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  • 1
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 3 ( 2012-01-20), p. 232-238
    Abstract: We studied BCR-ABL1 transcript levels in patients with chronic myeloid leukemia in chronic phase (CML-CP) at 3, 6, and 12 months after starting imatinib to identify molecular milestones that would predict for overall survival (OS) and other outcomes more reliably than serial marrow cytogenetics. Patients and Methods We analyzed 282 patients with CML-CP who received imatinib 400 mg/d as first-line therapy followed by dasatinib or nilotinib if treatment with imatinib failed. We used a receiver operating characteristic curve to identify the cutoffs in transcript levels at 3, 6, and 12 months that would best predict patient outcome. We validated our findings in an independent cohort of 95 patients treated elsewhere. Results Patients with transcript levels of more than 9.84% (n = 68) at 3 months had significantly lower 8-year probabilities of OS (56.9% v 93.3%; P 〈 .001), progression-free survival, cumulative incidence of complete cytogenetic response, and complete molecular response than those with higher transcript levels. Similarly, transcript levels of more than 1.67% (n = 87) at 6 months and more than 0.53% (n = 93) at 12 months identified high-risk patients. However, transcript levels at 3 months were the most strongly predictive for the various outcomes. When we compared OS for the groups defined molecularly at 6 and 12 months with the usual cytogenetic milestones, categorization by transcript numbers was the only independent predictor for OS (relative risk, 0.207; P 〈 .001 and relative risk, 0.158; P 〈 .001, respectively). Conclusion A single measurement of BCR-ABL1 transcripts performed at 3 months is the best way to identify patients destined to fare poorly, thereby allowing early clinical intervention.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
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  • 2
    In: Blood, American Society of Hematology, Vol. 115, No. 20 ( 2010-05-20), p. 4018-4020
    Abstract: Outstanding results have been obtained in the treatment of chronic myeloid leukemia (CML) with first-line imatinib therapy. However, approximately 35% of patients will not obtain long-term benefit with this approach. Allogeneic hematopoietic stem cell transplantation (HCT) is a valuable second- and third-line therapy for appropriately selected patients. To identify useful prognostic indicators of transplantation outcome in postimatinib therapeutic interventions, we investigated the role of the HCT comorbidity index (HCT-CI) together with levels of C-reactive protein (CRP) before HCT in 271 patients who underwent myeloablative HCT for CML in first chronic phase. Multivariate analysis showed both an HCT-CI score higher than 0 and CRP levels higher than 9 mg/L independently predict inferior survival and increased nonrelapse mortality at 100 days after HCT. CML patients without comorbidities (HCT-CI score 0) with normal CRP levels (0-9 mg/L) may therefore be candidates for early allogeneic HCT after failing imatinib.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 3
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 4052-4052
    Abstract: Abstract 4052 Introduction: Donor stem cells are traditionally infused fresh into recipients in the setting of allogeneic hematopoietic stem cell transplantation (allo-SCT). In this study, we investigated outcomes of 133 sibling allografts using cryopreserved peripheral blood stem cells. We demonstrate that cryopreservation did not have a negative impact on engraftment when compared to data from the IBMTR/EBMT, Seattle and the Canadian registry studies. Non-relapse mortality (NRM) and overall survival (OS) were within acceptable limits. Patients and Methods: We identified all recipients of HLA-matched sibling peripheral stem cells cryopreserved for a minimum of 7 days, who underwent allo-SCT at Hammersmith Hospital from January 1998 until May 2011 (n = 133). The median age at allo-SCT of 78 (59 %) males and 55 (41 %) females was 48 (17 – 65) yrs. Thirty-five (26 %) were transplanted for CML (including accelerated and blast phase), 42 (31 %) for AML, 11 (8 %) for ALL, 14 (11 %) for myeloma and 13 (10%) for other causes. Fifty-six (42 %) had myeloablative and 77 (58 %) had reduced intensity conditioning, with 23 (17 %) having in vivo T-cell depletion with monoclonal anti-CD52 antibody (alemtuzumab). Using validated institutional protocols hematopoietic progenitor cell collections were cryopreserved on the day of collection or on following morning. Cells are were mixed with 10 % v/v dimethyl sulfoxide, frozen to -−00°C at a controlled rate and then transferred to vapor phase liquid nitrogen ≤ −150°C. Thawing and infusion of cells were performed in accordance with a standard protocol defining thawing temperature and the maximum time between thawing and infusion. Median CD-34+ cell dose infused was 9.83 × 106/kg (range 2.4 – 33 × 106/kg). All cryopreserved peripheral blood stem cell collections were infused into the recipients. Engraftment was defined as a peripheral absolute neutrophil count (ANC) of 0.5 × 109/L for 2 successive days and platelet count of 〉 50 × 109/L for 2 consecutive days, both without support. G-CSF was used only in delayed neutrophil engraftment ( 〉 30 days). Results: Overall 125 (93 %) achieved neutrophil engraftment and median time to engraftment was 19 (range 10 – 42) days. Delayed neutrophil engraftment ( 〉 30 days) was present in 4 patients. Results are comparable to the registry data which showed neutrophil engraftment in a median of 14 – 19 days (Table 1). Cumulative probability of achieving ANC 〉 of 0.5 × 109/L for the whole cohort was 94 % (88 – 95). Eight of the 133 patients who died early ( 〈 day 30) failed to achieve neutrophil engraftment prior to death. The causes of death were sepsis (n = 6), myocardial ischemia (n = 1) and renal failure (n = 1).Three recovered counts with G-CSF and one patient required stem cell rescue. One hundred and thirteen patients (84 %) recovered platelets to 〉 50 × 109/L within a median time of 21 (range 0 – 240) days, which again is similar to registry data as shown in table 1. The cumulative probability of achieving platelets of 50 × 109/L was 84 % (77 – 88). Twenty patients (16 %) failed to achieve this threshold and causes were multiple. There was no association between CD34+ cell doses infused and delayed or non engraftment of platelets. The incidence of acute and chronic GvHD were 44 % (grade II-IV GvHD 31 %) and 30 % (50 % extensive) respectively. Day 100 NRM was 23 % and OS at 3 years was 50 %. Conclusion: This study provides evidence that cryopreservation and subsequent infusion of peripheral blood stem cell harvests is safe, ensures durable engraftment and is comparable to fresh stem cell infusions (Table 1). We do not routinely use growth factors to aid count recovery and as such the time to engraftment data is consistent. Cryopreservation importantly allows for flexibility in arranging admissions and scheduling regimens for both the donors and the transplant units. Although not observed in our cohort, there is a theoretical risk of not utilizing the cryopreserved cells, thus unnecessarily harvesting donors. One way to circumvent this possibility is by timing the collection close to the transplant. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 4
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 3488-3488
    Abstract: Abstract 3488 It is important to determine prognostic indicators which may predict outcome of hematopoietic stem cell transplantation (HCT). The European Group for Blood and Marrow Transplantation (EBMT) proposed a scoring system for CML which, after modification, also predicted outcomes for patients transplanted for other hematologic malignancies. The HCT comorbidity index (HCT-CI) developed by Sorror et al. enabled further selection of patients for HCT based on their comorbidities. We have recently shown that the level of C-reactive protein (CRP) measured shortly before transplantation is another important prognostic factor in patients transplanted for CML in first chronic phase. In this study we tested the value of CRP together with other known prognostic factors in an independent cohort of 263 patients transplanted in a single institution from 1992 through 2009 for ALL (N=38, 14%) AML (N=72, 27%), MDS (N=19, 7%), and advanced phase CML (N=134, 51%). For the 130 (49%) recipients of stem cells from matched siblings conditioning consisted of cyclophosphamide and TBI. For the 133 (51%) unrelated donor transplant recipients in vivo T-cell depletion with anti CD52 antibody (Campath) was used in addition. Serum CRP levels were measured at a median of 16 days before stem cell infusion using a standard latex immunoassay (normal range 0–9 mg/L) while the patients were well without infection and off antibiotics. Patients' comorbidities were defined and assigned different weights (1-3) by the HCT-CI and disease stage was assessed in accordance with EBMT criteria. Thus, patients transplanted for AML (N=32) or ALL (N=27) in first complete remission were classified as early stage (N=59). Those with CML in accelerated phase (N=70), CML in second (N=42) or third (N=5) chronic phase, AML (N=19) or ALL (N=6) in second complete remission and MDS (N=19) were classified as intermediate stage (N=161). Patients with CML in blast phase (N=17) and acute leukemia in 〉 2nd complete remission (N=26) or in relapse were defined as late stage (N=43). In univariate analysis, factors associated with day 100 nonrelapse mortality (NRM) were recipient's age at HCT, disease stage and preconditioning CRP level whereas disease stage, CRP level, and EBMT score were associated with overall survival (OS). In multivariate analysis only two factors showed independent prognostic value: late disease stage and elevated CRP level ( 〉 9 mg/L). Both predicted for inferior NRM (RR: 3.83, CI 1.65–8.92, P=.002 and RR: 1.51, CI 1.51–4.26, P 〈 .001 respectively) and OS (RR: 2.88, CI 1.80–4.62, P 〈 0.001 and RR: 1.56, CI 1.15–2.13, P= 0.005). The day 100 NRM was 41% for patients with CRP 〉 9 mg/L, 17% for those with CRP 0–9 mg/L (figure) and 25% for the whole cohort. The 5-year OS was 31.5% for patients with CRP 0–9 mg/L, 22.2% for those with CRP 〉 9 mg/L and 28% for the whole cohort. There was no association between elevated preconditioning CRP levels and infection, either as a comorbidity or as a cause of death. The HCT-CI did not have a prognostic role in this cohort. These results confirm the high prognostic value of disease stage. Importantly, they extend our findings in early phase CML to other hematologic malignancies and establish pretransplantation levels of CRP as an independent predictor of allogeneic HCT outcomes. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 5
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 1945-1945
    Abstract: Abstract 1945 Introduction: Identification of prognostic indicators which predict outcome of allogeneic stem cell transplantation (allo-SCT) is important for selection of patients who may benefit from the procedure. The European Group for Blood and Marrow Transplantation (EBMT) proposed a scoring system for CML which, after modification, also predicted outcomes for patients transplanted for other hematologic malignancies. We have recently shown that the level of C-reactive protein (CRP) measured shortly before transplantation is another important prognostic factor in patients undergoing myeloablative allo-SCT. Patients and Methods: In this study we tested the value of CRP together with other known prognostic factors in 187 consecutive patients who underwent reduced intensity HCT in a single institution from 1995 through 2010. Disease stage was assessed in accordance with EBMT criteria. Preconditioning serum CRP levels were measured at a median of 15 days before stem cell infusion using a standard latex immunoassay. The median age at HCT of the 116 (62%) males and 71 (38%) females was 49 (range 15–67) years. Fifty seven patients (31%) were transplanted in early stage, 34 (18%) in intermediate stage and 96 (51%) in late stage of their disease. The diagnoses included: AML (n = 36; 19%), Hodgkin and non-Hodgkin lymphoma (n = 42; 23%), CML in first chronic phase (n = 29; 16 %), advanced phase CML (n = 21; 11%), MDS (n = 15; 8%), myeloma (n = 16; 9%), ALL (n = 7; 4 %), myelofibrosis (n = 5; 3%), and other (n = 16; 9 %). Patients were transplanted after conditioning containing fludarabine in combination with busulfan (n = 81, 43 %), cyclophosphamide (n = 37, 20 %), and melphalan (n = 47, 25 %); and lomustine, cytarabine, cyclophosphamide and etoposide (LACE) conditioning (n = 21; 11 %). Donors were HLA matched (n = 116; 62 %) and 1 – 2 antigen mismatched (n = 8; 4 %) siblings, matched (n = 46; 25 %) and 1–2 antigen mismatched unrelated (n = 11; 6%), and HLA haploidentical family members (n = 6; 3 %). Results: In univariate analysis, factors associated with day 100 non-relapse mortality (NRM) were disease stage, preconditioning CRP level and donor and recipient HLA match; whereas disease stage, CRP level, HLA match and number of previous allogeneic stem cell transplantations were associated with overall survival. In multivariate analysis only two factors showed independent prognostic value: disease stage (early / intermediate versus late) and CRP level (above versus below 10 mg/L). A CRP level 〉 10 and late disease stage predicted for higher NRM (RR: 1.83, CI 1.1 – 3.1, P =.021) and (RR: 1.78, CI 1.0 – 3.0, P =.037), and inferior survival (RR: 1.61, CI 1.1 – 2.4, P =.016) and (RR: 1.58, CI 1.1 – 2.3, P =.023) respectively. The day 100 NRM was 31% (95% CI 22 – 44) for patients with elevated CRP, and 13 % (95% CI 8–21) for those with normal CRP (P =.002; figure) and 20 % (95% CI 15–27) for the whole cohort. The 5-year survival was 41 % (95% CI 27 – 56) for patients with normal CRP, 21% (95% CI 12 – 35) for those with elevated CRP (P =.004) and 34 % (95% CI 25 – 44) for the whole cohort. Conclusion: There is no obvious explanation for increased NRM and reduced survival in patients with elevated CRP before initiation of conditioning. Nevertheless our findings provide evidence that preconditioning level of CRP constitutes a key prognostic factor in allo-SCT and should be integrated into existing risk assessment tools when considering allo-SCT. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 6
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 677-677
    Abstract: Abstract 677 In 2009 the spread of influenza A (H1N1) satisfied the World Health Organization (WHO) criteria for a global pandemic and led to the initiation of a vaccination campaign to ensure protection for the most vulnerable patients. However, the immunogenicity of the 2009 H1N1 vaccine in immunocompromised patients has not been specifically evaluated. Furthermore, the number of doses of vaccine required for effective immunization against H1N1 has not been established. Whereas the European Medicines Agency (EMEA) and the UK Department of Health (DoH) recommended the injection of two doses of inactivated H1N1 vaccine 3 weeks apart in immunocompromised individuals, the Centers for Disease Control and Prevention recommended immunization with one dose of inactivated H1N1 vaccine for patients with cancer receiving chemotherapy, followed by a booster vaccine after completion of treatment if the pandemic continued. The aim of this study was to determine the safety and efficacy of the 2009 H1N1 vaccine in patients with hematologic malignancies. We prospectively evaluated the humoral and cellular immune responses to monovalent influenza A/California/2009(H1N1)v-like strain surface antigen vaccine in 97 adults with hematologic malignancies and 25 adult controls. Patients received two intramuscular injections of the vaccine 21 days apart and controls received one dose. Antibody titers, expressed as geometric mean, were measured using a hemagglutination-inhibition assay on days 0, 21 and 49 after injection of the first dose. The induction of virus-specific T-cell responses by H1N1 vaccination was assessed directly ex-vivo by flow cytometric enumeration of antigen-specific CD8+ and CD4+ T-lymphocytes using an intracellular cytokine assay for IFN-γ and TNF-α production on days 0 and 49. Of the 97 patients, 32 had chronic myeloid leukemia (CML) in chronic phase in complete cytogenetic response on the tyrosine kinase inhibitors imatinib or dasatinib, 39 had a B-cell malignancy in complete remission (CR) or untreated, and 26 were recipients of allogeneic hematopoietic stem cell transplantation (allo-SCT) in CR at least 6 months beyond transplant and without evidence of graft versus host disease. The vaccine was well tolerated, with no obvious difference in side effects for patients and controls. By day 21 post-vaccination, protective antibody titers of 1:32 or more were seen in 100% of controls compared to 39% of patients with B-cell malignancies (p 〈 0.001), 46% of allo-SCT recipients (p 〈 0.001) and 85% of CML patients (p=0.086). The effect of a booster dose was assessed with a paired sample analysis. After a second vaccine dose, the seroprotection rates increased to 68% (p=0.008), 73% (p=0.031), and 95% (p=0.5) in patients with B-cell malignancies, allo-SCT recipients and CML patients respectively. Patients vaccinated within 6 months of rituximab-based chemotherapy failed to mount a seroprotective antibody response. We also assessed the cellular response to H1N1 vaccine. Prior to vaccination, pre-existing T-cells against H1N1 could be detected in 10/23 controls compared to 2/25 allo-SCT recipients (p=0.007), 2/28 patients with B-cell malignancies (p=0.003) and 6/28 of CML patients (p=0.131). These pre-existing H1N1 T-cell responses may be related to previous exposure to 2009 H1N1 virus but more likely are due to the presence of cross-reactive seasonal and pandemic H1N1 specific T-cells. Following vaccination, H1N1-specific T-cells were induced in a significant proportion of allo-SCT recipient (10/25, p=0.008) and patients with B-cell malignancies (10/28; p=0.008), but not in CML patients or healthy controls. The limited ability of vaccines to significantly increase pre-existing influenza-specific T-cells has been previously reported although the mechanism for this phenomenon is not fully elucidated. These data demonstrate efficacy of H1N1 vaccine in the majority of patients with hematologic malignancies and unequivocally support the EMEA and the UK DoH official guidelines for the administration of 2 vaccine doses in immunocompromised patients to induce protective immune response against 2009 H1N1 influenza. Based on the WHO analyses, it is expected that the pandemic 2009 H1N1 virus will remain globally predominant in 2010–2011. These results may contribute towards the development of evidence-based guidelines for influenza vaccination in patients with hematologic malignancies. Disclosures: Marin: Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 7
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3753-3753
    Abstract: Abstract 3753 The tyrosine kinase inhibitors (TKIs) imatinib (IM), nilotinib (NIL) and dasatinib (DAS) are remarkably effective as single-agent therapy for chronic myeloid leukemia (CML) in chronic phase (CP). However little is known of their potential impact on the immune response. No human in vivo studies to assess how these molecular-targeted drugs affect immune function in patients are available and data from in vitro and animal studies with imatinib have been contradictory, ranging from impaired antigen-specific T-cell response to enhanced stimulation of tolerant T cells. Furthermore, although the immunomodulatory effects of TKIs on T cells, NK cells and dendritic cells have been explored in vitro, little is known of their potential impact on B cells. To characterize the in vivo immunomodulatory effects of TKIs, 51 patients with CP-CML in complete cytogenetic response (CCyR) on standard dose IM (n=26), DAS (n=14) or NIL (n=12) and 28 adult controls were recruited during two influenza seasons (2008 and 2009). Patients and controls were concomitantly immunized with an influenza vaccine (Ph. Eur. 2008/2009 or Ph. Eur. 2009/2010, CSL Biotherapies) and with the 23-valent polysaccharide pneumococcal vaccine (Pneumovax II; Sanofi Pasteur MSD). Peripheral blood mononuclear cells (PBMCs) and serum samples were collected from patients and donors prior to vaccination and T and B responses to vaccination were assessed at 4 weeks and at 2–3 months post-immunization. T-cell responses to influenza vaccine were analyzed quantitatively and qualitatively using flow cytometry and intracellular cytokine assay for TNF-α, IFN-γ, IL-2 and the cytotoxicity marker CD107a. Serum titers of IgM and IgG pneumococcal antibodies were determined by ELISA. Analysis of B cell subsets was performed using flow cytometry and correlated with the pneumococcal IgM and IgG humoral response. Following vaccination, Flu-specific T cells were detected in 24/51 (47.0%) patients on TKI and 15/24 (62.5%) healthy controls (p=0.16). Polyfunctional T-cell responses (defined as the production of 2 or more cytokines or one cytokine and the cytotoxic marker CD107a) were induced in 6/10 evaluable patients and 4/8 normal controls (p=1.0). T-cell independent humoral responses to vaccination were assessed in 45 patients and 12 healthy controls by measuring pneumococcal IgM titers. Four weeks postimmunization, 11/12 (92%) controls achieved IgM pneumococcal Ab titers 〉 80 U/ml compared to only 23/45 (53%) CML patients on TKI (p=0.010). The pneumococcal IgM titers were significantly lower in patients with CML on TKI compared to healthy controls (median, 89.0 U/ml, range 5–200 vs 200 U/ml, range 58–200, p=0.0006), suggesting that CML patients on TKI have impaired IgM responses to vaccination. To further characterize the humoral immune response to Pneumovax, we stratified CML patients based on their pneumococcal IgM titers. We found a significantly lower percentage of IgM memory B cell subset in CML patients who failed to mount a significant pneumococcal IgM response compared to patients who achieved a pneumococcal IgM response (median, 6.25% vs 16.4%, p=0.0059) and healthy controls (median, 6.25% vs 14.3%, p=0.0086). Furthermore, we found a significant correlation between anti-pneumococcal IgM titers and IgM memory B cell percentage (Spearman rank correlation test, r=0.61, p 〈 .0001). To investigate a putative role of TKIs for the loss of IgM memory B cell subsets in CML patients, we determined the frequencies of IgM memory B cells in paired samples collected from 15 CML-CP patients at diagnosis (i.e. prior to initiating IM) and once CCyR was achieved. We found a significant decrease in the percentage of IgM memory B cells in CML-CP patients treated with IM compared to the pre-treatment sample (median 9.4%, vs. 15.2% respectively, p=0.0023). In summary, patients with CML on TKIs can mount effective T-cell immune responses to influenza vaccination. Our data suggest that TKIs (IM, DAS and NIL) impair T-cell independent humoral immune responses, namely IgM responses to vaccination. This is associated with a loss of IgM memory B cell subsets. Further investigations to understand the mechanisms by which TKIs may impact B-cell subsets are underway. These results are of particular interest in terms of the long-term effects of TKI on tumor immune surveillance and susceptibility to infections and may have implication for vaccination strategies in CML patients. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 8
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 2378-2378
    Abstract: Autologous stem cell transplantation (ASCT) remains the standard consolidation therapy for patients with multiple myeloma (MM) and chemosensitive relapsed lymphoma (r-Ly). Peripheral blood as a source of stem cells (PBSC) has largely replaced marrow and has the advantage of improved engraftment rates. PBSC are routinely collected following administration of chemotherapy in combination with GCSF. However, the resultant pancytopenia poses a significant risk to patients and additional chemotherapy prior to ASCT may lead to increased end organ damage potentially precluding future therapies (including ASCT). Novel agents can achieve PBSC mobilisation without the use of cytotoxics. In the advent of such drugs, we reviewed the efficacy of, and complications experienced by patients during PBSC mobilisation. We also analysed the cost implications of adverse events. Of 151 consecutive attempts, 13.2% of patients failed to reach our criteria in order to attempt pheresis (1 × 104 CD34 cells/ml). Of those achieving target and undergoing pheresis, 6% did not achieve an adequate cell dose for future ASCT (2 × 106CD34+cells/kg) giving an overall failure rate of 19.2%. Furthermore 17.9% failed to harvest our ideal of 4 × 106/kg (permitting & gt;1 ASCT procedure). Factors contributing to failure in achieving target CD34+ve PB count on univariate analysis were; & gt;2 lines of previous chemotherapy and occurrence of neutropenic sepsis (NS (p=0.002, and 0.005 respectively). These factors remained significant on multivariate analysis (RR: 4.4 and 6.2). These same factors also affected CD34+ cell yield on both univariate and multivariate analysis (RR: 3.3 and 4.6). No differences were seen between MM and r-Ly. Overall, the complication rate was 34.4%, with 24.1% of patients suffering NS requiring admission. The mortality rate was 1.3% (NS and intra-cranial bleed). Of those developing NS, only 52% eventually harvested sufficient cells, but with a median delay of 3 days. The median cost of PBSC collection was $17,381.46 ($1,978.97–$39,355.73). NS significantly increased the cost of mobilisation at a median cost of $25,532.95 vs $16,4921) (p= & lt;0.0001). Conclusion: Our results suggest that patients who are potential candidates for ASCT should be harvested as soon as they achieve remission to prevent failure following additional therapy upon relapse. One fifth of patients will fail. The risks associated with current mobilisation protocols are substantial, and also impact greatly on cost, particularly relevant in the current climate of economic probity. Therefore these data suggests that transplant centres should consider the use of non-myelosuppressive agents either in place of, or as a dose reduction strategy for autologous stem cell procurement.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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  • 9
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 4103-4103
    Abstract: Abstract 4103 Donor lymphocyte infusions (DLI) produce molecular remission in the large majority of chronic myeloid leukaemia (CML) patients who relapse after allografting. Although response to DLI is associated with long-term clinical remissions, we asked whether minimal residual disease could still be detected. We identified 116 patients who had received escalating doses of donor lymphocytes between 1995 and 2010 for molecular, cytogenetic or haematological relapse following allogeneic hematopoietic stem cell transplantation for CML. These patients had serial monitoring of their response by quantitative reverse transcriptase–polymerase chain reaction (RT-PCR). 84 patients had achieved a complete molecular remission (CMR) (defined by 2 consecutive negative PCR), however 79 (94%) of these subsequently became positive again. All patients who achieved a complete molecular remission were allocated to 3 categories: (1) “persistently negative” or a single low level positive result (n=15 (18%); (2) “fluctuating low-level positive”, who had multiple positive results, but never more than 2 consecutive positive results (n=34 (40%)); and (3) “persistently low-level positive” (n=35(42%)), and the rates of relapse were compared in the three groups. The overall probability of relapse (defined by the initial molecular relapse criteria) at 10 years was low in all three groups (6.7%), and there was no significant difference in each category: 0%, 4.2% and 10.3% respectively (P=0.372) (figure 1), with no survival difference in the three groups. Furthermore, of the 32 patients who did not achieve a CMR, 11 achieved a fall in PCR to 〈 0.1 (major molecular remission (MMR)) following completion of their DLI protocol and had a non-inferior survival to those who achieve a CMR, in contrast to those who did not satisfy either of these criteria, and had a significantly inferior survival (p 〈 0.01) (figure 2). We conclude that the majority of patients who respond to DLI do not remain PCR negative, but low-level positive results do not predict relapse. This suggests that, although DLI does not completely eradicate the disease, it exerts a highly effective long-term disease control. The data presented also raises the question of whether persistent PCR negativity should be unequivocally pursued, or whether a threshold of MMR may be adequate.Figure 1.The probability of molecular relapse following complete molecular remission is low and not significantly different between those who are persistently negative, fluctuating low-level positive or persistently positive.Figure 1. The probability of molecular relapse following complete molecular remission is low and not significantly different between those who are persistently negative, fluctuating low-level positive or persistently positive.Figure 2.Patients who achieve a major molecular remission but not a complete molecular remission have non-inferior survival to those who do achieve a complete molecular remission, which is significantly better than those who do not achieve either of these.Figure 2. Patients who achieve a major molecular remission but not a complete molecular remission have non-inferior survival to those who do achieve a complete molecular remission, which is significantly better than those who do not achieve either of these. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 10
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 2539-2539
    Abstract: Abstract 2539 Invariant NKT (iNKT) cells are a potent, CD1d-restricted immunomodulatory subset of T cells that regulate a variety of experimental immune responses including alloreactivity and acute graft versus host disease (aGVHD).However, their role in human immune responses and in particular in the regulation of clinical aGVHD remains unknown. Given that the frequency of iNKT cells in the blood of normal individuals varies up to 1000-fold we surmised that there was likely to be similar variability in their frequency in peripheral blood stem cell (PBSC) grafts and that the graft iNKT cell dose might be important in the development of aGVHD. To address these hypotheses, using multiparameter flow-cytometry, we determined in G-CSF mobilised PBSC grafts of 61 sibling donors the frequency and the cell dose (in × 106 cells/Kg) of CD3+TCRVbeta11+Valpha24+ iNKT cells as well as of effectors (i.e., CD3+ T cells and CD3-CD56+CD16+ NK cells) or regulators (CD3+CD161+ T cells and CD3+CD4+CD25++FoxP3+ Tregs) of alloreactivity and aGVHD. The median (minimum-maximum) frequency of T cells in the grafts was 62.3% (44.8%–80.7%) of the mononuclear cells and the dose of T cells given with the graft 179.8 (28.7–607.3), while for the NK cells it was 3.3% (0.15%–19.7%) and 9 (0.27–99.6) respectively. The frequency of the CD3+CD161+ cells was 10.5% of the total T cells (1.2%–32.5%) and the dose 17.3 (1.3–120.2). The frequency of Tregs was 5.9% of the CD3+CD4+ population (1.7%–11.9%) and the dose given 6.1 (1.1–36.4). Unlike these cell populations and similar to peripheral blood, iNKT cell content in the grafts varied up to 1000-fold with median frequency 0.045% of the total T cells (0.001%–1.07%) and cell dose 0.075 (0.0014–1.6). There was no correlation between donor age or sex with the frequency or cell dose of any the above cell populations. To assess the role of graft iNKT cells in the development of aGVHD, we selected 41 of the 61 cases, whose G-CSF mobilised PBSC graft was used for a T cell replete, sibling HLA-identical allograft (myeloablative n=34, RIC n=7) for the treatment of haematological malignancies: CML (n=16), AML (n=16), ALL (n=4), MDS (n=3) and myeloma (n=2). aGvHD prophylaxis was cyclosporine-A plus methotrexate (n=39) or cyclosporine-A only (n=2). Only patients who survived 〉 100 days were included unless aGVHD developed earlier. Twenty one of the 41 recipients (51%) developed overall grade 0-I aGVHD (group 1) and 20 (49%) grade II-IV aGVHD (group 2). We found no difference in the CD34+ cell dose (median 5.14 vs 5.95, Mann Whitney p = 0.48), sex mismatched allografts (6 cases in each aGVHD group, chi square = 0.92), donor age (42.3yrs vs 46.1yrs, p = 0.4) or recipient age (44.2yrs vs 48yrs, p = 0.4) between the two groups. Similarly, there was no difference in the frequency or cell dose of CD3+ cells (63.3% vs 62.3% p = 0.9 and 179.8 vs 176.5 p = 0.9), CD3+CD161+ cells (14.1% vs 9%, p = 0.17 and 25.8 vs 19.6 p = 0.42), NK cells (3.5% vs 2.9% p = 0.36 and 10.8 vs 9.9 p = 0.35) and Tregs (6.3% vs 5.7% p = 0.68 and 6.1 vs 5.9 p = 0.9). In contrast, there was a significant difference in the graft iNKT cell content between the two aGVHD groups. Specifically, group 1 (grade 0-I) compared to group 2 (grade II-IV) received grafts with an almost 3-fold higher frequency (0.067% vs 0.024% p = 0.026) and dose (0.181 vs 0.07, p = 0.027) of iNKT cells. Further analysis of the relative role of the CD4+ and CD4- iNKT cell subsets revealed that the latter accounted for the protective effect of the high graft iNKT cell content (frequency 0.05% vs 0.014% p = 0.016 and cell dose 0.072 vs 0.023 p = 0.01) but not their CD4+ counterpart (0.038% vs 0.011% p = 0.12 and 0.051 vs 0.029 p = 0.14). Thus, this study is the first to demonstrate that graft iNKT cells are an important determinant of aGVHD in humans and suggests that enrichment of the graft with iNKT cells might be a useful strategy to prevent clinically significant aGVHD. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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