bluuebunny/crossref_metadata_2025 huggingface dataset:
Study of NHEJ Function and Expression of Protein Ku70 in CML Patients.
Authors: Chen Pei-shuai , Fu Zheng-zheng , Cen Jian-nong , He Jun , Qiu Qiao-cheng , Yuan Xiao-ni , Chen Zi-xing
Published: October 2019

The abnormal activity of DNA repair after DNA double strand breakage results in genome instability. It is also thought that the malfunction in DNA repair may be involved in the generation of variety of chromosomal translocations in human leukemia. To investigate the relationship between the activity of DNA repairing by NHEJ and the expression of protein Ku70 in CML cells, the expression of protein Ku70 deprived from the chromatin was determined by Western Blot, using TBP(TATA Box Binding Protein)as the internal control, in bone marrow cells of CML patients as well as the normal controls. Our preliminary result showed that the gray ratios of Ku70 protein band over TBP band in 24 normal BM cells were 0 to 0.235, with a mean level of 0.0983±0.0875, while which were 0.173 to 0.890 with a mean of 0.401±0.207 (p<0.001) in 27 CML cases. Furthermore, Among these 27 CML cases, the gray ratio of Ku70 versus TBP in 12 CML cases in accelerating of acute phase was significantly higher than that in 15 CML patients in chronic phase with a mean value of 0.565±0.2159 vs. 0.269±0.0381 (p<0.001). These results indicated that the activity NHEJ in CML cells was approximately 2-fold higher than that in normal controls. Ku70, as the key protein of NHEJ, was expressed significantly higher in CML than that in normal BM cells. Moreover, as the CML progressed from chronic phase to accelerating or acute phase in company with a remarkable increase of Ku70 expression, more clones with variety of chromosome abnormalities other than the typical t (9;22) translocation emerged, suggesting an error-prone repair activity of the increased NHEJ in CML. The overactive DNA repair ability of NHEJ associated Ku70 proteins found in CML cells may highly correlated to the chromosome aberration in CML, especially to the genome instability during the disease progression.
High Antileukemic Efficacy and Shortened Neutropenia of Dose-Dense Induction (Sequential-HAM Followed by Pegfilgrastim) in Primary Acute Myeloid Leukemia - Results of a Pilot Study of the German AML-CG.
Authors: Braess Jan , Spiekermann Karsten , Buske Christian , Staib Peter , Ludwig Wolf-Dieter , Gruneisen Andreas , Sauerland Christa , Unterhalt Michael , Fiegl Michael , Wormann Bernhard , Kern Wolfgang , Heinicke Achim , Berdel Wolfgang , Büchner Thomas , Hiddemann Wolfgang
Published: October 2019

Dose density during early induction has been demonstrated to be one of the prime determinants for antileukemic efficacy. The German AML-CG therefore pilots a dose dense induction regimen S-HAM (sequential HD-AraC [3g/m2/12h d1,2,8,9] and Mitoxantrone 10mg/m2 [d3,4,10,11] followed by pegfilgrastim) in which two induction cycles are applied over 11 – 12 days as compared to conventional double induction, in which two cycles are applied over 25 – 29 days - thereby increasing dose density ca. two-fold in the critical first weeks of treatment. In the past 2,5 years 168 patients with de-novo AML (excluding APL) have been recruited into the trial with a median age of 53 years (range 18 – 78). Of 136 patients evaluable for response the following results were achieved: CR 62%, CRi 22%, PL 7%, ED 9% - resulting in an overall response rate (ORR) of 84%. The early death rate (ED) of 9% and the toxicity profile compared favourably with a historical control group of the AML-CG 1999 study (de-novo AML, < 60 years, HAM-HAM double induction) which demonstrated an ED rate of 14% (ORR 68%, persistent leukemia (PL) 18%). The high antileukemic efficacy of S-HAM was also demonstrated by the fact that 89% of patients had a blast count of < 10% one week after therapy as compared to less than 48% of patients of the HAM-HAM double induction group. Whereas even for patients with unfavourable cytogenetics (including complex aberrations) a median overall survival of 13,5 months was reached (23% at 2 years), for patients with favourable karyotypes overall survival at 2 years was 81%and for patients with intermediate karyotypes 74% after S-HAM treatment. Importantly the compression of the two induction cycles into the first 11 – 12 days of treatment seems actually beneficial for normal hematopoesis as demonstrated by a significantly shortened duration of critical neutropenia of 30 days as compared to 45 days after conventionally timed double induction. This shortening of critical neutropenia by more than 2 weeks was highly relevant for the duration of hospital stay and hospital costs. In conclusion S-HAM with pegfilgrastim support is a highly effective regimen in primary de-novo AML with a very favourable safety profile and significantly shortened duration of neutropenia. This regimen will therefore constitute the (dose-dense) experimental arm for a randomized comparison with standard double induction in the next generation of the German AML-CG studies.
Long-Term Prognostic Impact of the Use of Erythropoiesis-Stimulating Agents (ESA) in Patients (pts) with Chronic Myeloid Leukemia (CML) Treated with Imatinib.
Authors: Alvarado Yesid , Kantarjian Hagop , Verma Dushyant , Mattiuzzi Gloria , Aribi Ahmed , Ravandi Farhad , Borthakur Gautam , Cortes Jorge
Published: October 2019

Background: ESA have been reported to effectively improve the hemoglobin (Hb) in pts with CML who develop anemia during the course of therapy with imatinib and other tyrosine kinase inhibitors. Recently, it has been suggested that when ESA were administered to target a Hb ≥12 g/dL, they may promote tumor growth and decreased survival among pts with advanced head and neck cancer receiving radiation therapy, pts with non-small cell lung cancer, and pts with metastatic breast cancer receiving chemotherapy. We thus investigated whether pts with CML who had received ESA during the course of therapy with imatinib had an inferior long-term outcome.

Methods: We analyzed the outcome of 565 pts with CML in chronic phase treated with imatinib in our institution (306 previously untreated, 259 post imatinib failure).

Results: Based on the Common Terminology Criteria for Adverse Events (CTCAE) V. 3.0 of the National Cancer Institute (NCI), grade 1 anemia occurred in 235 (42%) pts, grade 2 in 180 (32%), grade 3 in 47 (8%), and grade 4 in 12 (2%) pts. A total of 245 (43%) pts received ESA at some point during the course of therapy. The median nadir Hb among pts treated with ESA was 9.4 g/dL [45 (18%) with grade 3–4 anemia] vs 11.2 g/dL [14 (4%) with grade 3–4 anemia] in those not treated with ESA. Treated patients received therapy with variable intermittent doses during a median time of 14 months (mo) range (1–96 mo). The observed increase in Hb with ESA therapy was >3 g/dL in 132 (54%) pts, 2–3 g/dL in 64 (26%), 1-<2 g/dL in 35 (14%), and <1 g/dL in 14 (6%) pts. The median Hb level achieved with ESA was 12.6 g/dL. The table summarizes the 5-year overall survival and event free survival (EFS) among pts treated with ESA and those not treated with ESA: As previously reported (Cortes et al. Cancer2004; 100:2396–402), the presence of anemia itself has a significant adverse effect on outcome in this patient population. The 5-year EFS for pts with anemia grade 3–4 was 56% vs. 79% for those with grade 0–2 (p=0.002). Corresponding figures for 5-yr OS were 82% and 88% (p=0.006).

Conclusion: There is no evidence that the use of ESA to manage anemia associated with imatinib therapy in pts with CML in chronic phase adversely affects long term overall survival or event-free survival.

INF- failure (%) Frontline Imatinib (%) OS: overall survival, EFS: event free survival (event = loss of complete hematologic response, loss of major cytogenetic response, transformation to accelerated or blast phase or death from any cause), INF: interferon, ESA: erythropoiesis-stimulating agents. ESA use OS EFS OS EFS No 84 75 92 84 Yes 82 68 89 85 P Value 0.59 0.12 0.58 0.68
Incidence, Comorbidity and Treatment Survey of Chronic Myeoloid Leukemia in Germany.
Authors: Hasford Joerg , Tauscher Martin , Hochhaus Andreas
Published: October 2019

Background and objectives Reliable epidemiological data about the incidence of CML, the treatment and the comorbidity profile of patients in Germany was not available. Methods Thus, we used the data base of the Bavarian association of statutory health insurance accredited physicians, which covers 83.5% of all outpatient care in Bavaria with 10.4 million people. A CML-patient was defined as the combination of an ICD 92.1 CML diagnosis plus treatment with either imatinib, interferon alfa, hydroxyurea or busulfan for at least one year. Results In 2004, there were 201 new CML cases seen which results in a crude incidence of 1.93 / 100,000 / year. Adjusted to the World Standard Population the figures are 1.357 for males and 1.063 for females. The median age was 63 (m) and 65 (f) years. Comparing the comorbidities of CML patients with all other patients > 60 years non infectious enteritis and colitis (RR: 2.99), diseases of the oral cavity, salivary glands or jaws (RR: 2.49); infectious of the skin or subcutis (RR: 2.28), surgical complications (RR: 2.13) and symptoms of the GI-tract or abdomen (RR: 2.09) occurred more often in CML-patients, whereas hypertension (RR: 0.81), IHD (RR: 0.93); other heart diseases (RR: 0.87) and cerebrovascular diseases (RR: 0.78) occurred less often. In 2006, 58.8% of the CML-patients received imatinib alone; 10.2% imatinib in combination either with HU or IFN alfa, 25.8% HU, and 7.6% IFN alfa. Discussion and conclusions The true incidence may be slightly lower (about 10%) as some chronic myeloproliferative diseases may have been miscoded as CML, but we may have missed some CML-patients who have been treated as inpatients only, too. Thus, we think that our incidence estimate, and the age and sex distribution is fairly accurate. In addition and for the first time, current treatment comorbidity data of CML-patients in Germany are available.
Association of Fc Receptor-Like Protein Family with Chronic Graft-Versus-Host Disease.
Authors: Onizuka Makoto , Toyosaki Masako , Machida Shinichiro , Suzuki Rikio , Kojima Minoru , Miyamura Koichi , Kodera Yoshihisa , Inoko Hidetoshi , Ando Kiyoshi
Published: October 2019

Chronic graft versus host disease (cGVHD) is the most common cause of poor outcomes after hematopoietic stem cell transplantation (HSCT), while the pathophysiology of cGVHD remains poorly understood. We have revealed the association Fc receptor-like protein 3 (FCRL3) gene -169C/T single nucleotide polymorphism (SNP) and developing cGVHD. This gene is a member of Fc receptor-like protein gene family which contains 5 genes and well known as autoimmune disease associated gene. These 5 genes make cluster lesion on chromosome 1q21 to 23. In this current study, to investigate the relationship with another Fc receptor-like protein genes and cGVHD, we used 4 microsatellite polymorphisms belong to FCRL1, 2, 3 and 4 as a linkage analysis genetic marker. And we also investigated FCRL3 -169C/T SNP and another 3 SNPs to explore haplotype and the incidence of cGVHD. We analyzed 123 case of Japanese HLA-matched sibling recipients and their donor who underwent HSCT in the Japanese Red-Cross Nagoya First hospital. Before day 100, 11 patients died from severe acute GVHD, infection, thrombotic microangiopathy or disease relapse. Therefore, we analyzed 112 recipients and 108 donors for the relationship between gene polymorphisms and chronic GVHD. We analyzed microsatellite polymorphisms and SNPs by using TaqMan® assay. Chronic GVHD occurred in 54 out of 112 (48.2%) patients in this cohort. The nearest microsatellite marker from FCRL3 gene had significant different allele frequency between cGVHD and non-GVHD recipient (p=0.0034). There were no association with another microsatellites allele and developing cGVHD. FCRL3 gene haplotypes with frequency >0.01 were -TGGG-, -CACA- and -CGCA-. Chronic GVHD patients significantly less the frequency of -CACA- or -CGCA- allele than non GVHD patients (p=0.0040). There were no significant difference in donor allele frequency and incidence of cGVHD. In conclusion, our studies show FCRL3, which is autoimmune disease associated gene, is also the candidate of cGVHD associated gene and its protective haplotype may prevent from occurring cGVHD but not homologous another FCRL proteins.
Rituximab (RTX) as Salvage Therapy for Refractory Chronic Graft-Versus-Host Disease (cGVHD).
Authors: Mohty Mohamad , Marchetti Nicolas , El-Cheikh Jean , Faucher Catherine , Furst Sabine , Blaise Didier
Published: October 2019

The incidence of cGVHD is likely to continuously increase as a result of the increasing use of allo-SCT (especially with reduced-intensity conditioning regimens) in older patients, peripheral blood stem cells as stem cell source, and frequent donor lymphocyte infusions, all of which are known to increase the risk of cGVHD. Standard primary treatment of cGVHD remains a combination of corticosteroids (CS) and calcineurin inhibitors. There is no standard therapy for those who fail to respond to CS, and CS-resistant GVHD is associated with high morbidity. The aim of this report was to analyze the outcome of patients treated with RTX as salvage therapy for refractory cGVHD. 15 consecutive patients experiencing severe or refractory GVHD received IV infusions of RTX (375mg/m2/infusion) at weekly intervals for 4 weeks. Responding patients were allowed to receive additional courses of maintenance therapy. Response to RTX was assessed one month after the last infusion. Patients’ characteristics, GVHD features and outcome are summarized in the Table below. RTX was administered at a median time of 178 (range, 69–1136) days after allo-SCT, and patients received a median of 5 (range, 1–12) infusions. Most have received and failed at least 2 lines of immunosuppressive therapy prior to RTX. With a median follow-up of 118 days (range, 21–834) from first infusion of RTX, no major toxicities directly related to RTX were observed. Overall, 10 patients responded to RTX administration (66%; 95%CI, 42–90%) with 3 complete remissions. In those responding patients, the patient felt improvement as soon as one week after the first RTX infusion. In addition, RTX allowed a significant reduction of CS dosage (range, 0–83%). 4 patients did not respond and died from refractory GVHD, while one responding patient died of disease progression. With a median follow-up of 461 days from onset of cGVHD (range, 91–1192), the actuarial survival rate from the first RTX infusion was 60% at one year. We conclude that despite its limited size, this cohort demonstrates evidence of beneficial activity of RTX, mainly in the classical cutaneous, mucosal and liver cGVHD. Patients with involvement of other sites are not likely to benefit much from RTX. Results achieved with RTX in the cGVHD refractory setting, pave the way for further developments. As such, the addition of RTX to prednisone for the initial treatment of cGVHD is worth further investigations, both to increase the overall response rate, and to enable a more rapid CS taper while incurring less long-term toxicity.

Table. Patients’ characteristics, transplant procedures, GVHD features and outcome.
Anti-Thymocyte Globulin Induces Higher Response Rates and Less Graft-Versus-Host Disease in Multiple Myeloma Patients Undergoing Allogeneic Stem Cell Transplantation.
Authors: Ayuk Francis , Perez-Simon José A. , Shimoni Avichai , Sureda Anna , Zabelina Tatjana , Schwerdtfeger Rainer , Martino Rodrigo , Sayer Herbert G. , Alegre Adrián , Lahuerta Juan-José , Atanackovic Djordje , Wolschke Christine , Nagler Arnon , Zander Axel R. , Miguel Jesús San , Kroeger Nicolaus
Published: October 2019

Preclinical experiments have shown a strong anti-myeloma effect of polyclonal anti-thymo-cyte globulin (ATG). We evaluated ATG effect in a melphalan/fludarabine-based conditioning regimen in 138 multiple myeloma (MM) patients who underwent allogeneic stem cell transplantation with (n=79) or without (n=59) ATG. More patients in the group without ATG had experienced relapse to prior auto-transplant (63% vs. 47%, p = 0.08). Patient characteristics were otherwise well matched in both groups. A median ATG dose of 30 mg/kg BW (range, 10-90 mg/kg BW) was administered on days −3 to −1. GvHD prophylaxis was performed with cyclosporine A and short-course methotrexate. Overall response (93% vs. 78%, p=0.03) and complete response (59% vs. 39%, p=0.04) at day 100 were higher in the patients treated with ATG than in those without ATG. ATG led to a lower incidence of severe grade III/IV acute GvHD (11% vs. 22%, p=0.10), and chronic GvHD (23% vs. 65%, p<0.001). The rate of complete remissions increased in patients who had received the higher ATG dose: 57% in those who received ATG ≤ 30 mg/kg BW, vs. 63% in those who received ATG > 30 mg/kg BW. The rate of OR increased from 78% in the no-ATG group to 91% in patients who received ATG ≤ 30 mg/kg BW, and to 96% in patients who received ATG > 30 mg/kg BW (p=0.02). Separate analysis of patients transplanted from a sibling donor also showed a trend to better OR (86% vs. 78%) and CR (55% vs. 39%) for patients who received ATG (all patients received ATG at a dose ≤ 30 mg/kg) compared to the non-ATG group, however due to low numbers this difference did not reach statistical significance. Though the non-ATG group contained more patients who had relapsed to prior autografting, this as has been reported before, would not influence response rates. In the multivariate analysis of prognostic factors for achievement of a CR, ATG was the only significant prognostic factor (RR: 2.57; 95% CI: 1.17-5.64; P=0.02). The estimated overall survival (OS) at three years was 53% (95% CI: 40-66%) for the ATG group (p=0.46), and 43% (95% CI: 29-57%) for the non-ATG group (p=0.46), while progression-free survival (PFS) at three years was 39% (95% CI: 27-51%) for the ATG group, and 27% (95% CI: 14-40%), for the non-ATG group (p=0.55). The current results suggest a dose dependent beneficial effect of ATG in terms of myeloma cytotoxicity as well reduction of the incidence of chronic GvHD.
Subcutaneous Alemtuzumab May Be Useful in the Treatment of Steroid-Refractory Acute Graft-Versus-Host Disease.
Authors: Gomez-Almaguer David , Ruiz-Arguelles Guillermo J. , Gonzalez-Llano Oscar , Gutierrez-Aguire Homero C. , Cantu-Rodriguez Olga G. , Jaime-Perez Jose C. , Giralt Sergio
Published: October 2019

Background: Acute graft-versus-host disease (GvHD) is mediated by activated T lymphocytes. Alemtuzumab is an unconjugated, humanized IgG1 kappa monoclonal antibody which targets the CD52 antigen on T lymphocytes and other cells and has been used successfully in conditioning regimens for allogeneic transplantation to remove donor T cells so as to prevent GvHD.

Patients and methods: Eighteen patients with steroid-refractory acute GvHD ≥ grade II were analyzed to evaluate the safety and efficacy of alemtuzumab. The patients received subcutaneous alemtuzumab 10 mg daily on days 1–5. The proportion of patients with grade II, III and IV were eight, eight and two, respectively. The main organ involved was the liver in four, gut in five, skin and liver in three, and skin and gut in three patients.

Results: Fifteen out of 18 patients (83%) responded to alemtuzumab with 6 (33%) complete and 9 (50%) partial responses. All three unresponsive patients died of GvHD. Ten of 15 responders are alive at a median follow-up of 9 months (range 2–23) after alemtuzumab, with limited, extensive and no signs of chronic GvHD in 1, 4, and 5 patients, respectively. Fourteen patients (78%) developed some kind of infection; eleven of them developed cytomegalovirus reactivation. All patients tolerated alemtuzumab with minimal side effects; grade 3 neutropenia and thrombocytopenia were seen in six and four patients, respectively.

Conclusions: Alemtuzumab is a well tolerated agent and has a beneficial effect in the treatment of steroid-refractory acute GvHD. Infections are common and anti-infective prophylaxis is mandatory.
DAAM2 Polymorphism and Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Yi Hyeon Gyu , Piao Cheng Zhe , Kim Inho , Kim Hye Jin , Oh So Yeon , Kim Jin Won , Kim Dae-Young , Lim Joo Han , Seo Myung-Deok , Park Seonyang , Yoon Sung-Soo , Kim Byoung Kook , Kim Chul Soo
Published: October 2019

Background WNT signaling pathway is known to have important functions in embryogenesis, cellular proliferation and regeneration, stem cell renewal and oncogenesis. DAAM2 is one of the key protein of WNT/PCP signaling pathway. This study examines the association of DAAM2 polymorphism and the clinical outcomes in patients treated with allogeneic hematopoietic stem cell transplantation (HSCT). Objectives and methods Candidate SNPs associated with acute graft versus host disease (GVHD) were selected using DNA chip analysis with Illumina Infinium Human-1 microarrays™ in 15 patients who treated with allogeneic HSCT for various hematologic and oncologic diseases with or without acute GVHD. Six SNPs (rs2504787, rs2504086, rs2504082, rs3004067, rs882559, and rs3004070) on DAAM2 were proven to be associated with acute GVHD, and extended genotyping was executed by Taqman™ protocol in more large population of 239 patients in single institute. Retrospective analysis for medical records was performed to define correlation of these SNPs with clinical outcomes of the patients. Results rs882559 located upstream from exon 24, was proven to be associated with acute GVHD incidence. Acute GVHD incidence was significantly lower in the patients with CC genotype of rs882559 than those with CG or GG genotype (HR 0.466, 95% CI 0.224∼0.969, p=0.0409). The allele frequency of C was 55% and that of G 44%. The genotyping disclosed CC in 77, CG in 110, and GG in 52. Multivariate analyses on various parameters including sex, age, transplant method (reduced intensity conditioning vs. conventional conditioning), stem cell source, risk group, and DAAM2 genotypes, as parameters, identified high-risk group defined in our previous study (KH Lee et al., Haematologica, 2007;92 ; HR 2.41, 95% CI 1.47∼3.94, p<0.001), age over 50 years (HR 1.70, 95% CI 1.18∼2.45, p=0.004) and codominant genotype of rs2504082, i.e., an intron mutation upsteam from exon 15 (HR 1.326, 95% CI 1.02∼1073, p=0.0378) as risk factors for a shorter survival. Interpretation and conclusions This is the first clinical study for the DAAM2 polymorphism, furthermore, and its association with clinical outcomes of allogeneic HSCT. The role of rs882559 and rs2504082 were not identified by now, but its mutation might affect to the transcription of following coding genes causing the changes of its functions. This study suggested the clinical value of DAAM2 polymorphism as a predictive parameter of clinical outcomes of allogeneic HSCT, and its importance in WNT signaling pathway.
Similar Risks for Late-Onset Chronic Kidney Disease in Myeloablative and Reduced-Intensity Allogeneic Hematopoietic Cell Transplant Survivors.
Authors: Al-Hazzouri Ahmed , Cao Qing , Burns Linda J. , Weisdorf Daniel J. , Majhail Navneet S.
Published: October 2019

Chronic kidney disease (CKD) has been reported in nearly 20% of recipients of myeloablative (MA) allogeneic hematopoietic cell transplantation (HCT). HCT using reduced-intensity (RIC) conditioning is associated with lower morbidity and mortality, but the risk of CKD after RIC HCT is not well known. We conducted a retrospective cohort study to compare the incidence of CKD after MA and RIC HCT. Adult allogeneic HCT recipients were eligible if (1) they received an allogeneic HCT between 2000 and 2005, (2) survived for ≥ 1 year post-HCT, and (3) had no history of CKD pre-transplant. The dose of total body irradiation in MA and RIC regimens was 1320 cGy (165 cGy twice daily × 4 days) and 200 cGy (single fraction), respectively, and was given without kidney shielding. CKD was defined as glomerular filtration rate (GFR) < 60 ml/min/1.73m2 for ≥ 3 months (National Kidney Foundation definition) anytime after 180 days post-HCT. GFR was estimated using the Modification of Diet in Renal Disease equation [GFR = 186 × (SCr)−1.154 × (Age)−0.203 × (0.742 if female) × (1.210 if African American)]. Study eligibility criteria were met by 221 patients (MA=104, RIC=117); median follow-up was 28 (range, 12–75) months for MA and 25 (range, 12–67) months for RIC group. At the time of transplant, MA recipients were younger (median age 38 vs. 54 years, P<0.01), less likely to have HTN (7% vs. 22%, P<0.01) and more likely to have a body mass index of <30 (87% vs. 72%, P=0.01). The two groups were comparable with respect to prevalence of diabetes mellitus, smoking, HCT co-morbidity index scores, incidence of acute renal failure (ARF) within the first 180 days, and duration of cyclosporine (CSA) use. A total of 60 (MA=30, RIC=30) patients developed CKD, resulting in a 3-year cumulative incidence rate of 29% (95% confidence intervals, 20–37%) in MA and 27% (18–35%) in the RIC group (p=0.44). In multivariate analysis, conditioning regimen intensity had no impact on risk of developing CKD (relative risk [RR] for MA 1.60 [0.86–2.97] vs. RIC regimen). Factors independently associated with an increased risk of CKD were age at HCT (RR 1.05 [1.02–1.08] for each year increase), acute graft-versus-host disease (RR 2.16 [1.19–3.93]) and CSA use for >6 months (RR 3.48 [2.33–2.56]). ARF within the first 180 days also predicted the risk for CKD. Compared to severe ARF [lowest GFR ≤ 30], RR of CKD was 0.40 [0.23–0.69] for moderate ARF [lowest GFR 31–59] and 0 for no ARF [lowest GFR ≥ 60]. In conclusion, CKD is frequent in long term adult allogeneic HCT survivors. RIC is associated with similar risks of CKD as MA conditioning. Older age, ARF, acute graft-versus-host disease and prolonged CSA exposure increases the risk of CKD. Continuous monitoring of renal function is necessary in allogeneic HCT survivors and studies exploring prevention strategies are needed.
Higher Mycophenolate Dose Requirements in Children Undergoing Hematopoietic Cell Transplant (HCT).
Authors: Jacobson Pamala A. , Huang Jiayin , Rydholm Nancy , Tran MyHang , DeFor Todd , Tolar Jakub , Orchard Paul J.
Published: October 2019

Mycophenolate mofetil (MMF), a pro-drug of mycophenolic acid (MPA), is commonly used as part of the immunosuppressive regimen after hematopoietic cell transplantation (HCT). Although MMF is widely used in HCT transplant recipients, systemic exposure has not been thoroughly studied in pediatric HCT recipients. Hence, the dosing strategies used in children undergoing kidney transplantation have been adopted or the adult dose has been extended to HCT children. Therefore, we studied mycophenolate pharmacokinetics in 19 children with median age of 17 (3–140) months with nonmalignant diseases undergoing myeloablative HCT who received mycophenolate in combination with cyclosporine for graft-versus-host disease prophylaxis. All subjects, except two, received 15 mg/kg mycophenolate intravenously every 8 hours. Pharmacokinetics were studied once between days 3–7 and again between days 10–14 post-transplant. The median [range] MPA total area under the curve (AUC)0-8 was 12.6 mcg hr/ml [4.9–49.2] and unbound AUC0-8 was 0.274 mcg hr/ml [0.037–1.4]. Unbound MPA fraction was 1.7% [0.76–5.1]. The median total mycophenolic acid glucuronide (MPAG) AUC0-8 was 269.1 mcg hr/mL [127.6–957.0]. Total and unbound MPA trough concentrations were 0.24 [0.03–2.9] and 0.005 [0–0.034] mcg/mL, respectively, with 8 hour dosing. MPA troughs were not good surrogates for overall exposure (AUC)0-8,[r2≤0.55]. MPA exposures did not change significantly between weeks 1 and 2 (p≤0.51), although several patients had an increase or decrease in AUC by 50% or more. SCr, CrCl, bilirubin, age, weight and albumin were poorly correlated with MPA AUC0-8 (all r2<0.40). Twenty % of the AUC’s achieved a total MPA target previously associated with better donor chimerism and 54% met the unbound MPA targets associated with reduced acute GVHD risk in adults undergoing nonmyeloablative transplant. These data suggest that 15 mg/kg every 8 hours may be too low. However, whether these targets are relevant in the pediatric myeloablative setting is not known. MMF given 15 mg/kg every 8 hours intravenously in our patients achieved an exposure similar to that previously observed in adult nonmyeloablative HCT recipients receiving 1gm every 12 hours intravenously. MPA exposure in pediatric HCT recipients is lower than pediatric organ transplant recipients despite receiving a 33% higher dose. Children undergoing HCT should receive an MMF dose of at least 15 mg/kg intravenously every 8 hours to achieve systemic concentrations near those proposed to be therapeutic in the adult HCT population. The optimal MPA exposure target, particularly the upper limit of safety, in children undergoing myeloablative HCT has yet to be determined.
The Effect of In Vivo T-Cell Depletion with Alemtuzumab on Reduced-Intensity Allogeneic Hematopoietic Cell Transplantation for Chronic Lymphocytic Leukemia.
Authors: Delgado Julio , Pillai Srinivas , Benjamin Reuben , Caballero Dolores , Martino Rodrigo , Lovell Richard , Thomson Kirsty , Perez-Simon Jose A. , Sureda Anna , Kottaridis Panos , Miguel Jesus San , Peggs Karl , Sierra Jorge , Milligan Donald , Mackinnon Stephen
Published: October 2019

Reduced-intensity allogeneic hematopoietic cell transplantation (HCT) is increasingly considered as a therapeutic option for young patients with advanced chronic lymphocytic leukemia (CLL). We report 59 consecutive CLL patients who underwent allogeneic HCT following fludarabine and melphalan conditioning at four different institutions. For graft-versus-host disease (GVHD) prophylaxis, 38 patients (Cohort 1) received alemtuzumab (20–100 mg) and cyclosporine; and 21 patients (Cohort 2) received cyclosporine plus methotrexate or mycophenolate. Donors were 47 HLA-matched siblings and 12 unrelated volunteers, 6 of whom were mismatched. Median age at transplant was 53 (range, 34–64) years and median number of previous chemotherapy regimens was 3 (1–6), with 39% of patients being refractory to fludarabine. Nine patients had previously failed an autologous HCT. Fluorescent in-situ hybridization and IgVH mutation status data were available in 33 (56%) and 31 (53%) patients, respectively, being unfavorable (17p- or 11q-) in 22 (67%) and unmutated in 24 (77%) of them. All but 1 patient engrafted, and the median interval to neutrophil recovery (> 0.5 × 109/l) was 14 (range, 10–36) days. Twenty patients (34%), mostly from Cohort 1, received escalated donor lymphocyte infusions due to mixed chimerism or disease relapse. The overall complete response rate among 53 patients with measurable disease at the time of transplantation was 70%, whereas 21% had stable disease. Grade II-IV acute GVHD was observed in 14 (37%) and 12 (57%) patients from Cohorts 1 and 2, respectively (P = 0.17). Extensive chronic GVHD was observed in 3 (8%) and 10 (48%) patients from Cohorts 1 and 2, respectively (P < 0.01). The incidence of cytomegalovirus reactivation was not significantly different between cohorts (67% vs 47%, P = 0.23). With a median follow-up of 36 (range, 3–99) months for survivors, 18 (30%) patients have died, 3 of progressive disease and 15 of transplant-related complications. The 3-year overall survival (OS), progression-free survival (PFS) and non-relapse mortality were 66% (95% CI 48–84%), 38% (20–56%) and 21% (8–34%), respectively, for Cohort 1 and 65% (44–86%), 54% (32–76%) and 29% (10–48%) for Cohort 2 (P = 0.66; P = 0.33; and P = 0.53). Despite low patient numbers, alemtuzumab seemed particularly effective for unrelated donor recipients, with a 3-year OS and PFS of 54% and 40% for Cohort 1; and 33% and 0% for Cohort 2 (P = 0.02 and P = 0.07). In conclusion, results with reduced-intensity allogeneic HCT are promising for these poor-prognosis patients. Furthermore, the alemtuzumab-based regimen was effective in reducing the chronic GVHD rate with no negative effect on NRM, PFS or OS.
A Higher Ratio of Dose to Actual Weight of Conditioning Chemotherapy Leads to More Toxicity without Improvement in Outcome in Autologous HSC Transplant for DLBCL.
Authors: Costa Luciano J. , Micallef Ivana N. , Inward David J. , Johnston Patrick B. , Porrata Luis F. , Litzow Mark R. , Ansell Stephen M.
Published: October 2019

Background: High-dose chemotherapy and hematopoietic stem cell (HSC) transplantation is considered standard therapy in patients with chemosensitive relapsed diffuse large B cell lymphoma (DLBCL). BCNU, etoposide, cytarabine and melphalan (BEAM) is a standard widely used DLBCL conditioning regimen. Chemotherapy doses, both standard and high dose, are traditionally based in body surface area (BSA) and are often calculated using the corrected ideal body weight. However, this practice is empirical and the best way to dose chemotherapy is unknown. Weight-based dosing has been suggested to better predict toxicity of the conditioning regimen. We correlate the BEAM dose/actual weight ratio with toxicity and overall outcome in a uniform cohort of patients receiving HSC transplant for relapsed DLBCL

Methods: Retrospective analysis of 80 consecutive patients treated at Mayo Clinic, Rochester, MN between 2001 and 2006 who received a HSC transplant following BEAM conditioning was performed. All doses were based on BSA calculated using the corrected ideal body weight. Weight-based dose intensity was retrospectively calculated utilizing the melphalan dose/Kg as a surrogate for the entire regimen. Weight-based dose intensity was correlated with toxicity in the first 30 days after transplant and survival outcome.

Results: Median age at the time of transplant was 62 (interquartile range 53–65; range 26–77); 65% were males; median number of prior chemotherapy regimens was 2. Median dose of melphalan was 3.2 mg/Kg (interquartile range 2.9–3.6; range 2.2–4.5). Only one patient died within 30 days of the transplant. Patients who received > 3.6 mg/Kg of melphalan were more likely to have Grade 3 or 4 mucositis (44.4% v. 9.8%, P=0.001) than the remaining patients. Median numbers of days spent in the hospital in the first 30 days after transplant was 13 (3–18) for melphalan dose >3.6 mg/kg vs. 7 (0.5–10.5) for the remaining patients (P=0.043). Weight based dose intensity did not correlate with survival (P=0.8) or disease-free survival (P=0.3).

Conclusion: Weight based dose intensity of BEAM correlates with toxicity post autologous HSC transplant. Patients receiving doses corresponding to >3.6 mg/kg of melphalan are at increased risk of high-grade mucositis and prolonged hospitalization.

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Current Models for Predicting Warfarin Maintenance Dose Do Not Work in an Ambulatory Venous Thromboembolism Patient Population.
Authors: Wells Philip , Rodger Marc , Fleming Jennifer , Kassem Sarah
Published: October 2019

Warfarin is the most widely used anticoagulant for the treatment of conditions such as deep vein thrombosis and pulmonary embolism. Warfarin has a narrow therapeutic index, and individual patient response to the drug is highly variable. Models to predict the maintenance dose have been published but not validated in independent populations (Kamali et al, Sconce et al, and Gage et al). Most of the prior data was derived in patients with atrial fibrillation and these may not be applicable to our predominantly ambulatory VTE population. The prior models incorporate a variety of factors that have been predicted to have an effect on warfarin dosing, such as age, height, and polymorphisms in the vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 (CYP450) 2C9 enzyme. We enrolled 51 consecutive VTE patients on stable doses of warfarin as defined in the prior studies. As in those studies we excluded patients with known or suspected non-compliance, known liver disease and known congestive heart failure. All previously suggested predictive variables were collected. Mean warfarin dose, mean INRs, and gene polymorphisms were determined by previously described standard methods. In addition we are testing the recently identified coding VKORC1 Asp36Tyr polymorphism which predisposes to warfarin resistance. This study aimed to examine the accuracy of three previous models to predict individual warfarin dosing in pursuit of the development of a more accurate regression model. Preliminary results with the first 51 patients, through correlation analysis, indicate that none of the previous models provide an accurate prediction of warfarin maintenance dose. The mean maintenance dose of the patient population was 6.23mg. The doses predicted by the previous models were significantly lower at 4.4mg, 5.3mg, and 4.5mg for Kamali, Gage, and Sconce, respectively. The Pearson correlation coefficients were 0.047, 0.27, and 0.50, respectively. A preliminary model has been developed with a Pearson correlation coefficient of r=0.78, and a p-value <0.0001. The R2 value for the model was 61.5%. We have now recruited over 290 patients and are analysing the data. We will report more precise data on correlations with the other models and if a new model with a higher R2 can be determined it will be reported.
Allogeneic Stem Cell Transplantation in Multiple Myeloma: One Center Experience of 86 Patients.
Authors: Volin Liisa , Uotinen Heli , Juvonen Eeva , Nihtinen Anne , Ruutu Tapani
Published: October 2019

The role of allogeneic stem cell transplantation (SCT) in the treatment of multiple myeloma (MM) is unclear. High transplant-related mortality has been regarded as a particular problem. At the Helsinki University Central Hospital 86 patients with MM have been treated with allogeneic SCT since 1995. The conditioning was at first myeloablative (MA). Since 1999 reduced intensity conditioning (RIC) after autologous SCT has been used in most cases, but a number of young patients with aggressive disease have been transplanted with MA conditioning. Of the patients 42 were male and 44 female. The median age at SCT was 50 (27–64) years. The median number of chemotherapy lines before allogeneic SCT was 1 (range 1–7). Prior autologous SCT had been performed to 55 patients. The median time from diagnosis to allogeneic SCT was 12 (4–168) months, and the time between autologous and allogeneic SCT 6 (2–146) months. At the time of allogeneic SCT 9 patients were in CR, 63 in PR, 4 had stable disease, and 10 progressive disease. 72 patients had a sibling donor: 68 were HLA-identical, one 1 antigen mismatch, 3 identical twins. 14 patients had an HLA-matched unrelated donor. The conditioning was MA in 32 and RIC in 54 patients. The MA conditioning consisted of Cy/TBI in 22, Mel/TBI in 3, and Treosulfan/Fld in 7 patients. RIC was the Seattle protocol (Fld/TBI 2 Gy) in 45, reduced Treosulfan/Fld in 8, and Fld/Cy in 1 patient. 26 patients received a BM graft and 60 patients a PB graft. As GVHD prophylaxis, 18 patients were given CsA/Mtx, 20 CsA/Mtx/MP, 45 CsA/MMF, and 3 nothing (identical twins). The median follow-up time from allogeneic SCT was 39 (2–136) months, 46 (7–136) months for the MA patients and 34 (2–92) months for the RIC patients, respectively. The OS was 50% at 61 months post SCT and there have been no deaths after this time-point. The median PFS was 31 months. After this time-point the disease has progressed in one case, at 90 months. Of the 32 MA patients 16 (50%) and of the 54 RIC patients 22 (41%) have achieved CR after SCT. The cumulative incidence of acute GVHD grade II-IV was 28%. The cumulative incidence of chronic GVHD was 72%, 58% in the MA and 83% in the RIC patients (p=0.074). The incidence of extensive chronic GVHD was significantly (p=0.012) higher in RIC than MA patients, 66% vs. 23%. There were no statistical differences in the incidence of acute or chronic GVHD by donor type (72 siblings/14 unrelated). The cumulative 100-day transplant related mortality was 4.5% and that of the whole follow-up time 14%. 26 patients have died. The cause of death was myeloma in 15, GVHD in 7, and infection in 4 patients. In conclusion, in the present material transplant-related mortality was low and the survival encouraging, supporting the use of allogeneic transplantation with curative aim in selected cases. Developing chemotherapy, given prior to transplantation, may improve the results.
Allogeneic Stem Cell Transplantation with Dose-Reduced Conditioning in Relapsed Follicular and Mantle Cell Lymphoma - A Prospective Phase II Trial of the German Low Grade Lymphoma Study Group (GLSG).
Authors: Dreyling Martin H. , Beelen D.-W. , Schleuning Michael , Ho Anthony D. , Gramatzki Martin , Glas B. , Pfreundschuh Michael , Wilhelm Martin , Schmitz Norbert , Kolb Hans-Jochem , Unterhalt Michael , Hiddemann Wolfgang
Published: October 2019

Background: Conventional therapy achieves high initial response rates in follicular (FL) and mantle cell lymphoma (MCL), but even after introduction of combined immuno-chemotherapy, a continuous relapse pattern has been observed. The introduction of dose-reduced conditioning prior to allogeneic peripheral blood stem cell transplantation significantly reduced early treatment-associated toxicity of this curative approach. In 2003, the German Low Grade Lymphoma Study Group initiated a prospective phase II trial to investigate the feasibility and efficacy of this approach in a multi center approach.

Methods: Patients with a high risk profile (bulky disease, 3 lymph nodes >3 cm, elevated LDH, >20% bone marrow infiltration, hematopoietic insufficiency) received a conventional salvage chemotherapy, e.g. 2–4x (R-)FCM. Subsequently, all patients received a dose-reduced conditioning (30 mg/m2 fludarabine d-7-4, 30 mg/m2 cyclophosphamide d-4-3) and an optional low dose TBI (2–4 Gray, d-8). Immunosupression consisted of ATG-Fresenius (10mg/m2 bs d-3-1 if unrelated donor), cyclosporine A starting day −1 and mycophenolat (2× 15mg/kg). If T-cell chimerism was established after discontinuation of immunosuppression, donor lymphocyte infusion was applied on days +120, +150 and +180 with increasing doses (2× 105–107/kg) in cases of persistent lymphoma.

Results: After a median follow-up of 17 months, a total of 32 patients are evaluable (21 FL and 11 MCL). Median age was 48.5 years (34–62) with a median of 3 prior therapies (1–8). Eigth patients had a family donor and 24 were transplanted from an unrelated donor (no mismatch in 25 and 1 mismatch in 8 cases). 2 early infectious deaths were observed at day 30 and 87 resulting in a treatment-associated mortality (d100) of 6% and another death after 1014 days. After 2 years follow-up, failure-free and overall survival rates were 73% and 77%, respectively. As expected, failure-free survival rates differed significantly between FL (80%) and MCL patients (60%).

Discussion: This multicenter trial confirms allogeneic stem cell transplantation with dose-reduced conditioning achieving long-term remissions especially in patients with relapsed FL with rather low mortality. Thus, in younger high risk patients, this therapeutic option should be discussed in relapsed disease. Randomized or case-control trials are warranted to exactly define the role of allogeneic transplantation in FL and MCL.
Extended Thromboprophylaxis with Rivaroxaban Compared with Short-Term Thromboprophylaxis with Enoxaparin after Total Hip Arthroplasty: The RECORD2 Trial.
Authors: Kakkar Ajay K. , Brenner Benjamin , Dahl Ola E. , Eriksson Bengt I. , Mouret Patrick , Muntz Jim , Bandel Tiemo J. , Misselwitz Frank , Haas Sylvia
Published: October 2019

Venous thromboembolism (VTE) is a common, potentially fatal complication of major orthopaedic surgery. Pharmacologic thromboprophylaxis is recommended for patients undergoing total hip arthroplasty (THA) for a minimum of 10 days, and up to 35 days. However, extended thromboprophylaxis is not universally used. Therefore, this trial was conducted to evaluate the potential benefits of extended thromboprophylaxis after THA. RECORD2 is the largest, prospective, randomized clinical trial conducted to date, in this indication. This global, phase III, double-blind trial, was designed to compare short-term thromboprophylaxis with a low molecular weight heparin - enoxaparin - with extended thromboprophylaxis for up to 5 weeks with a novel, oral, direct Factor Xa inhibitor - rivaroxaban after THA. Patients received subcutaneous enoxaparin 40 mg once daily (od), beginning the evening before surgery, continuing for 10–14 days (short-term prophylaxis), and followed by placebo until day 35±4, or oral rivaroxaban 10 mg od beginning 6–8 hours after surgery and continuing for 35±4 days (extended prophylaxis). Mandatory, bilateral venography was conducted at the end of the extended treatment period. The primary efficacy endpoint was the composite of any deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE), and all-cause mortality. The main secondary efficacy endpoint was major VTE; the composite of proximal DVT, non-fatal PE, and VTE-related death. Major and non-major bleeding during double-blind treatment were the primary and secondary safety endpoints, respectively. A total of 2509 patients were randomized; 2457 were included in the safety population and 1733 in the modified intention-to-treat (mITT) population. Extended thromboprophylaxis with rivaroxaban was associated with a significant reduction in the incidence of the primary efficacy endpoint and major VTE, compared with short-term thromboprophylaxis with enoxaparin (Table). The incidences of major and non-major bleeding were similar in both groups (Table). In conclusion, extended duration rivaroxaban was significantly more effective than short term enoxaparin for the prevention of VTE, including major VTE, in patients undergoing THA. Furthermore, this large trial demonstrated that extended thromboprophylaxis provides substantial benefits for patients undergoing THA, and that the oral, direct Factor Xa inhibitor rivaroxaban provides a safe and effective option for such a strategy.

Short-term s.c. enoxaparin 40 mg od % (n/N) Extended oral rivaroxaban 10 mg od % (n/N) Relative risk reduction (%) P-value for difference DVT, non-fatal PE, and all-cause mortalitya 9.3% (81/869) 2.0% (17/864) 79% P<0.001 Major VTEb 5.1% (49/962) 0.6% (6/961) 88% P<0.001 Major bleedingc 0.1% (1/1229) 0.1% (1/1228) - P=0.980 Non-major bleedingc 5.5% (67/1229) 6.5% (80/1228) - P=0.246