bluuebunny/crossref_metadata_2025_split huggingface dataset:
Skin Changes on Continued Imatinib Therapy in Patients with Ph+ CML.
Authors: Saikia Tapan , Hazarika Nandini , Dhabhar Boman 
Published: October 2019

Abstract
We reported the skin changes (generalized hypopigmentation) caused by imatinib mesylate (IM) in patients with Ph+ CML or GIST (EHA 2004 & ASH 2004). Subsequent reports from MDACC confirmed such findings. Such changes could be different and more profound among the brown skinned people of India. A cohort of 200 Ph+ CML patients at various phases of the disease receiving IM in a daily dose of 300 mg - 800 mg (children 200 mg daily) were studied over a median period of 14 months (range 5 – 72 months). Skin changes of any kind or severity were noted in 120 (60%) patients. Hypopigmentation alone (usually generalized) was seen in 75 patients (32.5%), combined hypopigmentation and hyperpigmentation in 39 (19.5%), hypopigmentation + extreme thinning of the skin in 3 (1.5%) and the classical skin rash of grade 3/4 in 2 (1%). Skin changes occurred at all dose levels. Characteristically the hyperpigmented patches were localized to the facial area over the forehead and/or in a butterfly pattern across the malar areas and bridge of the nose. IM dose was not modified among patients with pigment changes alone. IM causes dose-independent hypo- or hyperpigmentation of the skin in a significant number of Indian patients with Ph+ CML. This apparently happens due to modified melanin metabolism through the tyrosine pathway. Some of these changes (hyperpigmentation and extreme thinning) are bothersome from cosmetic viewpoint.
Evaluation of Immune Responses to Seasonal Influenza Vaccination in Healthy Volunteers and in Patients after Stem Cell Transplantation.
Authors: Avetisyan Gayane , Aschan Johan , Hassan Moustapha , Ljungman Per 
Published: October 2019

Abstract
Influenza causes significant morbidity and mortality in immunocompromised stem cell transplant (SCT) recipients. Measurement of cellular and humoral immunological responses might increase our understanding of how to estimate a protective response to influenza vaccination. Eighteen healthy subjects and 14 SCT patients tested before and 4 weeks after influenza vaccination were included in the study. Peripheral blood lymphocytes were stimulated with four influenza peptides; three based on sequences from the hemagglutinin and one from the M1 protein. Elispot assays were performed to measure the production of intracellular interferon-gamma (IFN-) and interleukin-13 (IL-13). Pre-labeled MHC class I pentamers were used for the detection of influenza-specific CD8+ T-cells. B-cell Elispot was performed to enumerate influenza-specific antibody-secreting cells (ASCs). Finally, haemagglutination inhibition (HIA) was used to determine the serum titers of neutralizing antibodies. Influenza vaccination elicited strong cell-mediated immune responses in the healthy volunteers (p≤0.003 for all four peptides) and SCT patients (p≤0.008). The percentage of CD8+ influenza-specific cells increased significantly after vaccination of both volunteers (p=0.005) and patients (p≤0.003). The number of influenza-specific ASCs increased as well (in volunteers p=0.009, in patients p=0.01). Only 29% of the SCT patients developed protective antibody levels to the influenza A H1/N1 serotype while no patient had protective antibody levels to H3/N2 or influenza B types. All responses were lower in patients studied less than 6 months after SCT compared to those studied later after SCT. These results indicate that seasonal vaccination against influenza can boost the cellular immune response in SCT patients and healthy controls, while B-cell responses are suboptimal in SCT patients.
Symptomatic Improvement Following Intravesicular Cidofovir for the Management of BK Virus Associated Cystitis.
Authors: Buie Larry W. , Rao Kamakshi V. , Epstein Stacy , Shea Thomas C. , Comeau Terrence , Gabriel Don A. , Irons Robert , Eron Barbara , Serody Jonathan 
Published: October 2019

Abstract
BACKGROUND: Hemorrhagic cystitis (HC) is a complication of hematopoietic stem cell transplantation, occurring in 10 to 70% of transplant recipients. Factors that may contribute to the risk of developing HC include intensive preparative regimens, especially those including busulfan, high-dose cyclophosphamide or ifosfamide, transplantation from matched unrelated donors, infection with adenovirus, and the development of graft-versus-host disease. The reactivation of latent BK virus in the kidney is thought to lead to the development of late-onset HC in hematopoietic stem cell transplant patients. Early reports of cidofovir’s efficacy in BK virus-associated HC used intravenous cidofovir, but treatment was often complicated or compromised by excessive toxicity, especially renal compromise. Based on small single patient reports of the use of intravesicular cidofovir in the management of other viral causes of cystitis, we evaluated the use of intravesicular cidofovir for the management of BK virus associated cystitis.
METHODS: In patients undergoing stem cell transplant, BK viral loads were routinely monitored twice weekly. The presence of cystitis or hematuria in a patient with detectable BK viruria was considered the trigger for initiation of therapy. Patients were treated with cidofovir at a dose of 5 mg/kg. Drug was diluted with 60mL of normal saline and administered via foley catheter, which was clamped for one hour post administration. Weekly repeat dosing was allowed as long as symptoms persisted. In addition to symptom control, BK viral loads were measured before, during, and after treatment.
RESULTS: Four patients were included in this initial evaluation. All were recipients of allogeneic stem cell transplants; three were recipients of matched unrelated donor transplants and one received a transplant from a matched sibling. Patients received between 1 and 4 doses of cidofovir for initial therapy. All 4 patients experienced complete resolution of symptoms. The range for symptom resolution ranged from 2 days to 3 weeks. Symptoms reappeared in only 1 patient after discontinuation of therapy. Monitoring of BK urine viral loads revealed that 3 of the 4 patients had a greater than 50% decrease in urine BK viral load with initial dosing of cidofovir, indicating presence of antiviral activity when the drug is administered by this novel route.
CONCLUSION: Intravesicular cidofovir is safe, easy to administer, and associated with both elimination of symptoms and reduction in viral loads in patients with hemorrhagic cystitis following high dose therapy and allogeneic transplantation.
Adaptation of Coagulation and Fibrinolysis in Allogeneic Stem Cell Transplantation.
Authors: Pinomaki Anne , Volin Liisa , Joutsi-Korhonen Lotta , Virtanen Jussi Oskari , labtech Marja Lemponen , Ruutu Tapani , Lassila Riitta 
Published: October 2019

Abstract
Allogeneic stem cell transplantation (SCT) seems to result in activation of coagulation and fibrinolysis. We characterised the outcome of SCT and graft versus host disease (GvHD) in association with the adaptive mechanisms of coagulation and fibrinolysis. 30 patients given myeloablative conditioning with cyclophosphamide and total body irradiation underwent allogeneic SCT for a hematological malignancy. 19 patients received the transplant from a sibling and 11 from an unrelated donor. GvHD prophylaxis consisted of cyclosporine and methotrexate, and in addition methylprednisolone in case of a sibling donor. Eight patients developed GvHD during the 3-month follow-up. Several coagulation and fibrinolysis activities were serially assessed: antithrombin, protein C (PC), FVIII, prothrombin fragments 1+2 (F1+2), D-dimer, tissue plasminogen activator (tPA) and plasminogen activator inhibitor (PAI-1). During the conditioning therapy as an early sign of thrombin generation, F1+2 increased 3-fold and D-dimer 4-fold, compatible with enhanced fibrin turnover. The activity of tPA reached its maximum already before the engraftment and that of PAI-1 diminished accordingly. FVIII increased steadily from normal to reach maximum (up to 273% ±104%, median ±SD, p<0.001) after engraftment. Interestingly, the natural anticoagulant, PC rose (up to 189% ± 63%) in parallel with FVIII, but showed a 5-fold individual variability. After the engraftment the FVIII, PC and antihrombin levels were highly interrelated. Clinically relevant prognostic association was observed between early low PC activity and the appearance of GvHD: the level of PC lower than 90% during the conditioning therapy was associated and even predicted (p=0.007) acute GvHD (OR=16.7). After the transplantation the level of F1+2 over 2.5 nmol/l associated and predicted the non-relapse mortality (p=0.024). Three patients with the largest early thrombin generation all died during a longer follow-up (6–24 months). Also, elevated PAI-1 activity (>10 U/ml) predicted the non-relapse mortality (p=0.013). In conclusion, early activation of coagulation and fibrinolysis is followed by increased FVIII and PC activities in SCT. Early marked thrombin generation and elevated PAI-1 associated with the non-relapse mortality and low PC activity with the appearance of acute GvHD.
Allogeneic Hematopoietic Stem Cell Transplantation for Myeloma: Does the Melphalan Dose Matter?.
Authors: Mehta Jayesh , Chunduri Sandeep , Dobogai Lisa , Singhal Seema , Rondelli Damiano 
Published: October 2019

Abstract
The dose of melphalan affects the outcome of autotransplantation in myeloma significantly. Regimens not containing melphalan or doses of melphalan lower than 200 mg/m2 have been shown to result in inferior disease-free (DFS) and overall (OS) survival (Mehta J, Singhal S. High-dose chemotherapy and autologous hematopoietic stem cell transplantation in myeloma patients under the age of 65 years. Bone Marrow Transplantation advance online publication, 6 August 2007; doi:10.1038/sj.bmt.1705799). However, whether the melphalan dose affects the outcome of allogeneic HSCT is unknown. The outcome of 30 patients undergoing submyeloablative allogeneic HSCT after 100 mg/m2 (n=24) or 140 mg/m2 (n=6) melphalan was studied to determine the effect of melphalan dose-intensity. The higher melphalan dose was combined with 150 mg/m2 fludarabine. As the figures below show, DFS and OS appeared to be better after the higher dose of melphalan on unadjusted analysis.
Figure Figure
The following variables were studied for their effect on OS: patient age, donor age, chemorefractoriness, HLA mismatch, melphalan dose, performance status, and LDH level. The factors found to be significant in univariate analysis - donor age, performance status, LDH, and chemorefractoriness - were entered into a Cox model. The dose of melphalan was forced into the final model. The table below shows the factors found to significantly affect relapse, DFS and OS in multivariate analysis. No factor was found to affect transplant-related mortality significantly.
Adverse variable RR P Relapse Refractory disease 5.5 0.02 DFS Elevated LDH 3.5 0.017 Donor age >45 3.4 0.024 Refractory disease 3.5 0.044 OS Elevated LDH 8.0 0.002 Performance status 2/3 5.8 0.003 Donor age >45 4.1 0.031
The melphalan dose did not affect relapse (P=0.37), DFS (P=0.16) or OS (P=0.12) significantly. These data suggest that 100 mg/m2 and 140 mg/m2 melphalan doses appear to result in comparable outcomes after allogeneic HSCT in myeloma. This is probably because the immunologic graft-versus-myeloma effect compensates for the reduced anti-myeloma efficacy of the lower melphalan dose. Whether higher melphalan doses, used successfully as pre-allograft conditioning for hematologic malignancies (Singhal S, Powles R, Treleaven J, Horton C, Mehta J. Melphalan alone prior to allogeneic bone marrow transplantation from HLA-identical sibling donors for hematologic malignancies: alloengraftment with potential preservation of fertility. Bone Marrow Transplant1996; 18:1049–1055), confer any benefit for myeloma allografts remains to be seen.
Outcomes of Allogeneic Hematopoietic Cell Transplantation (HCT) after Non-Myeloablative Conditioning in Relapsed Diffuse Large B-Cell Lymphoma (DLBCL).
Authors: Rezvani Andrew R. , Norasetthada L. , Gooley T. , Sorror Mohamed , Forman Stephen J. , Agura Edward , Chauncey T. , Maziarz Richard T. , Maris Michael , Shizuru J. , Bruno B. , Wade James C. , Lange T. , Yeager Andrew , Sandmaier Brenda M. , Storb Rainer F. , Maloney David G. 
Published: October 2019

Abstract
BACKGROUND: We report on outcomes after non-myeloablative allogeneic HCT in patients (pts) with relapsed DLBCL.
PATIENTS: Thirty-two pts with relapsed DLBCL were treated at 11 centers with allogeneic HCT from related (n=21) and unrelated (n=11) donors following non-myeloablative conditioning with 2 Gy total body irradiation, with or without fludarabine. Median age was 51.8 years. Twenty-four pts (75%) had undergone prior high-dose therapy (HDT) with autologous HCT: 18 (56%) had failed HDT, and 6 (19%) underwent planned tandem autologous/allogeneic HCT. The remaining 8 pts (25%) were medically ineligible for HDT. Twenty-three pts (72%) had chemosensitive disease at HCT, while 9 (28%) were chemorefractory. Disease status at HCT was complete response (CR, 14/32, 44%), partial response (PR, 9/32, 28%), or relapsed/refractory (9/32, 28%).
RESULTS: All patients engrafted. Cumulative incidences of acute GVHD grades II-IV, acute GVHD grades III-IV, and chronic GVHD were 53%, 19%, and 47%, respectively. Median follow-up of surviving patients was 45 months. Of pts with measurable disease at HCT (n=18), responses were seen in 7/18 (39%), with 6 CR’s and 1 PR. Nine of these eighteen pts progressed, and 2/18 were not evaluable due to early death from non-relapse causes. Of pts in CR at HCT, 10/14 (71%) remained in CR while 4/14 (29%) progressed. Three-year estimated overall (OS) and progression-free survival (PFS) were 45% and 35%, respectively. Three-year cumulative incidences of relapse and non-relapse mortality were 41% and 25%, respectively (see Fig. 1). In multivariate models, chemosensitive disease and receipt of >4 lines of chemotherapy prior to HCT were associated with better overall survival. Pts with chemosensitive disease at HCT had 3-year OS and PFS of 56% and 43%, respectively, while those with chemorefractory disease had 3-year OS/PFS of 11% (see Fig. 2). Prior failed or tandem autologous HCT did not have a significant effect on outcome.
CONCLUSION: Non-myeloablative allogeneic HCT can produce sustained disease responses in pts with chemosensitive relapsed DLBCL. Patients with relapsed DLBCL who have failed or are ineligible for autologous HCT lack effective therapeutic options. Non-myeloablative allogeneic HCT is a promising treatment for such patients.
Figure Figure Figure Figure
Tacrolimus and Sirolimus without Methotrexate as Acute GVHD Prophylaxis after Matched Related Donor Reduced Intensity Conditioning (RIC) Stem Cell Transplantation (SCT).
Authors: Ho Vincent T. , Kim Haesook , Li Shuli , Cutler Corey , Koreth John , Armand Phillipe , Soiffer Robert J. , Antin Joseph H. , Alyea Edwin P. 
Published: October 2019

Abstract
We have previously shown that the combination of tacrolimus and sirolimus (TAC/SIR) without methotrexate (MTX) is a safe and effective regimen for GVHD prophylaxis after myeloablative SCT. However, TAC/SIR has not been investigated in the RIC setting. We hereby report a prospective phase II trial testing TAC/SIR as GVHD prophylaxis after RIC SCT from matched related donors (MRD). All patients received fludarabine (FLU) 30 mg/m2 IV and intravenous busulfan (BU) 0.8 mg/kg IV daily × 4 days (day -5 thru day -2) as conditioning, followed by transplantation of filgrastim mobilized peripheral blood stem cells. Filgrastim 5 mcg/kg SC QD was started on day +1 until neutrophil engraftment. Tacrolimus and sirolimus were started on day-3, and doses were adjusted to maintain target serum trough levels 5–10 ng/ml and 3–12 ng/ml, respectively. Twenty-six patients have been transplanted, with a median age of 52 years (range 29–64 yrs). Diagnoses include NHL (8), AML (6), HD (5), CLL/SLL (3), CML (2), MDS (1), MM (1). Median CD34+ cells infused was 8.06 × 106 cells/kg (range: 2.96–38.0 × 106 cells/kg). All patients had sustained hematologic engraftment. Only 4 (15%) patients developed neutropenia below ANC 500, and 6 (23%) had platelet counts below 20K. One patient had late graft failure at 7 months post transplant. Grade II-IV acute GVHD incidence was 20%, with grade III-IV incidence of 12%. No hepatic VOD or thrombotic microangiopathy was observed. Day +100 transplant related mortality (TRM) was 0%. The cumulative incidences of TRM and relapse at 1 year were 4% and 38%, respectively. The cumulative incidence of chronic GVHD at 1 year was 74%. A high level (>90%) of donor-derived hematopoiesis was achieved in 68% by 1 month post transplant. Median donor chimerism at between day 20–50 post transplant was 93.5% (range 32%-99%), and 94% (range 22%-100%) at day 85–115. With a median follow-up of 13.5 months among survivors (range 5.5–19 months), progression-free survival (PFS) and overall survival (OS) at 1 year were 58% and 79%, respectively. Compared to a historical cohort of 47 MRD transplant recipients treated with the same FLU/BU conditioning regimen and using TAC/SIR ± mini-MTX (5 mg/m2 IV day +1,3,6) as GVHD prophylaxis, there was no statistical difference between TAC/SIR vs. TAC/SIR/MTX in the incidence of grade II-IV acute GVHD (20% vs 11%, p= 0.48), cumulative incidence of relapse at year (38% vs. 57%, p= 0.25), 1-yr PFS (58% vs. 41%, p= 0.33), or 1-yr OS (79% vs. 73%, p= 0.79). These results demonstrate that omission of mini-MTX is permissible, and that the combination of TAC/SIR alone as GVHD prophylaxis following reduced intensity conditioning with FLU/BU is associated with low rates of acute GVHD, TRM, and high levels of donor chimerism after MRD SCT.
Myelofibrosis and Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation (RISCT).
Authors: Popat Uday R. , Rondon Gabriela , Alousi Amin M. , Anderlini Paolo , Andersson Borje S. , de Lima Marcos J. , Giralt Sergio A. , Hosing Chitra M. , Kebriaei Partow , Jones Roy , Nieto Yago , Shpall Elizabeth J. , Verstovesek Srdan , Qazilbash Muzaffar H. , Champlin Richard 
Published: October 2019

Background: Reduced intensity allogeneic transplantation was developed to harness graft versus leukemia immune effect to treat older patients and patients with comorbidities who are not eligible for conventional myeloablative transplant. Limited but encouraging data are available on outcome of patients with myelofibrosis undergoing this therapy. We therefore sought to prospectively study the safety and efficacy of reduced intensity HCT in patients with myelofibrosis.
Methods: Patients with intermediate or high risk MF were eligible if they had adequate organ function and at least 9/10 matched related or unrelated donor. Patients were conditioned with Fludarabine 40mg/m2 × 4 (days −5, −4, −3 −2) and Busulfan 130mg/m2 × 2 (day −3,−2). Thymoglobulin 2.5 mg/kg × 3 (day −3,−2 and −1) was additionally given to patients receiving unrelated donor graft. Tacrolimus and mini Methotrexate were used as graft versus host disease prophylaxis. All patients received standard supportive care.
Results: Twelve consecutive patients with myelofibrosis were enrolled between 1/2006 and 7/2007. There were 6 males and 6 female with a median age of 59 (range 40–65). Four patients had primary MF, 3 post PV MF and 5 Post ET MF. Based on Lile criteria, 8 patients had intermediate risk disease and 4 had high risk disease. Eight patients had circulating blasts (1%-8%). Six patients had splenectomy prior to transplant; median spleen size was 15 cms (range 5–28cms) below the costal margin in the remaining 6 patients. Seven patients had mutated Jak 2. Median peripheral blood CD 34 count was 77/μl (range 2–3770/μl). Karyotype was abnormal in 6 patients and diploid in 6. Donors were siblings for 3 patients, matched unrelated for 6, and one antigen or allele mismatched unrelated for 3 patient. All but 1 patient received peripheral blood stem cells. All patients engrafted with a median time to neutrophil engraftment of 13 days (0–27) days) and a median time to platelet engraftment of 14 (0–74) days. Day 100 non relapse mortality was 0%. One patient developed grade 3 acute graft versus host disease (GVHD) and died. One patient developed limited chronic GVHD. All Jak 2 positive patients achieved molecular remission post transplant with negative JaK 2. Three patients relapsed: 2 in blast phase and 1 in chronic phase. With a median follow up of 177 (29–563) days, six month overall survival is 87%.
Conclusion: RISCT induces molecular remission with very low non relapse mortality in older patients with myelofibrosis.
Bax Degradation Activity Is a Novel Poor Prognosis Marker of Chronic Lymphocytic Leukemia.
Authors: Agrawal Samir G. , Liu Feng-Ting , Wiseman Catherine , Shirali Sima , Liu Hongxiang , Lillington Debra , Du Ming Qing , Court Denise Syndercombe , Newland Adrian C. , Gribben John G. , Jia Li 
Published: October 2019

Abstract
B-cell chronic lymphocytic leukemia (CLL) is a highly heterogeneous disease, with prognosis varying from a normal lifespan to death early after diagnosis. A large number of prognostic markers are now available in CLL. Better understanding of the mechanisms underlying the association of these markers with poor outcomes may guide their use in the clinic, as well as identify new therapeutic targets. Bax is an essential pro-apoptotic protein and decreased levels in malignant cells lead to resistance to apoptosis and chemotherapy. Using a Bax degradation activity (BDA) assay, CLL cells were found to show variable Bax instability. However, BDA did not correlate with Bax protein levels, BDA positive and negative cases each showing high and low baseline Bax levels. We looked at a cohort of patients with CLL and compared Bax degradation activity with established prognostic markers: Ig VH mutation status, Zap-70, CD38, cytogenetics, as well as clinical stage and lymphocyte doubling time (LDT). BDA positive cases showed a marked accumulation of poor prognostic markers - unmutated immunoglobulin heavy chain variable genes (VH), ZAP-70 and CD38 positivity, 11q22 and 17p13 deletion, and short lymphocyte doubling time. Patients with BDA positive cells had a shorter median overall survival (OS) (126 months v. not reached, p = 0.011) and shorter time to first treatment (16 v. 156 months, p = 0.029) than BDA negative cases; while patients with dual BDA and ZAP-70 positivity had a median OS of 84 months (p = 0.012). The BDA assay reflects the differential intrinsic ubiquitin/proteasome activity of CLL cells and measures dynamic changes in Bax protein levels, as opposed to single time point measurements. Mechanistically, Bax protein instability may represent a final common pathway for disparate prognostic markers, as well as being itself an indicator of poor prognosis.