Allogeniec Stem Cell Transplantation for Primary and Post ET/PV Myelofibrosis At Mayo Clinic: A Retrospective Review Across a Geographically Diverse 3 Site Cancer Center.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2850-2850
Author(s):  
Veena Devi Salem Fauble ◽  
James L Slack ◽  
William Hogan ◽  
Vivek Roy ◽  
Jose Leis ◽  
...  
Keyword(s):  
Stem Cells ◽  
Overall Survival ◽  
Retrospective Review ◽  
Mayo Clinic ◽  
Research Funding ◽  
Graft Failure ◽  
Clinical Course ◽  
Cancer Center ◽  
Blast Phase ◽  
Graft Versus Host

Abstract Abstract 2850 Myelofibrosis (MF), both primary myelofibrosis (PMF) and post essential thrombocytosis/polycythemia vera myelofibrosis (post ET/PV-MF), are chronic myeloproliferative neoplasms characterized by a progressive clinical course that leads to shortened survival. The heterogeneous nature of MF lends itself to a variable clinical course that commonly includes hepatosplenomegaly, constitutional symptoms, and progressive cytopenias. Medical therapy for myelofibrosis has been effective in palliation of common symptoms related to anemia, splenomegaly but allogeneic stem cell transplantation (ASCT) remains the only potentially curative therapeutic modality. The timing of ASCT, choice of conditioning regimen, patient selection and the impact of co-morbidities are critical to optimal use of this modality. We have retrospectively analyzed our experience for patients undergoing ASCT for primary and post ET/PV myelofibrosis at Mayo Clinic across all 3 sites: Scottsdale Arizona; Rochester, Minnesota; and Jacksonville, Florida. Methods: We conducted a retrospective review of all patients from 1992 to 2012 with PMF or post ET/PV-MF who underwent an ASCT at Mayo Clinic. This retrospective review included a waiver of informed consent and was approved by the Mayo Clinic Institutional Review Board. Patients that transformed to the MPN blast phase and individuals who underwent a second transplant for either relapse or graft failure were also included. Overall survival was estimated using Kaplan-Meier. Associations between prognostic factors and overall survival were assessed using Cox regression. Results: Baseline Patient Characteristics: Forty-eight patients (29 male) with a median age of 57 yrs (range 31–73) underwent ASCT. DIPSS-plus risk score was low in 2, intermediate 1 in 2, intermediate 2 in 9 and high in 35 patients. Disease type was PMF in 24, PV-MF in 10, ET-MF in 10, and MPN/MDS overlap in 4 pts. Eight patients evolved to the MPN-blast phase prior to transplant. JAK-2 mutation was positive in 27 patients and negative in 12 patients with JAK-2 status unknown in 9 patients. The median time from PV/ET to MF was 136 months (83–189 months) and from MF diagnosis to transplant was 59 months (3–144 months). All but 2 patients were red cell transfusion dependent prior to transplant (96%). Eight patients underwent splenectomy prior to transplant. Transplantation Characteristics: Patients who underwent ASCT received either myeloablative (MA, 13 pts) or reduced-intensity conditioning (RIC, 35 pts) regimen. The graft was from an unrelated donor in 22 pts and related donor in 26 pts with 44 being matched and 4 being mismatched. The myeloablative regimens included Bu/Cy, TBI/Cy, and Bu/Flu. The RIC regimens included flu/mel, Bu/Flu, FBM, and TBI/Flu. GVHD prophylaxis was with tacrolimus/MTX, CSA/MTX, and tacrolimus/MMF. Nineteen patients received ATG. Infectious disease prophylaxis, CMV monitoring, and additional supportive care measures were according to institutional guidelines. A majority of patients received peripheral blood stem cells with only 1 patient receiving bone marrow as the source of stem cells. Outcomes: The median time to neutrophil engraftment was 17.2 days. Two patients received a second transplant for relapsed disease. The incidence of graft failure was 10%. Graft versus host disease both acute and chronic occurred in 33 patients and 15 patients respectively. Day 100 overall survival was 92% and 2 year survival was 62% (95% CI 45–75%). There were no statistically significant associations between individual prognostic factors (DIPSS-plus classification, age, and HLA match) and survival. Conclusions: The Mayo Clinic national experience of ASCT for MF across our geographically diverse Cancer Center is encouraging. Our centers have transplanted 48 patients over the past 10 years with very favorable outcomes. Our results from a multi center practice are consistent with regards to survival, graft versus host disease, and types of transplants being performed compared to currently available published data from large single location transplant centers. This data helps confirm the prevailing knowledge that ASCT is a useful treatment. Disclosures: Mesa: Incyte: Research Funding; Lilly: Research Funding; Sanofi: Research Funding; NS Pharma: Research Funding; YM Bioscience: Research Funding.

scholarly journals Co-transplantation of mesenchymal stem cells makes haploidentical HSCT a potential comparable therapy with matched sibling donor HSCT for patients with severe aplastic anemia

2020 ◽  
Vol 11 ◽  
pp. 204062072096541
Author(s):  
Zenghui Liu ◽  
Xiaoxiong Wu ◽  
Shunqing Wang ◽  
Linghui Xia ◽  
Haowen Xiao ◽  
...  
Keyword(s):  
Stem Cells ◽  
Overall Survival ◽  
Graft Failure ◽  
Graft Function ◽  
First Line ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Poor Graft Function ◽  
Matched Sibling ◽  
Grade Iii

The application of haploidentical hematopoietic stem cell transplantation (HSCT) with mesenchymal stem cell (MSC) infusion as a treatment regimen for severe aplastic anemia (SAA) has been reported to be efficacious in single-arm trials. However, it is difficult to assess without comparing the results with those from a first-line, matched-sibling HSCT. Herein, we retrospectively reviewed 91 patients with acquired SAA. They received HSCT from haploidentical donors combined with MSC transfer (HID group). We compared these patients with 103 others who received first-line matched-sibling HSCT (MSD group) to evaluate relative treatment efficacy. Compared with the patients in the MSD group, those in the HID group presented with higher incidences of grades II–IV and III–IV acute graft versus host disease (aGvHD) and chronic graft versus host disease (cGvHD) ( p < 0.05). However, the incidence of myeloid and platelet engraftment, graft failure, poor graft function, and extensive cGvHD were comparable for both groups. The median follow-up was 36.6 months and the 3-year overall survival rate was similar for both groups (83.5% versus 79.1%). Univariate and multivariate analyses revealed that time intervals greater than 4 months from diagnosis to transplantation, experienced graft failure, poor graft function, or grade III–IV aGvHD were significantly associated with adverse outcomes. All HID patients received MSC co-transplantation with hematopoietic stem cells. However, the infused MSCs were derived from umbilical cord (UC-MSC group; 43 patients) or bone marrow (BM-MSC group; 48 patients) and were administered at different medical centers. We first compared the outcomes between the two groups and detected that the BM-MSC group exhibited lower incidences of grade III–IV aGvHD and cGvHD ( p < 0.05). This study suggests that co-transplantation of hematopoietic and MSCs significantly reduces the risk and incidence of graft rejection and may effectively improve overall survival in patients with SAA even in the absence of closely related histocompatible donor material.

DNA Typing for HLA-A and HLA-B Identifies Disparities Between Patients and Unrelated Donors Matched by HLA-A and HLA-B Serology and HLA-DRB1

Blood ◽  
1999 ◽  
Vol 93 (1) ◽  
pp. 399-409 ◽  
Author(s):  
Vinod K. Prasad ◽  
Nancy A. Kernan ◽  
Glenn Heller ◽  
Richard J. O’Reilly ◽  
Soo Young Yang
Keyword(s):  
Bone Marrow ◽  
Graft Versus Host Disease ◽  
Graft Failure ◽  
Dna Typing ◽  
Outcome Studies ◽  
Cancer Center ◽  
Host Disease ◽  
Graft Versus Host ◽  
Related Variation ◽  
Unrelated Donors

Abstract High incidences of graft failure and graft-versus-host disease in the recipients of bone marrow transplantations (BMT) from unrelated donors (URD) may reflect the existence of allelic disparities between the patient and the URD despite apparent HLA identity at HLA-A, HLA-B, and HLA-DRB1 loci. To identify the extent and pattern of allelic disparities at HLA-A and HLA-B loci, 128 patients and 484 potential URD were evaluated by DNA typing. DNA typing for HLA-A, HLA-B, and HLA-DRB1 was performed at Memorial Sloan Kettering Cancer Center. HLA-A and HLA-B serotyping on URD was provided by the registries. By original typing (serology for HLA-A and HLA-B; DNA typing for DRB1) 187, 164, and 133 URD were 6/6, 5/6, and 4/6 matches, respectively. Following DNA typing, however, only 52.9% of the originally 6/6 matched URD remained 6/6, while 38.5%, 7.5%, and 1.1% were found to be 5/6, 4/6, and 3/6 matches. The level of disparity was higher in the originally 5/6 (P&lt; .01) and 4/6 (P &lt; .01) matched URD. A higher level of disparity was seen for HLA-B as compared to HLA-A. In addition, a serotype related variation was also noticed. For example, 24.1% of HLA-A2 and 60.1% of HLA-B35 seromatched URD were genotypically disparate, but no disparities were seen for HLA-A1 and HLA-B8. A higher percentage of HLA-A (67.4%) compared with HLA-B (35.4%) serologic homozygous URD remained genotypically homozygous (P = .01). The level of allelic disparity was lower (P &lt; .01 for 6/6; P = .02 for 5/6) if the patient had one of the 15 most common haplotypes (A1B8DR3, A2B7DR15, A3B7DR15, etc) in comparison to the rest of the group. Outcome studies will answer the question whether these disparities are associated with a higher rate of immunological complications seen with URD-BMT.

scholarly journals Conditioning Regimens and Outcomes after Allogeneic Hematopoietic Cell Transplant for Hyperinflammatory Inborn Errors of Immunity

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 36-37
Author(s):  
Rebecca A. Marsh ◽  
Soyoung Kim ◽  
Kyle Hebert ◽  
Christopher C. Dvorak ◽  
Victor Aquino ◽  
...  
Keyword(s):  
Overall Survival ◽  
Research Funding ◽  
Graft Failure ◽  
Mixed Chimerism ◽  
Unrelated Donor ◽  
Event Free Survival ◽  
Inborn Errors ◽  
Free Survival ◽  
Inborn Errors Of Immunity ◽  
Conditioning Regimens

Introduction: Inborn errors of immunity such as hemophagocytic lymphohistiocytosis (HLH) and chronic granulomatous disease (CGD) are characterized by hyperinflammation. Hematopoietic cell transplantation (HCT) in the setting of hyperinflammation leads to high morbidity and mortality. Consequently, there is increasing use of less intense conditioning regimens, which can increase risk of mixed chimerism or graft failure. We sought to study the effect of common regimens on outcomes after HCT using data reported to the Center for International Blood and Marrow Transplant Research. Methods : 365 patients aged &lt;21 years with HLH (n=263) and CGD (n=102) were transplanted in the US between 2005-2018. Included are recipients of HLA-matched sibling (n=58; 16%) and HLA-matched (n=149; 41%) and mismatched unrelated (n=158; 43%) donor HCT. The analysis considered 3 conditioning regimen intensity groups: 1) fully myeloablative conditioning with busulfan (Bu; median dose 16 mg/kg [IQR 13-17]), cyclophosphamide (Cy) ± anti-thymocyte globulin (ATG) or alemtuzumab, n=142; 2) reduced intensity conditioning consisting of fludarabine (Flu), melphalan (Mel; 140mg/m2 [60%], 100 mg/m2 [40%]) ± alemtuzumab or ATG, n=131; and 3) reduced toxicity myeloablative conditioning consisting of either Flu, Mel (140mg/m2 [75%], 100 mg/m2 [25%]), and thiotepa (TT; 8 mg/kg or 10 mg/kg), or Flu, Bu (12mg/kg, IQR 9-15) ± alemtuzumab or ATG, n=92. The cumulative incidence rates of veno-occlusive disease (VOD) and infections were calculated. The probabilities of overall survival and event-free survival were calculated using Kaplan-Meier estimator. For event-free survival, an event was defined as the first occurrence of any of the following: primary graft failure, secondary graft failure, cellular product intervention for mixed chimerism, donor chimerism &lt;5%, second transplant, or death. The Fine and Gray method for acute and chronic GVHD and Cox regression analysis for event-free and overall survival were used to determine factors affecting outcomes. Results : Patient demographics were similar across the three treatment groups. Patients with HLH were more likely to receive the Flu/Mel regimen. Although unrelated donor HCTs were predominant across the treatment groups, cord blood graft was more common in the Bu/Cy group. Conditioning regimens changed over the study period with most Flu/Mel/TT and Flu/Bu regimens used after 2010. Consequently, outcomes were censored 2-years post-HCT to account for differences in follow-up. The day-100 incidence of VOD was higher with Bu/Cy (18%) compared to Flu/Mel (4%) and Flu/Mel/TT or Flu/Bu (7%) regimens (p&lt;0.001). The 6-month incidence of bacterial infection was higher after Bu/Cy (50%) and Flu/Mel (58%) compared to Flu/Mel/TT or Flu/Bu (43%) regimens (p=0.013). Viral infections were higher in Flu/Mel group (72%) compared to Bu/Cy (44%) and Flu/Mel/TT or Flu/Bu (56%), p&lt;0.001. There were no differences in overall survival (Figure 1A), but event-free survival (Figure 1B) was lowest with the Flu/Mel regimen, after adjusting for donor type (Table 1). Compared to matched sibling, survival was lower with matched (HR 2.41, p=0.05) and mismatched (HR 2.89, p=0.01) unrelated donor HCT. Chronic GVHD but not grade II-IV acute GVHD was lower with Flu/Mel regimen. Table 2 shows the results of multivariate analysis for HLH disorders and findings consistent with the main analysis. Conclusion : The data does not support the use of a reduced intensity Flu/Mel regimen for hyperinflammatory inborn errors of immunity. Although we did not observe differences in event-free survival between Bu/Cy and Flu/Mel/TT or Flu/Bu regimens, lower incidences of VOD and bacterial infections favor Flu/Mel/TT or Flu/Bu regimens. Disclosures Pulsipher: Bellicum: Honoraria; Jasper: Honoraria; Novartis: Honoraria; Miltenyi: Honoraria, Research Funding; Mesoblast: Honoraria; Adaptive: Research Funding. Stenger:ISCT: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Research Funding.

Donor Characteristics Affecting Graft Failure and Survival after Unrelated Donor Transplantation with Reduced Intensity Conditioning Regimens (RIC) for Hematologic Malignancies.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1968-1968
Author(s):  
Jakob R. Passweg ◽  
Fangyu Kan ◽  
Mei-Jie Zhang ◽  
Vanderson Rocha ◽  
Luis M. Isola ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Resolution ◽  
Graft Versus Host Disease ◽  
Graft Failure ◽  
Unrelated Donor ◽  
Neutrophil Recovery ◽  
Graft Versus Host ◽  
Donor Characteristic ◽  
Conditioning Regimens ◽  
Donor Characteristics

Abstract Impact of donor characteristics is well described for standard intensity unrelated donor and matched sibling donor transplants but may differ in recipients of unrelated donor RIC transplants. Less immunosuppressive regimens at transplantation may lead to higher graft failure rates. We examined risk factors affecting graft failure, acute and chronic graft-versus-host disease (GVHD) and survival after RIC unrelated donor transplants in 715 patients with acute (n=394) and chronic leukemia (n=74), myelodysplastic syndrome (n=70) and non-Hodgkin lymphoma (n=177). Graft failure was defined as &lt;5% donor chimerism within 3 months after transplantation. 159 patients received bone marrow (BM) and 556 peripheral blood (PB) grafts. All transplantations occurred in 1999–2006 in the US. Median follow-up of surviving patients was 36 months (range 6–92). All donors and recipients were typed for HLA A, B, C and DRB1 using high resolution molecular methods. Mismatches at low resolution (antigen) and high resolution (allele) were considered together and are described collectively as mismatches. The day-28 incidence of neutrophil recovery (≥ 0.5 x 109/L) was 96%. After initial neutrophil recovery most patients (n=506) had &gt;95% donor chimerism. 63 patients had &lt;5% donor cells and the remaining 146 patients, 5–95% by 3-months post-transplant. In multivariate analysis, the only factor associated with graft failure was transplantation of BM vs. PB grafts (odds ratio 2.36, p=0.002). We specifically looked for an effect of donor-recipient sex match on graft failure and female donor parity on GvHD and found none. As expected risks of acute graft-versus-host disease (GVHD) were higher after mismatched transplants (p=0.015). No donor characteristic was associated with chronic GVHD. The only donor characteristic affecting overall survival was donor-recipient HLA disparity: 3-year overall survival rates were significantly lower at 23% after mismatched transplants compared to 42% after HLA-matched transplants (p=0.008). Additionally, mortality rates were significantly higher in patients older than 50 years (p=0.005), performance score &lt;90 (p=0.002) and when transplantation occurred with active disease (p&lt;0.001). As seen in recipients of myeloablative conditioning regimens, the only donor characteristic associated with survival is donor-recipient HLA disparity. Donor age, donor-recipient sex match, donor parity and donor cytomegalovirus serostatus were not associated graft failure or survival after unrelated donor RIC transplants.

HLA Homozygosity and Haplotype Bias Among Patients with Chronic Lymphocytic Leukemia: Implications for Disease Control by Physiologic Immune Surveillance

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1370-1370
Author(s):  
Nina Shah ◽  
William Decker ◽  
Ruth Lapushin ◽  
Dongxia Xing ◽  
Simon Robinson ◽  
...  
Keyword(s):  
Overall Survival ◽  
Clinical Outcome ◽  
Patient Population ◽  
Research Funding ◽  
Advanced Disease ◽  
Immune Surveillance ◽  
Prognostic Significance ◽  
Cancer Center ◽  
Cell Transplant ◽  
Hla Alleles

Abstract Abstract 1370 Background: Though the cancer immune surveillance hypothesis was first proposed a century ago, there has been limited evidence to support the role of antigen presentation in the detection or suppression of CLL. In this study we evaluated the frequencies of HLA haplotype and homozygosity and subsequent impact on clinical outcome in CLL patients with advanced disease. Methods: We performed a retrospective chart review of 249 CLL patients who were referred for allogeneic stem cell transplant at MD Anderson Cancer Center. We compared HLA allele frequencies of the patient population with those of local, race-matched controls and identified specific HLA alleles which were more frequent in the patient population. We also compared HLA homozygosity between the patient and control population. The Kaplan-Meier method was then used to determine the prognostic significance of the identified HLA alleles and homozygosity on clinical outcome within our patient population. Progression-free survival (PFS) was calculated from the time of first treatment to the time of progression or death. Results: CLL patients with advanced disease were significantly more likely to express HLA-A1 (OR=1.49, 95% CI 1.15–1.94, p=0.0003) or HLA- C7 (OR 1.24, 95% CI 1.00–1.53, p=0.05). In addition, these patients were more likely to be homozygous at any HLA locus than were controls (OR=1.20, 95% CI 0.97–1.48, p=0.04), particularly at HLA-C (OR=1.62, 95% CI 1.13–2.33, p=0.002) and at multiple HLA loci (OR=1.69, 95% CI 1.06–2.70, p=0.006). CLL patients who were HLA-A1+, HLA-A1/C7+ or homozygous at any allele demonstrated worse PFS in comparison with CLL patients without any of these HLA allelic characteristics. Median survival was 23.9 months for HLA-A1+ patients, 13.9 months for HLA-A1/C7+ patients and 25.7 months for patients with homozygosity, in comparison to 31.8 months for the population without any detrimental alleles or homozygosity (p=0.02, p=0.0008, and p=0.007 respectively, Figure 1: A, B, C). Analysis of patients possessing only HLA-C7 as a risk factor demonstrated a trend toward decreased PFS but was not quite statistically significant (p=0.07, data not shown). Conclusions: Patients with advanced CLL appear to express certain HLA alleles and exhibit HLA homozygosity more frequently than normal controls. In addition, these HLA characteristics may predispose CLL patients to a worse outcome. Because HLA allelic variation determines the specificity of antigens presented to the immune system, the data suggest that immune surveillance may play a physiologic role in the control of leukemic disease and provide a theoretical framework for the identification of CLL antigens which could eventually serve as targets for immunotherapy. A. Negative effects of HLA-A1 allele on overall survival of patients with advanced CLL are B. synergistically worsened by the presence of the HLA-C7 allele. C. Homozygosity at any HLA allele also imparted a negative impact upon overall survival. Disclosures: O'Brien: Novartis: Research Funding; BMS: Research Funding.

Nilotinib and Dasatinib Produce Synergistic Growth-Inhibitory Effects In Imatinib-Resistant CML Cells, Including Subclones Bearing the Multi-Resistant BCR/ABL Mutant T315I

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2280-2280
Author(s):  
Karoline V. Gleixner ◽  
Harald Herrmann ◽  
Irina Sadovnik ◽  
Karina Schuch ◽  
Winfried F Pickl ◽  
...  
Keyword(s):  
Stem Cells ◽  
Research Funding ◽  
Synergistic Effects ◽  
Chronic Phase ◽  
Leukemic Cells ◽  
Inhibitory Effects ◽  
Blast Phase ◽  
Drug Concentrations ◽  
Growth Inhibitory ◽  
Imatinib Resistant

Abstract Abstract 2280 In most patients with chronic myeloid leukemia (CML), complete cytogenetic remission can be achieved with the BCR/ABL tyrosine kinase inhibitor (TKI) imatinib. However, not all patients are long-term responders. A major cause of acquired resistance against imatinib is the development of BCR/ABL mutations in subclones. In most of these patients, a second generation TKI is prescribed. However, the T315I mutant of BCR/ABL introduces resistance against most TKI, including nilotinib and dasatinib. One approach to overcome drug resistance in BCR/ABL T315I+ CML cells may be to apply drug combinations. Recent data suggest that the mechanisms through which dasatinib and nilotinib act on BCR/ABL differ from each other and that both drugs act on multiple additional targets in CML cells. Here, we show that dasatinib and nilotinib cooperate with each other in producing growth inhibition in imatinib-sensitive and imatinib-resistant CML cells, including subclones bearing BCR/ABL T315I. The drug combination was tested on leukemic cells obtained from 9 patients with chronic phase (CP) CML and 3 with blast phase (PB) of CML. Samples were assessed from 4 patients at the time of diagnosis, and against cells from 8 patients (CP, n=5; BP, n=3) who had developed resistance against one or more BCR/ABL TKI. In all 3 patients in PB, the T315I mutant was detectable. As expected, nilotinib and dasatinib failed to inhibit proliferation of cells harbouring BCR/ABL T315I when applied as single agents. However, the combination xnilotinib+dasatinibx produced synergistic effects in most samples, including primary CML cells and Ba/F3 cells harbouring BCR/ABL T315I. Interestingly, in all 3 patients with BP (BCR/ABL T315I+), strong cooperative or even synergistic growth-inhibitory effects were observed in primary CML cells, resulting in substantial anti-leukemic effects seen at reasonable (pharmacologic) drug concentrations (< 1 μ M) (figure). Based on these results, we treated one patient with TKI-resistant CML in hematologic relapse in whom 2 BCR/ABL mutant-bearing subclones, one clinically resistant against nilotinib (F359V) and one clinically resistant against dasatinib (F317L) had been detected, with a combination of nilotinb (800 mg p.o. daily) and dasatinib (50 mg/day p.o., days 1–5 every third week). A transient hematologic response was obtained in this patient, and except for mild bone pain, no side effects were recorded. Moreover, we were able to show that during treatment with xnilotinib+dasatinibx, the number of CD34+/CD38-/CD33+ CML stem cells decreased from clearly measurable levels (0.005%) to nearly undetectable levels (0.0002%). Finally, ex vivo analyses of leukemic blood cells confirmed, that the combination xnilotinib+dasatinibx produced strong cooperative growth-inhibitory effects in both disease-components, i.e. the F359V-bearing subclone and the F317L-bearing subclone. In summary, our data show that the combination of dasatinib and nilotinib can override acquired TKI resistance in CML, and can suppress growth of various imatinib-resistant subclones including cells that bear BCR/ABL T315I or other BCR/ABL mutants. Whether this combination can suppress imatinib-resistant subclones in CML for prolonged time periods or even can eradicate neoplastic stem cells remains in CML patients to be determined. Synergistic effects of nilotinib and dasatinib on primary leukemic cells obtained from a patient with a BCR/ABL T315I+ blast phase of CML Disclosures: Valent: Novartis: Research Funding; Bristol-Myers Squibb: Research Funding.

Graft-Versus-Host Disease Following Myeloablative Busulfan Plus Fludarabine and Busulfan Plus Cyclophosphamide For Allogeneic Hematopoietic Stem Cell Transplantation In Acute Myeloid Leukemia In First Complete Remission

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3290-3290
Author(s):  
Qifa Liu ◽  
Hui Liu ◽  
Daihong Liu ◽  
Yongrong Lai ◽  
Jing Sun ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Research Funding ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Tnf Α ◽  
Before And After ◽  
First Complete Remission

Abstract Background Results from single institutions had shown that compared with busulfan plus cyclophosphamide (BuCy) conditioning, limiting tissue damage by myeloablative busulfan plus fludarabine (BuFlu) conditioning might decrease cytokines release, leading a lower incidence of the graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation (allo-HSCT). In our prospective, multicenter and parallel-group study, further comparison was made of the incidences and severities of GVHD following BuCy and BuFlu myeloablative conditioning regimens in patients undergoing allo-HSCT for AML in first complete remission (CR1), and analyzed plasma cytokines before and after the conditioning. Methods A total of 148 patients with AML-CR1 undergoing allo-HSCT were enrolled into BuCy (busulfan1.6mg/kg, iv q12 hours, -7 ∼ -4d; cyclophosphamide 60 mg/kg.d, -3 ∼ -2d) or BuFlu (busulfan 1.6 mg/kg, iv q12 hours, -5 ∼ -2d; fludarabine 30 mg/m2.d, -6 ∼ -2d) group between January 2007 and January 2013. For patients enrolled between January 2012 and January 2013, plasma concentrations of IL-6, IL-1β, TNF-α, CXCL-10 and IL-17A before and after conditioning were measured by Enzyme-linked immunosorbent assay (ELISA) and compared between the two groups. Regimen-related toxicity (RRT), incidences and severities of acute and chronic GVHD, and overall survival were compared between the two groups. Results Of the 148 patients enrolled in the study, the data of 142 cases were used to determine the endpoints in the intent-to-treat population (72 in BuFlu group and 76 in BuCy group). The levels of TNF-α and IL-6 were significantly higher after the conditioning (5.60±4.40 vs 8.94±5.50 and 2.19±1.24 vs 6.06±12.16 pg/ml, P <0.001 and P =0.045 ), however, there were no significant differences on these cytokines between the two groups. The levels of CXCL-10 in BuCy group was significantly higher than that in BuFlu group (P =0.012). The incidence of I-II° and III-IV° acute GVHD were 42.1% and 6.8%, and 36.1% and 5.7%, respectively, in BuCy and BuFlu group (P=0.363 and P=0.770, respectively). Chronic GVHD occurred in 29 of 69 (41.7%) and 30 of 72 (41.7%) patients, respectively, in BuCy and BuFlu group (P= 1.000). And the incidence of extensive chronic GVHD were 14.3% and 16.7%, respectively, in BuCy and BuFlu group (P= 0.670). The median follow up duration was 824 (range, 3–2345) days. The 5 year overall survival were 79.2 ± 4.4% and 78.6 ± 76.1% (P= 0.555), respectively in BuCy and BuFlu group Conclusion In this report, the incidences and severities of acute GVHD as well as chronic GVHD were similar between BuFlu and BuCy regimen in AML-CR1 patients undergoing allo-HSCT. Disclosures: Liu: National Natural Science Foundation of China (Grant No.81000231, No.81270647) and Science and Technology Program of Guangzhou of China (11A72121174).: Research Funding; It was supported by 863 Program (No. 2011AA020105), National Public Health Grand Research Foundation (Grant No. 201202017): Research Funding.

Influence of Prophylactic Antibiotics Aiming at Gut Decontamination on Gastrointestinal Graft-Versus-Host Disease and Overall Survival Following Allogeneic Haematopoietic Stem Cell Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4319-4319 ◽  
Author(s):  
Bertrand Routy ◽  
Caroline Letendre ◽  
Maxime Chenard-Poirier ◽  
Vikram Mehraj ◽  
David Enot ◽  
...  
Keyword(s):  
Stem Cells ◽  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Conditioning Regimen ◽  
Prophylactic Antibiotics ◽  
Graft Versus Host ◽  
Grade Ii ◽  
The Impact

Abstract Introduction: The impact of commensal bacteria harbored in the gastrointestinal tract known as the microbiota has long been recognized as a pivotal factor in allogeneic hematopoietic stem cell transplantation (aHSCT). The microbiota is at the origin of acute graft-versus-host disease (aGVHD) and infections, two important lethal complications in aHSCT. High-dose conditioning chemotherapy prior aHSCT disrupts the gut epithelial barrier allowing bacterial by-products to translocate into the peripheral blood and modulates T cell response and pro-inflammatory cytokines. Such observation led to an effort by certain transplant centers to eliminate bacterial colonization prior to aHSCT to decrease the risk of gram-negative bacterial translocation. In this study, we assessed whether patients' gut decontamination prior to allogeneic stem cell infusion influenced the frequency of aGVHD, pneumomatosis coli (PC) a significant complication of gastrointestinal (GI) GVHD and overall survival. Methods: We retrospectively reviewed the charts of 543 patients who had undergone a single myeloablative or nonmyeloabaltive aHSCT for hematological malignancies from two academic hospitals in the province of Quebec, Canada between January 2005 and December 2012. Exclusion criteria included prior aHSCT, syngeneic and haploidentical aHSCT. Each university hospital has implemented a different pre-transplant antibioprophylaxis guideline. At HMR hospital, ciprofloxacin or moxifloxacine were started at initiation of the conditioning regimen for gut decontamination, but were omitted in patients with fluoroquinolone or penicillin allergy and during nosocomial infections outbreak. On the other hand, in the CHU de Quebec patients were not prescribed prophylactic antibiotics (ATB). In addition, ATB used to treat infections before the stem cells infusion were considered. To determine the impact of ATB, we performed multivariable analyses adjusting for the following confounding factors: age, gender, stem cell origin (source), donor type/match, and conditioning regimens to compare the frequency of aGVHD, PC, leucocytes recovery at day+14 and overall survival (OS) in patients receiving or not ATB. Results: 500 patients were included and a total of 240 (48%) patients received ATB at the time of conditioning regimen. Demographics were similar in both groups with mean age of 48 years. Frequency of grade II-IV aGVHD was more elevated in patients receiving ATB compared to the no ATB group (42% vs 28% respectively with adjusted OR (aOR)=1.53 (p<0.05). The severity of the aGVHD in the ATB group was driven by the GI-GVHD with a higher level of grade II-IV (20.7%) compared to no ATB group (10.8%) with aOR=2.00 (p<0.01). Severity of skin and liver GVHD were similar in both groups. Among the 12 patients that developed PC diagnosed on CT-scan, all received ciprofloxacin during conditioning and PC was associated with 80% mortality. The difference of aGVH frequency may have translated into survival as the ATB group was associated to lower 1 year survival compared to no ATB group (74% vs 88%, OR=0.36 and aOR=0.38 (p<0.05). This significant survival difference at 1 year persisted over time and median OS was 4 and 5 years respectively (p<0.05). Taking into consideration the entire follow-up period of 10 years, the hazard rates associated with ATB were estimated at 1.61(p<0.06) and 1.43 (p<0.05) after adjusting for clinical parameters. Interestingly, post-hoc analysis revealed independent impact of the ATB on D+14 neutrophils. This was reflected by a lower neutrophil count in patients on ATB that received stem cells from a match-related donor compared to no ATB counterpart with a ratio of 0.38 (p<0.05). Discussion: This retrospective study indicated that ATB were associated to a more severe aGVHD driven by digestive manifestations of the GVHD and higher incidence of PC even after multivariable analysis. These life-threatening complications may impact on the 1-year and OS that were lower in the ATB group. Without undermining the role of ATB prophylaxis to prevent infection in aHSCT setting, treatment with ATB impact on the commensal microbiota and diminishes its diversity. This imbalance created by the ATB may have contributed to the pathophysiology of GI-GVHD. This ultimately highlights the importance to reconsider antibioprophylaxis to preserve an intact flora and its benefits in aHSCT. Disclosures No relevant conflicts of interest to declare.

scholarly journals Bortezomib, Lenalidomide and Dexamethasone (VRD) Followed By Autologous Stem Cell Transplant for Newly Diagnosed Multiple Myeloma; The Mayo Clinic Experience

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2147-2147
Author(s):  
M Hasib Sidiqi ◽  
Mohammed A Aljama ◽  
Angela Dispenzieri ◽  
Eli Muchtar ◽  
Francis K. Buadi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
High Risk ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Mayo Clinic ◽  
Research Funding ◽  
Advisory Committees ◽  
Post Transplant ◽  
Standard Risk

Abstract We retrospectively reviewed all patients receiving bortezomib, lenalidomide and dexamethasone induction followed by autologous stem cell transplantation (ASCT) within 12 months of diagnosis for multiple myeloma at the Mayo Clinic. 243 patients treated between January 2010 and April of 2017 were included in the study. Median age was 61 (interquartile range, 55-67) with 62% of patients being male. High risk cytogenetic abnormalities (HRA) were present in 34% of patients. 166 (68%) patients received some form of maintenance/other therapy post transplant (no maintenance (NM, n=77), lenalidomide maintenance (LM, n=108), bortezomib maintenance (BM, n=39) and other therapy (OT, n=19)). Overall response rate was 99% with complete response (CR) rate of 42% and 62% at day 100 and time of best response post transplant respectively. The four cohorts categorized by post transplant therapy were well matched for age, gender and ISS stage. HRA were more common amongst patients receiving bortezomib maintenance or other therapy post transplant (NM 18% vs LM 22% vs BM 68% vs OT 79%, p<0.0001). Two year and five year overall survival rates were 90% and 67% respectively with an estimated median overall survival (OS) and progression free survival (PFS) of 96 months and 28 months respectively for the whole cohort. OS was not significantly different when stratified by post-transplant therapy (Median OS 96 months for NM vs not reached for LM vs 62 months for BM vs not reached for OT, p=0.61), however post-transplant therapy was predictive of PFS (median PFS 23 months for NM vs 34 months for LM vs 28 months for BM vs 76 months for OT, p=0.01). High risk cytogenetics was associated with a worse OS but not PFS when compared to patients with standard risk (median OS: not reached for standard risk vs 60 months for HRA, p=0.0006; median PFS: 27 months for standard risk vs 22 months for HRA, p=0.70). In patients that did not receive maintenance therapy presence of HRA was a strong predictor of OS and PFS (median OS: not reached for standard risk vs 36 months for HRA, p<0.0001; median PFS: 24 months for standard risk vs 7 months for HRA, p<0.0001). Patients receiving maintenance therapy appeared to have a similar PFS and OS irrespective of cytogenetics (median OS: not reached for standard risk vs 62 months for HRA, p=0.14; median PFS: 35 months for standard risk vs 34 months for HRA, p=0.79).On multivariable analysis ISS stage III and achieving CR/stringent CR predicted PFS whilst the only independent predictors of OS were presence of HRA and achieving CR/stringent CR. The combination of bortezomib, lenalidomide and dexamethasone followed by ASCT is a highly effective regimen producing deep and durable responses in many patients. Maintenance therapy in this cohort may overcome the poor prognostic impact of high risk cytogenetic abnormalities. Table Table. Disclosures Dispenzieri: Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Lacy:Celgene: Research Funding. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Kapoor:Celgene: Research Funding; Takeda: Research Funding. Kumar:KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Gertz:Abbvie: Consultancy; Apellis: Consultancy; annexon: Consultancy; Medscape: Consultancy; celgene: Consultancy; Prothena: Honoraria; spectrum: Consultancy, Honoraria; Amgen: Consultancy; janssen: Consultancy; Ionis: Honoraria; Teva: Consultancy; Alnylam: Honoraria; Research to Practice: Consultancy; Physicians Education Resource: Consultancy.

scholarly journals Poor Outcomes with Hyper CVAD Induction for T-Cell Lymphoblastic Leukemia/Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3762-3762 ◽  
Author(s):  
Vamsi K Kota ◽  
Amanda Redden Hathaway ◽  
Bijal D. Shah ◽  
Deniz Peker ◽  
Ling Zhang ◽  
...  
Keyword(s):  
Overall Survival ◽  
Clinical Trials ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Cancer Center ◽  
Relapse Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Genetics Research

Abstract Background: T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) in adults is an aggressive bone marrow malignancy that historically has a poor prognosis. Hyper-CVAD/methotrexate-cytarabine (hyper CVAD) regimen is a commonly used induction regimen following the protocol developed at MD Anderson Cancer center. Recent reports from Swedish Cancer Registry showed that relapse rates were much higher than expected with this regimen. We report our retrospective experiences across three different centers, Winship Cancer Institute of Emory University (Atlanta), University of Alabama Cancer Center (Birmingham) and Moffitt Cancer Center, (Tampa), with the use of this regimen for management of T-ALL/LBL. Methods: We conducted a retrospective chart review of all adult T-ALL/T-LBL cases at three large cancer centers between the years 2005-2015, treated at the physician's discretion. Data collected included patient demographics, tumor characteristics (white count at diagnosis, flow cytometry, FISH, cytogenetics, bone marrow involvement), treatment regimens and patient outcomes. Since hyper CVAD is a commonly used regimen outside of clinical trials, we focused our analysis on outcomes with this regimen. This regimen consisted of 4 courses of hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone; the odd courses 1, 3, 5, 7); and 4 courses of MTX-Ara-C (methotrexate-cytarabine; the even courses 2, 4, 6, 8). CNS prophylaxis was given to all patients as per standard of care recommendations. All patients eligible for maintenance received 2 years of POMP (6 mercaptopurine, methotrexate, vincristine and prednisone) maintenance. Relapse-free survival (RFS) and overall survival (OS) were examined looking at medians and interquartile ranges of times to events. Kaplan Meier curves provided a graphical representation of the survival probability. Results: The final analysis included 95 adult patients with 64/95 (67%) patients receiving hyper-CVAD induction. Among the hyper-CVAD patients the median age at diagnosis was 30 (range 17-74). 71% of patients were male. Median white cell count (WBC) was 13.6/mm3 (1.7-500). Cytogenetic analysis revealed diploid in 36, complex (1 or more abnormalities in 16) and was not available in 12. WBC count was > 100,000/mm3 in 9 patients. 14 patients had mediastinal disease while 7 had CNS disease at diagnosis. Hyper-CVAD was the primary induction regimen in 56/64. Other patients either started on non-hyper CVAD induction prior to switching (n=3) or had asparaginase added to induction (n=5). The median number of cycles given as 7 (range 2-10) with 27(45%) patients receiving the planned 8 cycles. 37 patients did not complete 8 cycles due to stem cell transplant in remission (n=12), progressive disease (n=10) and unclear reasons (n=15). After induction therapy, remission status was unknown in 3 patients while 43/61 patients (70%) achieved remission. Maintenance with POMP was started in 21 patients that were in remission while 12 patients were taken to transplant without starting on maintenance. At the time of analysis, 23/64 (35%) patients are alive. The median relapse free survival was 387 days (12.9 months) and the median overall survival was 536 days (17.6 months). Excluding one patient lost to follow up, 44/63 (69.8%) relapsed. There was no difference in relapse versus non relapse patients in terms of median age (30 vs 33 years), median WBC at diagnosis (13.2 vs 13.6 mm3). Relapse rate was lower in patients with diploid karyotype (22/36, 61%) as compared to those with complex karyotype (14/16). Median survival in patients post relapse was 150 days. Only 9 patients were able to go for transplant after relapse with post transplant survival also being low (6 deaths). For the entire group, the two year survival was 35%. Conclusion: Our multi-institutional retrospective review shows that outcomes are poor across various centers in patients outside of clinical trials. This is the largest reported series of patients with adult T-ALL/T-LBL treated with hyper-CVAD outside of clinical trials. This data warrants investigation with newer agents to improve outcomes in this disease. Figure 1. Relapse free survival and overall survival in patients treated with hyper-CVAD (n=64) Figure 1. Relapse free survival and overall survival in patients treated with hyper-CVAD (n=64) Disclosures Kota: Leukemia Lymphoma Society: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Hathaway:OnQ Health: Research Funding. Shah:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acetylon: Membership on an entity's Board of Directors or advisory committees; PLexus Communications: Honoraria; Pharmacyclics: Speakers Bureau; Spectrum: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Honoraria; Rosetta Genomics: Research Funding; Seattle Genetics: Research Funding. Jillella:Seattle Genetics, Inc.: Research Funding. Borate:Genoptix: Consultancy; Seattle Genetics: Research Funding; Gilead: Speakers Bureau; Alexion: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Speakers Bureau.

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