Human Herpes Virus-6 and Clinical Manifestations After Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1960-1960
Author(s):  
Raffaella Greco ◽  
Francesca Lorentino ◽  
Daniela Clerici ◽  
Francesca Matteazzi ◽  
Alessandra Forcina ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cerebrospinal Fluid ◽  
Stem Cell ◽  
Viral Load ◽  
Hematopoietic Stem Cell Transplantation ◽  
Clinical Manifestations ◽  
Median Viral Load ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Clinical Complications

Abstract Abstract 1960 BACKGROUND: Human herpesvirus 6 (HHV-6) is increasingly recognized as an opportunistic and potentially life-threatening pathogen in recipients of allogeneic Hematopoietic Stem Cell Transplantation (HSCT). Reported clinical manifestations of HHV-6 infection in transplanted patients are skin rash, interstitial pneumonia, bone marrow suppression and encephalitis. Moreover, an increasing number of clinical reports suggest that HHV-6 can facilitate the occurrence of other severe clinical complications of allogeneic HSCT, including Graft-versus-Host Disease (GvHD), ultimately increasining transplant-related mortality. Still, the actual incidence of HHV-6 infection in recipients of HSCT and the causative link between infection and clinical complications remain elusive, mostly due to the small and heterogeneous patient cohorts analyzed to date. METHODS: From January 2009 to July 2011, we retrospectively evaluated 43 consecutive adult patients (median age 51 years) who developed positivity to HHV-6 after allogeneic HSCT for high-risk hematological malignancies. Stem cell donor was for 30 patients family haploidentical, for 5 an HLA identical sibling, and for 8 an unrelated volunteer (1 of which cord blood). The viral load was determined by quantitative PCR in cell-free body fluids such as plasma, bronchoalveolar lavage, cerebrospinal fluid, bone marrow aspirates or in gastrointestinal biopsies. At the time of positivity all patients were receiving acyclovir as viral prophylaxis except 5. Sixteen patients had clinical acute GvHD at time of HHV-6 positivity (grade III-IV in 14), and 33 were profoundly immunosuppressed with variable association of 2–4 immunosuppressive drugs (steroids included). Moreover concomitant CMV positivity was detected in 11 patients, while a severe neutropenia in 12. RESULTS: Median time from allogeneic HSCT to HHV-6 reactivation was 36 days (range: 7–625). In 19 patients HHV-6 was detected in plasma, with a median viral load of 19,454 cp/mL (34-4,524,600); 15 had concomitant fever, 5 skin rash of new onset, 4 impaired liver function, and 5 developed cytopenia subsequently to the infection. In 7 patients HHV-6 was detected in the bone marrow: the median viral load was 163'800 cp/mL (568-1'552'982). In 8 patients, all febrile, HHV-6 was observed in bronchoalveolar lavage samples with a median of 4'149 cp/mL (85–39250). In 16 patients, 10 with documented gut aGvHD, 11 with diarrhoea, HHV-6 was detected in gastrointestinal biopsies with a median of 7'510 cp/mL (120-4'524'600). HHV-6 was found in cerebrospinal fluid in 4 cases (all within 30 days after HSCT); the median viral load was 29'352 cp/mL (4'508-1'552'982); all these patients experienced encephalitis with confusion and anxiety, 2 suffered seizures and 3 showed abnormal findings on brain MRI. Amongst patients with organ localizations of HHV-6 only 28% had concomitant plasma positivity. HHV-6 positivity led to antiviral pharmacological treatment only when associated with clinical manifestations (n=21), using as first choice therapy foscarnet. Amongst the total 43 patients with documented HHV-6 positivity 11 completely solved the clinical event, whereas 19 (44%) died. CONCLUSIONS: HHV-6 infection/reactivation is associated with high morbidity and mortality in patients who undergo allogeneic HSCT. HHV-6 infection typically occurred close to the time of neutrophil engraftment. HSCT from an HLA-mismatched donor and steroid administration were associated with increased risk of active HHV-6 infection. Development of encephalitis was associated with high HHV-6 viral load. The regular monitoring of HHV-6 DNA in allogeneic HSCT recipients, using a real-time PCR assay, may be useful for identifying active HHV-6 infection and for the introduction of a pre-emptive treatment, possibly reducing the incidence of the most severe clinical complications. Disclosures: No relevant conflicts of interest to declare.

Human Herpes Virus 6 Reactivation and Disease After Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4539-4539
Author(s):  
Raffaella Greco ◽  
Francesca Lorentino ◽  
Lara Crucitti ◽  
Luca Vago ◽  
Maria Teresa Lupo Stanghellini ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Stem Cell ◽  
Viral Load ◽  
Hematopoietic Stem Cell Transplantation ◽  
Acute Gvhd ◽  
Clinical Manifestations ◽  
P Value ◽  
Hematopoietic Stem ◽  
Clinical Complications

Background Human herpesvirus type 6 (HHV-6) is a member of the beta herpesvirus subfamily (genus Roseolovirus) and two distinct variants have been described: types A and B. HHV-6 infection is recognized as the cause of a febrile disease and exanthem subitum in early childhood. The infection rarely causes serious events in healthy individuals, but viral reactivation in immunocompromised patients is frequently associated with severe clinical manifestations. Above all HHV-6 is increasingly recognized as an opportunistic and potentially life-threatening pathogen in recipients of allogeneic hematopoietic stem cell transplantation (AlloSCT). Approximately 60% of solid organ transplant and 40% of patients undergoing alloSCT experience HHV-6 reactivation, mainly of variant B. Reported clinical manifestations of HHV-6 infection in transplanted patients are skin rash, interstitial pneumonia, bone marrow suppression and encephalitis. Moreover, some clinical reports suggest that HHV-6 can facilitate the occurrence of severe clinical complications of alloSCT, increasing transplant-related mortality. Methods From January 2009 to February 2013, we retrospectively evaluated 54 consecutive adult patients (median age 50 years) who developed positivity to HHV-6 after alloSCT for high-risk hematological malignancies. Stem cell donors were family haploidentical (37), HLA identical sibling (8), unrelated volunteer (6), cord blood (3). The viral load was determined by quantitative PCR (Nanogen Advanced Diagnostic S.r.L) in cell-free body fluids such as plasma, bronchoalveolar lavage (BAL), cerebrospinal fluid (CSF), bone marrow (BM) aspirates or in gastrointestinal biopsies. Results Median time from alloSCT to HHV-6 reactivation was 34 days (range: 0-705). Thirty-one patients presented HHV-6 positive in plasma, 9/54 in BM, 33/54 in gut biopsies or BAL, 7/54 in CSF. At the time of viral positivity all pts were receiving acyclovir as viral prophylaxis except five. Twenty-nine patients had acute graft versus host disease (GvHD). Twenty-two out of these twenty-nine patients experienced a grade III-IV acute GvHD, requiring high dose steroids in twenty-six cases. A concomitant CMV positivity was detected in 15/54 patients. The median absolute count of CD3+ lymphocytes was 262 cells/mcl. In 52/54 cases we reported HHV-6 clinical manifestations: fever (43), skin rash (22), hepatitis (19), diarrhoea (24), encephalitis (10), BM suppression (18), delayed engraftment (11). HHV-6 positivity led to antiviral pharmacological treatment in 37/54 cases, using as first choice therapy foscarnet. Amongst the total fifty-four patients with documented HHV-6 positivity thirty-one solved the clinical event. However the mortality rate was relatively high in this population (only 30% of patients were alive), mainly related to severe infections or GvHD. A better overall survival is significantly associated with CD3+ cells higher than 200/mcl (p-value 0.011) and time after alloSCT more than 2 months (p-value 0.035). In this analysis the overall survival was not significantly influenced by steroids administration, presence of acute GvHD, plasma viral load and organ involvement. Conclusions This retrospective study further demonstrates the correlation between HHV-6 reactivation and high morbidity and mortality rates in patients after alloSCT. Despite HHV-6 detection typically occurred in the first month after AlloSCT, a better immune reconstitution has the potential to improve the outcome. The regular monitoring of HHV-6 DNA, using a real-time PCR assay, may be useful for identifying active HHV-6 infection and for the introduction of a pre-emptive treatment, possibly reducing the incidence of the most severe clinical complications. Disclosures: Bonini: MolMed SpA: Consultancy.

scholarly journals Detection of Cells with Low Side Scatter and Dimmer CD45 Expression after Allogeneic Hematopoietic Stem Cell Transplantation Predicts Good Survival

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3207-3207
Author(s):  
Yoshimitsu Shimomura ◽  
Hayato Maruoka ◽  
Yotaro Ochi ◽  
Yusuke Koba ◽  
Yuichiro Ono ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Bone Marrow Transplantation ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Cumulative Incidence ◽  
Marrow Transplantation ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct

Abstract <Introduction> Hematogones are lymphoblast-like cells that increase transiently in the bone marrow and have a characteristic profile of normal B cell precursors co-expressing CD10 and CD19. A cluster of hematogones is often found in the region of low side scatter and dimmer CD45 expression (SSC low CD45 dim), which also includes lymphoid and myeloid precursors, basophils, and partial components of natural killer cells. However, in steady state healthy adult bone marrow, SSC low CD45 dim populations are hardly detectable. In the bone marrow of patients recovering from chemotherapy or bone marrow transplantation, SSC low CD45 dim populations occasionally appear, with the majority of the population consisting of hematogones, especially in patients in complete remission (CR). Studies have shown that increased hematogones in patients with high-risk hematological malignancies after allogeneic hematopoietic stem cell transplantation (HSCT) improved survival. The specific detection of hematogones is difficult because multicolor flow cytometry is necessary to exclude myeloid/lymphoid blasts in active leukemia patients. However, after allogeneic HSCT in patients with leukemia and confirmed CR or malignant lymphoma without bone marrow invasion, hematogones can be easily detected as cells with SSC low CD45 dim populations. <Patients and methods> This retrospective case analysis included 88 patients treated with allogeneic HSCT at our hospitals from October 2010 to November 2014. The cases included acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) in CR at the time of allogeneic HSCT, chemo-naïve or azacitidine-treated myelodysplastic syndrome (MDS) and malignant lymphoma (ML) or adult T cell leukemia/lymphoma (ATL) with marrow CR or without bone marrow invasion. We excluded 8 patients without engraftment. The remaining 80 patients underwent bone marrow aspiration around 28 days after HSCT and were confirmed to be in CR. Bone marrow cells were stained with APC-Cy7-conjugated CD45 and analyzed using FACSCanto. Patients were defined as being simply detected hematogones (SHG)-positive if 0.6%, which is the median proportion of SSC low CD45 dim cells in this study, or more of total nuclear cells were SSC low CD45 dim; the others were defined as SHG-negative. <Results> The median follow-up of survivors of our cohort was 773 (81-1593) days. Primary diagnoses were AML (n=36), ALL (n=21), MDS (n=8), and ML or ATL (n=15). They were treated with bone marrow transplantation (n=51), peripheral blood stem cell transplantation (n=6), and cord blood transplantation (n=23). Among them, 40 were SHG-positive and 40 were SHG-negative. Overall survivals (OS) at 2 years was 94.8% and 58.2% (p<0.001), event free survival (EFS) at 2 years was 94.9% and 46.5% (p<0.001). Cumulative incidence of relapse at 2 years was 5.1% and 34.0% (p<0.001), and cumulative incidence of treatment related mortality (TRM) at 2 years was 0% and 20.6% (p=0.0059) in SHG-positive and SHG-negative groups, respectively. Cumulative incidence of acute graft-versus-host disease (aGVHD) at day 100 was 68.3% and 65.5% (p=0.31) and for severe aGVHD (grade II-IV) was 31.8% and 36.3% (p=0.87) in SHG-positive and SHG-negative groups, respectively. Age ≥50 years, sex, hematopoietic cell transplant-comorbidity index over 2, disease risk index (DRI), myeloablative conditioning regimen and donor source were entered into multivariate analysis, which identified SHG-positive and a low or intermediate DRI as independently associated with a good prognosis. <Conclusion> Thus, the presence of SHG at day 28 predicts improved OS and EFS, and a lower incidence of relapse and TRM. This population of cells is easily detectable, providing useful information for outcome predictions. Patients without SSC low CD45 dim populations should be carefully observed after allogeneic HSCT. Disclosures No relevant conflicts of interest to declare.

Forodesine in Patients with Refractory/Relapsed T-ALL Can Induce Prolonged Stable Remission with Minimal Toxicity before and after Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5340-5340 ◽  
Author(s):  
Mattias Stelljes ◽  
Joachim Kienast ◽  
Björna Berning ◽  
Nicola Gokbuget ◽  
Dieter Hoelzer ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Before And After ◽  
Conditioning Therapy

Abstract Background: Forodesine is a potent, rationally designed purine nucleoside phosphorylase (PNP) inhibitor that elevates plasma 2′-deoxyguanosine (dGuo) and intracellular deoxyguanosine triphosphate (dGTP) levels, leading to T-cell apoptosis. It has shown promising clinical activity in patients with T-cell malignancies. Here we describe our experience with three patients with refractory or relapsed T-cell acute lymphocytic leukemia (T-ALL) who received IV forodesine before or after allogeneic transplant (pts. treated within an ongoing study from BioCryst Pharmaceuticals, Inc, Birmingham, Alabama, USA; ClinicalTrials.gov Identifier: NCT00095381). Methods: Forodesine was given at 40 mg/m2 for 5 days per week (1 cycle) for ≥6 cycles. Patients 1 and 2 received forodesine at 443 and 161 days after allogeneic hematopoietic stem cell transplantation (HSCT), respectively. Patient 3 received forodesine until 4 days before conditioning therapy prior to allogeneic HSCT. Results: Patient 1 with T-ALL was transplanted in the 2nd CR (10/10 HLA-identical sibling donor), after conditioning therapy and developed extensive wide-spread nodal relapse. After 2 weeks of forodesine, he had a very good partial response. The patient developed new-onset chronic graft-versus-host disease (GVHD) of the oral mucosa and lung during treatment. After 6 cycles, treatment was stopped and corticosteroids were given for the GVHD. This patient has been in CR3 (minimal residual disease [MRD]-negative by molecular analysis and complete donor cell chimerism) for >6 months and is no longer receiving immunosuppressives. Patient 2 is a 3-year-old girl with T-ALL who, following two induction failures, proceeded to uncomplicated 6/6 unrelated marrow transplantation in CR1. She had a bone marrow relapse 5 months after transplantation and was started on forodesine on study. After 2 weeks of treatment she achieved a CR, was MRD-negative by flow cytometry, and had 100% donor chimerism. By the middle of week 3 of treatment, she developed GVHD of the liver and was treated with cyclosporine and prednisone. Twice-weekly forodesine was restarted, and all laboratory parameters returned to normal and repeat bone marrow showed continuous CR2. This patient received forodesine twice weekly for 9 additional months and remains in CR with 100% donor chimerism for >12 months (she is no longer receiving forodesine). Patient 3, who had refractory T-ALL and disease progression shortly after relapse therapy with cladribine, cytarabine, and V16, achieved stable remission after 2 weeks of forodesine and completed 6 weeks of treatment. He then received conditioning therapy followed by an HSCT from a 10/10 HLA-identical sibling donor, and remains in CR2. No drug-specific adverse events of grade 2 or higher were seen in these patients. Conclusions: These encouraging experiences in patients with relapsed and refractory T-ALL suggest that forodesine monotherapy can be effective before and after allogeneic HSCT with minimal toxicity and without affecting potential graft-versus-leukemia effects. Forodesine Treatment in Patients before and after Allogeneic HSCT Patient No. Age/Gender Diagnosis HSCT (prior/post forodesine Tx) Response Disease Status 1 28/M T-ALL, relapse Prior PR CR ongoing 215+ days 2 3/F T-ALL, relapse Prior CR CR ongoing 398 + days 3 27/M T-ALL, refractory Post CR CR ongoing 180+ days

Syngeneic and Allogeneic Hematopoietic Stem Cell Transplantation In Mice With Myelodysplastic Syndrome

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1515-1515
Author(s):  
Yang Jo Chung ◽  
Terry J Fry ◽  
Peter D Aplan
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Relapse Rate ◽  
Post Transplantation ◽  
Hematopoietic Stem ◽  
Clinical Model ◽  
Allogeneic Hsct ◽  
Relapse Rates

Abstract The myelodysplastic syndromes (MDS) are clonal hematopoietic malignancies characterized by dysplasia, ineffective hematopoiesis and a propensity for progression to acute myeloid leukemia (AML). Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative therapy for the majority of patients. However, overall survival (OS) of patients with MDS following allogeneic HSCT is only about 40%, due to both relapse and non-relapse mortality (NRM) including graft versus host disease (GVHD). Available data suggests that long-term survival following HSCT for MDS is due both to myeloablative therapy and a graft versus tumor (GVT) effect. Mice that express a NUP98-HOXD13 (NHD13) transgene develop MDS with virtually 100% penetrance. In order to develop a pre-clinical model for the study of MDS HSCT, we transplanted NHD13 mice, which are bred on a C57 Bl6 background, with bone marrow harvested from syngeneic C57Bl6 donors. Sub lethally irradiated (650 rad) recipient NHD13 mice transplanted with syngeneic donor cells relapsed early, with no therapeutic benefit in terms of hematologic parameters in peripheral blood or survival. However, lethally irradiated (1000 rad) recipient mice that were transplanted with syngeneic donor bone marrow (BM) showed complete normalization of peripheral blood counts significantly enhanced survival (median survival of 15 months) compared with non-transplanted NHD13 mice (median survival 10 months). Although there were no detectable MDS cells for up to 38 weeks post-transplant, all mice eventually relapsed and died. In order to determine if a GVT effect could enhance survival, we performed 3 types of allogeneic HSCT with donor BM that was mismatched at minor histocompatibility antigen loci (C3H.SW x C57Bl6 donors); donor BM only, donor BM with donor splenocytes (6 x 10E06 CD3+ T cells), and donor BM with donor regulatory T cells (Treg). None of these forms of allogeneic HSCT let to enhanced survival compared to that achieved with syngeneic HSCT. The early relapse rate for allogeneic HSCT with donor BM only was decreased compared to the syngeneic HSCT group (8.3% vs 28% at post-transplantation week 6 and 17% vs 43% at post-transplantation week 16); however, the relapse rate at 38 weeks was similar between the two groups (83.3% vs 85.7%). Adding donor splenocytes, containing reactive T-cells, dramatically decreased the relapse rate, such that the relapse rate was only 20% at post-transplantation week 38, suggesting a GVT effect. This GVT effect was accompanied by a severe GVH effect, and OS was not different between the allogeneic BM + splenocyte and the syngeneic HSCT groups. In an attempt to induce a GVT effect without a severe GVHD, we transplanted allogeneic Treg cells along with allogeneic BM, however, survival and relapse rates were similar to those with allogeneic BM only. Taken together, these findings suggest that a lethal dose of ionizing radiation (1000 rads) is insufficient to eradicate the MDS initiating cell, and that transplantation of donor CD3+ splenocytes leads to decreased relapse rates, but at the cost of severe GVHD. We suggest that the NHD13 mice are a feasible pre-clinical model for the study of HSCT for MDS. Disclosures: No relevant conflicts of interest to declare.

A Novel Prognostic Factor for Allogeneic Hematopoietic Stem Cell Transplantation Based on Bone Marrow Assessment on the Day of Stem Cell Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3471-3471
Author(s):  
Takahiko Sato ◽  
Naomi Kawashima ◽  
Masafumi Ito ◽  
Yoshiko Atsuta ◽  
Yusuke Kagaya ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Confidence Interval ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Residual Disease ◽  
Bone Marrow Aspiration ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct

Abstract [Introduction] Many factors predicting the outcomes of allogeneic hematopoietic stem cell transplantation (HSCT) recipient have been reported so far and widely used to assess the potential risk of undergoing allogeneic HSCT. Residual disease is considered one of the risk factors in HSCT, and mainly evaluated by bone marrow aspiration before HSCT. However, disease statuses at the point of stem cell infusion potentially differ from that of pre-transplant evaluation depending on the sensitivity for conditioning therapy or proliferation speed of the blast. In this study, we assessed residual disease by bone marrow aspiration on the day of stem cell transplantation (called "day 0" of HSCT) in order to analyze the relationship between day 0 marrow statuses and HSCT outcomes. [Methods] This study was designed as a retrospective observational analysis, and we collected the patients who received first allogeneic HSCT for hematological malignant diseases between 2010 and 2014. Extramedullary diseases were excluded from the analysis. All HSCTs were consecutive and performed in our center. Bone marrow aspirated material was examined histopathologically, and residual blasts were evaluated by specific markers by immunostaining. If it has detected residual blasts even if only a few cells, it was defined non complete remission (CR) on day 0 (abbreviated as "non-day0CR"). We divided the patients into two groups according to the existence of residual blast in bone marrow on day 0 of HSCT. [Results] We analyzed 121 HSCT recipients including 35 with acute lymphoblastic leukemia, 3 with acute undifferentiated leukemia, 65 with acute myeloid leukemia, 17 with refractory anemia with excess blasts and 1 with blast phase of chronic myelogenous leukemia. The median follow-up of survivors was 983 days (range 330 - 2092 days), and overall survival (OS) was 72% (95% confidence interval: 63 - 79%) at 1 year after HSCT. In univariate analyses, age higher than median 44 year-old, non-CR at the time of pre-HSCT assessment, hematopoietic cell transplantation specific comorbidity index (HCT-CI) at least 1 point, reduced intensity conditioning, and non-day0CR were extracted as predictors of poor OS. With multivariate analysis, HCT-CI and day 0 marrow status were significantly associated with OS. Furthermore, when patients were limited to pre-transplant non-CR subgroup, the patients achieving complete malignancies-free state on day 0 showed comparable prognosis with those who maintained CR before conditioning (Figure 1). Relapse after allogeneic HSCT was observed in 31 patients, and cumulative incidence of relapse was 11% (95% confidence interval: 6 - 17%) at 1 year after HSCT. With univariate and multivariate analyses, there were significant differences between the patients with CR marrow and those with residual malignancies on day 0 (P = 0.002). There was no significant difference in non-relapse mortality between the two groups (P = 0.18). [Conclusions] We showed that bone marrow status on day 0 was significantly associated with OS and cumulative incidence of relapse. To our knowledge, this is the first report about the association with day 0 marrow status and post-HSCT prognosis. A malignancies-free state on day 0 could predict favorable prognosis in allogeneic HSCT, and the patient with residual malignancies on day 0 had lower OS and higher relapse rate. For the patients with residual malignancies on day 0, rapid tapering of immunosuppressant or arrangement of scheduled donor lymphocyte infusion may improve the outcomes. Disclosures Miyamura: Nippon Shinyaku CO, LT: Honoraria; Pfizer Inc: Honoraria; Novartis Pharmaceutical: Honoraria; Alexion Pharmaceutical Inc: Honoraria.

scholarly journals A Step Forward Towards Cytomegalovirus Free Hematopoietic Stem Cell Transplantation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5708-5708
Author(s):  
Alfaraj Abeer ◽  
Daniel R Reed ◽  
Gina Petroni ◽  
Sandra Monson ◽  
Paige Williams ◽  
...  
Keyword(s):  
Stem Cell ◽  
Viral Load ◽  
Hematopoietic Stem Cell Transplantation ◽  
Median Time ◽  
Preemptive Therapy ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Post Transplant ◽  
Cmv Disease ◽  
Cmv Reactivation

Abstract Introduction: Cytomegalovirus (CMV) reactivation remains one of the most serious complications after allogeneic hematopoietic stem cell transplantation (HSCT) occurring in up to 30-50% of HSCT recipients. CMV reactivation can lead to adverse outcomes including end-organ damage and graft failure. Prevention of CMV infection may improve outcomes of HSCT recipients; however, CMV reactivation can still occur in HSCT recipients despite receiving prophylactic acyclovir. In this study, we used prophylactic ganciclovir pre-transplant to reduce the incidence of CMV reactivation and CMV disease. Methods: To reduce the incidence of CMV reactivation and disease, ganciclovir was administered before transplantation (5 mg/kg twice daily intravenously from day −8 to day −2) for all donor and recipient seropositive allogeneic HSCT. This was followed by high dose valacyclovir or acyclovir starting day 0 until one year post-transplant. Patients were monitored weekly with serum CMV PCR through Day 100 post transplantation. Preemptive therapy was started for an elevated CMV viral load. CMV reactivation was defined as a CMV viral load of more than 135 IU/ml. Over the course of the analysis period, two different PCR methods were used for CMV viral load; since 2015 Roche Cobas AmpliPrep/Cobas TaqMan CMV test was implicated. CMV disease was defined as detection of CMV by one of the following diagnostic tests including: culture, immunohistochemistry staining, or histopathology examination accompanied by documentation of disease signs and symptoms of the affected organ. Statistical analysis was performed using SAS version 9.4. Logistic regression models were explored to assess the association of age, graft source, and disease type on CMV reactivation. We performed a retrospective analysis of all recipient or donor CMV seropositive patients who received their first allogeneic HSCT at the University of Virginia between 2012 and 2017. Results: Seventy-nine consecutive patients were treated. The median age was 58 years (range 20 to 72). The most common diagnoses were acute myeloid leukemia (n=39, 49%) and acute lymphocytic leukemia (n=11, 14% ). Graft sources were matched related donor, (n=24, 30%), matched unrelated donor, (n=28, 35%), haploidentical (n=4, 5%) and cord blood (n=23, 29%). 43 patients (55%) received myeloablative (CyTBI, BuCy and FluBu) conditioning. 36 patients (45%) received reduced intensity/nonmyeloablative conditioning (Flu/Cy/TBI+/- ATG, Flu/Cy/ATG ,Flu Mel, Flu Bu and Cy ATG). All patients received calcineurin inhibitor based prophylactic immunosuppressive therapy for GVHD prevention. 24 patients (30%) had CMV reactivation with median time of reactivation of 47 days post-transplant (range 27 to 229). 22 out of the 24 (88%) patients required treatment for CMV reactivation with a median treatment duration of 37 days (range 14 to 315). Patients were treated with either ganciclovir or foscarnet, as clinically indicated. The cumulative incidence of CMV reactivation at day 100 post-transplant was 27% with a 95% CI (18%-37%). The median highest viral load was 2130 copies/ml (range 151 to 3,250,000 copies/ml). There were no patients with biopsy proven CMV disease. There were no deaths attributed to CMV reactivation or disease. The median time-to neutrophil recovery (ANC > 500 k/uL) was 18 days and the median time to platelet count greater than 20,000 k/ul unsupported was 19 days. The incidence of acute GVHD (Grades II-IV) was 25 %. The incidence of significant acute kidney injury defined by serum creatinine of more than 2.5 mg/dL was 2.4 %. 1 year overall survival estimate was 54% with 95% CI (42-65%). In multivariate analysis, patients who received cord blood transplants, were approximately 4 times more likely to have a CMV reactivation (Odds Ratio 3.9 with a 95% CI(1.4-10.9)), p= 0.01, than those who did not. Conclusions:The incidence of CMV reactivation by day 100 of 27% with pre-transplant ganciclovir may be improved compared to historical controls of 30-50%.The use of pre-transplant ganciclovir was associated with no CMV disease, in this single center study.The use of pre-transplant ganciclovir is safe, with low incidence of kidney damage. These data suggest that pre-transplant ganciclovir with Preemptive therapy for viral reactivation should be considered regardless of graft source. Future prospective randomized trials are needed to evaluate strategies for CMV prophylactic regimens. Disclosures No relevant conflicts of interest to declare.

Monitoring of Bone Marrow Chimerism after Allogeneic Hematopoietic Stem Cell Transplantation – Evaluation of a qPCR Based Chimerism Assay

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3866-3866 ◽  
Author(s):  
Roland Reibke ◽  
Andrea Dick ◽  
Max Hubmann ◽  
Eva Hoster ◽  
Reinhard Henschler ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Early Detection ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Donor Chimerism

Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) has become a valuable therapeutic option for malignant and non-malignant hematological diseases. Engraftment of donor cells is confirmed by repetitive testing for donor chimerism. Since the underlying malignant disease is host derived, the decrease of donor chimerism might precede or indicate the imminent relapse, enabling early intervention and presumably better outcome. STR-assay (Short-Tandem-Repeats-Assay) and XY-FISH (XY based Fluorescence in Situ Hybridization) respectively are routinely performed after HSCT. Furthermore CD34+ cell- chimerism and quantification of minimal residual disease in patients with informative markers might be used to detect early relapse. In this prospective, non-interventional study we evaluated the accuracy, reliability and feasibility of a qPCR based commercially available assay (Allele SEQR® Chimerism Assay, Abbott). In addition, the early detection of hematological relapse was analyzed as a clinical readout. Between May 2011 and January 2013 95 patients received allogeneic HSCT for MDS or acute leukemia (AML = 84) at our transplantation unit and were therefore included in our analysis. According to our local standard bone marrow samples were collected at standardized time points including days 30, 90, 180. The qPCR based Allele SEQR® Chimerism Assay consists of two parts: screening for discriminating, informative markers and subsequent actual quantification of the host DNA. For assay validation 68 patients were suitable. In all patient/donor pairs at least one informative marker could be found and quantitative results could be achieved. In 65/68 pairs (95.6%) even ≥ 2 markers could be identified, however, among 28 related donors three (10.7%) only revealed one discriminating marker. The sensitivity of the assay was proven by means of artificially spiked DNA samples mimicking an amount of 0.1%, 0.05% and 0.01% of “host“ DNA respectively. Testing was performed with 100ng/well patient DNA. The overall time needed for testing was less than four hours. We identified 61 patients with at least two samples in cytomorphological complete remission (CR) after allogeneic HSCT. The overall hematological relapse rate in our cohort was 23% until March 2014. To enable relapse prediction we quantified donor chimerism in CR samples. Scoring for suspicious results by the increase of host chimerism by at least one percent point, but not less than one third as compared to previous testing, was highly predictive for imminent relapse (overall relapse rate 86% vs. 15%, p=<0,001, Mantel-Byar Test). Median time from increased host chimerism to relapse was 68 days (25-201). Furthermore no patient relapsed within 120days without prior positive testing. The evaluated qPCR approach proved as a fast and highly sensitive tool for chimerism monitoring after HSCT. It may allow an early detection or exclusion of imminent relapse, enabling chimerism triggered therapy. In perspective we will validate this assay for peripheral blood samples, allowing more convenient and frequent testing. Disclosures Reibke: Abbott molecular Germany: Research Funding.

scholarly journals HUMAN HERPES VIRUS TYPE 6 INFECTION IN CHILDREN AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION IN THE REPUBLIC OF BELARUS

2020 ◽  
pp. 409-418
Author(s):  
E.P. KISHKURNO ◽  
◽  
T.V. AMVROSIEVA ◽  
YU.E. MAREYKO ◽  
E.V. DIVAKOVA ◽  
...  
Keyword(s):  
Stem Cell ◽  
Viral Load ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Blood Serum ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Clinical Manifestations ◽  
Hematopoietic Stem ◽  
The Republic

Objective: To evaluate the frequency of reactivation of HHV-6 infection in patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT); determine viral load in serum/plasma and associated clinical manifestations; to determine the criteria for initiating anti-viral prophylaxis and etiotropic therapy in patients with this infection in the Republic of Belarus. Methods: Monitoring of polymerase chain reaction (PCR) of blood serum in 42 patients after allo-HSCT. Results: In 31% of patients, HHV-6 DNA was detected in serum/plasma on 14-28 days after allo-HSCT. The concentration of HHV-6 DNA in blood serum was up to 2.3-6.5×103 copies/ml, in 3 patients (18.8%) with the concentration of DNA≥2.3×103 copies/ml, developed clinical manifestations in the form of hepatitis. Regular monitoring of HHV-6 infection revealed reactivation of the infection and, with a viral load of≥100 copies/ml, initiate timely preventive treatment with ganciclovir. Conclusions: HHV-6 DNA is detected in one-third of patients after allo-HSCT and in the form of hepatitis. Timely prevention and therapy with ganciclovir reduce the risk of severe complications and fatal outcomes. Keywords: Children, HHV-6, hematology, stem cells transplantation, hepatitis.

Allogeneic Hematopoietic Stem Cell Transplantation for Myeloma: Does the Melphalan Dose Matter?.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3035-3035
Author(s):  
Jayesh Mehta ◽  
Sandeep Chunduri ◽  
Lisa Dobogai ◽  
Seema Singhal ◽  
Damiano Rondelli
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Bone Marrow Transplantation ◽  
Hematopoietic Stem Cell Transplantation ◽  
Performance Status ◽  
Hematologic Malignancies ◽  
Refractory Disease ◽  
Donor Age ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct

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.

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