bluuebunny/crossref_metadata_2025 huggingface dataset:
Combination Chemotherapy Including Velcade in Patients with Refractory or Relapsed Multiple Myeloma.
Authors: Zhou YuHong , Yu QingHong , Hu ZhiPing , Ye BaoDong , Shen YiPing , Shen JianPing , Yu LongXi
Published: October 2019

PURPOSE: Velcade, a proteasome inhibitor, is a remarkably active agent in patients with advanced relapsed or refractory multiple myeloma (MM). We report velcade combination chemotherapy in MM patients at our center.

METHODS: The trial opened in March 2006, and 9 patients who were refratory or relapsed MM have enrolled before August. The median age of the patients was 60 years (range 44 to 75). The median bone marrow plasma cell percentage was 20% (range 10.5% to 66%). The median serum ß2- microglobulin level was 3.8mg/l (range 1.2 to 8.6mg/l).5 patients committed renal disfunction. The regimens were as follows: The V-MPT regimen(4 patients) included oral melphalan (5 mg/m2 on days 1-5), prednisone (50 mg/m2 on days 1–5), thalidomide (100~200 mg continuously), velcade (1.3 mg/m2 on days 1, 4, 15, 22). 5 patients who were renal disfunction accepted the V-VADT regimens consist of velcade (1.0mg/m2 on days 1, 4, 8, 11), vincristine (0.4mg on days 1–4), pharmorubicin (10mg on days 1–4), dexamethasone (20mg/m2 on days 1–4,9–12,17–20), thalidomide (200 mg continuously). The V-MPT was repeated every 5 weeks and the V-VADT every 4 weeks for a total of 6 cycles. All cycles were delivered in day hospital.

RESULTS: A median 2 cycles (range 1 to 4) were administered to the all patients. Response was defined as EBMT criteria.9 patients are presently evaluable for response after therapy.8 patients responsed to treatment: 2 complete responses (CR), 1 near CR, 3 partial responses and 2 minor responses. And one patient experienced progressive disease. Interestingly, creatinine turned to normal in 5 renal disfunction patients after 1–2 cycles therapy. Most common side-effects were nausea, vomiting, fatigue and peripheral neuropathy. Grade 3 hematological toxicities included thrombocytopenia (1 patient) and neutropenia (2 patents).

CONCLUSION: The combination therapy with velcade is safe and effective in the treatment of relapsed or refractory multiple myeloma, and well tolerated, even in renal disfunction patients.
Osteonecrosis of the Jaw or Maxilla after Intravenous Bisphosphonates for Multiple Myeloma and Breast Cancer: Long-Term Follow-Up Shows a Slow Rate of Healing.
Authors: Hu Mimi I. , Hoff Ana O. , Toth Bela , Altundag K. , Johnson Marcella , Warneke Carla , Nooka Ajay , Sayegh Gilbert , Guarneri Valentina , Desrouleaux Kimberly , Jeffrey Cui , Hortobagyi Gabriel N. , Gagel Robert F.
Published: October 2019

Osteonecrosis of the jaw or maxilla (ONJM) is a rare but clinically significant disorder recently reviewed in a large retrospective study by our group (Hoff et al, 27th ASBMR Meeting 2005, Presentation #1218). A subset of the ONJM patients with breast cancer or myeloma was followed at the University of Texas M.D. Anderson Cancer Center (UTMDACC) dental clinic. This analysis describes the natural history of ONJM in this subset. Thirteen of 29 ONJM patients treated with intravenous bisphosphonates (IVBP) at UTMDACC and 1 ONJM patient treated elsewhere were evaluated in the dental clinic for more than 6 months (myeloma, n=7; breast cancer, n=7). Measurement of the maximum length of exposed bone was documented at each visit. Each patient received a standard regimen of conservative dental care with debridement only when indicated. All patients received zoledronic acid (mean cumulative dose 80mg; range 24–152mg) and 10 patients also received pamidronate (mean cumulative dose 1665mg; range 90–2700mg). This subset was followed for a median duration of 18.2 months (range: 7.1–67.3 months). The mean length of exposed bone at initial evaluation was 11 mm (range: 2–29 mm). The lesion from baseline to the most recent clinic visit progressed in 7 patients (50%), remained stable in 2 (14%), regressed in 2 (14%), and resolved in 3 (21%). Persistent ONJ was seen if IVBP was stopped (n=8), decreased in frequency (n=1), or continued at the same dose/frequency (n=2) (Graphs 1, 2). Complete resolution occurred in 3 multiple myeloma patients; IVBP was decreased in one and discontinued in 2 of the resolved cases (heavy lines on Graph 1). Our experience shows that ONJM is a disorder with slow resolution in most patients, lasting as long as 5 years. In the oncologic setting where there is clear benefit of bisphosphonate therapy, studies to optimize the dosing regimen may be needed.

Graph 1. Myeloma (n=7) Graph 1. Myeloma (n=7) Graph 2. Breast Cancer (n=7) Graph 2. Breast Cancer (n=7)
Biological and Clinical Responses after Intradermal and Intravenous Administrations of Mature Dendritic Cells Loaded with Tumor Lysate in Follicular Lymphoma Patients.
Authors: Baudard Marion , Conge Anne Marie , Veyrune Jean-Luc , Condomines Maud , Klein Bernard , Rossi Jean-Francois
Published: October 2019

New therapeutic approaches have been developed to treat follicular lymphoma (FL), the most common type of indolent non-Hodgkin’s lymphoma which should still be regarded as an incurable malignancy with a relentless relapsing course, except in the subset of patients with localized disease. For vaccination purposes, dendritic cells (DC) generated and loaded with tumor antigens ex vivo are focus of attention for already 10 years. In 07/04 we started a phase II study to evaluate a vaccination strategy based on multiple injections of autologous DC loaded with tumor lysate (DC-lysate) in FL patients. We reported here the results we observed for the first 7 enrolled patients (3F/4M, age: 44–61; 1 to 8 previous lines of treatment, including autologous PBSC transplant in 2 pts) who completed their treatment consisting in 5 to 7 DC-lysate vaccinations. At time of inclusion an excisional biopsy of a peripheral lymph node was performed in all patients; tumoral B cells were isolated by negative T cell depletion (using immunomagnetic beads and anti-CD3 antibodies) and then lysed by 5 freezing/thawing cycles to produce tumor lysate. Immature DC were obtained from mononuclear cells collected after Cyclophosphamide (2g/m2) and G-CSF (10μg/kg) administration, cultured for 5 days with GM-CSF and IL-4, pulsed with lysate, and then induced to mature with TNFa and PGE2 for 24h. All DC preparation fitted the quality criteria of viability ≥60%, ≤20% CD14+ cells, ≥60% CD83+ cells. For each vaccine 107 DC-lysate were administered, both intravenously [IV] (5×106 cells) and intradermally [ID] (5×106 cells). Vaccinations were safe and well tolerated. All patients developed significant delayed-type hypersensitivity responses to DC-lysate after several vaccines administration, testifying of the induction of a response. Among the 4 patients vaccinated with measurable disease, 2 who presented with low tumor burden (1 stage I, 1 stage II) achieved CR (with normal CT and absolutely no more FDG uptake on PET), so far persistent 3 and 6 months after the last vaccine, while disease progressed in the 2 remaining patients who presented respectively a stage IV and stage II disease at time of vaccination. The 3 patients vaccinated while in CR showed no disease progression at last tumor evaluation (9 to 12 months post last vaccination). This study demonstrated that DC-lysate vaccines might be efficient in FL patients with low tumor burden disease. Because the cause of disease recurrence is the presence of minimal residual disease after conventional treatments, the adjuvant setting might be the most appropriate therapeutic strategy for active specific immunotherapy, when the immunosuppressive effects of bulky disease are virtually absent and when the effector-target ratio is favorable.
Use and Efficacy of Stem Cells Cryopreserved for More Than One Year.
Authors: Pawson Rachel , Smythe Jon , Mcdonald Dorothy , Guttridge Martin , Lubenko Anatole , Wiggins Claire , Pamphilon Derwood , Watt Suzanne M.
Published: October 2019

Adequate viability after cryostorage is essential to allow engraftment of autologous haematopoietic progenitor cells (HPC). Information on the effect of prolonged cryopreservation on HPC viability in humans is limited although donations are routinely stored for over a year. Long-term storage is expensive and demonstration of clinical efficacy of HPC after long-term cryopreservation is important in order to justify the use of resources. Available reports describe only isolated cases in which old cells have been infused. We have conducted a retrospective survey of transplants using HPC stored >1 year within the National Blood Service in England. In total 75 patients received HPC that had been frozen for >1yr in NBS Laboratories. Patients had AML (21), NHL (21), myeloma (18), CML (5), Hodgkins disease (6) and other diseases (4). Fifty seven patients received PBSCs cryopreserved for >1 yr with median time in storage of 23 (12.1–65) months and median infused CD34 dose of 4.6 (1.2–85) ×106/kg. Neutrophil recovery to >0.5 × 109/l was 12 (4–49) days and platelets to > 20 × 109/l was 13 (3–43) days. Thirteen patients received bone marrow that had been cryopreserved for >1 year (median 32 (13–67) months) with infused TNC dose of 1.7 (0.91 – 3.64) × 108/kg. Time to neutrophils >0.5 × 109/l was 17 (12–95) days and platelets > 20 × 109/l 16 (12–66) days. A further 5 patients received a mixture of PBSCs and BM products all of which had been stored for > 1 year. Delayed neutrophil engraftment (neutrophils <0.5 × 109/l at 21 days) occurred in 2/55 PBSC transplants and 2/8 BM transplants. Delayed platelet engraftment (platelets <20 × 109/l at 28 days) occurred in 4/48 PBSC transplants and 4/8 BM transplants. In this survey, although the use of HPC cryopreserved for more than one year was infrequent, satisfactory engraftment was achieved in most patients. The rate of delayed engraftment was higher in BM as compared to PBSC transplants but numbers are too small for statistical analysis. In vitro viability assays were not available in this study but may help inform decisions on the use of cells stored for long periods.
Treosulfan - Fludarabine as Ablative Conditioning Regimen for Patients with High Risk Hematologic Malignancies.
Authors: Baronciani Donatella , Rambaldi Alessandro , Pilo Federica , Mico Caterina , Deplano Simona , Depau Cristina , Dessalvi Paolo , Angelucci Emanuele
Published: October 2019

Allogeneic stem cell transplant (allo HSCT) is a potentially curative approach for patients with hematologic malignancies but it is associated with high treatment related morbidity and mortality. Because transplant related mortality increases with age, advanced disease, and unrelated donors, patients older than 50–55 years may be excluded from this procedure. Reduced intensity conditioning regimens showed a low success rate in long-term follow-up, so new ablative reduced toxicity regimens are of striking interest. The aim of this study was to evaluate toxicity and efficacy of the combination consisting of Treosulfan (Busulphan derivative water soluble alkylating agent) and Fludarabine as a preparative regimen for patients receiving HSCs from matched siblings or unrelated donors for advanced heavily pretreated hematologic malignancies.

From July 2005 to June 2006, 21 consecutive patients (10 males, 11 females) were enrolled.

Mean age was 45 years (range 17–65). Underlying diseases were: acute leukemia (6 ALL, 5 AML), 1 CML, 3 MM, 5 MDS, 1 hystiocytic sarcoma). All patients were heavily pretreated; only 8 of them were in CR at transplant.

Conditioning consisted of Treosulfan (12–14 gr/m2 for 3 days) in combination with Fludarabine (30 mg/m2 for 5 days).

Cyclosporine plus short MTX and anti-thymocyte globulin (Thymoglobulin) were used as GVHD prophylaxis. Eleven (11) patients received HSCs from an HLA identical sibling and 10 from a matched unrelated donor. Source of stem cells was bone marrow in 4 patients, and peripheral blood in 17.

Twenty (20) patients engrafted; mean time to neutrophil recovery >500 × 109/L was 14 (range 10–24) days, to platelets >20,000 × 109/L was 14 (range 10–21) days. One patient receiving bone marrow did not engraft and died with active disease. Two (2) patients experienced GI toxicity (grade 2), 5 patients had grade 1 liver toxicity and 1 patient grade 1 renal toxicity. Four (4) pts presented acute GVHD (2 grade I, 2 grade II).

Eleven (11) patients (52%) are alive in complete remission with a follow-up ranging from 30 to 270 days; 4 died for recurrent disease; 5 patients are alive with active disease. This preliminary report shows that Treosulfan-Fludarabine-ATG conditioning regimen is well tolerated and characterized by reduced toxicity in a cohort of high risk patients with advanced age, who should otherwise be excluded from any other conventional transplant procedure.
Transplantation from Related and Unrelated Donors in Elderly Patients - Equal Toxicity and Survival.
Authors: Shapira Michael Y. , Tsirigotis Panagiotis D. , Or Reuven , Resnick Igor B. , Bitan Menachem , Gesundheit Benjamin , Slavin Shimon
Published: October 2019

Most of the hematological malignancies where allogeneic stem cell transplantation (SCT) is a therapeutic option occur in elderly patients. Additionally, in this age group, the probability of finding a matched sibling donor decreases due to mortality and co-morbidities of patient’s siblings which may exclude them from donation. In such case, SCT from an unrelated donor (UD) can offer a therapeutic solution for elderly patients in need although such a procedure is considered more hazardous than SCT from a matched sibling (mostly due to procedure and GVHD related morbidity and mortality). We present our data on transplantation, in 68 elderly (age>/= 55 years) patients that underwent SCT from a matched sibling (n=51) or UD (n=17) mostly using fludarabine-based regimen (table 1).

Median recipient age was 58.3y in the sibling group and 60.8y in the UD group (NS) (range 55–69.5y and 55–75y, respectively). With a median follow-up of 40 months of the survivors after sibling SCT, the 1-year OS was 32%. Similarly, in the UD group the 1-year OS was 35% (survivors’ median follow-up 48.5m) (NS). Transplant related mortality occurred in 22/49 (45%) and 9/17 (53%) of the patients transplanted from sibling or UD respectively (NS). Occurrence of acute GVHD was noted in 26/43 and 7/11 (figure 1) evaluable patients transplanted from matched sibling or UD respectively (NS). Diagnosis of chronic GVHD was made in 50% (14/28) and 63% (5/8) of the patients in the sibling and UD group correspondingly. GVHD related mortality occurred in 11 and 2 patients, respectively.

We conclude that using fludarabine based regimen, allogeneic SCT from an UD is equally effective as in patients undergoing SCT from matched family member. Age per-se should not be currently used as an exclusion criterion for either initiation of donor search or SCT from UD.

Table 1- Patients’ characteristics Figure Figure
Synergistic Growth-Inhibitory Effects of Two Tyrosine Kinase Inhibitors, Dasatinib and PKC412, on Neoplastic Mast Cells Expressing the D816V-Mutated Oncogenic Variant of KIT.
Authors: Gleixner Karoline V. , Mayerhofer Matthias , Sonneck Karoline , Gruze Alexander , Samorapoompichit Puchit , Aichberger Karl J. , Lee Francis Y. , Manley Paul W. , Fabbro Doriano , Pickl Winfried F. , Sillaber Christian , Valent Peter
Published: October 2019

In a majority of all patients with systemic mastocytosis (SM) including aggressive SM and mast cell leukemia (MCL), neoplastic cells display the D816V-mutated variant of KIT. The respective oncoprotein, KIT-D816V, exhibits constitutive tyrosine kinase (TK) activity and has been implicated in malignant cell growth. Therefore, several attempts have been made to identify KIT-D816V-targeting drugs. We found that the TK-inhibitor dasatinib (BMS-354825) inhibits TK activity of wild type (wt) KIT and KIT-D816V in Ba/F3 cells with doxycycline-inducible KIT-expression. In addition, dasatinib was found to inhibit KIT D816V-induced cluster formation and viability in Ba/F3 cells as well as growth of HMC-1.1 cells (KIT-D816V-negative) and HMC-1.2 cells (KIT-D816V-positive). The effects of dasatinib on growth of HMC-1 cells were dose-dependent, with 100–1,000-fold higher IC50-values in cells harbouring KIT-D816V compared to cells lacking KIT-D816V. Furthermore, dasatinib was found to inhibit the growth of primary neoplastic mast cells in SM in all patients examined. The inhibitory effects of dasatinib in HMC-1 cells were found to be associated with apoptosis and a decrease in expression of CD2 and CD63 as determined by flow cytometry. In addition, dasatinib was found to cooperate with the tyrosine kinase inhibitors PKC412 (midostaurin), AMN107 (nilotinib), and STI571 (imatinib), as well as with 2CdA (cladribine) in producing growth-inhibition in neoplastic mast cells. In HMC-1.1 cells, all drug-interactions applied were found to be synergistic. By contrast, in HMC-1.2 cells, only the combinations “dasatinib+PKC412” and “dasatinib+2CdA” were found to produce synergistic effects. These drug-combinations may thus represent an interesting pharmacologic approach for the treatment of patients with aggressive systemic mastocytosis or mast cell leukemia.
Valganciclovir Is Safe and Effective as Pre-Emptive Treatment for CMV Infection in Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Pastano Rocco , Gigli Federica , Andreola Giovanna , Calabrese Liliana , Peccatori Fedro , Martinelli Giovanni
Published: October 2019

RATIONALE OF STUDY: Despite significant advances in prevention and therapy, cytomegalovirus (CMV) infection still represents an important cause of morbidity and mortality in patients undergoing allogeneic haematopoietic stem cell transplant (HSCT). The standard pre-emptive treatment is based on intravenous administration of Ganciclovir (GCV). Valganciclovir (VGC), the pro-drug formulation of GCV is characterised by an excellent bio availability, making this drug suitable for oral administration.

PATIENTS: Since March 2003 all patients treated with reduced (27 patients) or fully ablative (3 patients) conditioning regimens followed by sibling HSCT, were monitored with bi-weekly CMV/PCR and pp65/assays. Overall 15 episodes of CMV positivity were detected in seven patients. Patients resulted positive (3 cells pp65+ or 1000/100000 PCR +) started oral treatment with VGC 900 mg bid, for the first fourteen days, followed by 900 mg q.d. up to at least seven days after assays normalization. The median duration of therapy was 21 days (range 10–21 days). No significant toxicity was observed. All patients had a normalization of CMV/PCR and pp65/assays within fourteen days, with a response rate (RR) of 100%. In two patients the oral VGC therapy was changed to the intravenous administration of Foscavir, because of concomitant neutropenia and acute GvHD.

CONCLUSION: Pre-emptive treatment of CMV infection with VGC is safe, feasible and effective. Furthermore, the oral administration of this drug in an outpatient setting, reduces significantly the costs compared with a therapy that needs hospitalization as intravenous Ganciclovir.
Monitoring Immune Function by the Cylex Immuknow Assay in Pediatric HSCT Patients.
Authors: Yu Lolie C. , Britz Judy , Martin Martha , Kowalski Richard
Published: October 2019

A observational analysis of immune function in six pediatric HSCT patients (3 allogeneic/3 autologous) ranging in age from 3 to 16 years (median = 8.6) was conducted at Children’s Hospital; Louisiana State University Health Sciences Center using ImmuKnow®, an FDA cleared assay for assessing T cell activation. This whole blood assay measures the immune function of CD4+ T-helper cells by stimulating cells with phytohemagglutinin (PHA), selecting CD4+ cells with antibody coated magnetic particles and detecting ATP by bioluminescence, an indicator of activation. The immunknow assay was obtained weekly post-HSCT. On average, the ImmuKnow value for the allogeneic patients was 109 ng/mL ATP with a median value of 63 ng/mL ATP. In two of the three allopatients, a rapid and significant rise in immuknow levels correlated with clinical complications. One ALL patient, given an allogeneic PBSCT from a HLA-ID sibling, developed Veno-occlusive disease (VOD) of the liver, 18 days post BMT with a corresponding spike in the ImmuKnow level to 500 ng/mL ATP. Following treatment with defibrotide, the VOD resolved and ImmuKnow ATP levels decreased, stabilizing between 100–150 ng/mL ATP. A second allopatient showed dramatic rise in immuknow level at day 18 post transplant to 480ng/mL ATP that corresponded with gross hematuria secondary to urethritis. In autologous BMT patients, the average ImmuKnow value was 133 ng/mL ATP with a median value of 70 ng/mL ATP. Clinical correlations were less clear in this small sample of patients with fewer test values. ImmuKnow has previously been demonstrated to have clinical utility for managing immunosuppressive therapies in solid-organ transplantation (SOT)1 The range of immune function values in pediatric patients has previously been shown to be significantly lower than adult ranges.2 Our data suggest that this assay may also be useful as a marker for the development of complications post-HSCT. Additional studies are in progress to confirm these early findings that suggest that routine immune function monitoring is of clinical value in the allogeneic HSCT recipients.
Myelodysplasia after Autologous Stem Cell Transplantation for Multiple Myeloma.
Authors: Franz Gregory , McClune Brian , Buadi Francis , Walsh William , White Frank , Przepiorka Donna
Published: October 2019

Autologous stem cell transplantation (ASCT) increases the overall survival of patients with newly diagnosed multiple myeloma (MM), and it has become standard of care in this setting. Long-term survivors of ASCT transplanted for lymphoma or Hodgkin’s disease are known to have a high risk of developing myelodysplasia (MDS), but the risk of MDS is not clear for patients transplanted for MM. From 1996 through 2005, 82 patients underwent ASCT for MM at our center, survived at least 6 months and have adequate documentation of follow-up for review. The group included 47 males and 35 females of median age 56 years (range, 37–74 yrs). Median time from diagnosis to ASCT was 8.2 mos (range, 2.6–86.1 mos). Prior to coming to transplantation, 28% had received melphalan (MEL), 98% received some form of chemotherapy, and 34% received radiation. This prior therapy included 1 or 2 regimens for 48% of the patients, and more than 2 regimens for 52% of patients. Mobilization was effected using CYC plus growth factor for 79% of the patients, CAD or VAD plus growth factor for 17%, and growth factor alone for 4%. The median mobilization rate was 28.7 × 106 CD34/L blood processed (range, 2.0–250.1 × 106 CD34/L blood processed). A single ASCT was provided for 68%, and 32% underwent ASCT more than once. High-dose MEL alone was used as the preparative regimen for 83%, and the remainder received at least one ASCT with a more intensive preparative regimen. The median CD34 dose for the first ASCT was 5.1 × 106/kg (range, 0.4–113.0 × 106/kg). Nine patients developed MDS. The 5-yr actuarial risk was 26% (95% CI, 8–43%). On multivariate analysis, there was a trend for an increased risk of developing MDS with a CD34 cell dose <3 × 106/kg (HR 3.0, 95% CI 1.0–16.2, p=0.059), but there were otherwise no significant prognostic factors. Eight of the 9 patients with MDS had a PR or better as the best response to ASCT for MM. Five of the MDS patients had relapse of MM as well. Median survival after the diagnosis of MDS was 18.1 mos. Five patients with MDS have died, two from recurrent myeloma, two from AML, and one from sepsis and MDS. The median survival for all patients was 51.7 mos from ASCT and 69.1 mos from diagnosis, and there were no differences in survivals between those with or without MDS. We conclude that there is a relatively high risk of MDS after ASCT for MM, but development of MDS does not appear to worsen overall survival.
Results of CCG-5941: Intensified Multiagent Chemotherapy and Non-Cross Resistant Maintenance Therapy for Advanced Lymphoblastic Lymphoma in Children and Adolescents.
Authors: Abromowitch Minnie , Sposto Richard , Perkins Sherrie , Finlay Jonathan , Cairo Mitchell S.
Published: October 2019

The treatment of advanced (Stage III/IV) pediatric lymphoblastic lymphoma (LL) has recently utilized treatment strategies similar to childhood acute lymphoblastic leukemia (ALL) with prolonged maintenance chemotherapy for up to two years (Burkhardt et al JCO, 2006) compared to older treatment strategies of less intense lymphoma type therapy (Anderson et al NEJM, 1983). The CCG previously piloted a “NY regimen” for “lymphomatous” ALL with a new intensive induction/intensive conditioning and alternating non-cross resistant combination maintenance therapy (Steinherz et al JCO, 1986). We modified the NY regimen for lymphomatous ALL in children with advanced (Stage III/IV) lymphoblastic lymphoma with ≤25% BM lymphoblasts. Between July 1994 and June 1997, 85 eligible LL patients with advanced disease (Stage III/IV) were enrolled in a pilot study CCG-5941 to estimate toxicity, feasibility and efficacy of a short (12 month) aggressive multiagent chemotherapy regimen. Patients were staged according to the St. Jude staging system. Induction (3wks) consisted of VCR, Pred, Daunomycin, Cyclophosphamide, L-ASP and IT MTX/ARA-C. Consolidation (3wks) consisted of VCR, ARA-C, VP-16, HD MTX and IT MTX. There were six maintenance courses each consisting of 4 pulses: A (Cylcophosphamide, 6TG), B (VCR, Pred, Dauno), C (VCR, HD MTX, L-ASP) and D (ARA-C, VP-16). CNS positive pts received 1800 cGy-cranial and 600 cGy spinal at completion of chemotherapy (approximately 1 yr). Central pathology review (84%) and immunophenotyping were preformed with CD3, CD5, CD45RO, TDT, CD 79 and CD20. Neupogen (G-CSF) was given after each cycle to maintain dose intensity. Median age 10 yrs (1–18 yrs), 64% male, median f/u 7.2 yrs, 91% T-cell, 7% B-cell, 2% mixed lineage, 27% LDH ≥2nL, 12 % M2 BM, 5% CNS positive. Among the 85 patients there were four deaths unrelated to disease progression (4.7%), three due to infectious complications and one due to venoclusive disease of the liver. Two second malignant neoplasms (AML) have occurred. Hematopoietic (grade III/IV) toxicity occurred in approximately 80% of patients, resulting in delays in chemotherapy. The 5yr event free survival (EFS) is 78±4.5% and 3 yr overall survival (OS) is 85±3.9%. Analysis of EFS by age, sex, induction responses, marrow status at diagnosis (M2 vs M1), presence of CNS disease, LDH ≥2nL and presence of mediastinal mass was not significant. The prognosis in patients with progressive/relapsed disease was dismal with a 2 yr OS of 33±14%. These pilot results suggest that this experimental approach in children and adolescents with advanced LL is safe and feasible and results in similar long term efficacy as compared to more prolonged maintenance ALL type chemotherapy regimens.
Reduced-Intensity Bone Marrow Transplantation for Heavily Transfused Patients with Severe Aplastic Anemia - Japanese Single Center Experience.
Authors: Kozuka Teruhiko , Tanimoto Kazushi , Nakase Koichi , Nawa Yuichiro , Hara Masamichi
Published: October 2019

Background: Bone marrow transplantation (BMT) is a curative therapy for severe aplastic anemia (SAA). Outcome of BMT can be negatively affected when there is organ damage such as heart failure, liver dysfunction and diabetes mellitus after multiple transfusions in patients with long-standing SAA. Multiple transfusions also sensitize SAA patients with alloantigens and place them at high risk of graft rejection; it is an important problem after BMT for patients with multiply transfused SAA. We investigated the use of the combination of fludarabine monophosphate (FLU), cyclophosphamide (CY) and anti-thymocyte globulin (ATG) as the conditioning regimen in heavily transfused SAA patients.

Methods: Four patients with heavily transfused SAA were treated with allogeneic BMT from unrelated and sibling donor. They were treated with a reduced-intensity conditioning regimen that included FLU (120 mg/m2), CY (1,200 mg/m2) and ATG (horse 40 mg/kg, rabbit 15 mg/kg).

Results: The regimen was well tolerated, and engraftment rapidly occurred with some therapy-related toxicity encountered. Chimerism analysis on day 30 after transplant showed reconstitution with 100% donor cells in three patients. Among these three patients, two patients showed late graft rejection. At this time of reporting, only one patient is alive with complete donor chimerism.

Conclusion: The combination of FLU/CY/ATG was well tolerated also in heavily transfused SAA patients: problems such as graft rejection remain.
Comparison of Cord Blood Transplant Outcome between U.S. Versus Non-U.S. Transplant Centers for Cord Blood from a Single Source.
Authors: Wang Brian , Tseng Peggy , Wu Tina , Rosenthal Joseph , Jaing Tang-Her , Chan Lee Lee , Tan Ah Moy , Tan Poh-Lin , Lin Hai-Peng , Lin Allen , Yang Steven , Chow Tiffany , Gjertson David , Petz Lawrence , Tan Patrick , Chow Robert
Published: October 2019

Background: Cord blood transplantations (CBT) are performed in transplant centers (TC) worldwide; however, conditions for TC located around the world may be quite different, in particular, few studies have focused on CBT outcome in Asian TC. Factors such as patient populations, experiences, disease indications, available resources, and protocols may affect outcome as some have suggested.

Methods: In an effort to compare CBT performed by U.S. (n=129) and non-U.S. TC (n=63), a retrospective audited analysis was performed for all 192 patients with available engraftment and/or survival data using cord blood units (CBU) from a single source to minimize potential differences in quality.

Results: Kaplan-Meier estimates of engraftment for ANC500, platelet 20K and 50K were 91±3%, 80±5% and 74±5% for U.S. respectively, and 81±5%, 85±6%, and 81±7% for non-U.S. TC respectively. The relapse rate for the U.S. and non-U.S. TC were 26±5% and 17±5% respectively. TRM were 31±4% for U.S. TC and 22±5% for non-U.S. TC. The 3-year OS and DFS were 51±5% and 41±7% for U.S. and 68±6% and 61±7% for non-U.S. centers respectively. Factors including recipient age, CD34+ cell dose, #HLA matches, malignancy and wash status of the CBU were taken into consideration in a multivariate analysis which will be presented. In this study, non-U.S. TC were more likely to forego post-thaw wash of CB and perform CBT for benign indications, which appeared to affect outcome. Upon closer inspection of the individual TC, it appeared that there may be more heterogeneity in the TC results overseas, and that centers in the U.S. produced more consistent outcome. While it is possible that, due to many complex reasons, outcome at some non-U.S. TC may be somewhat uneven, many including several in Asia, produced outstanding results that rival the best TC anywhere.

Conclusion: It appears that many factors, including available resources, post-thaw wash, and CBT experience affect outcome, and outstanding outcome can be achieved, regardless of TC location.
Autologous Stem Cell Transplant (ASCT) in HIV-1 Positive (HIV+) Hodgkin Lymphoma (HL) Patients in the HAART Era: Are Clinical Results Comparable to Those in HIV-1 Negative (HIV−) HL Patients?.
Authors: Balsalobre Pascual , Serrano David , Carrion Rafael , Anguita Javier , Miralles Pilar , Berenguer Juan , Buño Ismael , Gomez-Pineda Alfonso , Varela Rosario , Loscertales Javier , Escoda Lourdes , Ribera Josep-Maria , Diez-Martin Jose L.
Published: October 2019

ASCT has been reported as a feasible, safe and effective treatment in HIV associated lymphoma patients (pts) receiving Highly Active Antiretroviral Therapy (HAART). Nevertheless comparative studies with HIV− lymphoma population have not yet been performed. We present a retrospective matched analysis comparing clinical outcomes in both HIV+ and HIV− auto-transplanted HL pts.

Patients and Methods: 6 HIV+ HL pts who underwent ASCT since June 2000 were included. Twelve transplanted HIV− HL auto-transplanted pts were selected as controls. Both groups (HIV+ vs HIV−) were comparable for the most relevant clinical features (Mann-Whitney or chi-square tests p value > 0.05): median age (40 vs 36), Ann Arbor advanced stage (50% vs 25%), status at ASCT (CR>1 or PR, 83% vs 75%), all 18 pts received 2 lines of chemotherapy before ASCT. BEAM was used as conditioning regimen in all 18 pts. In the HIV+ group HAART was maintained during mobilization and ASCT, except during the conditioning in 1 Pt, in which it was needed to be resumed due to an increase in viral load. The median number of infused CD34+ cells/kg was 3,65×106 in HIV+ pts and 4,75×106 CD34+ in HIV− pts (p: NS). G-CSF was used in all HIV+ pt until engraftment starting at a median of 5 days (d) after ASCT.

Results: All 18 pts engrafted, at a median of 13,5 (9–29) d after ASCT in HIV+ pts and 14 (11–18) d in HIV- pts. The incidence of acute infectious and toxic events was not different in both groups. All pts developed neutropenic fever. Documented infections were (HIV+ vs HIV−): Gram+ bacteraemia (2 vs 3), Gram− bacteraemia (1 vs 0), CMV antigenemia (2 vs 1). Pneumonia was documented in one pt from each group. One HIV+ pt showed grade II liver toxicity and grade II renal toxicity occurred in 1 HIV− pt. All events were succesfully resolved. In 4 out of 6 HIV+ pts, HAART was withdrawn due to gastrointestinal toxicity. The median follow-up time was 36,5 mo in HIV+ pts and 37,5 mo in HIV− pts. Two pts relapsed in each group. Within the HIV+ group 1 pt died, due to disease progression. Within the HIV− group 3 pts died, 2 of disease progression and 1 due to post-ASCT secondary acute leukaemia. The OS at 36 mo was 83% for HIV+ pts and 80% for HIV− pts (p=NS). EFS at 36 mo was 55% in HIV+ pts and 70% in HIV− pt (p=NS).

Conclusions: Our results show that clinical outcomes are comparable in HIV+ and HIV− HL pts undergoing ASCT. Engraftment, complication events and survival were not different. ASCT may be applied with guarantees in HIV associated HL on HAART pts in a similar way that in the HIV− setting.
Genetic Polymorphisms in the Homocysteine Metabolism Pathway and Thrombosis in Thai Children: A Case Control Study.
Authors: Sirachainan Nongnuch , Tapanapruksakul Pornsri , Sasanakul Werasak , Visudtibhan Anannit , Charoenkwan Pimlak , Kadegasem Praguywan , Udomtrupayakul Umaporn , Chuansumrit Ampaiwan
Published: October 2019

Hyperhomocysteinemia is a known risk factor for thrombosis in both adults and children. Mutations of genes encoding the enzymes in homocysteine metabolism are predicted to cause elevation of homocysteine and increase the risk of thrombosis. Therefore, this study objectives are to determine the prevalence of methylenetetrahydrofolate reductase (MTHFR) 677C->T, 1298A->C; methionine synthase (MS) 2756A->G, and cystathione β-synthase (CBS) 884ins68 in Thai ethnic patients, aged ≤18 years, and their relationship to thrombosis. The population consisted of 91 patients, from 2 medical institutes in Thailand, first diagnosed with thrombosis. The control group was 169 healthy, Thai children matched for age (mean ± SD in cases/controls = 9.4 ± 5.7 / 9.3 ± 5.7 years, p = 0.9) and sex (male/female in cases/controls = 57.1%/42.9%/53.8%/46.2%, p = 0.7). Genotyping was performed using standard PCR/restriction enzyme assays. The prevalence and allele frequency of the genes are shown in Table 1. The polymorphisms of individual genes and the combinations between the genotype did not affect plasma homocysteine level. The details are shown in Table 2. Conclusion, the prevalence of MTHFR 677C->T, 1298A->C, MS 2756A->G, and CBS 884ins68 in Thai population was lower than Caucasian population; and did not cause the increase risk for thrombosis in Thai children.

Table 1. Frequency of genetic polymorphisms between patients and controls. MTHFR 677A CC (%) CT (%) TT (%) T frequency (%) Controls 71.8 27 1.2 14.7 Patients 73.5 25.3 1.2 - p-value - 0.91 0.96 - MTHFR 1298 AA (%) AC (%) CC (%) C frequency (%) Controls 50.0 42.1 7.9 24.4 Patients 54.3 42.0 3.7 - p-value - 0.76 0.26 - MS 2756 AA (%) AG (%) GG (%) G frequency (%) Controls 78.9 21.1 0 10.5 Patients 75.9 24.1 0 - p-value - 0.63 - - CBS 884ins68 NN (%) NI (%) II (%) G frequency (%) Controls 98.7 0.6 0.6 1 Patients 98.7 1.3 0 - p-value - 0.55 - - Table 2. Homocysteine value and genetic polymorphisms. Genetic polymorphism (number) Plasma Hcy (μmol/L) p value MTHFR 677 CC (n=105) 7.4 ± 2.9 0.11 CT (n=29) 8.3 ± 2.7 MTHFR 1298 AA (n=64) 7.4 ± 2.4 > 0.05 AC (n=59) 7.5 ± 2.8 > 0.05 CC (n=12) 8.7 ± 5 MS 2756 AA (n=110) 7.8 ± 3 AG (n=25) 6.7 ± 1.9 0.055 CBS 884 ins 68 DD (n=137) 7.5 ± 2.8 ID (n=2) 10.3 ± 8.7 0.72 MTHFR 677 / MTHFR 1298 CT/AC (n=16) 8.7 ± 2.5 0.07 MTHFR 1298 / MS 2765 AC/AG (n=6)6.8 ± 1.6 6.8 ± 1.6 0.38 MTHFR 1298 / CBS884ins68 AC/IN (n=9) 6.8 ± 2.1 0.34
The Association of Delta Neutrophil with Severity of Sepsis.
Authors: Lee Jongwook , Song Kyung-Soon , Lee Kyungwon , Song Jaewoo , Choi Jong-Rak , Lim Jong-Baeck
Published: October 2019

Background: The entrance of microbes into blood stream results in rapid spreading of infection through circulation system progressing to sepsis with accompanying fever, leukocytosis and circulatory collapse necessitating prompt recognition and treatment. We calculated the difference between white blood cell counts measured in myeloperoxidase and basophil channel, designated as “delta neutrophil”, and found that the value correlates the progression of sepsis.

Methods: We categorized patients who were referred for automatic blood cell analysis according to the calculated value of delta neutrophil and analyzed positive rate of blood culture, mortality and laboratory data including hemoglobin, platelet count, prothrombin time, activated partial thromboplastin time, fibrinogen, fibrinogen degradation product, D-dimer, ESR, CRP. Delta neutrophil values were calculated as above mentioned from measured values from automatic blood cell analyzer, ADVIA® 120 automated Hematology System (Bayer Diagnostics, New York, USA). Among 1781 patients selected, those with delta neutrophil value less then 5 were categorized as group I, 5 to 10 as group II, 10 to 20 group III, 20 to 30 group IV, 30 to 40 group V, 40 to 50 group VI and greater than 50 as group VII, arbitrarily. Patients with hematologic malignancy or with Gynecologic malignancy were excluded in this study.

Results: The mortality and blood culture rate in group VII were 75.0% and 57.1% and in group VI 76% and 46.7%, group V 46.2% and 37.9%, respectively. On the contrary for group I the mortality and isolation rate were 3.3% and 17.1%. (The means of hemoglobin concentration for group I and II were 13.2 g/dL and 12.1 g/dL compared with 10.5 g/dL and 10.2 g/dL in group VI and VII.) With regard to consumptive coagulopathy, the means of platelet count were 263,700/mL and 259,200/mL in group I and II while those for group VI and VII were 107,200/mL and 112,600/mL. Antithrombin activities were 5.20 % and 7.98% in group VII and VI in contrast to 66.6% and 75.8% for group I and II.

Conclusion: The categorization by delta neutrophil value correlated with the isolation rate of bacteria from blood culture and mortality. The delta neutrophil value is expected to provide useful information for following up progression of sepsis.
Laparoscopic Splenectomy for Hematologic Disorders: A Safe Procedure.
Authors: Ghys Christophe , Capelluto Elie , Baize A. , Meuleman Nathalie , Bennani Jalil , Libertalis Marc , Cadiere Guy Bernard , Bron Dominique
Published: October 2019

Background : Splenectomy for hematological diseases remains controversial in many circumstances due to a high morbidity and mortality after a classical surgery. Laparoscopic surgery becoming more popular, spleen removal by this approach was more widely used and we retrospectively reviewed the outcome of 33 patients who underwent laparoscopic splenectomy in our institution.

Population : Between 1998 and 2006, laparoscopic splenectomy was performed in 33 patients (F=6, M=27) by an anterior approach. Median age was 62 (40–90) y.o. Indications for splenectomy was hemolytic anemia or discomfort in malignant hemopathies (CML, MF, NHL, CLL, HD) and autoimmune cytopenia or peripheral cytopenia in non malignant hemopathies (AIHA, ITP,.). Spleen weights ranged from 100g to 5000g. All the patients received anti-pneumococcal vaccination 2 weeks before surgery. After surgery, all patients were covered by penicillin and LMWH until discharge from the hospital.

Results : Perioperative mortality was 0% and major postoperative complications were observed in 3 patients (Pulmonary Embolism, DVT, Hemorrhage). Conversion was required in one patient. One patient died 4 years after splenectomy from extended deep portal thrombosis.

Improvement in hematological parameters and/or performans status was observed in 95% of the patients. Mean duration of hospital stay was 5 days.

Conclusion : Anterior laparoscopic splenectomy for splenomegaly is a safe and minimally invasive procedure in the hands of experienced surgeons. Howerer, a closed monitoring of the platelets count should be performed, even on an ambulatory basis, because of the risk of thrombotic complications.
Methyl-Green-Pyronin as a Differential Nucleic Acid Stain for Peripheral Blood Smears
Authors: PERRY SEYMOUR , REYNOLDS JOHN , BAKER MARY
Published: October 2019

A differential nucleic acid stain for peripheral blood and marrow smears using methyl-green and pyronin Y and Carnoy’s solution as a fixative is described. Characteristics of the various blood cells are quite distinct so that identification is readily accomplished.

If pyroninophilia is assumed to be a measure of RNA, morphologically identical and mature leukocytes are found to vary in the quantity of cytoplasmic RNA. Since cellular immaturity is associated with increased RNA, this must be an indication of the varying "age" of white blood cells in the peripheral blood. With the use of this stain a much more dynamic picture of white cell physiology is obtained than with other more conventional stains.

The quantity of cytoplasmic RNA in peripheral blood leukocytes, as measured by a scoring technic, was found to be increased as compared to normal in most infections, leukemias, pernicious anemia in relapse, and a variety of other conditions. With treatment, the score fell to normal levels in pernicious anemia and infections.
Roles of Flow Cytometry in Bone Marrow Staging of B-Cell Non-Hodgkin Lymphoma.
Authors: Nakorn Thanyaphong Na , Polprasert Chantana , Srisakham Jirawan , Assanasen Thamatorn
Published: October 2019

Background Bone marrow staging is important in determining the extent of disease and for making therapeutic decision in B-cell non-Hodgkin lymphoma (B-NHL). Flow cytometry has been widely used in this setting but its value has not been clearly demonstrated.

Objectives To determine the usefulness of bone marrow flow cytometry in staging of B-NHL.

Materials and Methods We compare the results of bone marrow studies using bone marrow aspirate (BMA), bone marrow biopsy (BMB) and three-color flow cytometry (FCM), in non-leukemic B-NHL patients performed during May 2003 to December 2006 at our institution and determine the concordant rate among these three methods in detecting bone marrow involvement by B-NHL.

Results Two hundred and sixty-eight bone marrow samples were analyzed in this study. Diffuse large B-cell lymphoma (DLBCL) was the most common histologic subtype (60.8%). Bone marrow (BM) involvement as confirmed by immunohistochemistry of BMB was observed in 66 samples (24.6%). Prevalence of BM involvement was slightly higher in indolent B-NHL (32.2%) as compared to aggressive B-NHL (20.8%). Agreement among all three methods was observed in 163 samples (60.8%). BMA had the sensitivity of 77.3% and specificity of 73.8%. FCM alone had the sensitivity of 63.6% and specificity of 89.6%. FCM failed to demonstrate clonal B-cells mainly in patients with focal involvement pattern. When FCM was combined with BMA, the sensitivity was increased to 87.9% but the specificity was decreased to 67.8%. They did not perform significantly better than using morphological criteria in BMB alone, which showed sensitivity of 80.3% and specificity of 94.5%.

Conclusion Based on these data, we conclude that flow cytometry may not be necessary in bone marrow staging of B-NHL in patients with non-leukemic presentation.
EBV-Associated Follicular Dendritic Cell Tumor of the Spleen.
Authors: Fekrazad M. Houman , Rosenbaum Lizabeth , Vasef Mohammad A. , Rabinowitz Ian
Published: October 2019

Epstein-Barr virus (EBV) expressing follicular dendritic cell proliferations in the spleen is an extremely rare but distinct variant of follicular dendritic cell tumor (FDCT). This neoplasm typically presents as an intra-abdominal mass with a predilection to involve spleen or liver with histologic features reminiscent of inflammatory pseudotumor (IP). However, in contrast to IP, this distinct FDCT consistently is associated with EBV. A subset of splenic tumors previously reported as examples of IP or inflammatory myofibroblastic tumor represent EBV-associated FDCT retrospectively. Despite morphologic similarity with IP, at least focal proliferation of follicular dendritic cells can often be demonstrated using follicular dendritic cell markers. Based on the limited published cases (Cheuk W, et al: Am J Surg Pathol, 2001;25:721–731), these proliferations can recur and/or metastasize but in contrast to classical intra-abdominal FDCT, their clinical behavior remains indolent. We report a case of 37-year-old gentleman who presented with a four month history of left-sided abdominal and flank pain, 8 lbs weight loss over a month, and on and off night sweats during the past two years. Initial blood tests including a CBC, LDH, electrolytes, renal and liver function were all within normal limits. CT scan of abdomen and pelvis revealed a 5.5 cm in diameter solitary splenic mass with cystic and solid components (Figure 1). There was no intra-abdominal or retroperitoneal lymphadenopathy. Hepatitis panel, EBV DNA PCR and also HIV serology were all negative. The patient underwent splenectomy due to clinical impression of a lymphoproliferative disorder. Pathology: The spleen weighed 237 grams and contained a solitary, 6 cm in greatest dimension, well circumscribed tumor. Histologically, the tumor was composed of a mixed population of small lymphocytes, histiocytes, plasma cells, and variable numbers of large oval to spindle cells. The spindle cells in some foci exhibited a storiform growth pattern. Neither overt cytologic atypia nor significant increased mitotic activity was present. Flow cytometric analysis revealed no monoclonal B-cell population or abnormal T-cell proliferation. Cytogenetic analysis revealed normal 46,XY karyotype in 20 metaphases. By paraffin immunohistochemistry, the spindled cells were positive for follicular dendritic cell markers CD21, CD35 and CD23. In situ hybridization using EBV RNA (EBER) probes revealed abundant EBV RNA transcripts in the nuclei of spindled and large oval cells (Figure 2). The spindle cells were negative for S-100 and ALK protein. The systemic symptoms resolved following splenectomy with no additional treatment. Six months after splenectomy, the patient remains asymptomatic and disease free at last clinical follow up.

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