Stem Cell Transplantation For Disease Research Articles

A retrospective study of the association of pre-autologous stem cell transplantation disease status with outcomes in patients with multiple myeloma: A single-center study.

e20013 Background: Autologous stem cell transplantation (ASCT) has improved long-term survival for many patients with multiple myeloma (MM), but not all patients respond to ASCT favorably, and many experience disease relapse. Our goal was to explore various disease parameters in patients with MM that might be associated with adverse outcomes after receiving ASCT. Methods: We performed a retrospective medical record review of adult patients with MM who underwent ASCT at Henry Ford Hospital between January 1, 2010 and November 1, 2020. Age, sex, international staging system stage, type of induction therapy, bone marrow cytogenetics and/or fluorescence in situ hybridization, International Myeloma Working Group (IMWG) treatment response criteria categories before ASCT, and the use of maintenance therapy were collected. Outcomes analyzed were time to relapse (TTR) and overall survival (OS). Cox regression analysis was performed. Results: A total of 321 patient records were analyzed: 194 (60.4%) patients were < 65 years old; 185 (57.6%) were men; 162 (50.5%) were Black, and 140 (43.6%) were White. IMWG treatment response categories before ASCT included 250 (78.2%) patients with partial response (PR) and very good partial response (VGPR) combined, and 40 (12.5%) with complete response (CR). There were 69 (21.4 %) patients classified with high-risk cytogenetics. Commonly used induction therapies included 96 (29.9%) patients receiving bortezomib/lenalidomide/dexamethasone, 21 patients (9%) receiving lenalidomide/dexamethasone, 80 patients (24.9%) receiving bortezomib/dexamethasone, and 30 patients (9.3%) receiving cyclophosphamide/bortezomib/dexamethasone, while other patients received a combination of other induction therapies. Mean time from ASCT and last follow-up date was 3.94 years. The overall mean TTR was 29.4 months and OS was 44.8 months. Univariate analysis showed that pre-ASCT treatment response status of combined PR/VGPR was associated with higher hazard of dying than CR (hazard ratio 3.03; 95% CI, 1.23-7.46); however, multivariate analysis showed that PR/VGPR status before ASCT was not significantly associated with increased TTR compared to CR (hazard ratio 1.29; CI, 0.65-2.59). Patients with pre ASCT CR status had longer OS than those with PR/VGPR status (hazard ratio 2.75; CI, 0.995-7.61; p < 0.05). No other variables, including cytogenetic risk were associated with a difference in OS or TTR. Conclusions: Being at CR status before receiving ASCT may indicate a reduced risk of death in MM patients compared to PR and VGPR status, regardless of upfront therapies. Since multiple factors, including treatment type, impact CR status in patients with MM, we believe that studying evolving risk-adapted front-line therapies will help guide optimized treatment strategies to improve overall survival.

Sitagliptin Reduced Graft-Versus-Host Disease in Stem Cell Transplantation

Sitagliptin Reduced Graft-Versus-Host Disease in Stem Cell Transplantation

Onconephrology: The intersections between the kidney and cancer.

Onconephrology is a new subspecialty of nephrology that recognizes the important intersections of kidney disease with cancer. This intersection takes many forms and includes drug-induced nephrotoxicity, electrolyte disorders, paraneoplastic glomerulonephritis, and the interactions of chronic kidney disease with cancer. Data clearly demonstrate that, when patients with cancer develop acute or chronic kidney disease, outcomes are inferior, and the promise of curative therapeutic regimens is lessened. This highlights the imperative for collaborative care between oncologists and nephrologists in recognizing and treating kidney disease in patients with cancer. In response to this need, specific training programs in onconephrology as well as dedicated onconephrology clinics have appeared. This comprehensive review covers many of the critical topics in onconephrology, with a focus on acute kidney injury, chronic kidney disease, drug-induced nephrotoxicity, kidney disease in stem cell transplantation, and electrolyte disorders in patients with cancer.

Cryptococcosis in Hematopoietic Stem Cell Transplant Recipients: A Rare Presentation Warranting Recognition.

Cryptococcosis, a life-threatening mycosis caused mainly by Cryptococcus neoformans, appears to be distinctly rare in hematopoietic stem cell transplant (HSCT) recipients. When it occurs, this fungal infection is a major limitation for a successful transplant. This review comprehensively analyses 24 cases, reported in the literature, of patients with haematological malignancies including leukemias, multiple myeloma, and lymphomas, as indication for HSCT, who presented with cryptococcosis after transplantation. Of the 24 cases, 11 each occurred in patients receiving allogeneic and autologous stem cell transplants, from bone marrow, peripheral blood, and umbilical cord blood. HSCT recipients were slightly more often male, and the age of the patients ranged from 12 to 74 years. Antifungal prophylaxis was reported in most cases. Clinical manifestations of cryptococcal disease included more frequently central nervous system involvement followed by fungaemia, disseminated infection, pulmonary cryptococcosis, cerebellitis, and diarrhea. Diagnosis differed depending on the clinical presentation but habitually included cryptococcal antigen assay, India ink, and culture. Notably, not only C. neoformans but also C. albidus, C. terreus, C. laurentii, and C. adeliensis were identified as the causal species, the last two including strains resistant to fluconazole. Amphotericin B, alone or in combination, was the most common antifungal drug used for the treatment of cryptococcosis in HSCT recipients. Due to the small number of cases, it was not possible to establish if mortality rate, which was the same as survival rate, depends on the effect of the immunosuppressive regimen, the site of cryptococcal infection, and/or the antifungal therapy used to control the mycosis. Although uncommon, the recognition of cryptococcal disease in stem cell transplant is essential for a timely and adequate treatment, improved prognosis, reduced morbidity and mortality, and successful transplantation.

Genome-wide surveillance of mismatched alleles for graft-versus-host disease in stem cell transplantation

AbstractAcute graft-versus-host disease (aGVHD) represents one of the major complications in allogeneic stem cell transplantation and is primarily caused by genetic disparity between the donor and recipient. In HLA-matched transplants, the disparity is thought to be determined by loci encoding minor histocompatibility antigens (minor H antigens), which are presented by specific HLA molecules. We performed a genome-wide association study (GWAS) to identify minor H antigen loci associated with aGVHD. A total of 500 568 single nucleotide polymorphisms (SNPs) were genotyped for donors and recipients from 1589 unrelated bone marrow transplants matched for HLA-A, -B, -C, -DRB1, and -DQB1, followed by the imputation of unobserved SNPs. We interrogated SNPs whose disparity between the donor and recipient was significantly associated with aGVHD development. Without assuming HLA unrestriction, we successfully captured a known association between HLA-DPB1 disparity (P = 4.50 × 10−9) and grade II-IV aGVHD development, providing proof of concept for the GWAS design aimed at discovering genetic disparity associated with aGVHD. In HLA-restricted analyses, whereby association tests were confined to major subgroups sharing common HLA alleles to identify putative minor H antigen loci, we identified 3 novel loci significantly associated with grade III-IV aGVHD. Among these, rs17473423 (P = 1.20 × 10−11) at 12p12.1 within the KRAS locus showed the most significant association in the subgroup, sharing HLA-DQB1*06:01. Our result suggested that a GWAS can be successfully applied to identify allele mismatch associated with aGVHD development, contributing to the understanding of the genetic basis of aGVHD.

BEAM-Campath Allogeneic Stem Cell Transplantation for Aggressive Non-Hodgkin's Lymphomas. An Analysis of Outcomes From the BSBMT

AbstractAbstract 2039▪▪This icon denotes a clinically relevant abstract Introduction.The role of allogeneic stem cell transplantation in the management of aggressive non-Hodgkin's lymphoma (NHL) remains to be established. Autologous stem cell transplantation (SCT) remains the standard salvage therapy for patients with diffuse large B cell lymphoma failing first line therapy although patients relapsing early after Rituximab based immunochemotherapy have a poor outcome. For patients with aggressive T cell lymphomas the role of consolidation or salvage transplant strategies also remains controversial. Reduced intensity allogeneic transplants have been employed in these diseases with variable success. In the United Kingdom the more intensive BEAM conditioning regimen has been employed prior to allogeneic stem cell transplantation in lymphoproliferative diseases. We report here the outcome of BEAM-CAMPATH conditioning prior to allogeneic stem cell transplantation for aggressive NHL as reported to the British Bone Marrow Registry. Methods.We retrospectively identified all patients reported to the BSBMT registry as having undergone an allogeneic stem cell transplant following BEAM-CAMPATH conditioning for aggressive non-Hodgkin's lymphomas. All patients received conditioning with BEAM (BCNU 300mg/m2, etoposide 800mg/m2, cytarabine 1600mg/m2, melphalan 140mg/m2) and CAMPATH-1H 10mg days -6 to -2. Cyclosporin A was administered for 90 days post transplant. Six transplant centres contributed data to this study. Results.46 patients (27 male, 19 female) with a median age of 45 (range 17–59) at diagnosis with DLBCL (29), Burkitt’s lymphoma (1) or T cell lymphoma (PTCL NOS 14, anaplastic large cell lymphoma 3, angioimmunoblastic lymphoma 1) were identified. 37 patients had stage III/IV disease at diagnosis and 56% of patients had a high or high-intermediate International Prognostic Score. They had received a median of 3 lines of prior therapy (range 1–5), 11 of 29 patients with B cell lymphomas had received Rituximab prior to transplant and 4 patients had received a prior autologous stem cell transplant. The median time from diagnosis to transplant was 11 months (range 3 months–13 years) and 22 patients had received the transplant in first response. At transplant 34 patients had chemosenstive disease and 11 patients had chemorefractory disease. Transplants from 32 siblings and 14 volunteer unrelated donors were performed using peripheral blood stem cells in 42 patients. 3 patients received a mismatched transplant. The Performance Status (PS) at transplant was good (KPS>80) in 40 of 46 patients. All patients engrafted with a median time to neutrophil recovery of 14 days (range 11–27). At last follow up 20 patients are alive with 17 in complete remission. 5 patients have died from non-relapse causes (infection 3, GVHD 1, respiratory failure 1) and 21 died following relapse of lymphoma. Acute GVHD grades II-IV developed in 7 patients and chronic GVHD in 13 (7 limited, 6 extensive) of 37 patients surviving beyond 100 days. The cumulative incidence (CI) of non-relapse mortality (NRM) was 7% at 100 days and 11% at 3 and 5 years post transplant. NRM was significantly worse for those with a poor PS, use of a VUD, prior autologous SCT and more lines of prior therapy. The relapse risk at 1 and 5 years was 51% and 53% respectively and was associated with use of a sibling donor. Disease status at transplant had no impact on the relapse rate. The progression free survival (PFS) was 41% and 36% at 1 and 5 years respectively with a trend to a higher PFS in patients under 45 years. The overall survival (OS) was 54% t 1 year and 42% at 5 years with a significantly better OS in CMV low risk transplants. Conclusion.BEAM-CAMPATH conditioning prior to allogeneic SCT is well tolerated in patients with aggressive NHL although there remains a significant relapse rate following this therapy. A significant minority of patients achieve durable disease free survival. The role of BEAM-CAMPATH allogeneic stem cell transplantation in these diseases warrants further investigation. Disclosures:No relevant conflicts of interest to declare.

Heparanase Promotes Engraftment and Prevents Graft versus Host Disease in Stem Cell Transplantation

BackgroundHeparanase, endoglycosidase that cleaves heparan sulfate side chains of heparan sulfate proteoglycans, plays important roles in cancer metastasis, angiogenesis and inflammation.Design and MethodsApplying a mouse model of bone marrow transplantation and transgenic mice over-expressing heparanase, we evaluated the effect of heparanase on the engraftment process and the development of graft-versus-host disease.ResultsAnalysis of F1 mice undergoing allogeneic bone marrow transplantation from C57BL/6 mice demonstrated a better and faster engraftment in mice receiving cells from donors that were pretreated with heparanase. Moreover, heparanase treated recipient F1 mice showed only a mild appearance of graft-versus-host disease and died 27 days post transplantation while control mice rapidly developed signs of graft-versus-host disease (i.e., weight loss, hair loss, diarrhea) and died after 12 days, indicating a protective effect of heparanase against graft-versus-host disease. Similarly, we applied transgenic mice over-expressing heparanase in most tissues as the recipients of BMT from C57BL/6 mice. Monitoring clinical parameters of graft-versus-host disease, the transgenic mice showed 100% survival on day 40 post transplantation, compared to only 50% survival on day 14, in the control group. In vitro and in vivo studies revealed that heparanase inhibited T cell function and activation through modulation of their cytokine repertoire, indicated by a marked increase in the levels of Interleukin-4, Interleukin-6 and Interleukin-10, and a parallel decrease in Interleukin-12, tumor necrosis factor-alfa and interferon-gamma. Using point mutated inactive enzyme, we found that the shift in cytokine profile was independent of heparanase enzymatic activity.ConclusionsOur results indicate a significant role of heparanase in bone marrow transplantation biology, facilitating engraftment and suppressing graft-versus-host disease, apparently through an effect on T cell activation and cytokine production pattern.

Graft rejection and hyperacute graft‐versus‐host disease in stem cell transplantation from non‐inherited maternal antigen complementary HLA‐mismatched siblings

Human leukocyte antigen (HLA)-mismatched stem cell transplantation from non-inherited maternal antigen (NIMA)-complementary donors is known to produce stable engraftment without inducing severe graft-versus-host disease (GVHD). We treated two patients with acute myeloid leukemia (AML) and one patient with severe aplastic anemia (SAA) with HLA-mismatched stem cell transplantation (SCT) from NIMA-complementary donors (NIMA-mismatched SCT). The presence of donor and recipient-derived blood cells in the peripheral blood of recipient (donor microchimerism) and donor was documented respectively by amplifying NIMA-derived DNA in two of the three patients. Graft rejection occurred in the SAA patient who was conditioned with a fludarabine-based regimen. Grade III and grade IV acute GVHD developed in patients with AML on day 8 and day 11 respectively, and became a direct cause of death in one patient. The findings suggest that intensive conditioning and immunosuppression after stem cell transplantation are needed in NIMA-mismatched SCT even if donor and recipient microchimerisms is detectable in the donor and recipient before SCT.

Oral valganciclovir leads to higher exposure to ganciclovir than intravenous ganciclovir in patients following allogeneic stem cell transplantation

AbstractCytomegalovirus (CMV) infection is a major complication after allogeneic stem cell transplantation (SCT). Valganciclovir (V-GCV) is an oral prodrug hydrolyzed to the anti-CMV drug ganciclovir (GCV). A randomized, multicenter, crossover, open-label clinical trial compared exposure to GCV after V-GCV and intravenous GCV (IV-GCV) as preemptive therapy for CMV disease in SCT. The primary objective was to compare exposure to GCV in patients with CMV infection stratified for intestinal graft-versus-host disease (I-GVHD). Secondary objectives were the assessment of safety and efficacy. Patients without I-GVHD had a higher exposure to GCV after V-GCV when compared with IV-GCV (area under the concentration-time curve from drug administration to last observed concentration after 12 hours [AUC0-12] 53.8 ± 17.97 μg/mL · h [mean ± SD] vs 39.5 ± 13.91; P < .001; ratio of V-GCV/IV-GCV was 1.4; 90% confidence interval [CI], 1.2-1.5). This was also true in patients with I-GVHD grades I-II (AUC0-12 52.9 ± 21.75 vs 33.1 ± 12.97 μg/mL · h; P = .018; ratio 1.6; 90% CI, 1.3-2.0). Absolute bioavailability of GCV after V-GCV was approximately 75% in individuals with or without I-GVHD grades I-II. No severe GCV-related toxicity was observed and efficacy and safety was comparable (84-day follow-up). This supports the use of V-GCV in SCT, even in patients with I-GVHD grades I-II. Due to higher exposure after V-GCV compared with IV-GCV, patients should be monitored carefully for safety reasons.

Decreased risk of acute gastrointestinal toxicity when substituting methotrexate with mycophenolate mofetil in the prevention of graft-versus-host disease in stem cell transplantation following myeloablative conditioning regimens

Decreased risk of acute gastrointestinal toxicity when substituting methotrexate with mycophenolate mofetil in the prevention of graft-versus-host disease in stem cell transplantation following myeloablative conditioning regimens

Microchimerism Detection by HLA-Specific Real-Time Polymerase Chain Reaction Analysis in Recipients of Allogeneic Epstein Barr Virus Specific Cytotoxic T Lymphocytes.

Adoptive immunotherapy with allogeneic EBV specific cytotoxic T lymphocytes (CTL) has been used as a treatment strategy for EBV induced lymphoproliferative disease in stem cell transplant and organ transplant recipients, and is currently being investigated for patients with EBV positive Hodgkin's disease. Currently available molecular methods for detecting chimerism, such as single tandem repeat (STR) analysis, have a sensitivity range that does not permit the detection of allogeneic effector cells when doses of 106 to 107 cells/kg are infused. We have demonstrated that the infusion of EBV CTL from allogeneic donors can be associated with clinical responses in patients with therapy refractory Hodgkin's disease, however donor cells could not be detected by STR analysis. We employed HLA-specific real-time polymerase chain reaction analysis (Q-PCR) to test for donor microchimerism in two groups of subjects with relapsed, therapy refractory, EBV positive Hodgkin's disease. Non-shared, donor-specific HLA sequences (HLA B, DRB1, DRB3, DRB4, DRB5, DQA1, and DQB1) were targeted to detect the DNA equivalent of 1 donor cell in a background of 500,000 host cells. The first cohort consisted of three subjects, each receiving three allogeneic EBV CTL infusions consisting of 5 x 106 cells/kg/dose, with no chemotherapy prior to the infusions. A second cohort received a single infusion of 1.5 x 107 EBV CTL/kg, which was preceded by fludarabine 30 mg/m2/day for three days (in order to attempt to achieve donor CTL chimerism). Informative HLA-specific Q-PCR assays were available for one subject not receiving chemotherapy and for the three subjects receiving fludarabine prior to a single CTL infusion. Results are expressed as genome equivalent number of donor cells per million host cells (gEq/mil). The subject who did not receive fludarabine had no detectable donor DNA prior to the CTL infusion and had 105 gEq/mil 2 days following the first infusion, 230 gEq/mil one day following the second infusion, and only 12 gEq/mil one day after the third infusion. This data suggests that the subject had been sensitized following the first CTL infusion and possibly rejected subsequent infusions. All three subjects who received fludarabine prior to a single EBV CTL infusion had increases in donor DNA post-infusion. One of these subjects had 13,061 gEq/mil one day post-infusion, which decreased to slowly to 124 gEq/mil by 21 days post-infusion, and was at 193 gEq at 3.5 months post-infusion. The other two CTL recipients who received immunosuppressive chemotherapy prior to CTL had increases in donor DNA post-infusion but not of the same maximum amplitude (5026 and 740 gEq/mil at one week post-infusion for each of these subjects). Since subsequent CTL infusions were not given to the second cohort, it is unclear whether the decrease in donor cells over time in this group represented cell rejection or the natural kinetics of allogeneic CTL infused in this setting. These studies demonstrate that quantification of donor cell microchimerism is feasible using Q-PCR for mismatched HLA alleles for subjects receiving allogeneic CTL.