Thomas G. Gross

Malignancy after transplantation.

As newer immunosuppressive regimens have steadily reduced the incidence of acute rejection and have extended the life expectancy of allograft recipients, posttransplant malignancy has become an important cause of mortality. In fact, it is expected that cancer will surpass cardiovascular complications as the leading cause of death in transplant patients within the next 2 decades. An understanding of the underlying pathobiology and how to minimize cancer risks in transplant recipients are essential. The etiology of posttransplant malignancy is believed to be multifactorial and likely involves impaired immunosurveillance of neoplastic cells as well as depressed antiviral immune activity with a number of common posttransplant malignancies being viral-related. Although calcineurin inhibitors and azathioprine have been linked with posttransplant malignancies, newer agents such as mycophenolate mofetil and sirolimus have not and indeed may have antitumor properties. Long-term data are needed to determine if the use of these agents will ultimately lower the mortality due to malignancy for transplant recipients.

X-linked lymphoproliferative disease: twenty-five years after the discovery.

The X-linked lymphoproliferative disease (XLP), one of six described X-linked immunodeficiencies, stems from a mutation at Xq25 which renders males impotent to mount an effective immune response to the ubiquitous EBV. Purtilo, who first observed this disease in 1969, established a Registry in 1980 to serve as a worldwide resource for the diagnosis, treatment, and research of this condition. Since Purtilos death in late 1992, the Registry and research unit have not only continued to function as a worldwide consultative service, but have contributed the following. First, the number of affected boys has continued to grow; some 272 among 80 kindreds have been identified. Second, some boys (10%) who inherit the mutated XLP gene are immunologically abnormal even before evidence of EBV exposure. Third, the search for the XLP gene has been narrowed to a small region on Xq25. Its identification is near at hand; once cloned, this gene may well illustrate how the body orchestrates the complex immune response to EBV. Therein lies the justification for the quest for this gene, not only for the benefit of the few surviving boys and those to be born to female carriers, but also for defining its role in defending the body against a ubiquitous DNA virus.

Hepatosplenic T‐cell lymphoma in adolescents and young adults with Crohn's disease: A cautionary tale?

Abstract Therapy for the inflammatory bowel diseases increasingly includes the use of immune‐modifying and biologic therapies. Recently, in young patients with IBD, an association has been noted between the use of infliximab along with concomitant purine analogues and the development of hepatosplenic T‐cell lymphoma (HSTCL)—a rare and all but incurable form of non‐Hodgkins lymphoma. This report briefly reviews the issue of lymphoma and IBD therapy. Additionally, a description of HSTCL and a summary of the known cases of this apparent therapeutic complication are presented. Clinical options in light of this new information are explored.

Low-Dose Chemotherapy for Epstein-Barr Virus–Positive Post-Transplantation Lymphoproliferative Disease in Children After Solid Organ Transplantation

PURPOSE To evaluate the efficacy of a low-dose chemotherapy regimen in children with Epstein-Barr virus (EBV) -positive, post-transplantation lymphoproliferative disease (PTLD) after organ transplantation who have experienced failure with front-line therapy for PTLD. PATIENTS AND METHODS Eligible patients received cyclophosphamide (600 mg/m2 intravenous for 1 day) and prednisone (2 mg/kg orally for 5 days) every 3 weeks for six cycles. RESULTS Thirty-six patients treated on study were assessable for analyses. Front-line therapies for PTLD before study entry included immune suppression reduction or withdrawal (n = 36), antiviral therapy (n = 33), surgical resection (n = 8), rituximab (n = 2), and interferon alfa (n = 1). Reasons for failure of front-line therapy included progressive disease (PD; n = 33) and persistent disease with concurrent allograft rejection (n = 3). Thirty patients (83%) had stage III to IV disease, 92% had extranodal disease, and 75% had > or = three sites of disease. The overall response rate was 83% (75% complete response + 8% partial response). The relapse rate was 19%, with only one of five relapsed patients alive and disease-free. Four patients presented with fulminant, disseminated PTLD; only one of these four patients achieved a response, and all four died of PD. Two patients died of treatment-related toxicity. Three patients (8%) experienced allograft loss, but two of the three patients are alive and disease-free after a second transplantation. The 2-year overall, relapse-free, and failure-free (without PTLD and with functioning original allograft) survival rates were 73%, 69%, and 67%, respectively. CONCLUSION This low-dose chemotherapy regimen is effective for children with EBV-positive, nonfulminant PTLD who have experienced treatment failure with front-line therapy, and this study represents the largest series of PTLD patients treated prospectively with a uniform chemotherapy regimen.

Hematopoietic recovery after allogeneic blood stem-cell transplantation compared with bone marrow transplantation in patients with hematologic malignancies.

PURPOSE To compare hematopoietic recovery, duration of hospitalization, and 100-day survival in patients who received allogeneic-blood stem cells (BSC) or conventional allogeneic bone marrow transplantation (BMT). PATIENTS AND METHODS From December 1994 to August 1995, 21 patients participated in a phase II study of allogeneic BSC transplantation. Cells mobilized with granulocyte colony-stimulating factor (G-CSF; 5 micrograms/kg/ d) were collected from human leukocyte antigen (HLA)-matched related donors and cryopreserved. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate. G-CSF (10 micrograms/kg/d) was administered posttransplant. The outcomes were compared with 22 identically treated historical patients who received allogeneic BMT. RESULTS The median infused CD34+ cell and granulocyte-macrophage colony-forming unit (CFU-GM) content were 7.73 x 10(4)/kg and 41.6 x 10(4)/kg, respectively. The median time to a neutrophil count greater than 500/ microL was 11 days after BSC and 16.5 days after BMT (P = .0003). A trend toward faster platelet and RBC recovery after BSC was observed. BSC patients received fewer platelet transfusions: 10 versus 19 (P = .015). The median length of hospitalization was shorter after BSC transplantation: 25 versus 31.5 days (P = .0243). The 100-day survival rates were similar: 83% after BSC and 75% after BMT (P = .3585). The incidence of acute GVHD grade II to IV was 57% and 45% for BSC and BMT, respectively (P = .4654). CONCLUSION In comparison to BMT, allogeneic BSC transplantation may result in faster hematopoietic recovery, shorter hospital stay, and similar early survival. Whether allogeneic BSC are superior to bone marrow needs to be determined in randomized trials.

Lymphocyte reconstitution after allogeneic blood stem cell transplantation for hematologic malignancies

Forty-one patients were studied at set times after allogeneic blood stem cell transplantation (alloBSCT) for recovery of lymphocyte numbers and function. Cells were mobilized with G-CSF from HLA-matched related donors and cryopreserved. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate; G-CSF was administered post-transplant. Median time to absolute lymphocyte count (ALC) ⩾500/μl was 17 days vs 41 and 49 days in historical alloBMT patients with G-CSF (n = 23) or no cytokine (n = 29) post-transplant, respectively (P < 0.0001). CD4/CD8+ ratio was 1.9 on day 28 after alloBSCT, then gradually declined to 0.8 at 1 year due to more rapid CD8+ cell recovery. Mean phytohemagglutinin-induced T cell responses were lower than normal on day +28 (P < 0.05), then tended to recover towards normal values. Natural-killer cytotoxicity remained low from day +28 to 1 year post-alloBSCT, but considerable lymphokine-activated killer cytotoxicity was induced from cells already obtained on day +28. Faster lymphocyte recovery correlated with better survival in alloBSCT patients (median follow-up 287 days, P = 0.002), ALC recovery was not affected by acute GVHD, CMV infections or doses of infused cells. ALC recovery did not correlate with survival in either historical alloBMT group. These data suggest that after alloBSCT lymphocyte reconstitution is faster than after alloBMT, and that quicker lymphocyte recovery predicts better survival in the alloBSCT setting.

De Novo Cancers Arising in Organ Transplant Recipients are Associated With Adverse Outcomes Compared With the General Population

Background. Transplant recipients are at increased risk of malignancy; however, the influence of transplantation on cancer outcomes has not been rigorously defined. The purpose of this study was to examine the influence of transplantation on the outcomes of individual cancers. Methods. De novo nonsmall cell lung cancer, colon cancer, breast cancer, prostate cancer, bladder cancer, renal cell cancer (RCC), and malignant melanoma data in 635 adult (>18 years of age) transplant recipients (from the Israel Penn International Transplant Tumor Registry) were compared with data from 1,282,984 adults in the general population (from the Surveillance, Epidemiology, and End Results database). Results. Compared with the general population, transplant patients were more likely to have early stage (AJCC stage 0–II) RCC, but more advanced (AJCC stage >II) colon cancer, breast cancer, bladder cancer, and malignant melanoma. Compared with the general population, disease-specific survival was worse in the transplant population for colon cancer (all stages), nonsmall cell lung cancer (stage II), breast cancer (stage III), prostate cancer (stage II, III, and IV), bladder cancer (stage III), and RCC (stage IV). Multivariate analyses demonstrated transplantation to be a negative risk factor for survival for each cancer studied, and transplantation and cancer stage at diagnosis to be the most profound negative survival predictors. Conclusions. These analyses indicate that, for several common cancers, transplant patients experience worse outcomes than the general population. The data also suggest that cancers in transplant recipients are more aggressive biologically at the time of diagnosis.

A study of rituximab and ifosfamide, carboplatin, and etoposide chemotherapy in children with recurrent/refractory B-cell (CD20+) non-Hodgkin lymphoma and mature B-cell acute lymphoblastic leukemia: A report from the Children's Oncology Group

To estimate the response rate and therapy related toxicities of the anti‐CD20 monoclonal antibody rituximab when combined with chemotherapy including ifosfamide, carboplatin, and etoposide (ICE) in patients with relapsed and refractory B‐cell non‐Hodgkin lymphoma and mature B‐cell acute lymphoblastic leukemia (B‐ALL).

Hematopoietic Cell Transplantation for Systemic Mature T-Cell Non-Hodgkin Lymphoma

PURPOSE To analyze outcomes of hematopoietic cell transplantation (HCT) in T-cell non-Hodgkin lymphoma. PATIENTS AND METHODS Outcomes of 241 patients (112 anaplastic large-cell lymphoma, 102 peripheral T-cell lymphoma not otherwise specified, 27 angioimmunoblastic T-cell lymphoma) undergoing autologous HCT (autoHCT; n = 115; median age, 43 years) or allogeneic HCT (alloHCT; n = 126; median age, 38 years) were analyzed. Primary outcomes were nonrelapse mortality (NRM), relapse/progression, progression-free survival (PFS), and overall survival (OS). Patient, disease, and HCT-related variables were analyzed in multivariate Cox proportional hazard models to determine association with outcomes. RESULTS AutoHCT recipients were more likely in first complete remission (CR1; 35% v 14%; P = .001) and with chemotherapy-sensitive disease (86% v 60%; P < .001), anaplastic large-cell histology (53% v 40%; P = .04), and two or fewer lines of prior therapy (65% v 44%; P < .001) compared with alloHCT recipients. Three-year PFS and OS of autoHCT recipients beyond CR1 were 42% and 53%, respectively. Among alloHCT recipients who received transplantations beyond CR1, 31% remained progression-free at 3 years, despite being more heavily pretreated and with more refractory disease. NRM was 3.5-fold higher (95% CI, 1.80 to 6.99; P < .001) for alloHCT. In multivariate analysis, chemotherapy sensitivity (hazard ratio [HR], 1.8; 95% CI, 1.16 to 2.87) and two or fewer lines of pretransplantation therapy (HR, 5.02; 95% CI, 2.15 to 11.72) were prognostic of survival. CONCLUSION These data describe the roles of autoHCT and alloHCT in T-cell non-Hodgkin lymphoma and suggest greater effectiveness earlier in the disease course, and limited utility in multiply relapsed disease. Notably, autoHCT at relapse may be a potential option for select patients, particularly those with anaplastic large-cell lymphoma histology.

Epstein-Barr virus-associated hemophagocytic syndrome and fatal infectious mononucleosis

Virus‐associated hemophagocytic syndrome (VAHS) has been thought to be a distinct clinical entity, characterized by intermittent fever, enlarged liver and spleen, and the appearance of hemophagocytosis. Hemopoietic cells are actively ingested by monocytes/macrophages in various organs, including lymph nodes, bone marrow, liver, and spleen. Epstein‐Barr virus (EBV) is now thought to be one of the major causes for the development of this unique syndrome. Additionally, VAHS is often associated with fatal infectious mononucleosis (IM). The relationship between EBV‐associated VAHS and fatal IM is discussed in this concise review.