Sirolimus and Thrombotic Microangiopathy after Allogeneic Stem Cell Transplantation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1834-1834 ◽  
Author(s):  
N. Lynn Henry ◽  
Shuli Li ◽  
Haesook T. Kim ◽  
Colm Magee ◽  
Edwin Alyea ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Thrombotic Microangiopathy ◽  
Simultaneous Occurrence ◽  
Control Group ◽  
Study Group ◽  
Gvhd Prophylaxis

Abstract Sirolimus (SRL) is a novel immunosuppressive agent that has been demonstrated to reduce GVHD and minimize morbidity after allogeneic stem cell transplantation (alloSCT). We have described a syndrome of thrombotic microangiopathy (TMA), characterized by microangiopathic hemolysis, thrombocytopenia, and renal dysfunction, whose incidence is increased when SRL is used in association with calcineurin inhibitors (CIs) but not with SRL monotherapy. To determine if SRL use potentiates the effects of CIs on TMA incidence and risk factors, we performed a retrospective cohort analysis of subjects who underwent alloSCT between 1997 and 2003. Methods: Subjects who received a SRL-containing GVHD prophylaxis after a myeloablative preparative regimen were compared with a cohort who received a non-SRL regimen. All subjects received CIs. Diagnosis of TMA required the simultaneous occurrence of: (1) creatinine elevation >2 mg/dL or >50% above baseline, (2) schistocytosis, (3) elevated LDH, and (4) no laboratory evidence of disseminated intravascular coagulopathy. Results: 111 patients who received SRL were compared with 216 patients who received no SRL during the first 100 days after alloSCT. The two groups of patients were balanced for demographic parameters; however, more patients in the SRL group received peripheral blood stem cells (50.5 vs. 18.1%, p<0.01) and had unrelated donors (58.6 vs. 42.6%, p<0.01). The incidence of TMA in the SRL group was 10.8% in comparison with an incidence of 4.2% in the non-SRL group (OR 2.57, p=0.03). Patients who received SRL developed TMA earlier than those who did not receive SRL (median 25 vs. 58 days, p=0.04). At the time of TMA diagnosis, median blood levels of immunosuppressive medications were in their respective therapeutic ranges: SRL (study group) 6.1 ng/ml, tacrolimus (study group) 9.9 ng/ml, tacrolimus (control group) 9.1 ng/ml; cyclosporine (control group) 418 ng/ml. In a multivariable logistic regression model, only the use of SRL (Adjusted Exact OR 3.49, p =0.02) and grade II-IV acute GVHD (Adjusted Exact OR 6.60, p = 0.0002) predicted the occurrence of TMA. Treatment of TMA consisted of discontinuation or dose adjustment of CIs. SRL was discontinued or dosed according to serum level. Two subjects in each group required temporary hemodialysis, and 3 subjects (1 SRL, 2 non-SRL) underwent plasmapheresis. 78% of surviving SRL-treated subjects regained normal renal function. No subject had a TMA recurrence if SRL was reintroduced. Overall survival after TMA diagnosis was better for SRL patients than non-SRL patients (58.3 vs. 11.1%, log rank p=0.02). Conclusion: SRL use is associated with an increased risk of TMA after alloSCT and may act by potentiating the effects of CIs. TMA associated with SRL appears reversible and does not affect overall survival after alloSCT. A careful monitoring strategy for TMA should be employed as part of a SRL-containing GVHD prophylaxis regimen.

Effect of Rituximab on the Incidence of GVHD in Lymphoma Patients who Received the BEAM-Conditioning and an Allogeneic Stem Cell Transplantation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4980-4980
Author(s):  
Issa F. Khouri ◽  
Rima M. Saliba ◽  
Daniel R. Couriel ◽  
Grace-Julia Okoroji ◽  
Sandra Acholonu ◽  
...  
Keyword(s):  
Stem Cell ◽  
B Cells ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Control Group ◽  
Study Group

Abstract It has been postulated that B cells functioning as antigen-presenting cells may have an important role in the pathogenesis of GVHD. Depletion of donor cells from B-cells resulted in a low incidence of GVHD in mouse model (Schultz et al. BMT1995:16:289–289). More recently, we observed a lower incidence of chronic (and to a lesser extent acute GVHD) in patients with CLL who received an allogeneic stem cell transplantation after a non-myeloablative conditioning regimen containing rituximab (Exp Hematol32:28–35, 2004). The purpose of this study is to investigate the effect of rituximab on GVHD in the setting of a more intense chemotherapy with BEAM, in patients who received an allogeneic peripheral blood stem cell from HLA-identical siblings. To test this hypothesis, we retrospectively studied 11 consecutive patients with non-Hodgkin’s lymphoma who received BEAM/Rituximab at the M. D. Anderson Cancer Center. We attempted to match these patients by age, donor-recipient gender, and donor-recipient CMV reactivity to a historical control of 44 patients with lymphoma, who received BEAM alone as a conditioning regimen, without the Rituximab. Tacrolimus and methotrexate were used for GVHD prophylaxis in both groups. A total of 10 patients in the study group, could be matched with 19 patients in the control group and were included in the final analysis. The outcome of the 2 groups is shown below: Rituximab-Study Group Control Group -value P No. of patients 10 19 Median age 41 44 0.4     (range) (19–55) (19–60) Patient-Donor sex-matched 9(82%) 18(95%) 0.6 Median # CD34 + cells infused (106/kg) 5.1 4.73 0.1 Patient or Donor CMV+ 9(82%) 18(95%) 0.6 Patient and Donor CMV − 1(10%) 1(5%) Median # prior chemoregimens 3 3 0.9     range (1–8) (1–9) Median follow-up 17 38     range (8–48) (27–77) Acute GVHD 2–4 (n,%) 5(50%) 7(37%) 0.5 Acute GVHD 3–4 (n,%) 3(30%) 5(26%) 0.6 Chronic GVHD (n, % cumulative incidence) 8 (90% + 15) 10 (53% + 12 0.01 Our data suggest that the described protective effect of Rituximab against GVHD in mouse models or in the setting of non-myeloablative allogeneic transplantation, may be overcome by the BEAM. This more intense conditioning regimen may induce more GVHD by enhancing T-cell cytokines release and by causing more gastrointestinal toxicity, thus allowing for a greater antigen presentation.

Monitoring of Donor Chimerism in CD34+ Peripheral Blood Progenitors Allows to Detect Minimal Residual Disease after Allogeneic Stem Cell Transplantation -Results of a Randomized Trial

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 340-340
Author(s):  
Martin Bornhaeuser ◽  
Uta Oelschlaegel ◽  
Gesine Bug ◽  
Uwe Platzbecker ◽  
Karin Lutterbeck ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Peripheral Blood ◽  
Residual Disease ◽  
Preemptive Therapy ◽  
Study Group ◽  
Minimal Residual

Abstract Relapse of hematological malignancy remains a major complication after allogeneic stem cell transplantation. This is especially true for patients receiving minimal or reduced-intensity conditioning therapy. Analysis of donor chimerism (DC) is an important diagnostic tool to assess the risk of relapse after allogeneic stem cell transplantation, especially in patients lacking a specific marker suitable for monitoring of minimal residual disease. The sensitivity of a standard PCR assay amplifying short-tandem-repeat sequences can be improved significantly by investigating sorted CD34+ peripheral blood cells. We prospectively compared the serial analysis of DC in selected CD34+ cells and unmanipulated whole blood (WB) within a randomised study in 131 patients with CD34+ hematological malignancies (AML, ALL and MDS) surviving more than 100 days after transplantation. The primary end-point was the association between decreasing CD34+ DC and haematological relapse. Whenever a decreasing CD34+ or WB DC was confirmed and no signs of active GvHD were present, a rapid taper of CsA or tracolimus (50% every 5–7 days) was suggested. If no GvHD occurred within 14 days after the stop of CsA or tacolimus, patients were scheduled to receive donor lymphocyte infusions (DLI) in incremental doses. The cumulative incidence of relapse was significantly increased in patients with decreasing or incomplete CD34+ DC (62% vs. 38%, p=0.01). This was associated with a lower probability of overall survival (20% vs. 39%, p=0.03). The interval between the decrease in CD34+ DC and hematological relapse was 35 days (range 0–567) in the study group compared to only 8 days (range 0–63) in the control group monitored by WB DC analysis (p=0.05). The median time between a decrease in CD34+ DC and WB DC was 14 days (range, 0 to 445). Patients receiving preemptive therapy triggered by decreasing CD34+ DC had a significantly higher probability of disease-free survival compared to cases monitored and treated according to WB DC (19% vs. 0%, p=0.009). Multivariate analysis revealed age, disease-risk and decreasing CD34+ DC as independent risk-factors for overall survival in the study group. In summary, we could demonstrate that the quantification of DC in CD34+ selected cells is a sensitive method to predict relapse and survival after allogeneic SCT. Although this technology opens a window for preemptive therapy, new treatment approaches have to be employed to improve the overall outcome of patients with recurrence of residual disease after allogeneic stem cell transplantation.

Allogeneic Stem Cell Transplantation in Angioimmunoblastic T-Cell Lymphoma (AITL): A Retrospective Survey from the Lymphoma Working Party (LWP) of the European Group for Blood and Marrow Transplantation (EBMT).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3042-3042
Author(s):  
Charalampia Kyriakou ◽  
C. Canals ◽  
G. Taghipour ◽  
J. Finke ◽  
H. Kolb ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Relapse Rate ◽  
Allogeneic Stem Cell Transplantation ◽  
Cell Lymphoma ◽  
T Cell Lymphoma

Abstract AITL is a rare peripheral T-cell lymphoma characterised by an aggressive behaviour, which primarily affects the elderly. Chemotherapy regimens fail to alter the high relapse rate and overall survival hardly exceeds 25% at 5 years. To date, there is no information on the potential role of allogeneic stem cell transplantation (allo-SCT) in the management of AITL. We report the outcome of 39 patients with a median age of 47 years (24–68), who underwent an allo-SCT between 1995 and 2004 for AITL, and were reported to the EBMT registry. The median time from diagnosis to transplant was 10 months (4–72). Thirty-four patients (87%) had previously received two or more treatment lines, and 16 patients (41%) a previous autologous SCT. Fifteen patients (38%) had a primary refractory disease, 13 (33%) were transplanted in partial remission and the remaining patients were in complete remission (CR) (mostly in 2nd and 3rd CR). Twenty-four patients were transplanted from an HLA-identical sibling and 15 from a matched unrelated donor. A myeloablative conditioning regimen (MAC) was used in 21 patients (cyclophosphamide + total body irradiation in 14), while 18 patients received fludarabine-based reduced intensity conditionings (RIC). Peripheral blood was the source of stem cells in 35 patients (90%). Three patients failed to engraft (one patient in the RIC group). Twenty-one patients (54%) developed acute graft versus host disease (grade I-II, n=16; grade III-IV, n=5). Twenty-eight patients (72%) achieved a CR after the allogeneic procedure. Nine patients died from transplant related mortality (TRM) and 5 patients from disease progression. The cumulative incidence of TRM at 12 months was 19% for the MAC and 26% for the RIC group. After a median follow-up for the surviving patients of 20 months (6–74), 25 patients are alive. Relapse rates at 1 and 3 years were estimated at 10% and 18% for the MAC and 16 and 20% for the RIC patients. Progression free survival rates at 3 years were 67% and 50% and the overall survival at the same time 71% and 56% for the MAC and RIC group of patients, respectively. Although follow up is rather short, these data suggest that allo-SCT results in good overall response and is associated with a low relapse rate in this group of poor risk heavily pre-treated and rather elderly group of AITL patients. Allo-SCT could be considered a therapeutic option for eligible high-risk AITL patients. Nevertheless, the impact of this approach should be further explored in prospective collaborative studies.

Serum miRNA Expression and Allogeneic Stem Cell Transplantation in Patients with B Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5791-5791 ◽  
Author(s):  
Issa F. Khouri ◽  
Simone Anfossi ◽  
Rima M Saliba ◽  
Lisa S. St. John ◽  
Jeffrey J. Molldrem ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Variable Region ◽  
Serum Levels ◽  
Serum Samples ◽  
Qrt Pcr ◽  
Serum Mirna ◽  
Gvhd Prophylaxis

Abstract Background: Noncoding RNAs play an important role in the pathogenesis of CLL. Recent publications suggested that higher miR-155 plasma levels (above 56th percentile) were associated with a significantly lower survival rate (P= 0.0122) in CLL patients treated with conventional treatments (Ferrajoli et al. Blood 2013;122:1891). Other studies revealed that expression of miR-29b or miR-181b significantly inhibits T cell leukemia/lymphoma 1(Tcl1) oncogene (Pekarsky et al. Cancer Res 2006;66:11590) whereas high Tcl1 expression correlates with aggressive CLL phenotype showing unmutated immunoglobulin variable region genes and ZAP70 positivity. The impact of these miR expressions in CLL patients undertaking allogeneic stem cell transplantation (alloSCT) is unknown. Methods and Patients: We identified 41 patients with relapsed/refractory CLL who had received a non-myeloablative alloSCT at our center and in whom pre-transplant serum samples collected before initiating the patients’ allogeneic conditioning were available. We measured the serum expression of miR-155 as well as miR-15a/16-1 cluster, miR-29b and miR-181b. Total RNA was isolated from 100 µL of serum using the Total RNA Purification Kit. Serum miRNA levels were measured by qRT-PCR (TaqMan MicroRNA assays). The relative serum levels of miR-155, miR -15, miR-29b, miR-181b, and miR-16-1 were calculated using the equation 2−ΔCt, where ΔCt = mean CtmiRNA – mean Ctcel-miR-39, and Ct = threshold cycle. Twenty fmol of synthetic C. elegans miRNA (cel-miR-39) was spiked into each serum samples to normalize the experimental qRT-PCR data (cel-miR-39 Ct mean ± SD = 17.777± 0.628). Forty one patients were initially evaluated. Thirteen of these 41 patients were later excluded as they received alemtuzumab for graft-versus-host disease (GVHD) prophylaxis. Therefore, our analysis was limited to 28 patients who received their alloSCT between 2000-2010. Median age (range) was 59 (45-70) years. Median number of prior therapies was 3 (range, 2-8). Eleven (39%) had a beta-2 microglobulin level of >3 mg/L. Ten of 12 (83%) patients with data that could be evaluated had unmutated immunoglobulin variable-region heavy-chain gene, and 4/19 (21%) had 17p13.1 deletion. 46% of patients had refractory disease at transplantation. The proportion of patients who received a matched related and a matched unrelated donor was 68% and 32%, respectively. All patients received non-myeloablative conditioning with fludarabine, cyclophosphamide, and rituximab as previously published (Khouri et al. Cancer 2011;117:4679). GVHD prophylaxis consisted of tacrolimus and methotrexate. Results: Median (range) follow-up months was 68 (43-141). OS from the time of alloSCT was studied according to the relative expressions of miR under investigation (low, below median; high, above median). The 5-year OS rates of patients with low and high mir-155 were 63% and 50%, respectively (HR=1.6, P=0.4; Figure). No statistically significant differences were found in the other miRs studied. The 5-year OS was 57% for both the low and high miR-15a expression. The 5-year OS in low and high miR-29b and miR-181b were 52% and 61% (HR=0.8; P=0.7), and 60% and 53% (HR=1.1, P=0.9), respectively. The 5-year OS in low and high miR-16 were 43% and 71% (HR=0.4, P=0.2). Conclusions: Our preliminary results suggest that serum levels of miR-155, miR -15, miR-29b, miR-181b, and miR-16 are not a statistically significant prognostic biomarker for survival in relapsed/refractory CLL undertaking alloSCT. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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