Preparative Regimen Research Articles

A Phase II Trial of Melphalan Based Reduced-Intensity Conditioning for Transplantation of T-Replete HLA-Haploidentical Peripheral Blood Stem Cells with Posttransplant Cyclophosphamide in Patients with Hematologic Malignancies.

T-replete haploidentical donor transplants using posttransplant cyclophosphamide (haplo) have greatly expanded donor availability and are increasingly utilized. Haplo were originally performed using truly nonmyeloablative conditioning and a bone marrow graft. We have also developed myeloablative conditioning and peripheral blood stem cell (PBSC) grafts for use with haplo. However, some patients may not tolerate myeloablative conditioning but may still benefit from a more dose-intensified preparative regimen to control malignancy and diminish graft rejection. To this end, we enrolled 25 patients on a prospective phase II trial utilizing a regimen of fludarabine 30 mg/m2/day × 5 days and Melphalan 140 mg/m2 on day -1 (flu/Mel) followed by infusion of unmanipulated PBSC graft from a haploidentical donor. GVHD prophylaxis included cyclophosphamide 50 mg/kg/day on days 3 and 4, mycophenolate mofetil on day 35, and tacrolimus on day 180. Median age was 57 years (range from 35 to 68). Transplantation diagnosis included AML (n = 11), ALL (n = 4), MDS/MPD (n = 6), NHL/CLL (n = 3), and MM (n = 1). Using the refined Disease Risk Index (DRI), patients were low (n = 1), intermediate (n = 13), and high/very high (n = 11). 22 out of 25 patients engrafted with a median time to neutrophil and platelet engraftment of 18 days and 36 days, respectively. All engrafting patients achieved full peripheral blood T-lymphocyte and myeloid donor chimerism at day 30. The 180-day cumulative incidence for acute GVHD grades II–IV and III-IV was seen in 20% (95% CI 8%–37%) and 8% (95% CI 2%–22%), respectively. The 2-year cumulative incidence of chronic GVHD was 16% (95% CI 5%–33%) (moderate-severe 12% (95% CI 3%–27%)). After a median follow-up of 28.3 months, the estimated 2-year OS, DFS, NRM, and relapse were 56% (95%CI 33–74%), 44% (95%CI 23%–64%), 20% (95% CI 8%–37%), and 36% (95% CI 17%–55%), respectively. Among patients with high/very high risk DRI, 2-year OS was 53% compared to 69% for low/intermediate DRI. When compared with a contemporaneous cohort of patients at our center receiving haploidentical transplant with nonablative fludarabine, Cytoxan, and total body irradiation flu/Cy/TBI regimen, the outcomes were statistically similar to the 2-year OS at 56% vs. 63% p=0.75 and DFS at 44% vs. 46% p=0.65.

Feasibility of an intensified myeloablative conditioning regimen consisting of busulfan, fludarabine, cytarabine, and total body irradiation before single cord blood transplantation in elderly patients.

The optimal conditioning regimen for stem cell transplantation in elderly patients remains to be established. We developed a novel preparative regimen using fludarabine 180mg/m2, intravenous busulfan 12.8mg/m2, cytarabine 8g/m2, and 4-Gy total body irradiation before cord blood transplantation (CBT) in patients older than 55years with various hematological malignancies. All but one patient received graft-versus-host disease (GVHD) prophylaxis consisting of cyclosporine (CsA) and short-term methotrexate (sMTX). Thirty-three patients were included in this study, with a median age of 64years (range 56-70). The disease risk index was high or very high in 67% of patients, and 73% had a disease status other than complete remission. The probabilities of overall survival and disease-free survival at 3years were 60 and 57%, respectively. The cumulative incidences of relapse and non-relapse mortality at 3years were 18 and 25%, respectively. Regimen-related toxicities were generally tolerable. Disease-free survivors (n = 20) stopped immunosuppressants at a median of 7.4months (range 2.6-25.0), in all cases by the time of the last follow-up. In conclusion, this highly myeloablative conditioning regimen resulted in a high probability of disease-free, GVHD-free, immunosuppressant-free survival after single CBT.(190 words).

Fludarabine modulates expression of type VII collagen during haematopoietic stem cell transplantation for recessive dystrophic epidermolysis bullosa.

Recessive dystrophic epidermolysis bullosa (RDEB) is a severe, complicated inherited blistering skin disease with few treatment options currently available. Recently, haematopoietic stem cell transplantation (HCT) has been used as an alternative therapy that can improve skin integrity, but it is not known if the preparative HCT regimen also contributes to the therapeutic response. To determine whether chemotherapy drugs used in the HCT preparative regimen influence type VII collagen (C7) expression, which is inherently reduced or absent in RDEB skin, and to explore the pathomechanisms of such responses, if present. Drugs from the HCT preparative regimen (busulfan, cyclophosphamide, ciclosporin A, fludarabine and mycophenolate) with inhibitors (PD98059, U0126, LY294002, SR11302, SIS3 and N-acetyl-l-cysteine) were added to normal human dermal and human RDEB fibroblasts. C7 expression was measured using reversetranscription polymerase chain reaction and immunoblotting. We uncovered a previously unknown consequence of fludarabine whereby dermal fibroblasts exposed to fludarabine upregulate C7. This effect is mediated, in part, through activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase, phosphoinositide 3-kinase/protein kinase B and transforming growth factor-β pathways. Activation of these pathways leads to activation of downstream transcription factors, including activator protein 1 (AP-1) and SMAD. Subsequently, both AP-1 and SMAD bind the COL7A1 promoter and increase COL7A1 expression. Fludarabine influences the production of type VII collagen in RDEB fibroblasts.

Live birth rate of twin pregnancies after frozen embryo transfer: natural cycle versus ovulation induction regimens.

Ovulation induction (OI) using letrozole or human menopausal hormone (hMG) is recently developed for endometrium preparation in frozen embryo transfer (FET) cycles. The purpose of this study is to compare the live birth rate of twin pregnancies between modified natural and OI regimens for endometrium preparation in FET cycles. This study included all consecutive twin pregnancies following FET with modified natural cycle (mNC-FET) or OI (OI-FET) regimen for endometrium preparation between January 2015 to June 2019. Primary outcome was the live birth of at least one twin per pregnancy. Multivariable logistic regression analysis was used to evaluate the potential association of endometrium preparation regimen and live birth. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated. During the study period, 269 twin pregnancies after mNC-FET and 177 twin pregnancies after OI-FET were included. The live birth rate of at least one twin per pregnancy was not significantly different between mNC-FET and OI-FET groups, 92.2% vs 90.4%; aOR 0.65; 95%CI 0.32-1.34. The multivariable regression analysis showed that twin pregnancies after OI-FET had decreased odds for gestational diabetes mellitus (aOR 0.37; 95% CI 0.16-0.87) in comparison to twin pregnancies after mNC-FET. In subgroup analysis, we found that the rate of live birth of at least one twin per pregnancy was significantly higher in OI-FET cycles using letrozole compared to those using hMG (94% vs 83.3%; aOR 3.45; 95%CI 1.24-9.57). The live birth rate in twin pregnancies after FET is comparable between mNC or OI regimens for endometrium preparation.

Myeloablative Busulfan/Melphalan Consolidation following Induction Chemotherapy for Patients with Newly Diagnosed High-Risk Neuroblastoma: Children's Oncology Group Trial ANBL12P1

Consolidation using high-dose chemotherapy with autologous stem cell transplantation (ASCT) is an important component of frontline therapy for children with high-risk neuroblastoma. The optimal preparative regimen is uncertain, although recent data support a role for busulfan/melphalan (BuMel). The Children's Oncology Group (COG) conducted a trial (ANBL12P1) to assess the tolerability and feasibility of BuMel ASCT following a COG induction. Patients with newly diagnosed high-risk neuroblastoma who did not progress during induction therapy and met organ function requirements received i.v. busulfan (every 24 hours for 4 doses based on age and weight) and melphalan (140 mg/m2 for 1 dose), followed by ASCT. Busulfan doses were adjusted to achieve to an average daily area under the curve (AUC) <5500 µM×minute. The primary endpoint was the occurrence of severe sinusoidal obstruction syndrome (SOS) or grade ≥4 pulmonary complications within the first 28 days after completion of consolidation therapy. A total of 146 eligible patients were enrolled, of whom 101 underwent BuMel ASCT. The overall incidence of protocol-defined unacceptable toxicity during consolidation was 6.9% (7 of 101). Six patients (5.9%) developed SOS, with 4 (4%) meeting the criteria for severe SOS. An additional 3 patients (3%) experienced grade ≥4 pulmonary complications during consolidation. The median busulfan AUC was 4558 µM×min (range, 3462 to 5189 µM×minute) for patients with SOS and 3512 µM×min (2360 to 5455 µM×minute) (P=.0142). No patients died during consolidation. From the time of study enrollment, the mean 3-year event-free survival for all 146 eligible patients was 55.6 ± 4.2%, and the mean 3-year overall survival was 74.5 ± 3.7%. The BuMel myeloablative regimen following COG induction was well tolerated, with acceptable pulmonary and hepatic toxicity.

Lentivirus-mediated gene therapy for Fabry disease

Enzyme and chaperone therapies are used to treat Fabry disease. Such treatments are expensive and require intrusive biweekly infusions; they are also not particularly efficacious. In this pilot, single-arm study (NCT02800070), five adult males with Type 1 (classical) phenotype Fabry disease were infused with autologous lentivirus-transduced, CD34+-selected, hematopoietic stem/progenitor cells engineered to express alpha-galactosidase A (α-gal A). Safety and toxicity are the primary endpoints. The non-myeloablative preparative regimen consisted of intravenous melphalan. No serious adverse events (AEs) are attributable to the investigational product. All patients produced α-gal A to near normal levels within one week. Vector is detected in peripheral blood and bone marrow cells, plasma and leukocytes demonstrate α-gal A activity within or above the reference range, and reductions in plasma and urine globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) are seen. While the study and evaluations are still ongoing, the first patient is nearly three years post-infusion. Three patients have elected to discontinue enzyme therapy.

Paperspray Ionization Mass Spectrometry as a Tool for Predicting Real-Time Optimized Dosing of the Chemotherapeutic Drug Melphalan.

Melphalan, an important component of hematopoietic stem cell transplantation (HSCT) preparative regimens, is associated with significant toxicity and large between patient variability in pharmacokinetics making it difficult to calculate the optimal dose for pediatric patients. Paperspray (PS) ionization generates gas phase analyte ions directly from a dried blood spot without the need for prior sample preparation or chromatography. With these advantages, a validated PS-MS/MS assay was developed and applied to the 'real-time' determination of melphalan pharmacokinetics (PK). Melphalan was quantified by stable-labeled isotope dilution analysis in whole blood by PS-MS/MS. Blood samples were obtained at timed intervals from patients during HSCT after administration of a very low (test) dose of melphalan to avoid toxicity. Pharmacokinetics parameters were calculated using WinNonlin v.6.4. From these data, the optimal therapeutic dose was estimated and full dose PK repeated. PS-MS/MS method was linear over a large dynamic range (25-50 000 ng/mL), intra- and interassay reproducibility of quality control samples was <15% CV. With essentially no prior sample preparation, PS-MS/MS measurement of blood melphalan concentrations showed excellent correlation (R2 = 0.959, n = 62) with a validated electrospray-LC-MS/MS method. Trapezoidal area under the curves calculated for 5 patients administered low dose melphalan showed a high linear correlation (R2 = 0.981) between the PS-MS/MS and LC-MS/MS methods. The faster PS approach permitted real-time PK evaluation of individual patients. A validated PS-MS/MS assay for melphalan in patients undergoing HSCT is described that facilitates pharmacokinetic-guided individualized precision dosing with immediate bedside dose adjustments to improve outcomes by balancing toxicity and efficacy of melphalan.

Haploidentical Hematopoietic Stem Cell Transplantation with Post-Transplantation Cyclophosphamide in Children with High-Risk Leukemia Using a Reduced-Intensity Conditioning Regimen and Peripheral Blood as the Stem Cell Source

The use of haploidentical donor hematopoietic stem cell transplantation with post-transplantation cyclophosphamide (Haplo-PTCy) in children is increasing; however, it is still not clear which preparative regimen is best in this setting. We present the long-term results of 42 patients age <18 years with high-risk leukemia who underwent this procedure using a reduced-intensity conditioning regimen (RIC) and peripheral blood as the stem cell source. Twenty-six patients had acute lymphoblastic leukemia, 13 had acute myelogenous leukemia, 2 had juvenile myelomonocytic leukemia, and 1 had blast crisis of chronic myelogenous leukemia. One-third of the patients were in first remission, 50% were in second remission, 14% were in third remission, and 3% had refractory disease. Neutrophil recovery occurred in 100% of the 40 patients alive at day +30, and transplantation-related mortality at 1 year was 14%. The incidence of acute graft-versus-disease (GVHD) grade III-IV was 17%, and the cumulative incidence of moderate to severe chronic GVHD at 1 year was 29%. The median duration of follow-up for surviving patients was 45 months; overall survival and event-free survival at 36 months were 56% and 46%, respectively. Long-term results of this series show that the use of an RIC regimen with peripheral blood stem cells as the cell source, in children with high-risk leukemia who underwent haplo-PTCy has tolerable toxicity, universal engraftment, and good survival rates.

Serotherapy-Free Regimen Improves Non-Relapse Mortality and Immune Recovery Among the Recipients of αβ TCell–Depleted Haploidentical Grafts: Retrospective Study in Childhood Leukemia

Depletion of αβ T cells from the graft prevents graft-versus-host disease (GVHD) and improves the outcome of hematopoietic stem cell transplantation (HSCT) from haploidentical donors. Delayed recovery of adaptive immunity remains a problem, which can be approached by adoptive T-cell transfer. In a randomized trial, we have assessed the safety and efficacy of low-dose memory (CD45RA-depleted) donor lymphocytes (mDLI) after HSCT with αβ T-cell depletion. Antithymocyte globulin (ATG) is viewed as an essential component of preparative regimen, critical for both prevention of graft failure and GVHD. Variable pharmacokinetics of ATG may significantly affect lymphocyte subpopulations after HSCT. To uncover the potential of mDLI, we replaced rabbit ATG with tocilizumab and abatacept. Here we compare post hoc the immune recovery and the key clinical outcomes, including nonrelapse mortality (NRM), overall- and event-free survival (OS and EFS), between the cohort enrolled in the prospective randomized trial and a historical cohort, comprised of patients grafted with a conventional ATG-based HSCT with αβ T cell depletion. A cohort of 149 children was enrolled in the prospective trial and 108 patients were selected as historical controls from a prospectively populated database. Patient population was comprised of children with high-risk hematologic malignancies, with more than 90% represented by acute leukemia. Median age at enrollment was 8.8 years. In the prospective cohort 91% of the donors were haploidentical parents, whereas in the historical cohort 72% of the donors were haploidentical. Conditioning was based on either 12Gy total body irradiation or treosulfan. Thiotepa, fludarabine, bortezomib, and rituximab were used as additional agents. Patients in the historical cohort received rabbit ATG at 5 mg/kg total dose, while prospective cohort patients received tocilizumab at 8 mg /kg on day -1 and abatacept at 10 mg/kg on days 0, 7, 14, and 28. Patients in the prospective trial cohort were randomized 1:1 to receive mDLI starting on day 0, whereas 69% of historical cohort patients received mDLI after engraftment, as part of previous trials. Primary engraftment rate was 99% in the prospective cohort and 98% in the historical cohort. The incidence of grade II-IV aGVHD was 13% in the prospective cohort and 16 % in the control group. Chronic GVHD developed among 13% (historical) and 7% (prospective) cohorts (P=.07). The incidence of cytomegalovirus viremia was 51% in the prospective cohort arm and 54% in the historical control arm (p=ns). Overall, in the prospective cohort 2-year NRM was 2%, incidence of relapse was 25%, EFS was 71%, and OS was 80%, whereas in the historical cohort 2-year NRM was 13%, incidence of relapse was 19%, EFS was 67%, and OS was 76%, difference non-significant for relapse and survival. NRM was significantly improved in the ATG-free cohort (P=.002). Recovery of both αβ- and γδ- T cells was significantly improved at days +30 and +60 after HSCT in recipients of ATG-free preparative regimens, as well as recovery of naïve T cells. Among the recipients of αβ T-cell-depleted grafts, replacement of ATG with nonlymphodepleting abatacept and tocilizumab immunomodulation did not compromise engraftment and GVHD control and was associated with significantly lower NRM and better immune recovery early after HSCT.

Total Body Irradiation in the Era of New Radiotherapy Techniques

Total body irradiation (TBI), in combination with chemotherapy which is most often cyclophosphamide, is widely used since it was introduces in the fifties by E.D.Thomas as a preparatory regimen before bone marrow transplant. Even if it is an important part for conditioning regimen for patients with acute myeloid leukemia (AML) or acute lymphoid leukemia (ALL) undergoing hematopoietic stem cell transplantation, it is responsible for many side effects. New irradiation technique, tomotherapy and VMAT achieved a significant dose reduction to the OARs and the feasibility of dose escalation in a BMT conditioning regimen.

Split dose bowel preparation before colonoscopy of PEG (Nulytely) in comparison to routine single dose bowel preparation.

Background:The aim of this study was to compare the efficacy and tolerability of polyethylene glycol (PEG) in single- or split-dose regimens for colonoscopy bowel preparation.Methods:This is a prospective, randomized, endoscopist blinded, single-center study, that included adult patients who underwent colonoscopy during the period from December 2017 to October 2018. Two groups were enrolled in the same period: One group used 4 L of PEG (Nulytely) in a single-dose preparation, administered a day before the procedure, and the other group received a split-dose regimen of 2 L PEG (Nulytely), given a day before the procedure and 2 L on the day of the procedure in the early morning. The Boston Bowel Preparation Scale (BBPS) was used for bowel preparation adequacy; scales 0 and 1 were considered inadequate, and scales 2 and 3 were considered adequate preparation.Results:Two hundred and forty patients were enrolled, 120 (50%) using the split-dose regimen and 120 (50%) using the single-dose regimen, for bowel preparation. Males constituted 51.6% of the study cohort. In the single-dose group, 62.5% achieved adequate bowel preparation compared to 89.2% in the split-dose group (p< 0.001). In addition, polyp detection in the split-dose group was 23.3% in comparison to 10.8% in the single-dose group (P = 0.016). We also found hypertension and diabetes as significant predictors of bowel preparation inadequacy, while sex and age were not related to bowel preparation adequacy.Conclusions:Split-dose bowel preparation for colonoscopy with PEG (Nulytely) is better than routine single-dose, in terms of adequate bowel preparation and polyp detection.

Allojenik Kök Hücre Nakli Yapılan Bir Hastada BK Virüsüne Bağlı Gelişen Hemorajik Sistitte Kullanılan Cidofovire Bağlı Olarak Ortaya Çıkan Akut Proksimal Tübüler Nekroz

Hemorrhagic cystitis (HS) is a frequently seen complication of bone marrow transplantation. This condition occurs depending on the preparatory regimen of bone marrow transplantation. The BK virus (BKV), a human polyomavirus, is a small double helix DNA virüs belonging to the Papovaviridae family. It is commonly found in societies as an occult infection. Whereas, cidofovir (CDV), an acyclic nucleoside phosphonate, is used as a proven antiviral agent against polyomaviruses. In this case report, acute proximal tubular necrosis due to cidofovir used in hemorrhagic cystitis caused by BK virus, and its treatment in a patient diagnosed with T-lymphoblastic lymphoma in remission, and underwent allogeneic stem cell transplantation, was presented.

A pragmatic multi-institutional approach to understanding transplant-associated thrombotic microangiopathy after stem cell transplant.

Transplant-associated thrombotic microangiopathy (TA-TMA) is a severe complication of hematopoietic stem cell transplantation (HSCT). A single-center prospective screening study has shown that the incidence of TA-TMA is much higher than prior retrospective studies that did not systematically screen. These data have not been replicated in a multicenter study. Our objective was to determine the incidence and risk factors for TA-TMA and compare outcomes of pediatric HSCT patients with and without TA-TMA. Patients were prospectively screened for TA-TMA at participating centers using a simple to implement and inexpensive strategy from the start of the preparative regimen through day +100. TA-TMA was diagnosed if ≥4 of 7 laboratory/clinical markers diagnostic for TA-TMA were present concurrently or if tissue histology showed TA-TMA. A total of 614 patients (359 males; 58%) received prospective TA-TMA screening at 13 pediatric centers. TA-TMA was diagnosed in 98 patients (16%) at a median of 22 days (interquartile range, 14-44) posttransplant. Patients with TA-TMA had significantly increased bloodstream infections (38% [37/98] vs 21% [107/51], P ≤ .001), mean total hospitalization days (68; 95% confidence interval [CI], 63-74 vs 43; 95% CI, 41-45; P ≤ .001), and number of days spent in the intensive care unit (10.1; 95% CI, 6.4-14; vs 1.6; 95% CI, 1.1-2.2; P ≤ .001) in the first 100 days after HSCT compared with patients without TA-TMA. Overall survival was significantly higher in patients without TA-TMA (93%; 490/516) compared with patients with TA-TMA (78%; 76/98) (P ≤ .001). These data support the need for systematic screening for TA-TMA and demonstrate the feasibility and efficacy of an easy to implement strategy to do so.

Improved Outcome for High-Risk Acute Myeloid Leukemia Patients Using Autologous Bone Marrow Transplantation and Monoclonal Antibody-Purged Bone Marrow

AbstractWe have conducted a 9-year multicenter trial of autologous bone marrow transplantation (ABMT) for acute myeloid leukemia (AML). Remission BM was purged in vitro using monoclonal antibodies (MoAbs; PM-81, AML-2-23) and complement targeting myeloid differentiation antigens (CD15, CD14). In 1988, the preparative regimen changed from 60 mg/kg/d cyclophosphamide × 2 and fractionated total body irradiation (TBI) total dose, 1,200 cGy (Cy/fTBI), to 4 mg/kg/d busulfan × 4 and 60 mg/kg/d Cy × 2 (Bu/ Cy2). Recent analysis (October 1, 1993) shows that the Bu/Cy2 regimen along with the same MoAb purging method yields an improved outcome. Seven first complete-remission (CR) (CR1), 45 second- orthird-CR (CR2/3), and 11 first-relapse (R1) patients were treated with chemotherapy and TBI or chemotherapy alone followed by ABMT with MoAb-purged BM. Median age at ABMT for those patients in CR 2/3 and R1 patients was 36 years. Twenty-nine CR 2/3 and R1 patients were conditioned with Cy/ fTBI, and 27 CR2/3 and R1 patients were conditioned with Bu/CY. Using the Kaplan-Meier method, the CY/fTBI, CR2/3, and R1 patients have a 3-year disease-free survival (DFS) of 21 %. On the other hand, the Bu/Cy2, CR2/3, and R1 patients have a 3-year DFS of 48%. Nineteen CR2/3 and R1 patients relapsed post-ABMT. On analysis by conditioning regimen, those treated with Cy/fTBI have a 3-year relapse rate (RR) of 58%, whereas the patients conditioned with Bu/Cy2 have a 39% 3-year RR. Long-term DFS can be achieved in about 50% of patients with advanced remissions and relapsed AML using Bu/Cy2 with MoAb-purged BM.

Cyclosporin A and short-term methotrexate versus cyclosporin A as graft versus host disease prophylaxis in patients with severe aplastic anemia given allogeneic bone marrow transplantation from an HLA-identical sibling: results of a GITMO/EBMT randomized trial

AbstractA randomized trial was carried out comparing cyclosporin A (CsA) and short-term methotrexate (MTX) versus CsA alone for graft versus host disease (GVHD) prophylaxis in patients with severe aplastic anemia (SAA) undergoing allogeneic bone marrow transplantation (BMT) from a compatible sibling. Seventy-one patients (median age, 19 years; range, 4-46 years) were randomized to receive either CsA and MTX or CsA alone for the first 3 weeks after BMT. Subsequently, both groups received CsA orally, with gradual drug reduction until discontinuation 8 to 12 months after BMT. Patients randomized in both arms had comparable characteristics and received the same preparative regimen (ie, cyclophosphamide 200 mg/kg over 4 days). The median time for neutrophil engraftment was 17 days (range, 11-31 days) and 12 days (range, 4-45 days) for patients in the CsA/MTX group and the CsA alone group, respectively (P = .01). No significant difference was observed in the probability of either grade 2, grade 3, or grade 4 acute GVHD or chronic GVHD developing in the 2 groups. The Kaplan-Meier estimates of 1-year transplantation-related mortality rates for patients given either CsA/MTX or CsA alone were 3% and 15%, respectively (P = .07). With a median follow-up of 48 months from BMT, the 5-year survival probability is 94% for patients in the CsA/MTX group and 78% for those in the CsA alone group (P = .05). These data indicate that the use of CsA with MTX is associated with improved survival in patients with SAA who receive transplants from compatible siblings.

Infectious complications in allogeneic hematopoietic cell transplant recipients: Review of transplant-related risk factors and current state of prophylaxis.

Allogeneic hematopoietic cell transplantation is a complex procedure that carries a significant risk of complications. Infections are among the most common of them. Several direct factors such as neutropenia, hypogammaglobulinemia, lymphopenia, mucosal barrier injury, and graft-versus-host disease have been shown to be associated with increased infectious risk post-transplant. Apart from direct factors, there are also indirect transplant-related factors that are the primary trigger to the formers' development. The most important of them are type of preparative regimen, graft source, donor type, graft-versus-host disease prophylaxis, and graft manipulation techniques. In this review, an attempt has been made to summarize the role of the transplant-related factors in the development of infectious complications and provide evidence underlying the current concept of infectious disease prophylaxis in patients after allogeneic hematopoietic cell transplantation.

Effectiveness and Tolerability of Very-low Volume Preparation for Colonoscopy: A Narrative Review

An adequate bowel preparation is essential for a successful colonoscopy, in particular, in the setting of colorectal cancer screening. However, up to one-quarter of colonoscopies are associated with inadequate bowel preparation, which may result in reduced polyp and adenoma detection rates, prolonged procedural time, and an increased likelihood of repeat the procedure. The ideal intestinal preparation should provide an optimal observation of the mucosa (at least &gt; 90% of the visible surface), with adequate acceptability and safety for the patient. With this premise, a very low-volume 1 L PEG-ASC solution (Plenvu; Norgine, Harefield, United Kingdom) has been recently introduced to improve patients' experience in colonoscopy by reducing the total intake of liquids to be consumed. This could represent a valid option for bowel cleansing, considering CRC screening and surveillance programs, improving both the quality of the examination and the patients' compliance. Nevertheless, it must be emphasized that a "one size fits all" preparation strategy is not feasible and that a bowel preparation regime must always be selected and tailored by the clinician for each patient, evaluating the best options on a case by case basis. This narrative review aims to sum up the evidence regarding new bowel preparation regimens in order to help clinicians to tailor the best choice for patients undergoing colonoscopy.

Bowel preparation for colonoscopy: is diet restriction necessary?

Background: Bowel preparation is essential for quality colonoscopy. Although most bowel preparation regimens recommend dietary restriction for 24 to 48 hours before the procedure, the evidence for this is poor. This study aimed to investigate whether dietary restriction during bowel preparation improves the quality of colonoscopy. Methods: A prospective, randomised controlled pilot study in which the dietary restriction (DR) group (control) was instructed not to ingest high fibre foods for 48 hours prior to the use of a polyethylene glycol (PEG) bowel preparation. The non-dietary restriction (NDR) group were given no dietary instruction but received instructions for the use of the PEG-based preparation. On the day of colonoscopy, the quality of the bowel effluent was assessed, and additional preparation given as necessary. The primary endpoint was quality of bowel cleansing using the Harefield Cleansing Scale during colonoscopy. The secondary endpoints were the need for additional bowel preparation and the quantity of additional bowel preparation given prior to endoscopy. Data were analysed on an intention to treat basis. Results: Twenty-three participants were randomised to the intervention group and thirty-four to the control group. Patient demographics were similar in both groups. Dietary restriction did not influence the success rate of bowel preparation: 97% successful bowel preparation in the DR group, vs 91% successful bowel preparation in the NDR group (p = 0.559). Additional bowel preparation requirement were similar in both groups: 35% in the DR group vs 39% in the NDR group (p = 0.768). Mean amount of additional bowel preparation required was similar: 560 ml in the DR group vs 460 ml in the NDR group (p = 0.633). Conclusion: The quality of bowel preparation was comparable in patients with and without dietary restrictions prior to colonoscopy. Non-restrictive diets prior to bowel preparation should be considered to increase compliance. The sample size of this pilot study prohibited definite statistical conclusions but demonstrated this to be a reasonable methodology for a larger study.

Cutaneous T-Cell Lymphoma Skin Microbiome Is Characterized by Shifts in Certain Commensal Bacteria but not Viruses when Compared with Healthy Controls

Cutaneous T-Cell Lymphoma Skin Microbiome Is Characterized by Shifts in Certain Commensal Bacteria but not Viruses when Compared with Healthy Controls

Comparison of Individualized Versus MAP-Bayesian Predicted AUC of Busulfan in FluBu4 Treated Patients Undergoing Allogeneic Transplant

Although myeloablative fludarabine/busulfan (FluBu4) has been widely adopted in clinical practice, considerable interpatient variability exists in systemic busulfan exposure (AUC) when using body weight or body surface area based-dosing, leading to decreased efficacy (i.e. relapse) or increased toxicity (i.e., mucositis, veno-occlusive disease). This well-defined dose-exposure-outcome relationship has led to the widespread clinical implementation of therapeutic drug monitoring (TDM). However, individualized TDM can be time and labor intensive as well as potentially biased due to the lack of incorporation of any previously established PK data (Bayesian prior). In contrast, Bayesian maximum a posteriori (MAP) PK models consider the Bayesian prior and individualized TDM to generate a revised probability distribution (Bayes conditional posterior) to more accurately and rapidly estimate the AUC with reduced bias. There are a paucity of data comparing busulfan AUCs using individualized PK versus MAP-Bayesian-based models in adults although these more sophisticated approaches may assist in optimizing dosing of busulfan in this vulnerable population. This was a retrospective, single-center study of patients who received FluBu4 with busulfan TDM between January 1999 and September 2019. 109 patients diagnosed with a hematologic malignancy who received either sequential (n=46) or concurrent (n=63) FluBu4 were analyzed. The median age was 48 (range: 18-66), and were Hispanic (n=38), White (n=46) or African-American (n=14). TDM was performed either after a test dose of 0.8 mg/kg (n=52) or after the first dose (3.2 mg/kg) of busulfan administered during the preparative regimen (n=71), with dosing was based on actual or adjusted body weight. For PK analysis, plasma busulfan concentrations were analyzed via gas chromatography with mass selective detection. Individualized PK data were generated using WinNonlin while the MAP-Bayesian approach utilized the Bayesian prior developed from McCune et al (Clin Cancer Res, 2014). An AUC of 4800 µM˖min/24 hours was targeted based on previous literature. Based on individualized PK data, total recommended busulfan doses ranged from 9.3-21.3 mg/kg (-27.1% to +66.7% compared to FDA labeled dose of 12.8 mg/kg). When first-dose busulfan PK was compared between busulfan given sequentially versus concurrently with fludarabine there was a trend towards a higher AUC with concomitant administration (4651 vs. 4988 µM˖min; p=0.13). A strong correlation between the AUC generated from both the individualized PK an MAP-Bayesian models was observed with both the test dose (R2=0.91) and first dose (R2=0.86) of busulfan. Using the MAP Bayesian model, AUC predictions were on average higher (mean AUC 5069 versus 4886 µM˖min, p&amp;lt;0.0001) compared to the patient-specific individualized PK estimates. Figure 1 shows the Bland Altman plots for comparison of the individualized AUC vs. MAP-Bayesian estimates for test dose and first dose. Our individualized busulfan PK approach generated relatively similar AUC values compared to MAP-Bayesian estimates, although the higher AUC generated via MAP-Bayesian predictions may allow for lower doses of busulfan to be administered thereby potentially reducing toxicity while maintaining efficacy. Further, use of the MAP-Bayesian method may allow for more rapid dose optimization and a decreased number of serum concentrations. Further prospective studies including more patients are warranted to confirm these findings. Figure 1 Disclosures Calip: Flatiron Health: Current Employment. Patel:Janssen: Consultancy; Amgen: Consultancy; Celgene: Consultancy.