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Robert J Soiffer

Publications and source records attributed to Robert J Soiffer.

At least 19 recordsLinked to original sources
PubMed2007

Extended follow-up of methotrexate-free immunosuppression using sirolimus and tacrolimus in related and unrelated donor peripheral blood stem cell transplantation.

We assessed the combination of sirolimus and tacrolimus without methotrexate after myeloablative allogeneic stem cell transplantation from 53 matched related donors (MRDs) and 30 unrelated donors (URDs). All patients received cyclophosphamide and total body irradiation conditioning followed by transplantation of mobilized peripheral blood stem cells. The median time to neutrophil engraftment was 14 days. The median time to platelet engraftment was 12 days. No differences between MRD and URD cohorts was noted. The incidence of grade II-IV and III-IV acute graft-versus-host disease (GVHD) were 20.5% and 4.8%. The cumulative incidence of chronic GVHD was 59.1%. There were no differences in acute or chronic GVHD incidence between MRD and URD cohorts. The omission of methotrexate was associated with low transplant-related toxicity, with 30-day and 100-day treatment-related mortality rates of 0% and 4.8%. Relapse-free survival at 1 and 2 years was 72.3% and 68.5%, respectively. Overall survival at 1 and 2 years was 77.1% and 72.2%, respectively. There were no differences in relapse-free or overall survival between MRD and URD cohorts. The substitution of sirolimus for methotrexate as GVHD prophylaxis is associated with rapid engraftment, a low incidence of acute GVHD, minimal transplant-related toxicity, and excellent survival. Differences between MRD and URD cohorts are not evident when effective GVHD prophylaxis is used.

Adolescent↗
PubMed2006

Differential epitope mapping of antibodies to PDC-E2 in patients with hematologic malignancies after allogeneic hematopoietic stem cell transplantation and primary biliary cirrhosis.

A unique characteristic of the autoimmune liver disease primary biliary cirrhosis (PBC) is the presence of high-titer and extremely specific autoantibodies to the E2 component of the pyruvate dehydrogenase complex (PDC-E2). Autoantibodies to PDC-E2 antigen have only been detected in patients with disease or in those who subsequently develop PBC. One exception has been a subgroup of patients with multiple myeloma (MM) who underwent allogeneic hematopoietic stem cell transplantation (HSCT) and received donor lymphocyte infusions (DLIs) after transplantation. These patients developed high-titer antibodies to a variety of myeloma-associated antigens, including PDC-E2, coincident with rejection of myeloma cells in vivo. To examine the specificity of autoantibodies to PDC in these patients, we screened sera from patients with MM, chronic leukemias, monoclonal gammopathy of unknown significance (MGUS), PBC, and healthy donors. Three of 11 patients with MM (27%) and 2 of 6 patients with chronic leukemias (33%) developed anti-PDC-E2 antibodies in association with DLI response; 2 of 12 (17%) patients in the MGUS pretreatment control population also had detectable anti-PDC responses. Interestingly, the epitope specificity of these PDC-E2 autoantibodies was distinctive, suggesting that the mechanisms leading to loss of tolerance in the transplantation patients are distinct from PBC.

Aged↗
PubMed2006

IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo.

IL-2 plays a critical role in the maintenance of CD4+CD25+ FOXP3(+) regulatory T cells (Tregs) in vivo. We examined the effects of IL-2 signaling in human Tregs. In vitro, IL-2 selectively up-regulated the expression of FOXP3 in purified CD4+CD25+ T cells but not in CD4+CD25- cells. This regulation involved the binding of STAT3 and STAT5 proteins to a highly conserved STAT-binding site located in the first intron of the FOXP3 gene. We also examined the effects of low-dose IL-2 treatment in 12 patients with metastatic cancer and 9 patients with chronic myelogenous leukemia after allogeneic hematopoietic stem cell transplantation. Overall, IL-2 treatment resulted in a 1.9 median fold increase in the frequency of CD4+CD25+ cells in peripheral blood as well as a 9.7 median fold increase in FOXP3 expression in CD3+ T cells. CD56+CD3- natural killer (NK) cells also expanded during IL-2 therapy but did not express FOXP3. In vitro treatment of NK cells with 5-aza-2'-deoxycytidine restored the IL-2 signaling pathway leading to FOXP3 expression, suggesting that this gene was constitutively repressed by DNA methylation in these cells. Our findings support the clinical evaluation of low-dose IL-2 to selectively modulate CD4+CD25+ Tregs and increase expression of FOXP3 in vivo.

Antigens, CD↗
PubMed2006

Impact of conditioning regimen intensity on outcome of allogeneic hematopoietic cell transplantation for advanced acute myelogenous leukemia and myelodysplastic syndrome.

We reviewed 136 patients with advanced acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) undergoing allogeneic transplantation to assess the impact of conditioning regimen intensity on outcome. Thirty-nine patients receiving nonmyeloablative stem cell transplantation (NST) were compared with 97 patients receiving myeloablative transplantation. Patients receiving NST were at high risk for treatment-related complications given that they were older, 57 vs 43 years (P < .001), and more likely had received previous or myeloablative transplantation (54% vs 2%; P < .0001). The cumulative risk of relapse was higher for patients after NST (61% vs 38%; P = .02). The 100-day mortality was less after NST (15% vs 32%) Overall survival (OS) at 2 years was 28% for NST and 34% for myeloablative transplantation (P = .89). Progression-free survival (PFS) at 2 years was 20% for NST and 31% for myeloablative transplantation (P = .31). Cox regression analysis showed that the intensity of the conditioning regimen had no effect on either OS or PFS. Despite the high-risk features of patients with advanced AML or MDS undergoing NST, OS and PFS in these patients was similar to those in patients receiving myeloablative transplantation. These results demonstrate that dose intensity plays a significant role in control of disease after transplantation, but that this benefit is negated by increasing treatment-related mortality. These results suggest that NST is a reasonable alternative for patients with advanced AML and MDS at high risk for complications after myeloablative transplantation.

Acute Disease↗
PubMed2006

Predictors of improved progression-free survival after nonmyeloablative allogeneic stem cell transplantation for advanced chronic lymphocytic leukemia.

Although chronic lymphocytic leukemia (CLL) remains an incurable disease with standard chemotherapy, the appropriate role and timing of transplantation are unclear. In this analysis, we report the outcomes of 46 patients with advanced CLL who underwent nonmyeloablative stem cell transplantation (NST) from HLA-matched unrelated (67%) or related (33%) donors. Fludarabine (30 mg/m2 x 4) and low-dose intravenous busulfan (0.8 mg/kg/day x 4) were used for conditioning. The 2-year overall survival (OS) and progression-free survival (PFS) rates in this refractory patient population were 54% and 34%, respectively, with a median follow-up of 20 months. The primary cause of treatment failure was relapse, with a 2-year cumulative incidence of 48%. High hematopoietic donor chimerism > or = 75% at day +30 was a significant predictor of 2-year PFS (47% vs 11%; P = .03). In multivariate analysis, chemotherapy-refractory disease at transplantation was associated with a 3.2-fold risk of progression (P = .01) and a 4.6-fold risk of death (P = .02). Increasing number of previous therapies and increasing bone marrow involvement were also associated with decreased PFS and OS. These results suggest that NST using fludarabine and low-dose intravenous busulfan is a reasonable treatment option for patients with advanced CLL, but that NST earlier in the disease course will likely be needed to achieve long-term disease control in a high proportion of patients.

Adult↗
PubMed2005

Immunization using autologous dendritic cells pulsed with the melanoma-associated antigen gp100-derived G280-9V peptide elicits CD8+ immunity.

PURPOSE: To determine the toxicity, maximal tolerated dose, and clinical and immunologic response to autologous dendritic cells pulsed with melanoma-associated antigen gp100-derived G280-9V peptide. PATIENTS AND METHODS: Twelve HLA-A*0201(+) patients with advanced melanoma were administered dendritic cells pulsed with G280-9V peptide. Cohorts of three patients were administered 5 x 10(6), 15 x 10(6), and 50 x 10(6) cells i.v. every 3 weeks for six doses according to a dose escalation scheme. Three additional patients were treated at the highest dose. No additional cytokines or therapies were coadministered. The immunogenicity of G280-9V-pulsed dendritic cells was measured by IFN-gamma ELISPOT assay, tetramer assay, and (51)Cr release assay comparing prevaccination to postvaccination blood samples. Response to treatment was assessed by Response Evaluation Criteria in Solid Tumors. RESULTS: CD8(+) immunity to the native G280 was observed in 8 (67%) patients as measured by ELISPOT and in 12 (100%) patients as measured by tetramer assay. Of the 9 patients tested, 9 (100%) had measurable high-avidity CTL activity as defined by lysis of allogeneic melanoma lines, which coexpress HLA-A*0201 and gp100. The median follow-up of the entire cohort is 43.8 months. Two (17%) partial responses were observed and 3 (25%) patients had stable disease. The median survival of the treated population was 37.6 months. At this time, three patients are alive, including one patient who continues to respond without additional treatment. CONCLUSION: The high rate of immunization as measured by three independent assays and the occurrence of clinical regression support continued investigation of G280-9V peptide as a candidate epitope in melanoma vaccine formulations.

Adult↗
PubMed2005

Autologous and allogeneic stem cell transplantations for poor-risk chronic lymphocytic leukemia.

We report here on the long-term follow-up on 162 patients with high-risk chronic lymphocytic leukemia (CLL) who have undergone hematopoietic stem cell transplantation (SCT) at a single center from 1989 to 1999. Twenty-five patients with human leukocyte antigen (HLA)-matched sibling donors underwent T-cell-depleted allogeneic SCT, and 137 patients without HLA-matched sibling donors underwent autologous SCT. The 100-day mortality was 4% for both groups, but later morbidity and mortality were negatively affected on outcome. Progression-free survival was significantly longer following autologous than allogeneic SCT, but there was no difference in overall survival and no difference in the cumulative incidence of disease recurrence or deaths without recurrence between the 2 groups. At a median follow-up of 6.5 years there is no evidence of a plateau of progression-free survival. The majority of patients treated with donor lymphocyte infusions after relapse responded, demonstrating a significant graft-versus-leukemia effect in CLL. From these findings we have altered our approach for patients with high-risk CLL and are currently exploring the role of related and unrelated allogeneic SCT following reduced-intensity conditioning regimens.

Adult↗
PubMed2005

Reduced frequency of FOXP3+ CD4+CD25+ regulatory T cells in patients with chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation but the immune mechanisms leading to the diverse clinical manifestations of cGVHD remain unknown. In this study, we examined regulatory T cells (Tregs) in 57 transplant recipients (30 with cGVHD and 27 without active cGVHD) and 26 healthy donors. Phenotypic studies demonstrated decreased frequency of CD4+CD25+ T cells in patients with cGVHD compared with patients without cGVHD (P < .001) and healthy individuals (P < .001). Gene expression of Treg transcription factor FOXP3 was reduced in cGVHD patients compared with patients without cGVHD (P = .009) or healthy donors (P = .01). T-cell receptor excision circle (TREC) assays for the evaluation of thymus activity revealed fewer TRECs in both transplant groups compared with healthy donors (P < .001 and P = .02, respectively) although no difference was observed between patients with or without cGVHD (P = .13). When tested in functional assays, Tregs from both patient cohorts and healthy individuals mediated equivalent levels of suppression. Collectively, these studies indicate that patients with active cGVHD have reduced frequencies of Tregs but the function of these cells remains normal. These findings support the development of new strategies to increase the number of Tregs following allogeneic hematopoietic stem cell transplantation to prevent or correct cGVHD.

Adult↗
PubMed2005

Graft-versus-leukemia target antigens in chronic myelogenous leukemia are expressed on myeloid progenitor cells.

PURPOSE: Donor lymphocyte infusion (DLI) reliably induces durable remission in 75% to 80% of patients with relapsed chronic myelogenous leukemia (CML) following allogeneic bone marrow transplantation. We previously reported the identification of a high titer-specific immunoglobulin G response against two novel leukemia-associated antigens, CML28 and CML66, which correlated with immune-induced remission. The present studies characterize expression of CML28 and CML66 in primary hematopoietic tissues. EXPERIMENTAL DESIGN: Specific monoclonal antibodies to CML28 and CML66 were developed and used to detect antigen expression in leukemia cell lines and primary leukemia tissue on Western blot and immunohistochemistry. Expression patterns were confirmed by antigen-specific real-time PCR. RESULTS: Both CML28 and CML66 were highly expressed in leukemic blasts from patients with acute myelogenous leukemia and CML blast crisis but barely detectable in normal bone marrow, normal peripheral blood, or leukemic cells from patients with stable-phase CML. In contrast, purified CD34+ progenitors from normal individuals and patients with stable-phase CML expressed high levels of CML28 and CML66 transcript and protein. Immunohistochemical staining for CML66 confirmed rare staining of myeloid precursors in normal marrow and diffuse staining of myeloblastic cells in acute myelogenous leukemia and blast crisis CML marrows. CONCLUSIONS: The expression patterns of CML28 and CML66 are strikingly similar and suggest that antigen expression may play a role in shaping the post-DLI antibody repertoire. The CD34+ restricted pattern of expression of CML28 and CML66 is particularly relevant in light of the notion that DLI likely exerts its curative effect by targeting antigens present in self-renewing malignant progenitor populations in CML.

Antibody Specificity↗
PubMed2005

Protective antibody responses to pneumococcal conjugate vaccine after autologous hematopoietic stem cell transplantation.

Patients undergoing autologous hematopoietic stem cell transplantation (autoHCT) are at increased risk for infection with Streptococcus pneumoniae and have impaired antibody responses to pneumococcal polysaccharide vaccines. We performed this study to examine the ability of autoHCT patients to respond to a heptavalent pneumococcal conjugate vaccine (PCV7) given after transplantation and to determine whether there was a potential benefit of immunizing these patients before stem cell collection. Sixty-one patients scheduled for autoHCT were randomized to receive either PCV7 or no vaccine before stem cell collection. After stem cell reinfusion, all study patients were immunized with PCV7 at 3, 6, and 12 months. Pneumococcal immunoglobulin G antibody concentrations were measured at the time of each immunization and 1 month after the 12-month dose. Serotype-specific pneumococcal antibody concentrations were significantly higher in patients immunized with PCV7 before stem cell collection compared with patients not immunized before their stem cells were collected for 6 of 7 serotypes at 3 months, 6 of 7 serotypes at 6 months, 4 of 7 serotypes at 12 months, and 3 of 7 serotypes at 13 months. After the 3-dose series of PCV7 after autoHCT, >60% of study patients had protective concentrations of antibody to all 7 vaccine serotypes regardless of immunization before stem cell collection. Pneumococcal conjugate vaccine is immunogenic in autoHCT patients and may be an effective strategy to prevent invasive disease after transplantation.

Adolescent↗
PubMed2004

Antibody responses to H-Y minor histocompatibility antigens correlate with chronic graft-versus-host disease and disease remission.

Minor histocompatibility antigens (mHAs) are known targets of donor T cells after allogeneic hematopoietic stem cell transplantation (HSCT). In contrast, B-cell responses to mHAs have not been extensively characterized and the clinical significance of antibodies to mHAs is unknown. We tested 121 patients who underwent HSCT and 134 healthy donors for immunoglobulin G (IgG) antibodies against 5 mHAs encoded by genes on the Y chromosome (DBY, UTY, ZFY, RPS4Y, and EIF1AY). Antibodies to at least one H-Y protein developed in 52% of male patients with female donors compared with 8.7% of male patients with male donors (P < .0001), and in 41.4% of healthy females compared with 7.8% of healthy males (P < .0001). H-Y antibodies develop 4 to 12 months after transplantation and persist for long periods. The clinical significance of H-Y antibodies was characterized in 75 male patients with hematologic malignancies who received stem cells from female donors (F --> M HSCT). The presence of H-Y antibodies correlated with chronic graft-versus-host disease (GVHD) by univariate (odds ratio [OR] = 15.5; P < .0001) and multivariable logistic regression analysis (OR = 56.5; P < .0001). Antibody response to Y-chromosome encoded histocompatibility antigens (H-Y antigens) was also associated with maintenance of disease remission (P < .0001). B cells may provide a new target for immune intervention in chronic GVHD.

Adult↗
PubMed2004

Comparative outcome of nonmyeloablative and myeloablative allogeneic hematopoietic cell transplantation for patients older than 50 years of age.

Nonmyeloablative stem cell transplantation (NST) is increasingly used in older patients. The impact of the shift from myeloablative transplantation to NST on relapse, transplant complications, and outcome has yet to be fully examined. We performed a retrospective analysis of 152 patients older than 50 years undergoing NST or myeloablative transplantation. Seventy-one patients received nonmyeloablative conditioning, fludarabine (30 mg/m(2)/d x 4) and intravenous busulfan (0.8 mg/kg/d x 4); 81 patients received myeloablative conditioning, primarily cyclophosphamide and total body irradiation. NST patients were more likely to have unrelated donors (58% versus 36%; P = .009), a prior transplant (25% versus 4%; P = < .0001), and active disease at transplantation (85% versus 59%; P = < .001). Despite the adverse characteristics, overall survival was improved in the NST group at 1 year (51% versus 39%) and 2 years (39% versus 29%; P = .056). There was no difference in progression-free survival (2 years, 27% versus 25%; P = .24). The incidence of grade 2 to 4 graft-versus-host disease was similar (28% versus 27%). The nonrelapse mortality rate was lower for NST patients (32% versus 50%; P = .01), but the relapse rate was higher (46% versus 30%; P = .052). Our experience suggests that, in patients over age 50, NST with fludarabine and low-dose busulfan leads to an overall outcome at least as good as that following myeloablative therapy.

Acute Disease↗
PubMed2004

Extended follow-up of patients treated with imatinib mesylate (gleevec) for chronic myelogenous leukemia relapse after allogeneic transplantation: durable cytogenetic remission and conversion to complete donor chimerism without graft-versus-host disease.

PURPOSE: Over the last several years, donor lymphocyte infusions have become the standard approach for patients with chronic myelogenous leukemia (CML) who relapse after allogeneic stem cell transplantation (SCT). Recent reports indicate that imatinib mesylate (Gleevec) can induce remissions in these patients as well. Less is known about the extent and durability of these responses. EXPERIMENTAL DESIGN: We studied 15 patients treated with imatinib for recurrent CML after SCT, 10 patients with stable phase CML (SP-CML), 1 with accelerated phase (AP-CML), and 4 with blast phase (BP-CML). The dose of imatinib was 600 mg (n = 10) or 400 mg (n = 5) daily. Patients were followed for hematological, cytogenetic, and molecular response. A susbset of responders was followed for changes in donor-derived hematopoietic chimerism. RESULTS: Of the 10 patients with SP-CML, all achieved a hematological response. Within 3 months, five of these patients had achieved a complete cytogenetic response (CCR). By six months, 9 of 10 patients had achieved CCR. The BCR-ABL transcript could not be detected by reverse transcription-PCR in 7 of these 9 patients. Patients who achieved CCR showed evidence of conversion to complete donor chimerism. No patient developed graft-versus-host disease. With a median follow up of 25 months, all patients are alive and 9 of 10 patients remain in CCR. Only one of the 5 patients with AP/BP-CML achieved a complete cytogenetic response. CONCLUSIONS: We find that imatinib is well tolerated in patients with SP-CML who relapse after SCT. Responses were rapid, durable, and associated with conversion to full donor chimerism without graft-versus-host disease. Imantinib was far less effective in patients who relapsed with AP/BP-CML. Imatinib should be evaluated as either an alternative or as an adjunct to donor lymphocyte infusions for patients with SP-CML who relapse after SCT.

Adult↗
PubMed2004

Effect of up-front daclizumab when combined with steroids for the treatment of acute graft-versus-host disease: results of a randomized trial.

The standard initial therapy for acute graft-versus-host disease (GVHD) is corticosteroids. Daclizumab is a humanized monoclonal antibody against the interleukin 2 (IL-2) receptor expressed on activated T lymphocytes. Because of daclizumab's favorable toxicity profile and response rate in steroid-resistant GVHD, a multicenter, double-blinded, randomized study of corticosteroids with or without daclizumab for initial treatment of acute GVHD was conducted. A total of 102 evaluable subjects of the targeted 166 were enrolled at 5 participating sites. Methylprednisolone at a dose of 2 mg/kg or daily equivalent was given in conjunction with daclizumab 1 mg/kg or placebo on study days 1, 4, 8, and weekly as long as clinically indicated. The groups were balanced for clinical characteristics. GVHD response rates by study day 42 were similar (53% vs 51%; P =.85). The study was halted after a planned interim analysis showed a significantly worse 100-day survival in the group receiving corticosteroids plus daclizumab (77% vs 94%; P =.02). Overall survival at 1 year was also inferior in the combination arm (29% vs 60%; P =.002). Both relapse- and GVHD-related mortality contributed to the increased mortality in the combination group. The combination of corticosteroids and daclizumab should not be used as initial therapy of acute GVHD.

Acute Disease↗
PubMed2004

Safety and efficacy of denileukin diftitox in patients with steroid-refractory acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

Denileukin diftitox (Ontak), a recombinant protein composed of human interleukin 2 (IL-2) fused to diphtheria toxin, has selective cytotoxicity against activated lymphocytes expressing the high-affinity IL-2 receptor. We conducted a phase 1 study of denileukin diftitox in 30 patients with steroid refractory acute graft-versus-host disease (GVHD). Seven patients received 9 microg/kg intravenously on days 1 and 15; 18 received 9 microg/kg intravenously on days 1, 3, 5, 15, 17, and 19; and 5 received 9 microg/kg intravenously on days 1 to 5 and 15 to 19. Hepatic transaminase elevation was the dose-limiting toxicity (DLT), and dose level 2 was the maximum tolerated dose (MTD). Overall, 71% of patients responded with complete resolution (12 of 24; 50%) or partial resolution (5 of 24; 21%) of GVHD. Eight of 24 patients (33%) are alive at 6.3 to 24.6 months (median, 7.2 months). Denileukin diftitox is tolerable and has promising activity in steroid-refractory acute GVHD.

Acute Disease↗
PubMed2004

Minor histocompatibility antigen DBY elicits a coordinated B and T cell response after allogeneic stem cell transplantation.

We examined the immune response to DBY, a model H-Y minor histocompatibility antigen (mHA) in a male patient with chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplant from a human histocompatibility leukocyte antigen (HLA)-identical female sibling. Patient peripheral blood mononuclear cells were screened for reactivity against a panel of 93 peptides representing the entire amino acid sequence of DBY. This epitope screen revealed a high frequency CD4(+) T cell response to a single DBY peptide that persisted from 8 to 21 mo after transplant. A CD4(+) T cell clone displaying the same reactivity was established from posttransplant patient cells and used to characterize the T cell epitope as a 19-mer peptide starting at position 30 in the DBY sequence and restricted by HLA-DRB1*1501. Remarkably, the corresponding X homologue peptide was also recognized by donor T cells. Moreover, the T cell clone responded equally to mature HLA-DRB1*1501 male and female dendritic cells, indicating that both DBY and DBX peptides were endogenously processed. After transplant, the patient also developed antibodies that were specific for recombinant DBY protein and did not react with DBX. This antibody response was mapped to two DBY peptides beginning at positions 118 and 536. Corresponding DBX peptides were not recognized. These studies provide the first demonstration of a coordinated B and T cell immune response to an H-Y antigen after allogeneic transplant. The specificity for recipient male cells was mediated by the B cell response and not by donor T cells. This dual DBX/DBY antigen is the first mHA to be identified in the context of chronic GVHD.

Adult↗