scholarly journals Impact of clinical factors and allograft leukocyte content on post-transplant lymphopenia, monocytopenia, and survival in patients undergoing allogeneic peripheral blood haematopoietic cell transplant

2014 ◽  
Vol 14 (1) ◽  
Author(s):  
Mary D Thoma ◽  
Jennifer Glejf ◽  
Eapen Jacob ◽  
Tanya J Huneke ◽  
Lori J DeCook ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Cell Transplant ◽  
Clinical Factors ◽  
Post Transplant ◽  
Haematopoietic Cell

High-Throughput Sequencing Of T Cell Receptors Detects Signatures Of T Cell Repertoire That Predict MRD Status In Patients With Mantle Cell Lymphoma Undergoing Immunotransplantation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4251-4251
Author(s):  
Malek Faham ◽  
Joshua Brody ◽  
Holbrook E Kohrt ◽  
Debra K Czerwinski ◽  
Ronald Levy
Keyword(s):  
T Cell ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Cell Vaccine ◽  
Cell Transplant ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Blood Samples ◽  
Post Transplant ◽  
Before And After

Background A clinical trial is ongoing at Stanford for MCL patients in first remission that interdigitates an autologous CpG-stimulated tumor cell vaccine with autologous peripheral blood stem cell transplant (PSCT) (NCT00490529). In this trial, blood samples collected before and after vaccination and serially post-transplant are assayed for minimal residual disease (MRD) and for T cell repertoire using the LymphoSIGHT™ sequencing method (Faham et al., Blood 2012). We identified a set of T cell clones that appear to be responding to the vaccine, and therefore we investigated whether the number of these clonotypes was correlated with MRD status. Methods Using universal primer sets, we amplified rearranged IgH variable (V), diversity, and joining (J) gene segments from genomic DNA. Amplified products were sequenced to obtain >1 million reads. The B cell tumor-specific sequence was identified for each patient based on its high frequency in the original tumor biopsy. The presence of the tumor cells was then monitored in serial blood samples with a sensitivity of 1 cell per million leukocytes. The same blood samples were used for amplification, sequencing and analysis of the entire TCRβ repertoire. To facilitate identification of tumor vaccine-induced TCRβ clonotypes, we sequenced the TCRβ repertoire immediately before and after the administration of both the priming vaccination and a booster vaccination. We developed a metric called the vaccine response score (V score). This metric is calculated for each clonotype and reflects the increase in frequency after the initial vaccination AND after the boost. The formula for calculating V score is: V = F1 x F2 x square root [1/ (|F1 – F2| + 1)], where F1 and F2 represent the fold-change of the priming and boost vaccinations, respectively. Clonotypes with a V score >10 were deemed to be vaccination-induced by virtue of these frequency changes. Results In a series of 12 vaccinated patients, the number of clonotypes with V score ≥ 10 ranged between 0 and 262, with a median of 57. We utilized an antigen-specific analysis to validate that clones with high V scores (≥ 10) were in fact tumor-specific. For this analysis, we incubated peripheral blood mononuclear cells (PBMCs) with the tumor and then sequenced the TCRβ repertoire from cells obtained after culture. Clones that were enriched after culture compared to pre-stimulation PBMCs were deemed to be antigen-specific. These clones that are antigen-specific are highly likely to have a high V score compared to a random frequency-matched set of clones (P two tailed = 1.8 x 10-10), providing further evidence that clones with a high V score are tumor-specific. We then analyzed the relationship between V score and clinical outcome. Patients could be stratified into two groups with “high” (> 25) or “low” (<25) numbers of vaccine-responsive clonotypes. Patients in the high V score group, who had larger numbers of putative tumor-specific T cells, were more likely to have sustained molecular remission during the first-year post-transplant compared with patients in the low V score group (P = 0.018) (Figure 1). Conclusions T cell repertoire analysis identified clonotypes responding to the vaccination, and the presence of these vaccine-specific clonotypes correlates with MRD positivity at the important landmark of one year post-PSCT. Further analysis of additional patients enrolled on the MCL trial is ongoing. This data underscores the prognostic relevance of the sequencing-based V score metric and provides a novel approach for assessment of cancer immunotherapy responses. Disclosures: Faham: Sequenta: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees.

Case Report: Haploidentical Stem Cell Transplantation In a 78 Year-Old Patient

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5468-5468
Author(s):  
Thiago Xavier Carneiro ◽  
André Domingues Pereira ◽  
Theodora Karnakis ◽  
Celso Arrais Rodrigues
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Peripheral Blood ◽  
High Dose ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Post Transplant

Abstract An older chronologic age has been a consistent predictor of poor outcomes in hematopoietic stem cell transplantation (HSCT), mainly due to non-relapse mortality (NRM). Therefore, non-curative treatment strategies are commonly adopted for these patients. However, mortality and treatment toxicity has decreased as a result of improved supportive measures, such as reduced intensity conditioning regimens and optimized infection management. T-cell replete haploidentical HSCT emerged as a feasible alternative for leukemia patients without substantial differences in outcomes when compared to fully matched related donor. We report an old adult woman treated with haploidentical HSCT. A 78 year-old female patient presented with anemia, leukocytosis, thrombocytopenia and blasts in the peripheral blood. Diagnosis of acute myelogenous leukemia was established. Conventional cytogenetic demonstrated chromosome eight trisomy, and FISH was negative for other common MDS/AML cytogenetic abnormalities. FLT3-ITD and NPM1 mutations were negative. Her medical history was negative except for heavy smoking. Considering the patients advanced age, the first attending physician chose not to administer intensive treatment and started on decitabine 20 mg/m2 for 5 days. She was refractory to the first-line treatment with persistent cytopenias and blasts in the peripheral blood four weeks after treatment was started. Comprehensive geriatric assessment was performed. She was considered independent for Basic Activities of Daily Living (ADL score 6) and Instrumental Activities of Daily Living (IADL score 27), without cognitive impairment in mini-mental state examination (MMSE score 30), at risk of malnutrition in mini nutritional assessment (MNA 9). As she was considered fit, we decided to perform high-dose chemotherapy with idarubicin and cytarabine, but, once more, the disease was refractory. A rescue regimen was attempted with high-dose cytarabine and mitoxantrone, again, with no response. After discussing pros and cons with the patient and the family, we decided to start Another regimen consisting of topotecan and high dose cytarabine immediately followed by allogeneic hematopoietic stem cell transplantation (HSCT). At day 14, she had 3% blasts in the BM aspirate a T-cell replete haploidentical HSCT using her 52 year-old son as donor and mobilized peripheral blood as stem cell source was performed. Conditioning regimen consisted of fludarabine, cyclophosphamide, TBI 2Gy and post-transplant cyclophosphamide. Graft versus host disease (GVHD) prophylaxis consisted of mycophenolate mofetil and cyclosporine. She had neutrophil engraftment with complete donor chimerism at day+15 and platelet engraftment at day+17. At day+48, she had mild (stage II) skin acute GVHD resolved with topical steroids. Cyclosporine was withdrawn at day+ 93. Due to high relapse risk, the patient was started on monthly post-transplant azacitidine 36 mg/m2. At day+100 the patient remained in complete remission, complete donor chimerism in peripheral blood and bone marrow. Functionality was preserved (ADL score 6 and IADL score 24), presented discrete cognitive impairment (MMSE 28) and malnoutrition (MNA 5). She is now at day+182, doing well and performing again all usual daily activities. To the best of our knowledge, this is the oldest patient treated with haploidentical HSCT. Post transplant cyclophosphamide as T cell depletion strategy in haploidentical HSCT is well tolerated and widely available, being therefore an excellent alternative for patients without conventional donors who require immediate transplant. Older adults with hematologic malignancies are a heterogeneous group and decisions based on chronological age alone are clearly inappropriate. Recently, geriatric assessment proved to be an important prognostic tool in acute leukemia and may be useful in HSCT. In experienced centers, haploidentical HSCT in older adults may be a safe procedure and more accurate pre-transplantation risk stratification tools should be developed. Figure 1 Timeline of main events during hematopoietic stem cell transplant. Figure 1. Timeline of main events during hematopoietic stem cell transplant. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Increased Early Mortality After Fludarabine and Melphalan Conditioning with Peripheral Blood Grafts in Haploidentical Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide

2021 ◽  
Author(s):  
Luke Eastburg ◽  
David Russler-Germain ◽  
John DiPersio ◽  
Thomas Fountaine ◽  
Jeffrey Andolina ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Peripheral Blood ◽  
Hematopoietic Cell Transplantation ◽  
Disease Free Survival ◽  
Hematopoietic Cell ◽  
High Rate ◽  
Cell Transplant ◽  
Post Transplant ◽  
Conditioning Regimens ◽  
Haploidentical Hematopoietic Cell Transplantation

Abstract Due to the evolving use of haploidentical donor grafts in hematopoietic cell transplantation, there is increased need to better understand the risks and benefits of using bone marrow versus peripheral blood grafts, as well as how specific pre-transplantation conditioning regimens impact patient safety and treatment outcomes. We performed a retrospective analysis of 38 patients at two centers who specifically underwent haploidentical hematopoietic cell transplantation using fludarabine plus melphalan-based conditioning regimens with post-transplant cyclophosphamide and peripheral blood donor grafts. We observed an unexpectedly high rate of early non-relapse mortality of 21% at 100 days and 34% at 1-year. In addition, 40% of all patients suffered from severe cytokine release syndrome and 45% of all patients suffered from kidney injury, often necessitating renal replacement therapy. The poor outcomes with 1-year overall survival of 34%, disease-free survival of 29%, and non-relapse mortality of 34% motivate us to reconsider the appropriateness of the combination of fludarabine and melphalan conditioning with T-cell replete peripheral blood grafts in the setting of haploidentical hematopoietic cell transplant with post-transplant cyclophosphamide.

Transmission of Chromosomally Integrated HHV6 by Allogeneic Peripheral Blood Stem Cell Transplantation Associated with the Development of a Fatal Macrophage Activation (Haemophagocytic) Syndrome.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5278-5278
Author(s):  
Mark Crowther ◽  
Pamela Molyneaux ◽  
William F. Carman ◽  
Kate N. Ward ◽  
Dominic J. Culligan
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Peripheral Blood ◽  
Macrophage Activation ◽  
Stem Cell Transplant ◽  
Peripheral Blood Stem Cell ◽  
Cell Transplant ◽  
Chromosomal Integration ◽  
Post Transplant

Abstract It is estimated that at least 1% of the UK population have chromosomal integration of HHV6 leading to persistently high levels of detectable viral DNA (Clark DA et al, JID2006: 193, p912–916). As far as we are aware transmission of integrated HHV6 by allogeneic stem cell transplantation has been described in the literature on only one previous occasion and this was not associated with disease (Clark DA et al, JID2006:193, p912–916). Indeed it remains controversial as to whether HHV6 ever causes disease in the post transplant setting. A 35-yr-old male with a past history of treated Hodgkins lymphoma (HL) developed stage 4 diffuse large B-NHL (DLBL). He achieved a CR with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) + rituximab × 8 cycles but subsequently relapsed. Following salvage chemotherapy with IVE (ifosfamide, etoposide, epirubicin) + rituximab × 3 cycles he underwent a fully HLA matched sibling allogeneic peripheral blood stem cell transplant in second CR of the DLBL using BEAM (carmustine, etoposide, cytarabine, melphalan) + alemtuzumab conditioning. On day +32 he presented with fever, pneumonitis and pancytopenia. Bone marrow examination revealed haemophagocytosis of red cells and platelets. He had a mild coagulopathy and grossly elevated ferritin (63,303 ug/l). A diagnosis of macrophage activation syndrome (MAS) probably secondary to infection was made. Cultures of blood, urine and broncho-alveolar lavage (BAL) were negative apart from HHV6 levels of 62,000 DNA copies/ml in serum. There was no clinical or radiological evidence of relapse of HL or DLBL and no evidence of CMV reactivation. He deteriorated despite intensive care unit support and treatment with broad spectrum antibiotics, aciclovir, cidofovir, caspofungin and cyclosporin-A. He showed slight improvement with high dose steroids but died on day +78. Further investigations revealed the patient was negative for serum HHV6 immediately prior to transplantation whilst his donor had very high levels of serum HHV6 (750,000 DNA copies/ml) suggestive of chromosomal integration (Ward KN et al, J Clin Microbiology2006: 44, p1571–1574). It is, therefore, highly likely that HHV6 was transmitted via the allogeneic stem cell transplant. The case raises some difficult issues in relation to the management of post transplant complications that maybe virally driven. Chromosomally integrated HHV6 is not thought to cause active infection and it has been suggested, therefore, that post-transplant patients demonstrating high levels of HHV6 should be investigated for chromosomal integration in the donor and if present not subsequently treated with potentially toxic anti-viral drugs. However, HHV6 has been associated with MAS in the non transplant setting. In our case HHV6 was the only identifiable infectious agent during this severe illness. Given the association of HHV6 with MAS and the uncertain pathogenecity of integrated HHV6 in the context of post transplant immune dysregulation, this scenario makes diagnosis and treatment challenging.

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