bluuebunny/crossref_metadata_2025 huggingface dataset:
Equivalence of Liquid and Freeze-Dried Formulations of WinRho® SDF.
Authors: Sinclair Christopher J. , Ruckle Jon , Swearingen Dennis , Kisicki James C. , Marbury Thomas C. , Genereux Maurice , Brooks William
Published: October 2019

WinRho® SDF is licensed in the USA, Canada and Europe to treat ITP and prevent Rh isoimmunization. Although safe, efficacious and cost-effective, WinRho® SDF has only been available in a freeze-dried formulation. In order to simplify injection preparation and reduce the possibility of preparation errors, a liquid formulation of WinRho® SDF has been developed. The pharmacokinetics and tolerability of the liquid and freeze-dried preparations were compared in 2 randomized, double-blind, multi-center phase 1 studies that were conducted in healthy adult volunteers. Subjects were administered one of the formulations either IM (300 μg or 15 μg/kg) or IV (50 μg/kg). Pharmacokinetics (AUC, Cmax, t1/2, tmax) and safety data (adverse events and laboratory assessments) were assessed over 84 days. In total, 142 subjects received either the liquid or freeze-dried formulations (N=71 each group). Following IV or IM administration, the ratios (90% confidence intervals) for AUC and Cmax were within the FDA required acceptance range of 80–125% to demonstrate bioequivalence. Both formulations had comparable half-lifes of ~18–19 days and ~26 days following IV or IM administration, respectively. While tmax occurred immediately following IV administration, tmax was ~3–7 days after IM administration. Both formulations were similarly tolerated following either IV or IM administration. The most common adverse events were headaches and neck/back pain. Liquid WinRho® SDF was demonstrated to be bioequivalent to the freeze-dried formulation following IV or IM administration. This suggests that liquid WinRho® SDF may be therapeutically equivalent to the freeze-dried formulation and provide a more convenient presentation for use.
The Predictive Value of D-Dimers on the Occurrence of Thromboembolic Events and Death: A Prospective Multicentric Study.
Authors: Mahe Isabelle , Drouet Ludovic , Chassany Olivier , Sollier Claire Bal dit , Mazoyer Elizabeth , Minh-Muzeaux Sophie , Caulin Charles , Bergmann Jean-François
Published: October 2019

Background: Atrial fibrillation (AF) is the most common arrhythmia, especially in elderly subjects (more than 10% of those older than 80). The main complication is the occurrence of ischemic stroke. Oral anticoagulants reduce by 2/3 the thromboembolic risk but increase the risk of bleeding. The question for the clinician is to identify patients at highest thromboembolic risk who would the most benefit from anticoagulant therapy: in this way, the dosage of D-dimer, a marker of activation of coagulation may be of interest.

Primary aim: To assess the predictive value of D-dimer levels on the occurrence of thromboembolic event or death.

Methods: Patients with AF were included whatever the treatment they received, when they were in a stable clinical condition and when the antithrombotic treatment remained unchanged during the last month. It is a prospective multicentric study performed in 25 departments of AP-HP. Patients had visits and biologic dosages including D-dimer every 4 months. At every visit, patients were questioned about ischemic events (stroke, transient attack, systemic embolism, myocardial infarction), venous thromboembolic events, the occurrence of disease and bleeding events since the last visit. D-dimer dosage was centralised in the Laboratory of Pr Drouet (Lariboisière hospital). The usual management of the patient was in charge of the practitioner and not modified by the study. The planned duration of follow-up was 1 year to 2 years.

Results: 434 patients were included (mean age 80 years) from 02/01/01 to 04/06/30. Antithrombotic treatments at inclusion were: oral anticoagulant (n=240), antiplatelet agents (n=57), no antithrombotic therapy (n=45). Follow-up has ended on 05/06/30.

Discussion: Clinical events have been recorded. D-dimer measurements are ongoing. Results will be provided at the meeting (including D-dimer levels and clinical events).
The Outcome of Pregnancy in Patients with Thrombophilia after Anticoagulation.
Authors: Jiang Qingqi , Andersen Judith
Published: October 2019

Background: Both inherited and acquired thrombophilia predispose pregnant women to venous thromboembolism and recurrent fetal loss. The safety profile and tolerability of low molecular heparin (LWMH) has allowed us to evaluate effects of anticoagulation in the outcome of pregnancy in patients with thrombophilia.

Methods: 20 patients with thrombophilia received either tinzaparin or enoxaparin combined with aspirin before and during pregnancy and the outcome of pregnancy was monitored for a period of 2 years. The median age of the patients was 28 years (25–49); 75% were Caucasians, 20% were aferican-american, 5% were others. The inherited and acquired thrombophilias include Factor V leiden mutation, prothrombin mutation in G20210A, mutation in methylenetetrahydrofolate (MTHFR), protein S deficiency, protein C deficiency, hyperhomocyteinemia, antiphospholipid syndrome, sticky platelet syndrome, etc. The majority of patients had more than 2 thrombophilia factors and had history of miscarriage. 15 of 20 patients (75%) received tinzaparin and 4 of 20 (20%) patients received enxoparin subcutaneously before they were conceived. Only one patient received unfractionated heparin. The LWMH was continued during pregnancy until 34 to 36 weeks gestation when it was changed to unfractionated heparin in order to prevent large amount of bleeding from upcoming delivery. All of the patients also received aspirin prior, during, and after the pregnancy. There were 21 live births including one triplet and one twins. Only two patients were complicated with miscarriage. There was no episode of severe bleeding or thromboembolism during pregnancy or postpartum.

Conclusion: LWMH and aspirin has been effective in the prevention of fetal loss in women with thrombophilia disorders.
Molecular Typing for Kidd Blood Group in Taiwan.
Authors: Tzeng Cheng-Hwai , Lyou Jau-Yi , Chen Pei-Shan , Liu Hsueng-Mei , Chen Ying-Ju , Liu Jin-Hwang
Published: October 2019

Background:The Kidd (JK) blood group system is clinically important intransfusion medicine. Alloantibodies to antigens in this system may be produced following blood transfusion or during pregnancy and can result in serious hemolytic transfusion reactions and hemolytic disease of the newborn (HDN). The two major codominant alleles of the JK gene, Jka and Jkb, have a similar frequency in Caucasian populations (0.51 and 0.49, respectively) and define 3 common phenotypes Jk(a+b+), Jk(a+b-), Jk(a-b+), while frequency of Jk(a-b-) or Jknull phenotype is exceedingly rare. Many individuals of Polynesian extraction have been identified as Jknull. Its frequency and molecular characterization for Chinese people in Taiwan, however, has not yet been clarified.

Study design and methods: By using the lately developed single-tube allele-specific primer/multiplex PCR technique, a total of 320 random whole blood samples were analyzed. In addition, three samples already serologically proven as Jknull phenotype in our Lab were also investigated.

Results: None of the 320 random whole blood samples was serologically typed as Jk(a-b-), while the frequencies of three other phenotypes were 47.5% for Jk(a+b+), 23.1% for Jk(a+b-), and 29.4% for Jk(a-b+). Interestingly, two Jka/Jk and four Jkb/Jk were identified, resulting in a gene frequency of Jka - 46.72%, Jkb - 52.34% and silent Jk - 0.94%. As for the three samples of Jknull phenotype all belonged to the so-called Polynesian type, i.e.3′-acceptor splice site G->A mutation of intron 5 that resulted in the skipping of exon 6 (called mutation JKΔ6).

Conclusion: The present study confirms that the single-tube allele-specific primer/multiplex PCR technique has enabled genomic typing of the Kidd blood group easier and reliable. The frequency and molecular characterization of JK phenotypes for Chinese people in Taiwan have been clearly characterized.
A Comparison of Administration Time between Red Blood Cell Transfusion and Chemotherapy.
Authors: Chin-Yee Ian H. , Xenocostas Anargyros , Cheung Wendy W. , Hibbert Anita S.
Published: October 2019

In oncology patients, the majority of chemotherapy and red blood cell (RBC) transfusions occur in outpatient ‘chemotherapy’ units, where they compete for resources such as nursing time and “chair-time”. This study was to accurately assess the “chair-time” consumed by transfusion patients, in order to estimate the chemotherapy administration opportunities lost to RBC transfusions. Over four weeks, “chair-time”, defined as the time difference between the admission of each patient into care to their time of discharge, was prospectively evaluated in a tertiary-care outpatient cancer clinic with a referral population base of 2 million. Chair-times were then grouped into three types of care - RBC transfusions, chemotherapy administrations, and “other” (phlebotomy, central line catheter care, etc.) - to enable comparison. Chair-time is reported as a mean (+/− SD). Patient demographics (age, sex, diagnosis, chemotherapy regimen, pre-transfusion hemoglobin) were also recorded. A total of 1354 visits to the chemotherapy suite were captured over one month. Of these, 1279 visits had evaluable data for further analysis, and can be divided as follows: 1023 (80%) chemotherapy administrations, 44 (3.4%) RBC transfusions, and 212 (16.6%) “other”. 38 patients accounted for the 44 RBC transfusions. Of those, 14 were hematological malignancy patients (ALL, AML, CLL, HD, Myeloma, Lymphoma), 12 were solid tumor patients and the remaining 12 had other hematological disorders (Aplastic Anaemia, Myelodysplasia, Myelofibrosis). Among the malignant patients, 20 were receiving chemotherapy during the study period. The mean chair-time for all accurately recorded events was 1 hr 49 min (+/− 1 hr 39 min). Divided into types of care, the mean chair times were: 1 hr 59 min (+/− 1 hr 40 min) for chemotherapy, 3 hr 51 min (+/− 47 min) for RBC transfusion, and 34 min (+/− 43 min) for “other” care. The average time per RBC unit transfused was 1 hr 49 min (+/− 19 min) and the average number of units per transfusion was 2.2 units. When chemotherapy chair-times were examined, and patients were grouped by diagnoses, it was found that patients with lymphoma (most commonly treated with R-CHOP, or other Rituximab containing regimens), and gynecological cancers (most commonly treated with regimens containing carboplatin) had the longest chair-times, at 4 hr 20 min (+/− 1 hr 24 min) and 3 hr 50 min (+/− 2 hr 11 min) respectively. Although RBC transfusions make up only 3.4% of all events in our chemotherapy suite, they occupy almost twice as much chair-time as compared to chemotherapy. Depending on the patient population, clinics with a high rate of RBC transfusions might consider transfusion alternatives, as emerging monoclonal antibody chemotherapies augment the time necessary for administering chemotherapy, and chair-time becomes an increasingly valuable resource.
HE2100 (androst-5-ene-3β, 17β-diol), an Adrenal Hormone, Protects Rhesus Macaques from Lethal Total Body Irradiation (TBI)- Induced Severe Neutropenia and Thrombocytopenia.
Authors: Stickney Dwight R. , Dowding Charles , Authier Simon , Garsd Armando , Onizuka-Handa Nanette , Reading Chris , Frincke James
Published: October 2019

HE2100 (androst-5-ene-3,17β-diol) is a naturally occurring adrenal steroid hormone being developed for the treatment of acute radiation syndrome (ARS). Previous studies of lethally irradiated rodents demonstrated a significant survival advantage for HE2100 treated groups (Whitnall et. al., Int. J. Immunopharm. 2000). In HE2100 treated rhesus macaques we have previously reported a tri-lineage recovery (neutrophils, platelets and red blood cells) of bone marrow following sublethal irradiation and a reduction in lethality following 6.00 Gy 60Co TBI. Studies were conducted to further investigate the effects of this compound to prevent very severe radiation induced cytopenias and to enhance survival following TBI. Results refer to absolute neutrophil count <500 cells/μL and platelet count <20,000 platelets/μL. We report a meta-analysis of five studies involving 100 animals receiving TBI in the range of 6.00 – 6.34 Gy 60Co. Animals were either untreated, or given vehicle, or 5–15 mg/kg of HE2100 IM for 5 consecutive days starting 2–3 hours after TBI. No clinical support such as transfusions or antibiotics was given in any of the studies. Animals were continuously monitored for core body temperature with an implanted telemetric thermometer. Blood counts were measured daily during expected cytopenic days. Studies were performed after Institutional Animal Care and Use Committee review and approval, observing strict euthanasia criteria. HE2100 afforded protection of the unsupported animals from lethal irradiation, decreasing the lethality overall, from 42% in the control group to 22% in the HE2100 treated group (mid-p=0.044). All deaths occurred between Study Days 14 and 26. The majority of animals (28/32, 87.5%) died by Study Day 20 reflective of ARS. Based on an analysis of days at risk, the cumulative incidence of days of severe neutropenia was reduced by 1.10 days (p=0.002), whereas the cumulative incidence of days of thrombocytopenia was reduced by 2.31 days (p=0.02). No cytopenias were recorded after Study Day 26 on surviving animals. Death in these animals correlated with severe thrombocytopenia and opportunistic infections from the gut and skin flora leading to hemorrhagic sepsis as the primary cause. HE2100-related increases in cellularity were noted in the bone marrow, spleen, and lymph nodes on Study Day 40. HE2100 appears to stimulate multi-lineage recovery, via early bone marrow hematopoietic stem cell progenitors following TBI injury in rhesus macaques.
Correlation of Acute GVHD with CD4+CD25+ Regulatory T Cells of the Donates and Receipients in Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Min Zhai Zhi
Published: October 2019

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (aHSCT). CD4+CD25+ T cells are characterized in suppression of autoimmunity and induction of transplantation tolerance. Recently several studies have shown that CD4+CD25+ T cells from donor are able to effectively suppress acute GVHD (aGVHD) in murine models. However the relationship of aGVHD with the levels of CD4+CD25+ T cells in donor and receipients undergoing aHSCT in human is not clear. Here we examined the CD4+CD25+ T cells in both donors and receipients after aHSCT.

Methods: donors and receipients were divided into two groups: group 1 without or with grade I aGVHD and group 2 with aGVHD above grade II. Age match with donors and receipients of normal peoples were taken as control separately. aGVHD was diagnosised and graded according to standard criteria. The peripheral blood was obtained from the donors 1 week before aHSCT, and receipients 4weeks after aHSCT for treatment of malignancy, mostly chronic myelogenous leukemia. CD4+CD25+ T cells and CD4+CD25+ bright were assessed by double color immunoflurecence labeling and FACScan. The ratio of CD4+CD25+ T cells and CD4+CD25+ bright in CD4 T cells was calculated.

Results: There is no difference in CD4+CD25+ T cells between normal control and group 1 of the donors who’s stem cells were infused into the receipients underwent grade I aGVHD. CD4+CD25+ T cells were significantly decreased in group 2 of donors compared to normal control and group 1 of donors (see table 1). CD4+CD25+ T cells and the CD4+CD25bright T cells subpopulations in group 2 of receipients were significantly lower than normal control and group 1 of receipients (see table 2).

Summary: the severity of aGVHD is correlated to the levels of CD4+CD25+ T cells in both donors and receipients after aHSCT. aGVHD occur less in the donor with normal levels of CD4+CD25+ T cells. Lower levels of CD4+CD25+ T cells in receipients indicate high incidents of server aGVHD. These data suggested that CD4+CD25+ T cells could have important role in prevention of aGVHD.

Table 1. lymphocytes, CD4+ T cells, CD4+CD25+ and CD4+CD25bright T cells (%) in donates lymphocytes lymphocytes CD4+ CD4+CD25+ CD4+CD25bright *P<0.01 vs normal control and group 1. **P< 0.001 vs normal control and group 1 Normal control n=10 34.27±8.62 37.25±5.38 11.29±1.89 1.36±0.53 Group 1 donate n=6 33.65±10.06 36.43±9.50 11.23±1.69 1.41±0.76 Group 2 donate n=4 23.90±11.67 32.57±3.40 5.64±1.57** 0.69±0.48* Table 2. WBC count, CD4+CD25+ and the CD4+CD25bright T cells in receipients (%) WBC(×109) CD4+CD25+ CD4+CD25bright *P<0.01 vs normal control and group 1. **P< 0.001 vs normal control and group 1 Normal n= 10 6.38±1.23 11.29±1.89 1.36±0.53 Group 1 n= 6 5.16±4.49 17.10±4.19 2.23±1.52 Group 2 n=4 4.34±2.85 1.52±0.61** 0.00±0.00*
Does Early Myeloid Recovery Predict Superior Survival in Children and Young Adults Undergoing Hematopoietic Stem Cell Transplantation?.
Authors: Imran Hamayun , Khan Shakila P. , Arndt Carola A.S. , Rodriguez Vilmarie , Allen Julia A. , Trotz Barbara A.
Published: October 2019

Introduction: Slow rate of myeloid recovery at the end of induction chemotherapy reflected by a low absolute neutrophil count (ANC) is highly predictive of relapse in children with ALL (Laughton et al, 2005). Whether rate of myeloid recovery is predictive of outcome post-hematopoietic stem cell transplantation (HSCT) in children and young adults has not been studied.

Objective: To explore the association between early ANC recovery and survival in children and young adults undergoing allogeneic and autologous HSCT for leukemia or lymphoma.

Methods: Retrospective chart review was performed for all consecutive patients (age 6 months to 21 years) undergoing first HSCT for hematologic malignancies and lymphomas at Mayo Clinic, Division of Pediatric Hematology/Oncology from 1995 to 2004. Day 15 and day 28 ANC were calculated for all patients. The primary end point was 1-year relapse free (RFS) and overall survival (OS). To explore the association between ANC and primary outcome, patients were stratified in 2 groups: ≥ or < than median ANC and Kaplan Meier survival curves were generated for both the groups and compared with the log-rank test. Matched related donor (MRD), matched unrelated donor (MUD) and haploidentical (as one group) and autologous transplantations were analyzed separately.

Results: There were a total of 50 patients. 28 received MRD, 2 MUD, 10 haploidentical and 10 autologous. The underlying malignancies were (AML n =25, Biphenotypic Leukemia n=1, ALL n =7, NHL n=3, HD n=7, JMML n=5, CML n=2, CLL n=1). No patient was lost to follow up during that time and data was available for all except (day 28 ANC) for one patient. The 1-year RFS and OS rate was the same; 81% for the MRD, 50% for MUD and haploidentical and 70% for autologous transplant populations, respectively. In patients receiving MRD transplants, higher ANC at either day 15 or day 28 post transplantation was associated with better, albeit statistically non-significant, RFS/OS rates at 1 year (86% for ≥ median (0.68) vs. 76% for < median p=0.44 and 92% for ≥ median (2.2) vs. 72% for < median p= 0.18 respectively). Opposite results were observed for MUD and Haploidentical transplantation group (33% for ANC ≥ median (0.47) at day 15 vs. 66% for < median p=0.28, 43% for ANC ≥ median (1.9) at day 28 vs. 60% for < median p=0.48). For autologous transplant group, higher ANC at day 15 was associated with better, albeit statistically non-significant, RFS/OS rates at 1 year (80% for ANC ≥ median (0.42) vs. 60% for < median p=0.60) while opposite results were observed on day 28 (60% for ANC ≥ median (0.46) vs. 75% for < median p=0.54).

Conclusions: Our data generated conflicting findings of the association between ANC and RFS/OS in different patient populations undergoing HSCT. However, our results are limited by the small sample size. Further collaborative studies are needed to explore this association.
Patterns of Early Infectious Complications in Adult Unrelated Cord Blood Transplantation (UCBT). A Single Center Experience.
Authors: Benn Howard , Maroules Michael , Ojha Rakesh , Arcilla Theresa , Nath Rajneesh
Published: October 2019

The major cause of non-relapse transplant related mortality (TRM) in UCBT continues to be infectious, with blood stream infections (BSI) constituting the majority of these events. However, CMV antigenemia and BK virus associated late onset hemorrhagic cystitis (LOHC) are increasingly important causes of morbidity and mortality. We review our single institution experience. We identified 13 patients with hematological malignancies in our database that had undergone UCBT in the period June 2002 - January 2005 and analyzed these data to document the incidence and patterns of infectious complications. The median age was 48 (range 19–62) years. All patients received infectious prophylaxis with Ciprofloxacin, Acyclovir, Voriconazole, Bactrim/nebulized Pentamidine. Eleven patients underwent conditioning with standardized Thiotepa/Busulfan/Cytoxan and GVHD prophylaxis with Tacrolimus/Mycphenalate Mofetil/ATG and the remaining 2 patients received TBI based conditioning. The median total nucleated cell (TNC) was 1.70E+07 and the median CD34 (+) cell count was 8.0E+04. The HLA matches were 4/6 in 9, 5/6 in 3 and 6/6 in 1 patient. All patients engrafted with a median time to neutrophil engraftment (TNE) of 25 (range 16–34) days. Twelve of thirteen patients achieved full donor chimerism at day 30 and 10 of 12 patients with full chimerism at day 100. Five patients developed grade II-IV acute GVHD requiring additional steroid therapy and 1 patient died of steroid refractory GVHD at day 50. Four patients had positive blood cultures at transplant. All patients developed documented bacterial infections: Gram positive in 12 (92%) (VRE in 23%, Steotrophomonas maltophilia in 31%); Gram negative in 8 (61%) (E. cloacae in 15%, Acinobacter spp. in 2 cases). Ten patients were CMV seropositive and 9 of these developed antigenemia requiring Gancyclovir/Foscarnet therapy. Nine patients had documented BK viruria with consequent late onset hemorrhagic cystitis (LOHC) and 5 patients developed BK viremia. There was 1 case of fungal BSI, while 8 patients had documented fungal tongue cultures. Four patients had positive bronchial washings (3 bacterial, 1 C. glabrata). Twelve (92%) patients were alive at day 100. Of note 62% of BSI and all cases of LOHC and CMV antigenemia developed after neutrophil engraftment. In our series of patients, viral infections (CMV, BK virus) were the most significant causes of morbidity. The high rate of BSI, especially after myeloid recovery, argues for a major influence of impaired immune recovery.
Successful Reversion of Chronic Myelogenous Leukemia with Myelofibrosis by Allogeneic Peripheral Blood Stem Cell Transplantation.
Authors: Pang Ying , Hua Jiaye , Chen Ruizhen , Feng Ying
Published: October 2019

Objective: To observe the effect of allogeneic peripheral blood stem cell transplantation (allo-PBSCT) on hematopoietic reconstitution of chronic myelogenous leukemia (CML) and reversion of myelofibrosis (MF).

Methods: A 39 years old male patient diagnosed with CML complicated with MF and hepatitis B carrier condition (HBsAg+)underwent allo-PBSCT. The donor was the patient’s sibling, his 48 years old sister. Six loci on HLA-A, B, and DRB1 were completely matched with that of the recipient and HbsAb(+). Four days after the administration of G-CSF (250ug/day), PBSCs were collected from the donor for 3 consecutive days. A total volume of 168 ml was harvested. A median nucleated cell (MNC) count of 8.54 ×108/kg with 5.1 ×106 /kg of CD34+ cells were actually administered to the recipient. The conditioning regimen was busulfan/cyclophosphamide (BU/CY). The recipient was started on intravenous infusion (IV) of cyclosporine A (CSA) on Day -1 and a plasma concentration of 150–250 ng/L was maintained. IV methotrexate (MTX) 10mg/m2 was given on Days +1, +3, +6, and +11. Oral mycophenolate mofetil (MMF)was given from Days +1 to +28 for prophylaxis of acute graft-versus-host disease (GVHD). If the concentration of hemoglobin (Hb) decreased to less than 70 g/L and/or platelet count (BPC) less than 10×109 /L, the recipient was transfused with 60Co 25cGy irradiated and leuko-depleted red blood cells (RBCs) and/or single-donor platelets. Started from Day +3, the recipient was given G-CSF until white blood cells (WBC) increased to at least 3.0× 109 /L. EPO and Interleukin-11 were also given to stimulate the proliferation of the progenitors of erythrocytes and megakaryocytes. The recipient also received anisodamine with a 24 hour-maintenance dose to improve the microenvironment of hematopoiesis in bone marrow.

Results: DNA-STR on Day +30 indicated a complete chimerism in the recipient. Bone marrow biopsy on Day +50 showed a dramatic decrease of myelofibrosis in the ground substance and active hematopoiesis. Reticulinfibers reduced to 1+. No significant change on splenomegaly was observed but the hepatitis B antigen had turned negative and HBsAb had appeared.

Conclusion: 1. In order to prevent aggravation of MF, Allo-PBSCT needs to be considered as early as possible once the diagnosis of CML complicated with MF is made. 2. Transfusion with a large quantity of donor hematopoietic stem cells is beneficial for engraftment. 3. Strict Immunoinhibition of the recipient will decrease the incidence and degree of GVHD and improve engraftment. 4. The addition of agents which improve the microenvironment of hematopoiesis will enhance engraftment. 5. Recovery of the platelet count is promising post-transplantation whereas significant changes on splenomegaly was not observed. 6. Allo-PBSCT may be a promising therapy for hepatitis B.
High Dose Chemotherapy and Autologous Stem Cell Transplantation in Multiple Myeloma: Comparison of Four Preparative Regimens.
Authors: Alessandrino Emilio P. , Bragotti Letizia Zenone , Colombo Anna A. , Algarotti Alessandra , Bernasconi Paolo , Maffioli Margherita , Caldera Daniela , Corso Alessandro , Rumi Elisa , Troletti Daniela , Lazzarino Mario
Published: October 2019

From 1996 to 2003, 113 consecutive patients with multiple myeloma were treated with four different high dose approaches rescued by autologous peripheral blood progenitor cells (PBPC) after four cycles of VAD or other combinations. The median age was 53 years 31–68), 58% were male and 42% female, the median interval from diagnosis to transplant was 252 days (range 160–3116 days).

Twenty-five patients received as preparative regimen Carmustine, Etoposide and Melphalan (BVM) at the total dose of 600 mg/m2, 900mg/m2 and 140–180 mg m2 respectively. Nineteen pts had as preparative regimen Thiotepa and Melphalan at the total dose of 10 mg/kg and 140–180 mg/m2 respectively, 38 pts received a double transplant with Melphalan given as a single agent at the dose of 200 mg/m2, while 31 pts received a single transplant with Melphalan 200 mg/m2. In patients with poor performance status at transplant or previous history of infection or renal impairment, the dose of melphalan was reduced by 20% respect to the standard planned dose.

in the group of 25patients treated by BVM, 10 had progressive disease, 6 stable disease (SD), 7 partial remission (PR), 1 very good partial remission (VGPR). At day +90 from transplant, 17 patients were in CR or PR (68%). The actuarial probability of overall survival and event free survival at 5 years were 40% and 20%, respectively. One pt died of transplant, one developed a solid tumor 24 mos after transplant. in the group of 19 pts treated with TT and Mel (TT-Mel), 3 pts were with progressive disease, 3 with stable disease, 6 in partial remission, 3 with minimal response, 3 in VGPR, 1 in CR. At day +90, 15 pts were in CR or PR (78%). The actuarial probability of survival was 50% at 5 years, and event free survival 28%. in the group of 38 pts who received a double transplant, 7 pts were with progressive disease, 3 with stable disease, 14 in PR, 12 in VGPR or CR. At day +90 after the second transplant, 31 of 38 patients (81%) were in CR or PR. Overall survival and event free survival was respectively 48% and 20% at five years. in the group of 31 pts receiving a single transplant with Melphalan alone, 8 were with progressive disease, 1 with stable disease, 6 in VGPR, 1 in CR, 13 in PR. At day +90, 21 of 31 patients (67%) were in CR or PR. Overall survival and event free survival was respectively 45% and 22% at five years. In conclusion, double transplant seems better than one transplant with melphalan alone in terms of EFS and OS (p<0.03); the BVM combination produces high response rates, the regimen, however, is toxic with a high rate of life threatening mucositis. the addition of Carmustine and Vepeside or Thiotepa to Melphalan does not produce significant improvement of OS and EFS.
Transfusion and Iron Overload in Thalassemia and Sickle Cell Disease: Impact of Infusion Chelation Therapy on Quality of Life.
Authors: Abetz Linda , Baladi Jean Francois , Jones Paula , Rofail Diana
Published: October 2019

Introduction: Blood transfusions are required as supportive care in thalassaemia and sickle cell patients. Regular blood transfusions may result in iron overload (IO) and, left untreated, in morbidity and earlier morality. Current infusion chelation therapy (ICT) requires 8–12 hour infusions, 5–7 days per week, potentially limiting quality of life (QoL) and inhibiting adherence in patients already limited by thalassaemia and sickle cell disease.

Methods: To assess the impact of ICT on the QoL of patients with thalassemia and sickle cell disease and adherence, a literature review in Medline (539 abstracts; 130 articles), analysis of IO patient transcripts (4 thalassaemia, 1 sickle cell disease) and five IO clinical expert interviews were conducted.

Results: Few published studies (11) used validated QoL instruments and even fewer assessed IO in thalassaemia (4) and sickle cell patients (7). No IO-specific QoL instruments were found. ICT in sickle cell patients may cause additional needle-site pain/discomfort, and may impact on evening social life and sleep, recreational activities, as well as emotional and physical well-being, occupational capacity and feelings of independence. ICT in thalassaemia patients may impact on emotional wellbeing such as self-esteem and worry about the future, family relationships and development of intimate relationships. Published articles and patient and clinician input suggested that QoL impact inhibited prescription of and adherence to ICT and therefore there is a need for easier, efficacious and safe oral chelation therapy (OCT).

Discussion: Limited empirical studies assessed ICT’s impact on QoL in patients with thalassaemia or sickle cell disease, though results indicated that ICT’s QoL impact is significant and prescription and adherence rates would likely improve with OCT. We recommend further qualitative and empirical studies to assess the impact of ICT and OCT in IO patients with thalassaemia and sickle cell patients, using validated instruments.
Influence of Age and Needle Gauge on Bone Marrow Biopsy Specimen Adequacy.
Authors: Goldenberg Alec , Kelley Priscilla , Ibrahim Sherif , Sen Filiz , Liu Cynthia
Published: October 2019

Introduction. The quality and length of bone marrow biopsy core specimens should facilitate accurate diagnositic interpretation of marrow histopathology. A 11G specimen of length 1.6 cm or greater is considered adequate for pathologic evaluation by some authors. The length of specimens recovered with 11G needles appears to depend on needle design. We explored the possibility that the adequacy of bone marrow biopsy specimens may be influenced by patient age and the gauge of biopsy needles.

Methods. 88 bone marrow core specimens were recovered from 72 patients using 11G SNARECOIL bone marrow biopsy needles. The mean age of these patients was 61.4 and the m/f ratio was 45/27. The clinical diagnoses were isolated anemia, cytopenias, leukemia, lymphoma, myeloma and other in 18.0%, 33.3%, 13.8%, 13.8%, 5.5% and 15.2% of the patients, respectively. 10 patients underwent multiple procedures (2–6) for evaluation of treatment efficacy. 106 patients underwent 127 bone marrow biopsy procedures using 8G SNARECOIL needles. The m/f ratio was 56/50 and the mean age of the patients was 63.1years. The clinical diagnoses were isolated anemia, cytopenia, leukemia, lymphoma, myeloma or other in 22.2%, 19.6%, 14.9%, 21.2%, 12.5% and 9.4% patients respectively. 13 patients underwent multiple procedures (range 2–4) for evaluation of response to treatment.

Results. Although the mean length of the 11G and 8G specimens were statistically significantly the same (mean±SEM, 1.97±0.07 cm vs. 1.99±0.05 cm, respectively, p = 0.8), the distribution of specimen lengths was asymmetric or skewed for the 11G specimens (skewness(skw) =0.52) and nearly normal for the 8G specimens (skw =0.04). The deviation from a normal distribution suggested additional variable(s) might be effecting specimen length. The possible influence of age on specimen length relative to needle gauge was considered. The mean age of the patients biopsied with 11G needles was 61.4. The m/f ratios of the patients ≤64 and ≥65 were statistically the same (27/12 vs. 18/15, respectively, p = 0.2). The mean age of the patients biopsied with 8G needles was 63.1. The m/f ratios of the patients ≤64 and ≥65 were statistically the same (30/26 vs. 26/23, respectively, p =0.5). 11 G specimens from younger patients, ≤64, were more frequently adequate (1.6 cm or greater) (39/53 = 73.5%) than specimens from older patients ≥ 65 (18/35 = 51.4%), p = 0.03. Conversely adequate 8G specimens were recovered as frequently in older patients ≥65 years (40/55 = 72.7%) as they were in younger patients ≤64 years, (59/72 = 81.9%) p = 0.21. Moreover, in older patients, adequate biopsy specimens were recovered more frequently by 8G needles then by 11G needles (40/55=72.7% vs. 18/35 = 51.4%, respectively, p = 0.04).

Conclusions. 1. Age influences the rate of recovery of adequate bone marrow core biopsy specimens. 2. 8G needles recover adequate specimens more frequently than 11G needles in older patients.
Are We Ready? A Case for Making Hematology Fellows Competent in Treating the Booming Culturally Diverse Minority Populations.
Authors: Iqbal Uzma
Published: October 2019

United States is at an important phase of its growth since the dawn of the new century. US population has grown by 13% from 248 million to 281 million between 1990–2000. Projected increase in population by mid century will be 460 million. According to 2000 census, 11% of US population is foreign born and 17.9% speaks a language other than English at home. Population demographics indicate very significant trend changes. The projected race and ethnic changes are occurring sooner because of higher than expected increase in immigration rates. By 2050 the minorities will make about 50% of US population. Ethnically and culturally diverse minorities are projected to grow exponentially. Asians are expected to grow by 213% to 60 million, while Hispanics will increase in their ranks by 188% to 102.6 million i.e. roughly one quarter of the population. The black population will see a 71% increase to 61 million while Whites will grow by 7% to 210 million. These trends indicate that Asian and Hispanic populations will triple in number by mid century. This poses special challenges to the health care industry and physicians in particular. The Hematologists will be diagnosing and treating a much larger number of the diseases common in these ethnic groups e.g. Sickle cell disease, hemoglobinopathies including Thalassemias and thrombotic and hypercoaguable disorders etc. interaction with these ethnically and culturally diverse clients will be challenging for the Hematology fellows since no formal training in cultural competency training is incorporated in fellowship program structure. Review of the curricula of the training programs has revealed most of these are deficient in this regards. Some awareness of the issue is found in nursing training literature. There is awareness regarding the cultural competency issue at a national level where Health and Human Services have issued national standards for culturally and linguistically appropriate services in health care (CLAS). This initiative can be used as a road map for providing cultural competency training to Hematology fellows. This will enable them to appreciate, think and act in ways that acknowledge, respect and build upon ethnic, socio cultural and linguistic diversity. Fellows can be trained and evaluated during their training in core competencies such as self-awareness, effective communication, cultural knowledge, humility and proper use of interpreters. In conclusion I emphasize that I order to deliver quality health care to ethnically diverse populations and to decrease disparities in health care, cultural competency should be an integral part of Hematology training programs.
Use and Outcomes of Epoetin Alfa and Darbepoetin Alfa for Anemic Cancer Patients in Outpatient Community Practice Settings.
Authors: Fahrbach Kyle R. , Frame Diana , Sercus Brian , Schenkel Brad
Published: October 2019

Objective: To assess the treatment patterns and hematologic outcomes associated with epoetin alfa (EPO) and darbepoetin alfa (DARB) for the treatment of anemic cancer patients in the community practice setting.

Methods: A retrospective observational study design was used. De-identified data from patients receiving care in community oncology practice settings were obtained from an electronic medical record system. Eligible patients were >= 18 years of age, had a cancer diagnosis, and were treated with an erythropoiesis stimulating agent (ESA: EPO or DARB) during the period July 2002 – July 2004, with baseline anemia (Hb<=11 g/dL) and at least one follow-up Hb value. No other selection criteria were applied (e.g. ESA dose, tumor type, chemotherapy treatment) in keeping with the objective of characterizing outcomes in a real-world setting. Data were summarized by treatment overall and by using a multivariate model adjusting for age, gender, baseline Hb, clinic site, ECOG performance score, type of cancer (solid vs hematologic) and chemotherapy (platinum vs non-platinum vs. none). Patient selection criteria and analytic methods were determined prospectively. The cost for each ESA was calculated based on 2004 average wholesale prices ($13.36 per EPO 1,000 U; $4.99 per 1 mcg DARB).

Results: 2382 EPO and 1399 DARB patients were eligible for analysis. The two groups were comparable in terms of baseline characteristics (62% female, 75% solid tumors, mean baseline Hb 9.9 g/dL). Only about two-thirds of patients were treated with standard dosing regimens of the two agents in the US (EPO 40,000 U qw, DARB 200 mcg q2w). Hematologic outcomes observed in patients receiving EPO were consistently better than those in patients receiving DARB.

Table 1. Hematologic outcomes by ESA treatment EPO DARB p value Week 4 Hb change (g/dL) 0.79 0.59 <0.001 % Early Hb response (Hb change >=1 g/dL at 4 weeks) 61.5 55.2 0.004 % Hb response (Hb change >=2 g/dL by end of treatment episode) 41.4 34.7 <0.001 % Hematopoietic response (Hb change >= 2 g/dL or reaching 12 g/dL by end of treatment episode) 52.3 44.6 <0.001

The mean treatment durations for patients receiving EPO and DARB were 55.3 and 62.5 days, respectively. Mean cumulative doses were 231,211 U for EPO and 857 mcg for DARB. These doses resulted in an average cost per patient of $3,089 for those receiving EPO and $4,276 for those receiving DARB.

Conclusion: These results, based on over 3000 community-treated cancer patients, reinforce previous findings of earlier and greater overall hematologic response for EPO vs. DARB in this setting. Additionally, based on mean cumulative doses, the cost of DARB per patient was substantially greater than that of EPO. Additional studies of variations in dosing regimens used in the community setting are warranted, as are well-powered, randomized, controlled trials to further confirm the clinical results observed here.
Rituximab vs Observation after High-Dose Consolidative First-Line Chemotherapy (HDC) with Autologous Stem Cell Transplantation in Poor Risk Diffuse Large B-Cell Lymphoma. Final Analysis of the LNH98-B3 GELA Study.
Authors: Haioun Corinne , Mounier Nicolas , Emile Jean François , Feugier Pierre , Coiffier Bertrand , Tilly Hervé , Recher Christian , Fermé Christophe , Gabarre Jean , Herbrecht Raoul , Morschhauser12 Frank , Gisselbrecht Christian
Published: October 2019

We have shown (Haioun, JCO 2000) that consolidative HDC provides a better survival for patients (pts) with aggressive non-Hodgkin’s lymphoma presenting with 2 or 3 adverse age-adjusted International-Prognostic-Index (aa-IPI) factors in complete remission after induction treatment. In the same time, rituximab had been evaluated as a single therapeutic agent in aggressive lymphomas with promising efficacy (Coiffier, Blood 1998). More recently, rituximab maintenance therapy has been successfully used after chemotherapy or after ASCT to keep responding patients in remission.

The primary objective of the present study was to evaluate the potential benefit, as randomly compared to observation, of rituximab - 375 mg/m2/week for 4 weeks - 2 months after HDC, in decreasing the relapse rate (second randomization: R2). A secondary objective was to improve the response rate before HDC treatment using the intensified ACE chemotherapy regimen (doxorubicin 75mg/m2 d1, cyclophosphamide 1g/m2 d1-d2, etoposide 150mg/m2 d1–d3) as compared to the standard GELA ACVBP induction regimen (first randomization: R1). Induction regimens were delivered every 15 days for 4 cycles. In responding pts, peripheral blood stem cell (PBSC) collection was performed after the third or fourth cycle. HDC (mitoxantrone 45 mg/m2, cyclophosphamide 1500 mg/m2 x 4d, etoposide 250 mg/m2 x 4d and carmustine 300 mg/m2) was started between d80 and d90 after one or two courses of high-dose methotrexate.

From 10/99 to 05/03 (closing date), 476 pts younger than 60 years with diffuse large B-cell lymphoma and aa-IPI 2 or 3 (aa-IPI 3: 29%). were enrolled. We here present the results of the final analysis, performed in July 2005 with 235 pts assigned to receive ACE and 241 to ACVBP. Complete response (CR+CRu) rates to induction treatment did not significantly differ between the 2 regimens (65% and 63%, respectively, p=0.71) and toxic death rates were similar (2% and 3%, respectively) despite higher NCIC grade 3–4 infectious toxicity with the ACE regimen. Among the 331 pts who received HDC, 269 were randomized (R2) to receive either rituximab (n=139) or observation (n=130). 545 infusions of rituximab were administered with no clinically relevant infectious toxicity except two resolutive VZV infections. With a median follow-up of 3 years after R2, a trend toward a better 3y-EFS was observed in the rituximab group (80% vs 72%, p=0.10).

Early and brief rituximab maintenance is feasible after HDC. We hypothesize that prolongation of treatment may improve the results as well as selection of patients more likely to respond to rituximab therapy.
New Transplant Strategies Utilizing Radioimmunotherapy (RIT) Based Regimens To Reduce Relapse in High Risk Mantle Cell Lymphoma (MCL).
Authors: Krishnan Amrita , Raubitschek Andrew , Forman Stephen J. , Fung Henry , Molina Arturo , Yamauchi David , Falk Peter , Spielberger Ricardo , Popplewell Leslie , Rodriguez Roberto , Parker Pablo , Chow Warren , Nakamura Ryoto , Nademanee Auayporn
Published: October 2019

The treatment of high-risk MCL remains a challenge. High dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) has been used for some of these patients (pts). However, relapse rates remain high. RIT with single agent 90Yttrium(90Y) ibritumomab tiuxetan (Zevalin®) has demonstrated activity in pts with relapsed MCL. Therefore, we postulated that the combination of 90Y with HDC and ASCT may reduce relapse rates of pts with high- risk MCL. Between 5/00 and 9/04 eighteen pts with MCL were enrolled on one of two RIT ASCT trials. The first was a phase I/II dose escalation trial of high-dose 90Y + cyclophosphamide 100mg/kg (day -4) and etoposide 60mg/kg(day-2). Pts underwent dosimetry day-21 with 5mCi Indium111 followed a week later by 90Y to deliver a maximum target dose of 1000cGy to normal organs. The second study was a phase I/II trial of standard dose 90Y (0.4mCi/kg) administered day-14 and BEAM (day-8 to day-2, BCNU300mg/m2, cytarabine 800mg/m2, etoposide 800mg/m2, melphalan 140mg/m2). Ten pts who were>60yrs or had received prior dose-limiting radiation were placed on the 90Y BEAM trial while the other 8 received high-dose 90Y. The median age at ASCT was 58 years (range 44–72). Disease status at ASCT included 1st CR -9(high or high intermediate IPI score), 1st PR-4, 1st relapse -4, 2nd CR-1. Fifty percent had received HyperCEVAD chemotherapy and 56% had Rituximab prior to ASCT. Thirteen pts had stage IV disease, 5 had stage III disease. The median 90Y dose administered was 40mCi (range 27–100). Treatment was well tolerated. Engraftment to anc>500 occurred at a median of 10 days (range 9–26). Reversible grade 3 pulmonary toxicity occurred in 5 pts. This included steroid responsive pneumonitis in four and acute respiratory distress related to sepsis in one. One pt with a prior history of heavy alcohol use died of liver failure at four months post ASCT. Four pts have relapsed and two have died of disease progression. With a median follow up of 19 months (range 6–60), the estimated overall survival and disease free survival at two years are 79% (CI 55–91) and 59% (CI 43–73) respectively. By univariate analysis 90Y dose did not correlate with risk of relapse. To date, no relapses were seen beyond the first twelve months (see figure). In conclusion 90Y based transplant conditioning regimens are well tolerated, even in older pts. The apparent plateau in the relapse rate is encouraging and suggests that this approach may lead to durable remissions in pts with high-risk MCL.

Figure Figure
Application of FASTTM Fragment-Based Lead Discovery and Structure-Guided Design to Discovery of Small Molecule Inhibitors of BCR-ABL Tyrosine Kinase Active Against the T315I Imatinib-Resistant Mutant.
Authors: Burley Stephen K.
Published: October 2019

The Philadelphia chromosome translocation creates a BCR-ABL fusion gene that encodes a constitutively active BCR-ABL tyrosine kinase, which gives rise to chronic myelogenous leukemia (CML). The clinical success of imatinib (Gleevec) demonstrated that BCR-ABL tyrosine kinase inhibitors can provide effective treatment for CML. However, some CML patients treated with imatinib develop resistance leading to disease progression. The majority of resistance is due to point mutations in BCR-ABL, which give rise to active mutant enzymes that are insensitive to imatinib. In all, ~30 imatinib-resistant BCR-ABL mutants have been identified in clinical isolates. The T315I mutant represents ~20% of clinically observed mutations, making it one of the most common causes of resistance. Second-generation BCR-ABL inhibitors, including AMN-107 and BMS-354825, inhibit many of the clinically relevant mutants but not T315I. Mutant T315I BCR-ABL is, therefore, an important and challenging target for discovery of CML therapeutics. We have applied a proprietary X-ray crystallographic fragment-based lead discovery platform (FASTTM) and structure-guided lead optimization to identify potent inhibitors of wild-type BCR-ABL and the four most common mutants, including T315I. Our lead discovery efforts yielded five chemical series that inhibit both wild-type (WT) and T315I BCR-ABL. Compounds in our most advanced lead series potently inhibit proliferation of K562 cells and Ba/F3 cells with WT BCR-ABL and the four major clinically relevant BCR-ABL mutations (T315I, E255K, M351T, Y253F; see below). Further details describing in vitro and in vivo profiling of these novel BCR-ABL T315I inhibitors will be presented.

Ba/F3 cell proliferation for BCR-ABL Inhibitors (EC50, nM) BCR-ABL Form Imatinib AMN-107 BMS-354825 SGX-70430 WT 790 33 12 11 T315I > 10000 > 10000 > 10000 21 Y253F 5700 370 8 334 E255K 8300 350 7 77 M351T 2000 38 28 15 Control Assay Ba/F3 (T315I) + IL3 > 10000 > 10000 > 10000 > 10000