Response to Adjuvanted Monovalent Influenza A (H1N1)v Vaccine In Allogeneic Hematopoietic Stem Cell Transplant Recipients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1269-1269
Author(s):  
Nathalie Dhedin ◽  
Jacques-Olivier Bay ◽  
Patricia Ribaud ◽  
Mathieu Coudert ◽  
Marie T Rubio ◽  
...  
Keyword(s):  
Stem Cell ◽  
Immunosuppressive Therapy ◽  
Hematopoietic Stem Cell ◽  
Influenza A ◽  
Immunosuppressive Drugs ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Adjuvanted Vaccine ◽  
Influenza A H1n1 ◽  
Antibody Titers

Abstract Abstract 1269 Background: Influenza is a potentially serious infection after hematopoietic stem cell transplantation (HSCT). Prolonged immunosuppression leads to impaired immunity to infectious agents that contributes to the poor outcome after HSCT. Vaccination is the main prophylactic approach in individuals at an increased risk for severe influenza disease, but it is less effective in immunocompromised patients. Nevertheless, annual vaccination against influenza is recommended for HSCT recipients, starting at 6 months after transplant. In 2009, due to the emergence of a pandemic influenza A (H1N1)v virus, the development of safe and effective vaccines was a public health priority. Some oil-in-water-emulsion adjuvants were used in some 2009 influenza A (H1N1) vaccines to increase their immunogenicity. In France, the use of 2 doses of such vaccines was recommended for HSCT recipients. Methods: This study, conducted by the Société de Greffe de Moelle et de Thérapie Cellulaire, has evaluated the safety and the efficacy of an adjuvanted monovalent influenza A (H1N1)v vaccine in allogeneic HSCT recipients. Patients between the age of 18 and 65 years who were vaccinated from 3 months to 5 years post-transplant were included in the study. Patients in relapse of their hematological disease or receiving immunoglobulins were excluded. Patients were separated into two groups: patients with graft-versus-host-disease (GVHD) treated by immunosuppressive drugs (G1) and those without GVHD or immunosuppressive therapy (G2). Antibody responses were measured by means of a hemagglutination-inhibition assay on days 0, 21 and 42 after injection of the first dose of vaccine. Results: Seventy nine patients were included and 70 who received the 2 doses of adjuvanted vaccine (at day 0 and 21) were analyzed: 41 in G1, 29 in G2. Median patient age was 53 yr (range 21–65). Median interval between transplant and vaccination was11 months in G1 and 21months in G2. Fifty five % of patients received stem cells from peripheral blood and 44% received a myeloablative conditioning regimen. No severe post-vaccination side effect was observed, except in 2 patients who presented with an aggravation of their GVHD. No case of influenza A (H1N1)v infection was observed. At day 21 after the first dose, antibody titers, expressed as geometric means (GMT), were 20 and 69 in G1 and G2, respectively, whereas, they were 43 and 223, respectively, at day 42 after the second dose. By day 21, antibody titers of 1:40 or more were observed in 34% of patients in G1 and 73% in G2. By day 42, after the second dose of vaccine, antibody titers of 1:40 or more were observed in 47 % of patients in G1 and 86% in G2. The reverse cumulative distribution curves of antibody titers in serum at D0, D21 and D42 are shown in Figure 1. Conclusions: These data show that adjuvanted vaccine is safe in recipients of allogeneic HSCT. The humoral response was improved by the second dose of vaccine. The use of 2 doses of adjuvanted vaccine allows a seroprotection in almost all recipients without GVHD and immunosuppressive therapy and in half of the patients with GVHD and treated by immunosuppressive drugs. These data also suggest that addition of an adjuvant to improve the efficacy of a vaccine offers an advantage in recipients of HSCT. Disclosures: No relevant conflicts of interest to declare.

Immunosuppressive Therapy in Children with Refractory Anemia: Results of Japanese Childhood MDS Study Group Trial (MDS99).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2674-2674
Author(s):  
Daisuke Hasegawa ◽  
Hiroshi Yagasaki ◽  
Yoshitoshi Ohtsuka ◽  
Masami Inoue ◽  
Akira Kikuchi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Disease Progression ◽  
Immunosuppressive Therapy ◽  
Hematopoietic Stem Cell ◽  
Refractory Anemia ◽  
Study Group ◽  
Observation Group ◽  
Hematopoietic Stem ◽  
Monosomy 7

Abstract Myelodysplastic syndrome (MDS) is a hematopoietic stem cell disorder and uncommon in childhood. Especially, refractory anemia (RA), which is a subgroup of MDS without an increased number of blasts, is quite rare in this age group. Although hematopoietic stem cell transplantation (HSCT) is thought to be a curative therapy for pediatric MDS, it may cause severe complications and mortality. Several reports have shown encouraging results with immunosuppressive therapy (IST) in adult patients with RA. We report the outcome of 12 children with RA enrolled on a prospective multicenter trial conducted by Japanese childhood MDS study group. In this study, a child who was suspected of having RA required repetitive bone marrow aspiration at 6–8 weeks intervals. If the disease was stable and blood transfusion was not urgent, the patient could be monitored closely without any therapy. If physicians decided to start therapy due to progression of cytopenia, the patient received IST consisting antithymocyte globulin (ATG), cyclosporine (CyA) and methylprednisolone (mPSL). Of the 12 children, 9 received IST (IST group), 2 were followed without treatment (observation group) and one underwent HSCT without IST. Seven children showed hematological response in the IST group, and a response rate was 77.8%. Of note, 1 patient with monosomy 7 showed complete cytogenetic response after IST and remained in remission. One patient became refractory to IST after relapse and underwent bone marrow transplantation (BMT) from a human leukocyte antigen (HLA) 1-antigen mismatch relative, and she is alive without disease on 351 days after HSCT. One patient received BMT from an HLA-matched unrelated donor without IST because he had monosomy 7, but he relapsed and died from disease progression. Neither of 2 patients in the observation group experienced disease progression. There were 8 children who showed chromosomal abnormalities, including monosomy 7 and trisomy 8, 7 of whom received IST and 6 children showed hematological response. No severe adverse events related to IST were reported in this study. Eleven of the 12 patients are alive after a median follow-up of 1,319 days. The probability of survival at 5 years was 88.9%, which was superior to our previous retrospective analysis of children with RA. We conclude that IST for children with RA seems an effective modality and warrants an international clinical trial.

The Activating KIR Genes 2DS1 and 2DS2 Regulate NK Alloreactivity In Vitro.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 927-927
Author(s):  
Joseph H. Chewning ◽  
Charlotte N. Gudme ◽  
Bo Dupont
Keyword(s):  
Stem Cell ◽  
Nk Cells ◽  
Hematopoietic Stem Cell ◽  
Hla Class I ◽  
Class I ◽  
Target Cells ◽  
Ligand Specificity ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct

Abstract The role of Natural Killer (NK) cells in host protection against viral infection and malignant transformation has been well described. NK cells may also lead to a reduction in post-transplant relapse and improved survival in hematopoietic stem cell transplantation (HSCT) for acute myelogenous leukemia (AML). It has been hypothesized that the genotype for the inhibiting killer immunoglobulin-like receptor (KIR) of the hematopoietic stem cell donor in combination with the HLA class I genotype of the recipient could control NK alloreactivity leading to a reduction in post-transplant complications. The KIR gene family encodes however both activating and inhibiting receptors. Here we test the hypothesis that activating KIRs with ligand specificity for HLA class I may contribute to alloreactivity, and potentially could be a genetic factor of significance in allogeneic HSCT. We tested this hypothesis in studies of two pairs of inhibiting and activating KIRs with highly homologous codon sequences in the extracellular domain, namely KIR2DL2/3-KIR2DS2 and KIR2DL1-KIR2DS1. Both the inhibitory 2DL1 and activating 2DS1 have ligand specificity for HLA-Cw group 2, and 2DL2 and 2DL3, have ligand specificity for HLA-Cw group 1, while the activating 2DS2 does not bind in vitro to C1 group. Using an EBV-transformed B-lymphoblastoid cell line (EBV-BLCL) target cell panel homozygous for HLA Class I alleles, we found that NK cells from donors with KIR haplotypes lacking KIR2DS1 or 2DS2 were not cytotoxic to allogeneic EBV-BLCL, independent of the target HLA class I genotype. Polyclonal NK cells obtained from KIR2DS1 positive and C1 group positive donors mediated NK cytotoxicity against C2 positive targets. In contrast, NK cells from KIR2DS1 positive, C2 group homozygous donors displayed minimal cytotoxicity against the C2 group targets (p<0.01). NK clones generated from 2DS1 positive, C2-group negative individuals were cytotoxic to C2-group target cells, while such NK clones could not be obtained from individuals positive for 2DS1 and cognate ligands. Similar findings were made for the relationship between 2DS2, 2DL2/3 and cognate ligand C1 group. Both polyclonal IL-2 propagated NK cells and NK clones from individuals positive for 2DS2 and homozygous for C2 group displayed specific cytotoxicity against C1 positive target cells. The cytotoxicity of 2DS2 positive, C1 group positive NK cells against the C1 positive BLCLs was minimal (p<0.01). These studies demonstrate that 2DS1 and 2DS2 are activating receptors that can induce an alloantigen response. We also present a model for combinations of KIR and HLA genotypes in which the allogeneic function of KIR2DS1 and 2DS2 is consistently seen in donor NK cells. Activating KIR may therefore play a role in allogeneic HSCT, and could contribute to the balance between activating and inhibiting signals for NK cells in HLA-Cw incompatible donor-recipient combinations. Activating KIR interactions with cognate ligand could potentially also play a role in the innate immune response. In the normal host, the increased affinity of the inhibiting KIR isoforms for HLA class I may prevent auto-reactivity, while the activating isoforms may only function in an HLA restricted pattern in context of specific pathogens or transformed cells. It is possible that the low affinity activating KIR may require additional co-stimulating signals that are up-regulated during cellular stress.

Influenza A H1N1 Virus Infection in Two Hematopoietic Stem Cell Transplant Recipients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1169-1169 ◽  
Author(s):  
Diogo Assed Bastos ◽  
Celso Arrais Rodrigues ◽  
Poliana Patah ◽  
Beatriz Souza Dias ◽  
Vanderson Rocha ◽  
...  
Keyword(s):  
Stem Cell ◽  
Virus Infection ◽  
Influenza A ◽  
Stem Cell Transplant ◽  
H1n1 Virus ◽  
Clinical Course ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Influenza A H1n1 ◽  
H1n1 Virus Infection

Abstract Abstract 1169 Poster Board I-191 In April 2009, a novel swine-origin influenza A (H1N1) virus (S-OIV) was identified in Mexico. Since then, several cases have been reported, with subsequent cases observed in many other countries. Clinical presentation may range from mild symptomatic patients to cases of severe clinical presentation and death due to pneumonia and respiratory failure. Definition of high risk groups are thought to be similar to those defined for seasonal influenza, including young children and elderly patients, pregnant women and patients with chronic medical conditions, especially immunocompromised hosts. Hematopoietic stem cell transplant (HSCT) recipients are at high risk for infectious complications, including severe viral infections. To our knowledge, there are no reported cases of S-OIV infection in HSCT recipients to date. The clinical features and the possible consequences of this novel influenza virus in this setting remain unknown. We describe two HSCT recipients with confirmed influenza H1N1 virus infection and a benign clinical course after oseltamivir treatment. The first case is a 12 year-old male patient with diagnosis of acute myelogenous leukemia in second complete remission who underwent an unrelated umbilical cord blood transplant with two 4/6 HLA-mismatched cord blood units. Graft-versus-host disease (GVHD) prophylaxis consisted of the association of cyclosporine and mycophenolate mofetil. Additionally, he was also being treated for an invasive aspergillosis with oral voriconazole. On day+3 after transplant, he developed fever, rhinorrhea, and dry cough. A nasal wash and a nasal swab were positive for influenza A by direct immune fluorescence and for influenza A H1N1 by real-time polymerase chain reaction (RT-PCR). Computed tomography of the nasal sinus and thorax were unremarkable. Oseltamivir therapy (75 mg po twice daily for 10 days) was initiated the same day with progressive improvement of symptoms. Oseltamivir was well tolerated and there was no interference with serum levels of cyclosporine. The second case is a 30 year-old female patient with gray zone non-Hodgkin lymphoma in relapse after autologous stem cell transplant that underwent an HLA-matched related HSCT in September 2008. She relapsed 6 months after the transplant. Cyclosporine was withdrawn. Ten days later, she developed fever rhinorrhea, and myalgia. Influenza A H1N1 was confirmed by RT-PCR of a nasal wash specimen. Treatment with a 5-day course of oseltamivir (75 mg po twice daily) was initiated and the patient had a favorable clinical course, with no complications. These two cases of confirmed influenza H1N1 virus infection in HSCT recipients with a benign clinical course highlight the need for a better understanding of the clinical course and management of this novel viral agent in severely immunocompromised hosts. Disclosures: No relevant conflicts of interest to declare.

Screening For Anti-Leukemic CTLs After Allogeneic Hematopoietic Stem Cell Transplantation Applying Streptamer Technology

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5493-5493
Author(s):  
Falk Heidenreich ◽  
Elke Rücker-Braun ◽  
Sebastian Tuve ◽  
Marc Schmitz ◽  
Rebekka Wehner ◽  
...  
Keyword(s):  
Stem Cell ◽  
Immune System ◽  
T Cell ◽  
Hematopoietic Stem Cell ◽  
Leukemic Cells ◽  
Hematopoietic Stem ◽  
Effector Cells ◽  
Allogeneic Hsct ◽  
Specific Ctls ◽  
Graft Versus Leukemia

Abstract Introduction Greiner et al. demonstrated data suggesting a promising link between CD8+ T cell responses with a specificity of NPM1mut and graft versus leukemia effect (GvL). In patients with acute myeloid leukemia (AML) who underwent hematopoietic stem cell (HSC) transplantation, effector cells of the newly established immune system are thought to elicit a potent graft versus leukemia (GvL) effect eradicating residual leukemic cells. Cytotoxic T-lymphocytes (CTLs) specific for leukemia associated MHC-presented peptides may play a crucial role in the anti-tumor reaction and in achieving complete molecular remission. Leukemic cells are detectable after allogeneic HSCT in AML at least at the level of minimal residual disease (MRD). Malignant cells could therefore be identified and targeted by effector cells of the new immune system and stimulation of CTLs by antigen is assured. Detectable leukemia-specific CTLs will allow studies which address the correlation of the course of CTLs and clinical events. Further, it could allow for an assessment of the functional properties of these cells with respect to GvL effects. Methods We screened HLA-A0201 positive patients with AML and chronic lymphocytic leukemia (CLL) biweekly from day 28 after transplantation until day 112 for antileukemic CTLs applying streptamer technology. For AML a panel of 7 MHC peptide complexes was used to label CTLs from peripheral blood: phycoerythrin-(PE)-labeled streptamers refolded with peptides (number of different peptides) derived from the amino acid sequence of the proteins WT1 (1), PR3 (1), RHAMM (1), mutated NPM1 (2), and survivin (2). For CLL peptides derived from RHAMM (1), survivin (2) and fibromodulin (4) were chosen for screening. Peptides from cytomegalovirus (CMV) protein pp65 and from Influenza matrix protein M1 were used as positive controls. A peptide of the HIV reverse transcriptase served as negative control. Results Up to now neither for AML (n = 9) nor for CLL (n = 1), leukemia specific CTLs were detected according to the respective panel at any time point. However, it was possible to detect CMV-specific CTLs in most of the CMV seropositive patient-recipient pairs and frequencies increased when CMV reactivation occurred. Increasing frequencies of CMV-specific CTLs were even measured in CMV seropositive patients who received allogeneic HSC grafts from CMV seronegative donors, proving the adequacy of the method and reflecting the stimulation and proliferation of CMV-specific CTLs. Discussion Different reasons may account for our negative results so far: the limited numbers of selected peptides, which may not be immunodominant or the small number of screened patients are two of them. It must be considered that the CTL immune response to virus infection and concomitant CMV clearance may not represent a proper model for the GvL effect, which possibly is characterized only by a weak proliferation of CTLs resulting in cell counts below the detection limit of the applied flowcytometric measurements. We will further extend our screening approach to a minimum of 18 individuals per specificity. If frequencies above the limit of detection will not be detected in at least one out of 18 patients the 95 % confidence interval of the true percentage of patients with measurable CTLs of this specificity should be < 15 %. Conclusions This study highlights the difficulties to study leukemia-specific CTLs. So far, leukemia-specific CTLs have only been measured in single patients after allogeneic HSCT. Information on cohorts of patients who have been monitored longitudinally for specific CTLs is very rare. The kinetics of leukemia-specific CTLs which mediate GvL effects are almost unknown. Further research on delineating T-cell mediated GvL-effects and realistic estimates for frequencies of specific CTLs at well defined time-points are urgently needed. Disclosures: No relevant conflicts of interest to declare.

The Use of Imatinib with Chemotherapy and Allogeneic Hematopoietic Stem Cell Transplantation Improves Survival of Philadelphia Positive Acute Lymphoblastic Leukemia in Adults

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3653-3653
Author(s):  
Josefina Perez-Nuñez ◽  
Antonio Jimenez-Velasco ◽  
Katy Hurst ◽  
Manuel Barrios-Garcia ◽  
MJ Moreno ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Lymphoblastic Leukemia ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct

Abstract Philadelphia positive acute lymphoblastic leukemia (Ph + ALL) accounts for approximately 20% -30% of all adult ALL. The prognosis of patients with Phi + ALL is unfavorable when treated with standard chemotherapy schemes, presenting a long-term survival of 15% -20%. Since the introduction of Imatinib (IM) to treatment regimens the survival of these patients has improved, although allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative option. We conducted a retrospective analysis of Ph + ALL patients before and after IM became available in order to analyze the impact of IM on survival in adult Phi + ALL. Patients and methods Between April 1997 and April 2013 we diagnosed 120 over 15 year old patients with ALL (B and T lineage), 31 (25.8%) of which were Phi +, all B lineage. Of these 31 cases, 30 were treated with protocols from Spanish group PETHEMA with curative intent. 14 of them (47%) were treated with chemotherapy and Imatinib (IM cohort) and 16 (53%) with chemotherapy (pre-IM cohort). In 17 of the 30 cases allogeneic HSCT was performed, 7 in the pre-IM cohort and 10 in the IM cohort. In the post-transplant period, two patients were treated with Dasatinib due to positive minimal residual disease (BCR-ABL1 positive). The probabilities of overall survival (OS) (death) and event free survival (EFS) (no response, relapse or death) were estimated using the Kaplan-Meier product limit method. Differences between groups were tested using the X2 test. Univariate analysis was performed using Cox regression models or log-rank test. Multivariate analysis was performed using Cox proportional hazards regression model. The study was conducted in accordance with the Declaration of Helsinki. Results The median age was 38 years (range, 15-66 years), 17 patients were males and 13 females. The whole series survival was 32.4 ± 9.2%. The OS mean of the pre-IM cohort was 3.1 years (CI 95%, 0.5-5.7) and 6.9 years (CI 95%, 4.4-9.4) in the IM cohort (figure 1). The main characteristics of both groups are reflected in Table 1. When we analyzed the EFS, the variables that influenced it were being treated with IM (48% in the IM cohort versus 12.5% in the pre-IM cohort, p = 0.03), having received an allogeneic HSCT (45% versus 8%, p = 0.004) and being in first complete remission before allogeneic HSCT (51% versus 0%, p <0.001). In the analysis of OS, the only variables with prognostic significance were: treatment with IM (63% in the IM cohort versus 12.5% in the pre-IM cohort, p = 0.01) and having received an allogeneic HSCT (55 % versus 0%, p <0.001). When the 17 patients that received allogeneic HSCT were analyzed separately, OS in the pre-IM cohort was 29 ± 17% versus 79 ± 13% in the IM cohort (p = 0.057). Table 1. Patient characteristics (N=30) Characteristic Pre-IM cohort(N=16) IM cohort(N=14) P Female/Male 7/9 6/8 0.96 Age ² 40 years 12 (75%) 10 (71%) 0.82 ³ 50 x109/L WBC 8 (50%) 4 (29%) 0.23 Transcript type: e1a2 b2a2/b3a2 12 (75%) 4 (25%) 11 (79%) 3 (21) 0.83 Morphological CR after induction 13/15 (88%) 13/13 (100%) 0.17 No. of Allo-HSCT 7 (44%) 10 (71%) 0.13 CR pre Allo-HSCT: 1CR 2CR 5 (71%) 2 (29%) 10 (100%) 0 (0%) 0.07 Relapse 8/13 (61.5%) 4/13 (31%) 0.12 Exitus 14 (87.5%) 5 (36%) 0.003 Abbreviations: IM, imatinib. WBC, white blood cells. CR, complete remision. Allo-HSCT, allogenetic hematopoietic stem cell transplantation. Figure 1 Figure 1. Conclusions In our study we show how adult Phi + ALL patients who are treated with chemotherapy associated with IM and subsequently receive an allogeneic HSCT exhibit a higher overall survival rate than those treated in the pre-IM era. Although Phi + ALL is still considered of very high risk, in our series of patients treated in the IM era, with a follow-up of over 7 years, overall survival was of 63%, higher than that of historical series of adults with Phi negative ALL. This work has been financed by a grant from the Malaga Association for Research in Leukemia "AMPILE" and the FIS 11-01966 project. Disclosures No relevant conflicts of interest to declare.

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