotype were independently associated with subtherapeutic tacrolimus trough concentrations while CYP3A5*1*3 or CYP3A5*3/*3 genotypes, myeloablative allogeneic HSCT conditioning regimen (MAC) and increased weight were independently associated with supratherapeutic tacrolimus trough concentrations. Future lines of prospective research inquiry are warranted to use both germline genetic and clinical data to develop precision dosing tools that will optimize both tacrolimus dosing and clinical outcomes among adult HSCT patients.

Longitudinal Analysis of Infrared Meibography in Patients Undergoing Hematopoietic Stem Cell Transplantation.

To evaluate meibomian gland (MG) changes in patients undergoing hematopoietic stem cell transplantation (HSCT) by infrared meibography and to further investigate possible correlations with hematological characteristics. Thirty-three patients were included: infrared meibography of the lower eyelid, Schirmer test, tear break-up time, ocular surface staining, and Ocular Surface Disease Index questionnaire were conducted before (V0) and 4 months after HSCT (V1). A paired samples t test was used to compare parameters before and after HSCT. A mixed analysis of variance was used to assess the effect of hematological characteristics on changes of MG loss (MGL) after HSCT. MGL and corneal staining significantly increased after HSCT (respectively, from 24.3% ± 10.1% to 32.2 ± 15.0 and from 1.2 ± 1.5 to 2.0 ± 1.7; always P < 0.011), whereas tear break-up time significantly decreased (from 6.6 ± 4.2 seconds to 3.2 ± 2.2; P < 0.001). At V1, 19 patients (57.6%) belonged to ocular graft-versus-host disease severity grade 0, 8 (24.2%) to grade I, and 6 (18.2%) to grade II. The percentage of MGL at V0 and the increase of MGL from V0 to V1 did not differ between patients who developed ocular graft-versus-host disease and those who did not (always P > 0.05). At V1, MGs' quality reduced in 16 patients (48.5%), remained unchanged in 14 (42.4%), and improved in 3 (9.1%). The increase of MGL after HSCT was higher in patients receiving myeloablative conditioning regimen (P = 0.005). MG function, loss, and quality significantly worsened after HSCT. Myeloablative conditioning regimen was associated with higher MGL.