bluuebunny/crossref_metadata_2025 huggingface dataset:
Acute Renal Failure Following Myeloablative Autologous and Allogeneic Haematopoietic Cell Transplantation.
Authors: Lopes José A. , de Almeida Edgar , Silva Sónia , Jorge Sofia , Abreu Fernando , Lourenço Fernanda , Martins Carlos , Lacerda João Forjaz , Carmo José Alves do , Lacerda João Manuel Forjaz , Prata Mateus Martins
Published: April 2020

Acute Renal Failure (ARF) is a common complication in the early period of myeloablative autologous and allogeneic haematopoietic cell transplantation (HCT). Reported incidence varies from 30% to 80%. This study evaluates retrospectively the incidence of ARF, defined as the doubling of serum creatinine within the first 100 days after HCT, associated risk factors, the need of dialytic therapy as well as mortality of HCT patients who received a myeloablative autologous or allogeneic HCT in our Hospital between January 2003 and December 2004. One-hundred and forty patients (86 men, mean age: 32,9±14,69 years) were studied: 90 patients (53 men, mean age: 33,6±13,73 years) had an allogeneic HCT and 50 (33 men, mean-age: 31,71±16,25 years) an autologous HCT; 82 patients (51 men, mean age: 33,17±14,1 years) received a peripheral blood stem cell (PBSC) transplantation and 58 (35 men, mean age: 32,51±15,61 years) a bone marrow (BM) graft. The incidence of ARF was 21,5% (30/140) (16 men, mean age: 31,53±13,21 years) but did not reach a statistically significant difference between patients who received an allogeneic or autologous HCT (27% vs 12%, p=0.07) or were transplanted with BM graft or PBSC (10% vs 17%, p=ns). Nephrotoxicity (n=20), septic shock (n=16), graft vs host disease (n=6) and veno-occlusive disease (n=3) were the most common etiologies associated with ARF. The incidence of dialysis-dependent ARF was 30% (9/30) and was higher in patients with a BM graft (50% vs 7%, p<0.03) but did not differ in patients who received an allogeneic or autologous HCT (33% vs 16%, p=0.08); 4 patients were treated with intermittent hemodialysis and 5 with continuous dialytic therapy (continuous veno-venous hemodiafiltration). Among patients who received only medical therapy (n=21), 11 had complete renal function recovery (RFR) and 2 had partial RFR. Overall mortality rate was 16,4% (23/140) and was higher in patients with ARF (57% vs 6%, p=0.0001), particularly if there was a need of dialysis therapy (100% vs 38%, p=0.006).

This study shows that ARF is prevalent during the early period of HCT and increases mortality, particularly if it is dialysis-dependent. However, in our cohort of patients the incidence of ARF was lower than the previously described in other studies. Low occurrence of veno-occlusive disease could explain this phenomenon, which may be related to adequate prophylactic measures.
Peripheral Blood Stem Cell Transplantation in Fanconi Aplastic Anemia: Report of Ten Cases.
Authors: Kupesiz O. Alphan , Tezcan Gulsun , Hazar Volkan , Yesilipek M.Akif
Published: April 2020

Allogeneic hematopoietic stem cell transplantation (SCT) from healthy donors is the only treatment modality for the correction of hematological abnormalities in Fanconi aplastic anemia (FAA) patients. We have performed SCT by using two different non total body irradiation conditioning regimens. While anti-thymocyte globulin (ATG, 10–30mg/kg/day, 3 days), cyclophosphamide (5mg/kg/day, 4 days) and thoraco-abdominal radiation (total 5Gy) were used for six patients (regimen A), fludarabine (120–150mg/m2 totally), cyclophosphamide (10mg/kg/day, 4 days), ATG (30mg/kg/day, 3 days) were given to four patients (regimen B). Six of the patients received regimen A and 4 regimen B. Donors were HLA-matched sibling in 5, HLA-matched parent in 2, partly HLA-matched parent in 2 and HLA-matched unrelated donor in one. All patients and donors were screened by diepoxybutane (DEB) test. Seven of the patients were DEB positive. All donors were DEB negative. Median age of the patients was 10 years. All patients received antimicrobial, antifungal prophylaxis and intravenous immunoglobulin (IVIG, 500 mg/kg weekly) from day −7 to day +180. Cyclosporin A (CsA) was used for graft-versus-host disease (GVHD) prophylaxis in eight patients and CsA plus mycophenolate mofetil in one matched unrelated patient. Neutrophil and platelet engraftment occurred in all patients on day 10 (median) and day 21 (median), respectively. Grade II-IV acute GVHD occurred in two patients who received regimen A. Conditioning-related toxicity was milder in regimen B than that in regimen A. Three patients succumbed from complications of grade IV acute GVHD, post-transplant acute myeloid leukemia and fungal pulmonary infection in regimen A group. All of the regimen B group were alive with normal hematological parameters. Totally, seven patients are alive with sustained engraftment and transfusion independent with median follow-up 19 months (range 2–50). We conclude that fludarabine based conditioning regimen is well tolerated and ideally suited to reduce regimen-related toxicities while achieving sustained engraftment in FAA patients SCT using sibling, related and unrelated donor.
The Impact of Methylenetetrahydrofolate Reductase C677T Gene Polymorphism on Engraftment after Allogeneic Hematopoetic Cell Transplantation.
Authors: Soydan Ender A. , Topcuoglu Pervin , Ozcan Muhit , Arslan Onder , Gurman Gunhan , Beksac Meral , Arat Mutlu , Ilhan Osman
Published: April 2020

Methotrexate (MTX) is an antifolate agent used to prevent graft versus host disease (GVHD) in allogeneic hemapoietic cell transplantation (AHCT). The effectiveness of MTX is largely attributable to its role of MTHR and its gene polymorphism is a common (10–12% homozygote and 40% heterozygote) variation in the population. It was shown by Ulrich et al that C677T polymorphism leads to variations in toxicities. Depending on to this finding, we investigated whether methylenetetrahyrofolate reductase (MTHFR) C677T gene polymorphism has any affect on engraftment kinetics of patients undergoing AHCT. We retrospectively analyzed our cohort of 82 allogeneic stem cell recipients whose MTHFR gene polymorphism of C677T region was analyzed by RQ-PCR for the pretransplant evaluation of hereditary thrombophilia. The patient’s median age was 31 (range, 14–50) years, with a M/F: 50/32 and diagnosis; 35 AML, 26 CML, 12 ALL and 9 other. Nearly all the patients received ablative conditioning regimen (BU-CY) or CY-TBI. All the patients received CSA and short term MTX for GVHD prophylaxis. Stem cell source was bone marrow (BM) in 23 and peripheral blood (PB) in 59. MTHFR gene polymorphism was detected in 32 (39%) of all patients, whose 90% were heterozygote (MTHFR HeZ). When we compared the engraftment kinetics, granulocyte engraftment was found to be late in MTHFR HeZ group (neutrophil 1000 median 19 vs 17 d; p=0.01) but no difference in platelet engraftment. In order to eliminate the effect of stem cell source on engraftment kinetics we have done the same analysis for BM and PB group separately. We have observed that MTHFR gene polymorphism had a prominent effect on BM recipients, as both neutrophil 500 and 1000 and also platelet engraftments were affected (granulocyte 500 median 21 vs 15 p=0.005; granulocyte 1000 median 22.5 vs 17 p=0.0001 and plt 20 median 27 vs 21 p=0.03) significantly. On the contrary, there was no difference in the PB group. There was no difference in acute GVHD incidence. Our knowledge on epigenetic data will help us on tailoring the chemotherapy regimen for conditioning and GvHD prophylaxis in transplant recipients. Our data on a limited patient size suggests that the presence of MTHFR HeZ may have an impact on allo HCT recipients’ engraftment kinetics while using MTX for GVHD prophylaxis and BM as stem cell source.
Beta 3 Integrin Phosphorylation and VEGF Signaling.
Authors: Mahabaleshwar Ganapati H. , Philips David R. , Byzova Tatiana V.
Published: April 2020

The process of angiogenesis is critical for tumor survival as well as for ischemic remodeling of vasculature after thrombotic occlusion. This process is a result of finely tuned co-operation between angiogenic growth factors, primarily from the VEGF family, and their receptors and cell receptors for extracellular matrix, the integrins. The role of alpha v beta 3 integrin in neovasculature development appears to be controversial asthe blockade of this receptor with antibodies inhibited angiogenesis while the genetic ablation of the beta3 subunit resulted in increased angiogenesis due to the over-expression of VEGFR2 on endothelial cells (EC). In order to understand the role of beta 3 integrin in VEGF-induced responses, we utilized knock-in mice with a mutation within the beta 3 subunit (Y747/759 to F, DiYF) that results in beta 3 that is unable to undergo tyrosine phosphorylation, an event critical for integrin outside-in signaling. Using EC isolated from WT and DiYF mice, we have found that defective tyrosine phosphorylation resulted in impaired EC adhesion and spreading on vitronectin but not on fibronectin, laminin and collagen. Migration in response to VEGF was reduced in DIYF EC by 3 fold compared to WT when vitronectin and fibrinogen but not fibronectin and collagen were used as substrates. In a wound healing assay on vitronectin, DiYF but not WT EC failed to close the wound. Video microscopy of migrating EC revealed that WT EC form forward protrusions and then retract the back of the cell, which results in successful directed migration. DiYF EC also formed protrusions, but could not form stable adhesion and retract the tail of the cell. As a result, DiYF EC were moving forward and then back again, failing to migrate in the direction of the wound. Importantly, DiYF but not WT EC were not able to form complete capillaries on Matrigel in response to VEGF and the average length of EC tubes was 3.5 fold lower compared to WT. Interestingly, the DiYF mutation resulted in impaired integrin activation (inside-out signaling) in response to VEGF as well as PMA based on soluble fibrinogen and WOW-1 binding. We have found that VEGF treatment of WT EC resulted in beta 3 integrin phosphorylation, which occurred 5 minutes after stimulation and reached the maximum at 30 min. In DiYF EC, this response was absent. Most importantly, immediately after VEGF stimulation, VEGFR2 formed a complex with beta 3 integrin. This complex was not observed in DiYF EC. Moreover, phosphorylation of VEGFR2 (but not the total protein level) was significantly reduced in DiYF EC compared to WT. As a result, major intracellular signaling events triggered by VEGF stimulation, such as phoshorylation of Akt, ERK1/2 and p38 MAPK, were severely impaired in DiYF EC. The finding that beta 3 phosphorylation regulates an activation of VEGFR2 and subsequent signaling events in EC provides novel insights on EC biology and mechanisms of VEGF-induced angiogenesis.
Duration to Engraftment Requires Significantly Much More Time in Myelodysplastic Syndrome (MDS) Patients as Compared to Acute Myeloid Leukemia (AML) Patients Following Allogeneic Stem Cell Transplantation.
Authors: Bitan Menachem , Shapira Michael Y. , Resnick Igor B. , Gesundheit Benjamin , Zilberman Irena , Ackerstein Aliza , Samuel Simcha , Elad Sharon , Slavin Shimon , Or Reuven
Published: April 2020

Normal hematopoiesis is characterized by the balanced interplay between hematopoietic stem cells and the cells and molecules that forms part of the microenvironment in which blood cell production takes place. Myelodysplastic syndrome (MDS) marrow stroma cells are known to fail in supporting the growing of normal stem cells. We therefore retrospectively analyzed the duration to engraftment of absolute neutrophil count (ANC) ≥0.5 x 109/L and ≥1.0 x 109/L and the time interval to platelet recovery of ≥20 and ≥50 x 109/L in 42 MDS patients as compared to 42 patients suffering from primary acute myeloid leukemia (AML), following allogeneic stem cell transplantation (SCT). Significant shorter time to engraftment was documented in AML as compared to MDS patients in all 4 parameters. These results hold true even if we sub-grouped the patients according to gender, age, with the age of 50 years old being the cutoff between young and elderly patients, or when the donor was related to the patient. Moreover, sub-grouping the patients from each diagnosis according to the conditioning regimens that were given prior to transplantation revealed the same significant better results for the AML patients when received a non-myeloablative regimen. To the best of our knowledge, this is the first time that such a comparison is being made. We suggest that duration to engraftment in MDS patients takes significantly longer time and this may influence and worsen their course of transplantation in terms of morbidity as well as mortality.
Donor/Recipient Matching for the -174G/C SNP Polymorphism in the IL-6 Gene Promoter Influences the Outcome of Stem Cell Transplantation.
Authors: Manzano Cintia , Balsalobre Pascual , Serrano David , Carrion Rafael , Gomez-Pineda Alfonso , Diez-Martín Jose Luis , Buño Ismael
Published: April 2020

Background: Polymorphisms in regulatory sequences of cytokine genes are known to influence their expression and, therefore, the intensity of the immune response. Some of such polymorphisms have been associated with the outcome of stem cell transplantation (SCT), which supports the hypothesis of a genetic predisposition towards certain complications post-transplants.

Objective: To evaluate the association between donor (D) and recipient (R) genotype in the IL-6 gene -174G/C SNP polymorphism with the development of complete or mixed chimerism (MC) and, consequently, with complications such as graft rejection, graft versus host disease (GVHD) and survival after SCT.

Patients and methods: The study included 16 SCT (9 ablative, 3 T cell depleted, 4 reduced intensity conditioning). The IL-6 -174G/C SNP genotypes were determined by PCR on genomic DNA from Rs and Ds, using allele-specific oligonucleotides (ASO-PCR) as primers (forward: 5′-ccctagttgtgtcttgcc-3′ or 5-′ccctagttgtgtcttgcg-3′; reverse: 5′-gagcttctctttcgttcc-3′). Logistic regression was applied to identify associations between the polymorphism, the development of MC and of the mentioned complications. The reduced number of SCT analyzed, precluded the use of Pearson’s and/or Fisher’s p values or further statistics.

Results: The frequency of the different genotypes was 44.4% CC, 33.3% GC and 22.2% GG for Rs, and 33.3% CC, 44.4% GC and 22.2% GG for Ds. 88.9% D/R pairs were matched for the polymorphism and 11,1% mismatched. None of the patients transplanted from matched donors showed MC at any time post-SCT while all mismatched patients developed MC (Table 1). MC in the D/R mismatched group was associated with a greater rate of graft rejection and with a reduced incidence of acute GVHD (aGVHD) when compared with the D/R matched group (Table 1). No association was observed in this sample between the polymorphism analyzed and the development of chronic GVHD (cGVHD). Although graft rejection was early diagnosed and successfully treated with immunosuppression withdrawal and donor leukocyte infusion, the D/R matched group showed higher mortality rate that the mismatched group (Table 1).

Conclusions: The present study suggests an association between D/R matching for the IL-6 gene -174G/C SNP polymorphism and the development of MC and, consequently, of different complications after SCT. The analysis of a larger number of patients will eventually allow to confirm these observations as well as to establish this type of studies as a means for an improved management of transplanted patients.

Table 1 IL6 -174G/C MC rejection aGVHD cGVHD Exitus D/R matched 0% 0% 75% 87.5% 50% D/R mismatched 100% 100% 0% 100% 100%
First Report of Dengue Virus Infection in a Bone Marrow Transplant Patient.
Authors: Figueroa Myrna S. , Clavell Luis A.
Published: April 2020

Dengue virus infections are a frequent cause of morbidity and mortality in certain endemic areas of the world but it has never been reported to occur in a bone marrow transplant patient. We describe a pediatric patient with ALL on her first bone marrow relapse undergoing allogeneic bone marrow transplant who developed sepsis and irreversible shock that on postmortem autopsy proved to be secondary to dengue virus infection Type 4. A 6 years old female with ALL underwent an allogeneic bone marrow transplant from her sibling (6/6 match) on Nov 10, 1994. She received TBI (1200 rads) and ARA-C (3gm/m2 per dose per 12 doses) as preparative regimen. She developed generalized skin erythema on day +5 followed by fever on day +6. The following days were characterized by continued fever spikes, severe mucositis, persistence of the erythematous skin rash (first degree burn like) and gross hematuria in spite of broad spectrum antibiotic coverage. Blood cultures were reported negative. She developed irreversible shock and finally died on day +11 post-transplant. At autopsy (Nov 22, 1994), Dengue virus type 4 was isolated from blood, ascitic fluid, liver and spleen by routine viral culture at San Juan C.D.C. Dengue Branch. Results were confirmed by polymerase chain reaction. Her donor also developed low grade fever the day after bone marrow donation. Further blood testing on donor (Dec 2, 1994) showed positive IgM antibodies against Dengue virus Type 4. The recipient viral cultures matches with donor acute titers for Dengue Type 4, suggesting infection through bone marrow transplant. Dengue virus infection may cause significant morbidity and mortality to blood and bone marrow recipients in endemic areas of the world.
Steroid Complications in Patients with Acute Graft Versus Host Disease.
Authors: Betul Oran , Lee Hun , de Lima Marcos , Couriel Daniel , Giralt Sergio , Saliba Rima
Published: April 2020

Background: High dose steroid treatment remains to be the first line therapy for acute graft versus host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Although effective in controlling aGVHD, high dose steroids can cause multiple serious complications which can result in increased morbidity and mortality.

Purpose: Our aim was to determine the frequency of steroid induced complications and to analyze risk factors for steroid-myopathy in patients with AML who developed grade 2 aGVHD after allogeneic HSCT.

Patients and Methods: Inclusion criteria were:

1) AML/MDS patients who received allogeneic HSCT between 1/1996 and 12/2001

2) grade 2 aGVHD treated with at least 2mg/kg of methylprednisolone

3) post transplantation overall survival at least 100 days.

Steroid induced complications reviewed were: cataracts, headaches, mood swings, hypertension, gastritis, hyperglycemia, osteopenia, myopathy, avascular necrosis, edema, hypokalemia and infections. Pre- and post-transplantation characteristics analyzed as risk factors for steroid-myopathy were: age, gender, race, history of diabetes, body mass index, HLA types, steroid use after HSCT prior to grade 2 acute GVHD and duration of steroid use for acute GVHD. Logistic regression analysis was used for risk factor evaluation. Steroid-myopathy was defined as proximal muscle weakness, atrophy and myalgia in the absence of genetic, inflammatory or drug-induced etiologies other than steroid use.

Results: 178 AML /MDS patients were transplanted during the study period. 70 patients (37 males and 33 females) with a median age of 43 (range, 21–66) were eligible for our study. Median duration of follow-up and median duration of steroid use after grade 2 aGVHD were 269 days and 127 days respectively. The number of patients and their frequency distribution of steroid induced complications were as follows: hyperglycemia, 43 (61.4%); hypertension, 35 (50%); cataracts, 10(14.3%); headaches, 7 (10%); mood swings,12(17.1%); gastritis, 7 (10%); myopathy, 32(45.7%); avascular necrosis, 1 (1.4%); edema, 22 (31.4%); hypokalemia, 52 (74.3%); bacterial infections, 55 (78.6%); viral infections, 39(55.7%); and fungal infections, 22(31.4%). For steroid-induced myopathy, male gender (RR=4.0, 95% CI=1.01–16.4, p=0.05), steroid use before acute GVHD grade II (RR=5.5, 95% CI=1.35–22.14, p=0.02) or steroid use more than 4 months after developing acute GVHD grade II (HR=6.4, 95% CI=1.38–29.94, p=0.02) were independent risk factors. 47 of 70 patients died with median overall survival of 10 months. 22 of 47 (46.8%) had steroid-myopathy and there was no increased mortality with steroid induced myopathy.

Conclusion: Steroid therapy for aGVHD after allogeneic HSCT in AML/MDS patients is associated with frequent toxicities. The possibility of identifying prognostic factors for steroid toxicities support the study and development of strategies that may ameliorate or prevent steroid induced complications.
Safety of a Weekly Administration of 7.5 mg/kg of Liposomal Amphotericin B (LAB) for Antifungal Prophylaxis in Patients Receiving High Dose Corticosteroids (CS) for Acute GVHD after Reduced Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation (allo-SCT).
Authors: El-Cheikh Jean , Faucher Catherine , Furst Sabine , de Lavallade Hugues , Blaise Didier , Mohty Mohamad
Published: April 2020

Background. RIC regimens are increasingly used for allo-SCT in elderly or patients not eligible for standard myeloablative allo-SCT. Such regimens have yielded promising results in terms of decreasing early transplant-related toxicities. However, acute GVHD remains a matter of concern in this setting. Of note, the use of high dose CS for GVHD treatment increases the risk of severe fungal infections in this high risk population usually presenting several comorbidities. Therefore, prophylactic strategies aiming to reduce this risk are needed.

Patient and Methods. We conducted a pilot single centre study in 15 adult patients receiving high dose CS (2 mg/Kg/day) for acute GVHD therapy after RIC allo-SCT. Treatment consisted of a 2 hour weekly infusion of 7.5 mg/kg LAB with a maximum of 8 total doses. The primary endpoint was the incidence of serious adverse events occurring during the course of prophylaxis treatment. Of note, safety was monitored with particular attention to nephrotoxicity in this relatively elderly population receiving concomitant nephrotoxic drugs such as cyclosporin A.

Results. Median age of these 15 patients with various hematological and non-hematological malignancies was 54 years (range, 40–70). Patients received a median of 4 weekly doses of LAB (range, 1–8), with 8 patients (53%) receiving at least 4 consecutive weekly doses. In terms of toxicity, 6 patients (40%) didn’t experience any sign of toxicity. One patient experienced a violent chest pain with transient extra-systoles, during the first infusion of LAB, and did not receive any subsequent infusions. Other mild and transient infusion-related reactions (fever, flush, tachycardia, orthostatic hypotension, pruritous, bone pain, abdominal pain) were observed in 5 patients, usually at time of first LAB infusion. Despite concomitant administration of cyclosporin A in all 15 patients, only 4 patients (27%) had to interrupt the course of prophylactic LAB (respectively after 3 (n=2), 4 and 7 infusions) because of renal toxicity (increase of serum creatinine ≥1.5 times from baseline values).

Conclusions. Although long term efficacy of such antifungal prophylactic strategy is yet to be established, the results of this feasibility study demonstrate that a weekly dose of 7.5 mg/Kg of LAB is relatively safe and well tolerated when given as prophylaxis in high-risk immuno-compromised patients receiving high dose CS for GVHD after RIC allo-SCT, despite concomitant administration of multiple nephrotoxic drugs.
PBSCT Similar to BMT Allows Active B-Lymphopoiesis Unless Severe GVHD Occurs.
Authors: Winkler Julia , Biller Armin , Schub Natalie , Rösler Wolf , Eckart-Schäfer Kerstin , Wandt Hannes , Kluender Claudia N. , Schwerdtfeger Rainer , Hahn Joachim , Holler Ernst , Winkler Thomas H. , Gramatzki Martin
Published: April 2020

Long-term engraftment after stem cell transplantation is dependent on pluripotent hematopoietic stem cells capable to multi-lineage reconstitution. The engraftment and prolonged repopulation of B lymphoid progenitor cells is dependent on pluripotent hematopoietic stem cells. We have recently shown that a high number of B-cell progenitors is detectable in the bone marrow from patients both after allogeneic PBSCT and after allogeneic BMT. The percentage of CD19/CD10+ pro-B/pre-B cells showed a high variability and ranged from 0 to 98% of all B-lymphocytes. Interestingly, no difference in numbers of precursor B-lymphocytes between BM recipients and PBSC recipients was found. In micro-satellite analysis, both in PBSC and in BM recipients the B cell precursors were derived exclusively from the donor. To identify predictors of B lymphopoiesis in the bone marrow after stem cells transplantation, a stepwise, multiple regression analysis was performed. The stem cell source, BM or PBSC, the occurrence of GVHD, the conditioning with or without TBI and whether ATG was given, were entered as categorical variables. Time point of BM sampling after transplantation, age of the donor and the recipient, the quantity of stem cell transplanted and the T cell content of the BM sample served as continuous variables. Time elapsed after transplantation (p=0.002) and severe GVHD (aGVHD grade III/IV or extensive cGVHD) (p=0.036) could be identified as parameters with an independent influence on the percentage of B cell precursors. The highest percentage of precursor B cells was found during the first year after transplantation, unless severe GvHD was present, leading to neglible precursor B-cells. This hyperactive B lymphopoiesis in the first year after transplantation contrasts to low circulating B cell counts. Finally, it could be formally demonstrated, that G-CSF mobilized PBSC contain hematopoietic stem cells capable of long-term reconstitution of the B cell compartment.
Cidofovir: A Treatment for BK Virus Cystitis after Allogenic Bone Marrow Transplantation.
Authors: Le Du Katell , Rohrlich Pierre-Simon , Larosa Fabrice , Herbein Georges , Deconinck Eric
Published: April 2020

Late-onset hemorrhagic cystitis (HC) is a common complication after bone marrow transplantation (BMT) with an incidence ranging from 7 to 70 %. Viral infections are the main risk factors of HC and the BK virus (BKV) is an emerging micro-organism implicated in interstitial nephritis, ureteral stenosis and HC in immunocompromised patients. Most of anti-viral treatments (aciclovir, foscavir, ganciclovir, ribavirine, vidarabine) are inefficient, excepted cidofovir, a cytosine nucleoside analog, usually used in the treatment of cytomegalovirus retinitis in AIDS patients.

The pathogenicity of BKV after BMT remains to be precised. Ten allogenic bone marrow transplanted patients were treated with cidofovir for a severe and refractory HC between December 02 and January 05. BKV replication was diagnosed by real-time Polymerase Chain Reaction on blood and urinary samples. The majority of patients had a severe cellular immunosuppression (absolute lymphocyte count <100 cells/microl) and they were all treated with immunosuppressive drugs (steroids, tacrolimus, mycophenolate, ciclosporine) for an uncontrolled graft versus host disease (GVHD). Cidofovir was administered by intravenous injection (5 mg/kg) with an average of four doses per patient and was generally well tolerated. Complete remission was obtained in 5/10 patients with a clinical improvement and a significant decreasing of urinary viral load in 60 days.

In conclusion, cidofovir might be proposed in the treatment of refractory BKV hemorrhagic cystitis after allogenic stem cell transplantation.
Improved Outcome of Patients with Invasive Pulmonary Fungal Infection Complicated by Respiratory Failure Due to the Use of New Antimycotis Agens and Early Tracheostomy after Allogeneic Transplantation.
Authors: Koldehoff Michael , Elmaagacli Ahmet H. , Steckel Nina K. , Trenschel Rudolf , Hlinka Michal , Ditschkowski Markus , Biersack Harald , Beelen Dietrich W.
Published: April 2020

The mortality rate associated with respiratory failure due to invasive fungal infections (IFI) after allogeneic hematopoietic stem cell transplantation (HSCT) is exceedingly high. Here we compared in a retrospective analysis the influence of the antimycotic agents and early tracheostomy on the outcome of patients (pts) with required artificial respiration (AV) due to pulmonary IFI. The first cohort presented pts, who were treated at our center before the new antimycotic agents became available. This cohort consisted 16 pts from 236 consecutive allogeneic transplant recipients (median age 38 years [range 22–59], 88% had a leukemic disorder) died during or soon after weaning from AV (median survival: 64 days). The mean weaning time was 16 days, only one patient could be tracheotomized. In contrast to this, within a second cohort of 24 pts from 279 consecutive allogeneic transplant recipients, who required AV after the introduction of the new antimycotic agents 9 (38 %) pts could be brought back to spontaneous breathing. The median survival of these pts was 370 days. The weaning time was 24 days, 67% of those pts underwent tracheotomy within ten days after initiation of AV. There were no differences between the two cohorts regarding the underlying diseases, engraftment time or the ratio of myeloablative and reduced intensity conditioning regimens. However, the cohort of pts who were transplanted during the era of new antimycotic agents had a higher median age (43 years, range 20–65, not significantly) and included more mismatched and unrelated grafts with a higher incidence of GVHD grade II-IV (79% vs. 69%). To date, four of those pts are still alive and well (mean survival 463 days, range 240 to 732). We propose that our observations reflect an improved management of these pts nowadays mainly due to the use of new antimycotics and more effective antifungal treatment approaches, as well as the advantages of early tracheostomy may contribute to better outcomes in the treatment of respiratory failure due to pulmonary IFI following allogeneic HSCT.
T Cell Receptor Excision Circles (TRECs) Decrease in Patients after Allogeneic Stem Cell Transplantation.
Authors: Du Xin , Li Yangqiu , Geng Shuxia , Weng Jianyu , Lu Zesheng , Guo Rong
Published: April 2020

Human thymus is required for establishment of a T-cell pool in fetal life, T-cell emigration from thymus (thymic recent emigrants [TRECs]) is a continuous thymic-dependent process. To analyze the content of signal joint Tcell receptor excision DNA circles signal joint T cell receptor excision DNA circles(sjTRECs) within peripheral blood mononuclear cells (PBMCs), thereby to infer the level of naive T cells and the recent thymic output function in patients with allogeneic stem cell transplantation. We used real-time polymerase chain reaction (PCR) to quantify SjTRECs in 5 patients with chronic myeloid leukemia-chronic phase. Five patients(4 males, 1 females; median age 37 years,) who underwent HLA-matching sibling BMT and/or peripheral blood stem cell transplantation (PBSCT) at our department. Quantitative detection of sjTRECs in DNA of peripheral blood mononuclear cells from 13 normal individuals. The median value of sjTRECs copies P1 000 PBMCs was 4.37±3.64 in normal individuals whereas it was 0.57±0.51 copies P1 000 PBMCs in patients at least two years after allogeneic stem cell transplantation (P < 0. 03). We conclude that these Patients decrease in recent thymic output function,. Therefore, measurement of sjTREC may provide an important tool for predicting thymus-dependent T-cell reconstitution after transplantation.
Successful Treatment of Severe Hemorrhagic Cystitis Following Allogeneic Stem Cell Transplantation by Selective Embolization of Bilateral Hypogastric Arteries.
Authors: Tang Xiaowen , Wu De Pei , Liu Yizhi
Published: April 2020

Objective Hemorrhagic cystitis(HC) is a common complication of allogeneic stem cell transplantation occurring in 7–52% of transplant recipients. The severity of HC can range from mild hematuria to life-threatening bleeding with urinary tract obstruction or renal insufficiency. Severe HC is often refractory to the conventional therapy. Currrent treatment modalities for severe HC include selective embolization of the hypogastric arteries and hyperbaric oxygen. We studied 6 patients with refractory severe HC to investigate the therapeutic value of embolization in severe HC following allogeneic stem cell transplantation. Methods 6 patients underwent allogeneic stem cell transplantation developed severe HC with a median onset time of 33 d after transplatation. All these patients had been resistant to conservative managements and received the treatment of selective embolization of hypogastric arteries. Results 8 times of embolizations were performed for 6 patients. The HC resolved in 4 patients and the HC improved in 1 patient, yielding a response rate of 83%. One patient didn’t respond to this measure. For the patients with response, macroscopic hematuria disappeared 7 to 10 days after the treatments and microscopic hematuria vanished 20 to 30 days after the intervention therapy. Both procedures were tolerated well and no severe adverse effects were observed. Conclusion It suggest that selective embolization of hypogastric arteries seems to be a safe and effective treatment for severe HC. This measure can be proposed for patients undergoing refractory and persistent severe HC.
The Effect of Dipeptiven in Patients after Allogenic Hematologic Stem Cell Transplantation.
Authors: Huang He , Shou Lihong , Luo Yi , Shi Jimin , Zhu Xiaoli , Cai Zhen , Lin Maofang
Published: April 2020

Total parenteral nutrition (TPN) is provided to patients undergoing allogenic hematologic stem cell transplantation (allo-HSCT) to help minimize nutritional consequences of both conditioning regimens as well as complications resulting from the procedure such as GVHD, VOD and so on, and glutamine could to improve the clinical course of patients after transplantation while given with parenteral nutrition as it is considered that it has stimulatory effects on lymphocytes and mucosa cells in vitro. In the study, we investigated the effect of dipeptiven, N(2)-L-Alanyl-L-Glutamine, which has dipeptides as free glutamine is rather unstable and poorly soluble, added to standard TPN preparations on complication and recovery of patients with allo-HSCT. 40 patients who suffered hematologic malignancies and received allo-HSCT were randomly assigned to receive either standard TPN (control group, n=20), or dipeptiven supplemented TPN (DPT group, n=20). The Bu/Cy2 regimen was used in conditioning with Bu (16mg/kg) plus Cy (120mg/kg) and all patients were given mycophenolate mofetil, CsA and MTX to prevent GVHD. The nutritiona support was started about 1 to 12 days after transplantation and 1.5ml/kg.d dipeptiven was added to the DPT group. During the period of nutritiona support, serum albumin, total protein, creatinine, total bilirubin, leukocytes, lymphocytes were monitored, and time to neutrophil engraftment, decrease of body weight, hospital stays, and other data related to hospital infection and acute GVHD were evaluated for all patients. As a result, the levels of serum albumin fell in the two groups on the 7-day, but on the 28-day those in the DPT group returned to normal and were significantly better than those in the control group (P<0.05). The total bilirubin and creatinine concentration did not change much. And lymphocytes of the patients in the DPT group recovered more rapidly than in the control group (P<0.05). There were less cases with clinical infection and microbial colonization in the DPT group than the control group (10 vs 16,11 vs 17, P<0.05). Also days for antibiotic requirements, days of diarrhea, changes of body weight and hospital stays reduced in the DPT group (16.5±10.6d vs 25.4±16.3d, 4.7±4.5d vs 8.2±6.0d, 2.0±2.0kg vs 3.3±1.6kg, 49.2±18.8d vs 58.0±20.2d, P<0.05, respectively). There were no different between the two groups of incidence of acute GVHD. In the conclusion, DPT-supplemented parenteral nutrition was beneficial in allo-HSCT patients for the nutritional status improving, the incidence of infection and damage of intestine, liver diminishing were all reduced, and the incidence of acute GVHD not increasing.
Vancomycin Resistant Enterococcus (VRE) Bloodstream Infections (BSI) in Patients with Hematological Malignancies: Is the Sick Getting Sicker?.
Authors: Dubberke Erik R. , Holland James , Georgantopolis Peter , Augustin Kristan , Dipersio John F. , Mundy Linda , Khoury Hanna J.
Published: April 2020

Patients with hematologic malignancies and hematopoietic stem cell transplant (HSCT) recipients are at high risk for bacterial BSI. Data describing the prognosis and outcomes of VRE BSI in this patient population is limited. We performed a retrospective chart review of all cases of VRE BSI occurring between February 1996 and December 2002 on the Leukemia/HSCT unit at Barnes-Jewish Hospital. 68 episodes of VRE BSI were observed in 60 patients with acute (53%) or chronic (8%) leukemia, NHL (22%), or other malignant hematologic disorders (17%).46 were autologous (13%), related (32%) and URD (32%) transplant recipients. Forty days prior to the VRE BSI, 70% were colonized with VRE, 95% had broad-spectrum antibiotic exposure and 42% had non-VRE BSI, 35% pneumonia, 22% CMV reactivation, 10% fungal infection. At the time of the VRE BSI, 42% of allograft recipients had active acute GVHD and 32% chronic GVHD. Only 57% were neutropenic, 52% had refractory/relapsed malignancy, and 60% had end organ dysfunction with a median APACHE II score of 17. VRE was easily eradicated from the bloodstream after initiation of anti-VRE therapy (median time to clearance 1 (range 1–9) day). 3 patients died within 48 hours of the VRE BSI from causes unrelated to the BSI. Median survival after VRE BSI was 19 days. Only 4 deaths were directly attributable to the VRE BSI. Age, ECOG PS ≥ 2 on admission, HSCT, pneumonia, mechanical ventilation, acute neurologic dysfunction, receipt of anti-fungal drugs, and low APACHE II score were significant factors associated with death by univariate analysis, while pneumonia, receipt of anti-fungal drugs, and low APACHE II score at the time of the VRE BSI remained significant after multivariate analysis.

In summary, our analysis suggests that in patients with hematological malignancies, VRE does not have the microbiologic behavior of a virulent pathogen. VRE BSI may simply be a marker of these patients’s already existing critical medical condition.
Ganciclovir Suppresses Human T Lymphocyte Proliferation In Vitro.
Authors: Battiwalla Minoo , Wu Yiyuan , Nakamura Ryotaro , Radovic Marija , Bajwa Rajinder P.S. , Elefante Anjana , Segal Brahm , Almyroudis Nikolaos , McCarthy Philip L.
Published: April 2020

Clinically significant cytomegalovirus (CMV) infection in allogeneic blood or marrow transplant recipients has dramatically declined in recent years by the strategy of early detection of reactivation and pre-emptive therapy with Ganciclovir (GCV). We have previously shown that even in the absence of overt CMV disease, persisting post-transplant antigenemia predicts for increased late relapse and treatment failure. (Nakamura, et al BBMT 2004) In other words, frequent CMV reactivation serves as a surrogate for impaired post-transplant immune reconstitution. To explain the observed association between CMV reactivation and relapse we also raised the possibility that several weeks of GCV therapy could exert a deleterious effect on a fragile immune system. Clinical association between GCV administration and impaired lymphocyte function has not received attention previously; perhaps because of confounding effects from the underlying conditions (HIV or post-transplant) that induce CMV reactivation. We examined the effect of GCV in vitro on normal human PBMCs. Human PBMCs were extracted from normal volunteers and subjected to mitogenic stimulation (PHA) in the absence or presence of varying concentrations of GCV. PHA-induced proliferation, measured by uptake of 3[H]-thymidine after 5 days incubation in RPMI-10% AB serum, was reduced by 35% at peak therapeutic concentrations (10mg/ml) of GCV as opposed to 73% by Tacrolimus (10ng/ml). GCV did not induce lymphocyte apoptosis in the presence or absence of stimulation. Flow cytometry-based BrdU incorporation assays show that GCV exerts a time-dependent impairment of DNA synthesis in lymphocytes. Collectively, these results show that GCV suppresses T-lymphocyte proliferation in vitro at therapeutic concentrations and the likely mechanism of action is inhibition of DNA synthesis. Further work is ongoing to evaluate the effect of GCV on proliferative responses to specific antigens and to confirm these effects in comparison to other drugs used in the transplant setting.

Figure Figure
Measurement of Minimal Residual Disease (MRD) after Consolidation Therapy as a Means of Early Detection of Relapse in Adult Acute Lymphoblastic Leukemia (ALL).
Authors: Kneba Michael , Brüggemann Monika , Gökbuget Nicola , Reutzel Regina , Hoelzer Dieter , Raff Thorsten
Published: April 2020

Outcome for patients with adult ALL after relapse is poor, even if a second remission is achieved by salvage therapy and is consolidated by an allogeneic stem cell transplantation. There is considerable evidence from studies in childhood ALL and other hematologic malignancies that administration of salvage therapy in early molecular relapse may improve prognosis. We therefore investigated the value of continuous MRD-monitoring in prospectively monitored standard risk patients of the German Multicenter ALL-studies 06/99 and 07/03 during and after maintenance treatment beyond the first year of therapy. MRD was assessed by quantitative realtime PCR using clone-specific primers for the leukemia-specific Ig/TCR gene rearrangements. MRD high risk-patients (those with MRD > 10−4 at two successive time points after induction during the first year of therapy) are candidates for early therapy escalation according to the study protocol and were thus excluded from this analysis. Of the 108 remaining patients (77 male, 31 female), 30 (28%) became MRD-positive again after a median follow-up of 18 months after the end of consolidation treatment. Of these, 17 (57%) already relapsed. When only considering patients with MRD measurable within the quantitative range of the PCR 16/19 (84%) already relapsed. Of the MRD-negative patients only 5 of 78 (6%) have relapsed after a median follow up of 23 month after end of initial therapy. After conversion to MRD positivity, the median time to relapse was 9.5 months, with a median time to relapse of only 2.5 months once the patients’ MRD was within the quantitative range of the PCR assay. Taken together, these data indicate that, if done at regular intervals, MRD-monitoring allows for accurate and timely identification of patients in need for treatment escalation in the vast majority of cases and may help to avoid overtreatment for those patients who are cured by conventional chemotherapy alone.
A Two Step Nonmyeloablative Allogeneic Transplantation Protocol Using In Vitro T-Cell Depleted Mobilized Stem Cells Followed by Donor Lymphocyte Infusions in Patients with Advanced CLL.
Authors: Barge Renee M.Y. , Hoogendoorn Mels , Marijt Erik W.A. , Beaumont Floor , Starrenburg Ingrid , Smit Willem , Posthuma Ward , Fibbe Willem E. , Falkenburg Frederik , Willemze Roelof
Published: April 2020

Transplantation of stem cells that are T-cell depleted using Campath 1H incubation following non-myeloablative (NM-alloSCT) conditioning leads to durable donor engraftment with minimal GVHD using HLA-identical family sibling and unrelated donors. The high levels of donor chimerism allow the subsequent use of DLI to treat residual disease (Exp. Hematol.2003; 31: 865–872). Patients with chemotherapy-refractory chronic lymphocytic leukemia (CLL) have a short life expectancy. We analyzed 12 patients with advanced CLL (9), PLL (1) or M. Waldenstrom (2) treated with NM-alloSCT. Median age was 56 years. Recipient conditioning consisted of fludarabine (30 mg/m2, 6 days), ATG (10 mg/kg, 4 days) and busulphan (3.2 mg/kg, 2 days). High numbers of G-CSF mobilized peripheral blood CD34+ cells from 11 related and 1 unrelated donors were collected (median 12 x 106/kg). The graft was T-cell depleted by 30 minutes incubation with 20 mg Campath 1H. No post-transplant GVHD prophylaxis was administered. The transplant procedure was very well tolerated. All patients engrafted rapidly. Only 1 patient experienced GVHD gr I (skin) after alloSCT. Sequential chimerism studies of bone marrow showed sustained mixed chimerism with a median donor percentage at 3 months after alloSCT of 86% (range 8–100%). At a fixed time period of 6 months after NM-alloSCT, low dose DLI was administered (5 x 106 CD3+ cells/kg) in 8 patients (3 pts too early after alloSCT and one pt died before DLI). The disease status pre-DLI was persistent disease in 4 pts and CR in 4 pts. After DLI, four patients experienced severe aGVHD (≥ grade 2) and 1 limited cGVHD. Importantly, the observed GVHD after low dose DLI was well managable. One patient received a second transplant from the original donor after myeloablative conditioning due to progressive disease with concommitant decreasing mixed chimerism. Donor chimerism increased after DLI with a median donor percentage of 98% (range, 3–100%) at 3 months after DLI. Presently at a median follow-up of 423 (range 46–1572) days, 9 patients are alive. Four patients are in complete remission, 3 with partial remission and 2 with progressive disease. Three patients have died, two due to infection and one by unknown cause.

In conclusion, in-vitro T-cell depleted NM-alloSCT followed by low dose DLI is a well tolerated strategy in older patients with advanced CLL. The low incidence of GVHD and the high levels of donor chimerism after NM-alloSCT allow the use of DLI to treat residual CLL. Our results demonstrate a profound GVL effect in patients with advanced CLL. NM-alloSCT may prolong survival for this group of patients.
Minimal Residual Disease Monitoring after Reduced Intensity Conditioning (RIC) Allogeneic Transplantation: May Help To Individualize Post-Transplant Immunotherapeutic Strategies.
Authors: Diez-Campelo Maria , Perez-Simon Jose A. , Perez Jose J. , Caballero Dolores M. , Vidriales Belen , Alcoceba Miguel , Vazquez Lourdes , Gonzalez Marcos , Canizo Consuelo M. , Lopez-Berges Consuelo M. , Lopez-Fidalgo D Jesus , Miguel J.F. San
Published: April 2020

We have analyzed the impact of MRD monitoring (detected by flow cytometry) on the outcome of 56 patients undergoing RIC allogeneic SCT. Of them, 67% reached complete remission (CR), 11% partially responded (PR) and 22% progressed or did not respond. MRD assessment after transplant distinguished different risk populations. At day +100, 80% of patients with high MRD levels (>10−2 leukemia asocciatted immunophenotypical cells, LAIP cells) versus 27% of patients with low MRD (<10−4) had relapsed. Accordingly, 3 categories could be clearly idenitified in terms of relapse free survival (RFS) at 5 years: 62% of patients with low MRD levels (<10−4) were event free as compared to only 28% and 20% among patients with intermediate (>10−4 and <10−2) and high MRD (>10−2) (p=0.0047). In multivariate analysis, patients’ age > 60 years (HR: 4,005; 95% CI 1.1–14.1, p=0.03), advanced disease status at transplant (HR: 4,087; 95% CI 1.3–12, p=0.01), failure to develop acute (HR: 4,785; 95% CI 1.2–18, p=0.02) and chronic GVHD (HR: 8,166; 95% CI 2.5–26.1, p=<0.001) and MRD levels, ≥10−4 on day +100 (HR: 5,795; 95% CI 1.7–19.1, p=0.004) adversely influenced RFS. Our study suggests that monitoring of MRD is a useful tool for predicting risk of relapse.