A Prognostic Score for Patients with Acute Leukemia or Myelodysplastic Syndromes Undergoing Allogeneic Stem Cell Transplantation

AbstractAllogeneic hematopoietic stem cell transplantation (SCT) has the potential to cure patients with acute leukemia or myelodysplastic syndromes (MDS), but a number of prognostic factors can influence the outcome of transplantation. At present, no transplantation-specific risk score exists for this patient population. We propose a simple scoring system for patients with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), or MDS, based on a retrospective analysis of 445 patients undergoing SCT at our institution (divided into training and validation subsets). The score depends on 5 variables: age, disease, stage at transplantation, cytogenetics, and pretransplantation ferritin. It divides patients into 3 groups of comparable size, with 5-year overall survival (OS) of 56% (low risk), 22% (intermediate risk), and 5% (high risk). This prognostic score could be useful in making treatment decisions for individual patients, in stratifying patients entering clinical trials, and in adjusting transplantation outcomes across centers under the new federal reporting rules

Genetic characterization of Barbari goats using microsatellite markers

Genetic variation in Barbari goats, a highly prolific breed distributed widely in the northern part of India, known for better milk and meat quality, was studied as a part of genetic characterization and conservation. The genomic DNA from 50 unrelated Barbari goats were amplified via PCR with a panel of 21 microsatellite markers, and resolved through 6 per cent denaturing polyacrylamide gel electrophoresis followed by silver staining. The number of alleles ranged from 4 to 11, with allele sizes ranging from 88 to 220 bp. The distribution of allele frequencies was between 0.0104 and 0.5208. Polymorphism information content varied from 0.5563 to 0.8348. The population was not in Hardy-Weinberg equilibrium for all except two microsatellite loci (ILSTS044 and ILSTS060). The observed heterozygosity ranged from 0.8478 to 1.0000 while the expected heterozygosity ranged from 0.6208 to 0.8509. Based on the results of the present study, there is a good scope for exploiting the genetic variability in the Barbari goats for further improvement of performance

Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials.

The optimal treatment of acute myeloid leukemia (AML) in first complete remission (CR1) is uncertain. Current consensus, based on cytogenetic risk, recommends myeloablative allogeneic stem cell transplantation (SCT) for poor-risk but not for good-risk AML. Allogeneic SCT, autologous transplantation, and consolidation chemotherapy are considered of equivalent benefit for intermediate-risk AML

Long-Term Follow-up of Reduced Intensity Allogeneic Stem Cell Transplantation for Chronic Lymphocytic Leukemia: Prognostic Model to Predict Outcome

CLL remains incurable with chemoimmunotherapy, and allogeneic hematopoietic stem cell transplantation (HSCT) offers potential for cure. We assessed the outcomes of 108 CLL patients undergoing first allogeneic HSCTs, 76 with reduced intensity (RIC) and 32 with myeloablative (MAC) conditioning between 1998 and 2009 at Dana-Farber Cancer Institute. With median follow-up 5.9 years in surviving patients, the 5 year OS for the entire cohort is 63% for RIC regimens and 49% for MAC regimens (p=0.18). The risk of death declined significantly starting in 2004 and we found that 5 year OS for HSCT between 2004–2009 was 83% for RIC regimens compared to 47% for MAC regimens (p=0.003). For RIC transplantation, we developed a prognostic model based on predictors of PFS, specifically remission status, LDH, comorbidity score and lymphocyte count, and found 5-year PFS 83% for score 0, 63% for score 1, 24% for score 2, and 6% for score >= 3 (p<0.0001). We conclude that RIC HSCT for CLL in the current era is associated with excellent long-term PFS and OS, and, as potentially curative therapy, should be considered early in the disease course of relapsed high-risk CLL patients

A Bortezomib-Based Regimen Offers Promising Survival and Graft-versus-Host Disease Prophylaxis in Myeloablative HLA-Mismatched and Unrelated Donor Transplantation: A Phase II Trial

AbstractHematopoietic stem cell transplantation (HSCT) recipients lacking HLA-matched related donors have increased graft-versus-host disease (GVHD) and nonrelapse mortality (NRM). Bortezomib added to reduced-intensity conditioning can offer benefit in T cell–replete HLA-mismatched HSCT and may also benefit myeloablative conditioning (MAC) transplants. We conducted a phase II trial of short-course bortezomib plus standard tacrolimus/methotrexate after busulfan/fludarabine MAC in 34 patients with predominantly myeloid malignancies. Fourteen (41%) received 8/8 HLA-matched unrelated donor (MUD) and 20 (59%) received 7/8 HLA-mismatched related/unrelated donor peripheral blood stem cell grafts. Median age was 49 years (range, 21 to 60), and median follow-up was 25 months (range, 11 to 36). The regimen was well tolerated. No dose modifications were required. Neutrophil and platelet engraftment occurred at a median of 14 (range, 10 to 33) and 17 (range, 10 to 54) days, respectively. Median 30-day donor chimerism was 99% (range, 90 to 100), and 100-day grades II to IV and III to IV acute GVHD incidence was 32% and 12% respectively. One-year chronic GVHD incidence was 50%. Two-year cumulative incidence of both NRM and relapse was 16%. Two-year progression-free and overall survival rates were 70% and 71%, respectively. Outcomes were comparable to an 8/8 MUD MAC cohort (n = 45). Immune reconstitution was robust. Bortezomib-based MAC HSCT is well tolerated, with HLA-mismatched outcomes comparable with 8/8 MUD MAC HSCT, and is suitable for randomized evaluation. (clinicaltrials.gov: NCT01323920.

dynamics of immune cell reconstitution in allogeneic hematopoietic cell transplant patients receiving post transplant cyclophosphamide ptcy

In the setting of haploidentical hematopoietic cell transplantation (haplo-HCT), post-transplant cyclophosphamide (PTCy) selectively eliminates alloreactive T cells in-vivo, resulting in favorable graft versus host disease (GVHD), non-relapse mortality (NRM) and relapse outcomes. However, few studies have examined the impact of PTCy on immune reconstitution (IR). We quantified IR in 63 patients after haplo-HCT with PTCy, mofetil mycophenolate and tacrolimus (TAC) and compared results to 93 patients with 8/8 HLA matched related or unrelated donors (MD) receiving TAC, methotrexate and sirolimus for GVHD prophylaxis. Both groups received reduced intensity conditioning for hematologic malignancies. The median age of the Haplo-PTCy and MD cohorts was 55 and 57 years. Patient samples were analyzed using multi-color flow cytometry panels to characterize distinct lymphocyte populations. All IR values are expressed as median absolute cell count per μL. One month after HCT, recovery of all T cell subsets (CD3, CD4Tcon, Treg, CD8) was significantly reduced in the PTCy cohort compared to MD (Figure A, B, C). Recovery of CD4Tcon was also reduced at 2 and 3 months after PTCy (p NK cells were lower 1 month after PTCy (52.7 vs 91.1, p=0.08), but were significantly higher at 2, 3 and 6 months (153.4 vs 94.8, p=0.001, 153.7 vs 87.5, p=0.008, 180 vs 102, p=0.01, respectively, Figure D) compared to the MD cohort. Delayed NK cell recovery at 1 month after PTCy was due entirely to reduced numbers of CD56dim NK cells (Figure E). Subsequently recovery of CD56dim NK cells was similar in both cohorts. Recovery of CD56bright NK cells was significantly increased in the PTCy cohort (p Consistent with prior reports, 1 year cumulative incidence of extensive cGvHD was lower in the PTCy cohort compared to the MD cohort, 13% (5-26%, 95% CI) and 40% (30-50%, 95% CI) respectively, p=0.003, without increased NRM (p=0.28) or relapse (p=0.17). In summary, the effect of PTCy on IR was most pronounced 1 month after transplant with significantly delayed recovery of CD3, CD4Tcon, Treg, CD8 and CD56dim NK cells. Slow recovery of CD4Tcon persisted for 3 months and delayed recovery of Treg persisted for 1 year. Beginning 2 months after HCT, recovery of both CD56dim and CD56bright NK cells was more rapid in the PTCy cohort. Further studies will examine the effects of these differences in IR on clinical outcomes such as relapse, infections and GVHD

BK virus-specific T-cell immune reconstitution after allogeneic hematopoietic cell transplantation

© 2020 by The American Society of HematologyClinical disease caused by BK virus reactivation is a frequent complication of allogeneic hematopoietic cell transplantation (HCT). Because of the lack of effective antiviral agents, BK virus-specific T cells are emerging as a potential therapy for BK virus disease, but the immune response to BK virus after allogeneic HCT has not been well characterized. Our study describes reconstitution of BK virus-specific T-cell immunity in 77 adult patients after HCT. All patients had urinary symptoms, and urine was tested for BK virus replication; 33 patients were positive for BK virus (cases), and 44 were negative (controls). In BK virus cases, the median time to first positive test was 75 days (range, 2-511). BK virus cases had lower CD4 T-cell counts 3 to 9 months after transplant, but CD8 T-cell counts were similar in cases and controls. BK virus-specific T cells were identified by cytokine flow cytometry in cryopreserved samples collected prospectively. BK virus-specific CD4 T cells producing T helper 1 (Th1) cytokines recovered quickly after HCT. BK virus-specific T cells were detected more frequently in patients with BK virus reactivation at most time points, and CD4 T cells producing Th1 cytokines were more frequent than BK virus-specific cytolytic CD8 T cells. Early detection of interferon-γ+ and cytolytic BK virus-specific CD4 T cells was associated with lower rates of hematuria among cases. Overall, our study describes recovery of BK virus-specific T cells after HCT and the distinct roles for BK virus-specific T cells in the development and resolution of clinical symptoms.This work was supported by a Collaborative Research Grant from the Harvard Medical School–Portugal Program in Translational Research HMSP-ICT/0001/201, National Institutes of Health, National Cancer Institute grants CA183559, CA183560, and CA229092, and the Pasquarello Tissue Bank in Hematologic Malignancies. E.E. is a PhD candidate at Universidade de Lisboa, and this work is submitted in partial fulfillment of the requirement for a PhD and was supported by a grant for medical fellows enrolled in a PhD program (Subsídios aos Internos Doutorandos–SINTD) from Fundação para a Ciência e Tecnologia, number SFRH/SINTD/135312/2017info:eu-repo/semantics/publishedVersio

FADS2 Function Loss at the Cancer Hotspot 11q13 Locus Diverts Lipid Signaling Precursor Synthesis to Unusual Eicosanoid Fatty Acids

Background: Genes coding for the fatty acid desaturases (FADS1, 2, 3) localized at the cancer genomic hotspot 11q13 locus are required for the biosynthesis of 20 carbon polyunsaturated fatty acids (PUFA) that are direct eicosanoid precursors. In several cancer cell lines, FADS2 encoded D6 and D8 desaturation is not functional. Methodology/Principal Findings: Analyzing MCF7 cell fatty acids with detailed structural mass spectrometry, we show that in the absence of FADS2 activity, the FADS1 product D5-desaturase operates to produce 5,11,14–20:3 and 5,11,14,17–20:4. These PUFA are missing the 8–9 double bond of the eicosanoid signaling precursors arachidonic acid (5,8,11,14–20:4) and eicosapentaenoic acid (5,8,11,14,17–20:5). Heterologous expression of FADS2 restores D6 and D8-desaturase activity and normal eicosanoid precursor synthesis. Conclusions/Significance: The loss of FADS2-encoded activities in cancer cells shuts down normal PUFA biosynthesis, deleting the endogenous supply of eicosanoid and downstream docosanoid precursors, and replacing them with unusual butylene-interrupted fatty acids. If recapitulated in vivo, the normal eicosanoid and docosanoid cell signaling milieu would be depleted and altered due to reduction and substitution of normal substrates with unusual substrates, with unpredictable consequences for cellular communication