Esperanza B. Papadopoulos

Infusions of Donor Leukocytes to Treat Epstein-Barr Virus-Associated Lymphoproliferative Disorders after Allogeneic Bone Marrow Transplantation

BACKGROUND Lymphoma associated with Epstein-Barr virus (EBV) is a complication of bone marrow transplantation that responds poorly to standard forms of therapy. The lymphoma is usually of donor origin. We hypothesized that treatment with infusions of donor leukocytes, which contain cytotoxic T cells presensitized to EBV, might be an effective treatment. METHODS We studied five patients in whom EBV-associated lymphoproliferative disorders developed after they received a T-cell-depleted allogeneic bone marrow transplant. Biopsy specimens were immunophenotyped, subjected to the polymerase chain reaction to determine the origin of the lymphoma (donor or host) and to detect the presence of EBV, and analyzed by Southern blotting for the presence of the clonal EBV genome and immunoglobulin-gene rearrangement. Patients were treated with infusions of unirradiated donor leukocytes at doses calculated to provide approximately 1.0 x 10(6) CD3+ T cells per kilogram of body weight. RESULTS Histopathological examination of biopsy specimens from all five patients demonstrated monomorphic, malignant lymphomas of B-cell origin. Each of the four specimens that could be evaluated was of donor-cell origin. Evidence of clonality was found in two of the three samples adequate for study. EBV DNA was detected by the polymerase chain reaction in all five samples. In all five patients there were complete pathological or clinical responses. The responses were first documented histologically within 8 to 21 days after infusion. Clinical remissions were achieved within 14 to 30 days after the infusions and were sustained without further therapy in the three surviving patients for 10, 16, and 16 months. CONCLUSIONS In a small number of patients, infusions of unirradiated donor leukocytes were an effective treatment for EBV-associated lymphoproliferative disease that arose after allogeneic bone marrow transplantation.

Adoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV+ lymphomas after allogeneic hematopoietic cell transplantation.

We evaluated HLA-compatible donor leukocyte infusions (DLIs) and HLA-compatible or HLA-disparate EBV-specific T cells (EBV-CTLs) in 49 hematopoietic cell transplantation recipients with biopsy-proven EBV-lymphoproliferative disease (EBV-LPD). DLIs and EBV-CTLs each induced durable complete or partial remissions in 73% and 68% of treated patients including 74% and 72% of patients surviving ≥ 8 days after infusion, respectively. Reversible acute GVHD occurred in recipients of DLIs (17%) but not EBV-CTLs. The probability of complete response was significantly lower among patients with multiorgan involvement. In responders, DLIs and EBV-CTLs regularly induced exponential increases in EBV-specific CTL precursor (EBV-CTLp) frequencies within 7-14 days, with subsequent clearance of EBV viremia and resolution of disease. In nonresponders, EBV-CTLps did not increase and EBV viremia persisted. Treatment failures were correlated with impaired T-cell recognition of tumor targets. Either donor-derived EBV-CTLs that had been sensitized with autologous BLCLs transformed by EBV strain B95.8 could not lyse spontaneous donor-derived EBV-transformed BLCLs expanded from the patients blood or biopsied tumor or they failed to lyse their targets because they were selectively restricted by HLA alleles not shared by the EBV-LPD. Therefore, either unselected DLIs or EBV-specific CTLs can eradicate both untreated and Rituxan-resistant lymphomatous EBV-LPD, with failures ascribable to impaired T-cell recognition of tumor-associated viral antigens or their presenting HLA alleles.

Biology and adoptive cell therapy of Epstein‐Barr virus‐associated lymphoproliferative disorders in recipients of marrow allografts

Summary: Epstein‐Barr virus (EBV) is an ubiquitous herpesvirus which is carried as a latent infection of B lymphocytes and salivary gland epithelial cells in over 90% of normal adults. Latently infected IBV‐transformed B cells circulate at low frequency in the blood for the life of the host. These transformed B cells stimulate a heterogeneous and complex host cell response, ultimately leading to the development and maintenance of high frequencies of HLA‐restricted T cells specific for the EBV‐encoded nuclear antigens EBNA2–EBNA6 and the latency membrane proteins LMP‐1 and LMP‐2. Responses to latent EBV‐encoded proteins are hierarchical with responses to certain epitopes predominating, dependent upon the HLA genotype of the host. Profound suppression of T‐Cell immunity may permit the emergence of polyclonal, oligoclonal or monoclonal EBV antigen‐expressing lymphoproliferative disorders or malignant B‐cell lymphomas expressing these latent EBV antigens. Adoptive transfer of small numbers of peripheral blood mononuclear cells or HLA‐partially matched T cells from in vitro expanded EBV‐specific T‐cell lines derived from a seropositive marrow donor has induced durable regressions of bulky, widely metastatic monoclonal EBV lymphomas in a high proportion of cases. This review describes the current state of knowledge and hypothesis regarding the biology and immunology of EBV infection in the normal host, the features of donor, host and virus which contribute to the development of EBV‐associated lymphoproliferative diseases and the mechanisms whereby they are controlled by adoptive transfer of immune T cells.

Construct Validity of the Posttraumatic Stress Disorder Checklist in Cancer Survivors: Analyses Based on Two Samples.

The measurement of posttraumatic stress disorder (PTSD) is critically important for the identification and treatment of this disorder. The PTSD Checklist (PCL; F. W. Weathers and J. Ford, 1996) is a self-report measure that is increasingly used. In this study, the authors investigated the factorial validity of the PCL with data from 236 cancer survivors who received a bone marrow or stem cell transplantation. The authors examined the fit of these data with the clinical model of 3 symptom clusters for PTSD, as proposed in the Diagnostic and Statistical Manual of Mental Disorders, and alternative models tested in prior research. By using confirmatory factor analysis the authors found that a 4-first-order-factor model of PTSD provided the best fit. The relations of PTSD symptoms with sociodemographic and medical variables were also explored.

Availability of Cord Blood Extends Allogeneic Hematopoietic Stem Cell Transplant Access to Racial and Ethnic Minorities

Allogeneic transplant access can be severely limited for patients of racial and ethnic minorities without suitable sibling donors. Whether cord blood (CB) transplantation can extend transplant access because of the reduced stringency of required HLA-match is not proven. We prospectively evaluated availability of unrelated donors (URD) and CB according to patient ancestry in 553 patients without suitable sibling donors. URDs had priority if adequate donors were available. Otherwise ≥4/6 HLA-matched CB grafts were chosen utilizing double units to augment graft dose. Patients had highly diverse ancestries including 35% non-Europeans. In 525 patients undergoing combined searches, 10/10 HLA-matched URDs were identified in 53% of those with European ancestry, but only 21% of patients with non-European origins (P < .001). However, the majority of both groups had 5-6/6 CB units. The 269 URD transplant recipients were predominantly European, with non-European patients accounting for only 23%. By contrast, 56% of CB transplant recipients had non-European ancestries (P < .001). Of 26 patients without any suitable stem cell source, 73% had non-European ancestries (P < .001). Their median weight was significantly higher than CB transplant recipients (P <.001), partially accounting for their lack of a CB graft. Availability of CB significantly extends allo-transplant access, especially in non-European patients, and has the greatest potential to provide a suitable stem cell source regardless of race or ethnicity. Minority patients in need of allografts, but without suitable matched sibling donors, should be referred for combined URD and CB searches to optimize transplant access.

Global meaning and psychological adjustment among survivors of bone marrow transplant

The purpose of the present study was to examine global meaning (i.e. the belief that life has purpose and coherence) and psychological adjustment in survivors of bone marrow transplantation (BMT). Eighty‐five survivors of BMT participated in a telephone interview. Regression analyses demonstrated that after controlling for physical functioning, stressor severity, and gender, global meaning was inversely related to global psychological distress and BMT‐related psychological distress (i.e. posttraumatic stress disorder‐like symptoms related to the cancer treatment). Global meaning was also positively related to mental health aspects of quality of life Lpar;e.g. emotional functioning and social functioning). These findings suggest that global meaning may be an important factor in the psychological adjustment of BMT survivors. Copyright

Recombinant human interleukin-7 (CYT107) promotes T-cell recovery after allogeneic stem cell transplantation

Delays in immune recovery after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are associated with increased risks of infection and relapse. IL-7 has a central role in T-cell development and survival and enhances immune recovery in murine models of allo-HSCT. We performed a phase 1 trial of r-hIL-7 (CYT107) in recipients of T-cell depleted allo-HSCTs. Twelve patients were treated with escalating doses of r-hIL-7 administered weekly for 3 weeks. The study drug was well tolerated with only one patient developing acute skin GVHD. At baseline, patients were profoundly lymphopenic. CYT107 induced a doubling in CD4(+) and CD8(+) T cells. The main effect of IL-7 was an expansion of effector memory T cells, the predominant subset identified in our patients. There was no significant effect on CD4(+)CD25(+)FoxP3(+) T cells, NK, or B cells. Importantly, we not only saw quantitative increases in T cells after a short course of IL-7 but also demonstrated an increase in functional T cells, including viral-specific T cells that recognize CMV. Enhanced TCR diversity was also observed after treatment. Our results indicate that r-hIL-7 can enhance immune recovery after a T cell-depleted allo-HSCT without causing significant GVHD or other serious toxicity (www.clinicaltrials.gov; NCT00684008).

Cytoreduction with iodine-131-anti-CD33 antibodies before bone marrow transplantation for advanced myeloid leukemias

Summary:The monoclonal antibodies M195 and HuM195 target CD33, a glycoprotein found on myeloid leukemia cells. When labeled with iodine-131 (131I), these antibodies can eliminate large disease burdens and produce prolonged myelosuppression. We studied whether 131I-labeled M195 and HuM195 could be combined safely with busulfan and cyclophosphamide (BuCy) as conditioning for allogeneic BMT. A total of 31 patients with relapsed/refractory acute myeloloid leukemia (AML) (n=16), accelerated/myeloblastic chronic myeloid leukemia (CML) (n=14), or advanced myelodysplastic syndrome (n=1) received 131I-M195 or 131I-HuM195 (122–437 mCi) plus busulfan (16 mg/kg) and cyclophosphamide (90–120 mg/kg) followed by infusion of related-donor bone marrow (27 first BMT; four second BMT). Hyperbilirubinemia was the most common extramedullary toxicity, occurring in 69% of patients during the first 28 days after BMT. Gamma camera imaging showed targeting of the radioisotope to the bone marrow, liver, and spleen, with absorbed radiation doses to the marrow of 272–1470 cGy. The median survival was 4.9 months (range 0.3–90+ months). Three patients with relapsed AML remain in complete remission 59+, 87+, and 90+ months following bone marrow transplantation (BMT). These studies show the feasibility of adding CD33-targeted radioimmunotherapy to a standard BMT preparative regimen; however, randomized trials will be needed to prove a benefit to intensified conditioning with radioimmunotherapy.

Randomized Clinical Trial of Telephone-Administered Cognitive-Behavioral Therapy to Reduce Post-Traumatic Stress Disorder and Distress Symptoms After Hematopoietic Stem-Cell Transplantation

PURPOSE A significant number of survivors of hematopoietic stem-cell transplantation (HSCT) report enduring adverse effects of treatment, including illness-related post-traumatic stress disorder (PTSD) symptoms and general distress. We report results of a randomized clinical trial that tested the effects of a 10-session, telephone-administered cognitive-behavioral therapy (CBT) intervention on PTSD, depression, and distress symptoms. METHODS Survivors who had undergone HSCT 1 to 3 years earlier (N = 408) were assessed for study eligibility. Those who met study eligibility criteria (n = 89) completed a baseline assessment that included a clinical interview and self-report measures of PTSD symptoms (the primary outcome) and depression and general distress (the secondary outcomes). Next, they were randomly assigned to CBT or an assessment-only condition. Survivors in the CBT group completed 10 individual telephone-based CBT sessions (T-CBT) that included strategies to reduce PTSD symptoms, depression, and general distress. Follow-up assessments occurred at 6, 9, and 12 months after the baseline assessment. RESULTS Linear mixed-model analyses revealed that, compared with HSCT survivors in the assessment-only condition, survivors who completed T-CBT reported fewer illness-related PTSD symptoms, including less avoidance (P < .001) and fewer intrusive thoughts (P < .05) as well as less general distress and fewer depressive symptoms (P < .05) even after controlling for potential demographic and medical covariates. These results were consistent across the three follow-up assessments. CONCLUSION A brief, telephone-administered CBT intervention developed for HSCT survivors is an efficacious treatment for reducing illness-related PTSD symptoms and general distress.

Donor-Derived Human Bone Marrow Cells Contribute to Solid Organ Cancers Developing After Bone Marrow Transplantation

Bone marrow‐derived stem cells have been shown to participate in solid organ repair after tissue injury. Animal models suggest that epithelial malignancies may arise as aberrant stem cell differentiation during tissue repair. We hypothesized that if bone marrow stem cells participate in human neoplasia, then solid organ cancers developing after allogeneic bone marrow transplantation (ABMT) might include malignant cells of donor origin. We identified four male patients who developed solid organ cancers (lung adenocarcinoma, laryngeal squamous cell carcinoma, glioblastoma, and Kaposi sarcoma) after myeloablation, total body irradiation, and ABMT from female donors. Donor‐derived malignant cells comprised 2.5%–6% of the tumor cellularity The presence of donor‐derived malignant cells in solid organ cancers suggests that human bone marrow‐derived stem cells have a role in solid organ cancers carcinogenesis. However, the nature of this role is yet to be defined.