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PubMed2006

Management of patients with post-transplant lymphoproliferative disorder: the role of rituximab.

Post-transplant lymphoproliferative disorder (PTLD) is a serious complication of solid organ and bone marrow transplantations. Rituximab (Rituxan, Mabthera), a chimeric monoclonal antibody to the CD20 antigen on the surface of B-cell lymphocytes, has been used increasingly in the treatment of PTLD. Rituximab was initially approved for the treatment of low-grade non-Hodgkin lymphomas, but multiple case studies, retrospective analyses, and phase II trials demonstrate the benefit of rituximab in PTLD. This paper reviews the current data on rituximab and its promising role in the management of PTLD.

Antibodies, Monoclonal↗
PubMed1996

Presence of human herpesvirus type 6 in sporadic lymphoproliferative disorders. A comparative study.

A supportive or causal role for human herpesvirus 6 (HHV-6) in lymphoproliferative disorders is still controversial. Different results were obtained in both tissue-based and serological investigations. We investigated 243 lymph node and salivary gland tissue biopsies for the presence of viral DNA by using a newly developed, highly sensitive nested polymerase chain reaction method. HHV-6 was detected in 39% of the non-Hodgkin's lymphomas, in 52% of Hodgkin's diseases, 64% of non-neoplastic lymph nodes, 23% of tumor metastases, and 50% of salivary gland biopsies. When correlating the patients' ages with the occurrence of HHV-6, we found a significantly higher percentage of positive samples in patients younger than 60 years of age (54%) than in older patients (35%). This age-related difference was found in all the lymphoproliferative disorders studied as well as in salivary gland biopsies. Taking patient's ages into account, we found no significant difference between the various groups of disorders concerning the percentage of HHV-6-positive samples.

Adolescent↗
PubMed2008

Pediatric T-cell post-transplant lymphoproliferative disorder after solid organ transplantation.

Post-transplant lymphoproliferative disorder (PTLD) is the most common treatment related malignancy that occurs after solid organ transplantation (SOT). PTLD has extended from its initial description as an Epstein-Barr virus (EBV)-driven B-cell proliferation to include EBV-negative and non B-lineage cases. T-cell PTLD (T-PTLD) is rare in both adults and children. We report two cases of pediatric T-PTLD after SOT (liver and lungs) and review cases reported in the literature. Both patients had a bimodal response to therapy with initial eradication of bulky nodal disease with regimens typically used to treat leukemia, but persistence of low-level clonal T-cells in marrow, CSF and lung in one case.

Child, Preschool↗
PubMed1991

T-gamma-lymphoproliferative disorder arising in a background of autoimmune disease and terminating in plasma cell dyscrasia with primary amyloidosis.

T-gamma-lymphoproliferative disorder, a syndrome of T-cell lymphocytosis with neutropenia has been described in patients with various autoimmune disorders, especially rheumatoid arthritis. We report a case of T-gamma-lymphoproliferative disorder occurring in a 42-year-old white woman with a long history of dermatitis herpetiformis and subsequent development of Coomb's positive autoimmune hemolytic anemia and polymyositis. The peripheral blood lymphocytes showed the T-suppressor cell phenotype (CD2-, CD3-, CD8-, and CD4-). DNA analysis of the peripheral blood lymphocytes revealed a T-cell receptor beta-chain gene rearrangement and an immunoglobulin heavy-chain gene rearrangement. The patient's course was marked by numerous bouts of infection. The unique factor in this patient was the development of a plasma cell dyscrasia and amyloidosis prior to death.

Adult↗
PubMed1981

[Chronic lymphoproliferative disorder resembling hairy-cell leukemia (author's transl)].

Seven patients are presented with a chronic lymphoproliferative disorder characterized clinically by splenomegaly, no or discrete lymphnode enlargement, and a varying degree of cytopenia. In blood and bone-marrow smears lymphoid cells of "hairy" appearance are demonstrable which may contain tartrate-resistant acid phosphatase. The finding of a nodular bone-marrow infiltration without fibrosis as well as that of a nodular infiltration of the spleen originating in the white pulp are incompatible with the diagnosis hairy-cell leukemia and place the disease near to chronic lymphocytic leukemia (CLL) or leukemic immunocytoma respectively. A detailed cytologic and cytochemical examination of the infiltrating cells shows deviations from the typical enzymatic pattern of hairy cells and from known enzymatic constellations in CLL and related lymphoproliferative disorders. Thus, we are dealing with an intermediate form, difficult to classify, the separation of which nevertheless seems to be important for therapeutical reasons.

Acid Phosphatase↗
PubMed1996

Molecular genetics and lymphoproliferative disorders.

Clonality of T- and B-cell lymphoproliferative disorders can be determined by gene rearrangement studies when morphology and surface immunostaining are nondiagnostic. TcR and lg gene rearrangements have been demonstrated in many different hematologic disorders and TcR gene rearrangement has been particularly useful in the diagnosis of patients with CD8 large granular lymphocyte leukemias. TcR gene rearrangement may also be useful to distinguish Hodgkin's disease from T-cell non-Hodgkin's lymphoma. Gene rearrangement is usually performed by Southern analysis, and it is beneficial to run multiple enzyme-probe combinations to maximize the detection of clonal rearrangements. More recently, several laboratories have begun to use polymerase chain reaction (PCR) for gene rearrangement analysis. PCR offers an improved turnaround time, eliminates partial digestion artifacts, and allows for the use of paraffin embedded material. In addition to rearrangements of the TcR and lg genes, analysis of alterations in other genes such as bcl-1, bcl-2, bcl-6, and c-myc are also useful as clonal markers and aid in the classification of lymphomas.

Blotting, Southern↗
PubMed1983

Routine flow cytometric diagnosis of lymphoproliferative disorders.

The results of the analysis of suspected lymphoproliferative disorders using flow cytometry (FACS II) over the past 12 months have been evaluated and assessed with respect to "conventional" microscopical examination. The major advantages in using these methods is the speed, the number of parameters which are capable of measurement, the sensitivity, and the ability to quantitate large numbers of cells for a particular criterion. These qualities have proved extremely helpful in the diagnosis of chronic lymphocytic leukemia, acute lymphoblastic leukemia, lymphoma, and other abnormalities. The combination of flow cytometry and a panel of monoclonal antisera (many of which are available commercially) allows the investigator a system of fine resolution which can confidently identify or characterize an abnormal clone or population of cells. With the increase in advanced flow cytometers, it is suggested that time should be allocated for the routine analysis of possible lymphomas and leukemias to allow quick and accurate evaluations of the disease status.

Antibodies, Monoclonal↗
PubMed2001

Post renal transplantation human herpesvirus 8-associated lymphoproliferative disorder and Kaposi's sarcoma.

Post-transplantation lymphoproliferative disorders (PTLDs) and Kaposi's sarcoma (KS) are immunosuppression-related tumours developing in solid organ transplant patients. Although the Epstein-Barr virus (EBV) is detected in the majority of the PTLDs during the first year after transplantation, the proportion of EBV-negative PTLDs has increased in recent years. We report a case of a 17-year-old man who developed severe immune haemolytic anaemia, KS and human herpesvirus 8 (HHV-8)-associated, polymorphic-type PTLD 9 months after allogeneic renal transplantation from his HHV-8-seropositive father. It is suggested that: (i) HHV-8 may be associated with EBV-negative, polymorphous-type PTLD occurring less than 1 year after transplantation, and (ii) PTLD may be listed among other tumours, including KS, Castleman's disease and primary effusion lymphoma (PEL), that are related to HHV-8 infection.

Adolescent↗
PubMed2001

Pleural posttransplantation lymphoproliferative disorder following liver transplantation.

A case of posttransplantation lymphoproliferative disorder (PTLD) involving the pleura is reported. The patient was a 57-year-old man who underwent liver transplantation 2 years prior to the development of PTLD. The PTLD was pleural-based and was first detected by radiologic studies as a pleural effusion. Transbronchial biopsy and cytologic examination of 2 pleural fluid specimens were nondiagnostic. Subsequent open-wedge biopsy revealed a monomorphic PTLD, composed of large immunoblasts with plasmacytoid differentiation. Immunohistochemical studies demonstrated B-cell lineage with expression of monotypic cytoplasmic immunoglobulin kappa light chain and CD79a, and absence of T-cell antigens. Immunohistochemical and in situ hybridization studies demonstrated Epstein-Barr virus protein and RNA, respectively. No evidence of human herpesvirus 8 DNA was detected by polymerase chain reaction. We report this case because pleural-based PTLD is rare. The diagnosis of this entity is made more difficult by the fact that PTLD is often underrepresented in pleural fluid cytology samples.

Epstein-Barr Virus Infections↗
PubMed1993

OKT3 monoclonal antibodies induce interleukin-6 and interleukin-10: a possible cause of lymphoproliferative disorders associated with transplantation.

The risk of posttransplantation lymphoproliferative disorder (PTLD) has increased with the use of new, highly potent immunosuppressive agents. Monoclonal anti-T-cell antibodies such as OKT3 have been associated with a particularly high risk of these frequently fatal Epstein-Barr virus (EBV)-related B-cell neoplasms. OKT3 is a powerful mitogen, raising the possibility that T-cell activation and cytokine release may facilitate the development of PTLD. Interleukin-6 and interleukin-10 have recently been shown to play major roles in B-cell neoplasia in general, and particularly in EBV-induced B-cell transformation and outgrowth. The development of PTLD after treatment with OKT3 might be mediated by the release of those cytokines. On the other hand, OKT3-related PTLD may simply be the result of the profound T-cell depletion induced by the drug, and the mechanisms for lymphomagenesis may be no different than those operative in PTLDs arising in other immunosuppressed patients. A clearer understanding of the relevant mechanisms will require further work with in vivo models of the disease and may have significant implications for the design of new immunosuppressive agents.

Animals↗
PubMed1998

Morphologic bone marrow changes in patients with posttransplantation lymphoproliferative disorders.

The clinical workup of patients with posttransplantation lymphoproliferative disorders (PTLPDs) frequently involves bone marrow biopsies. However, little is known about the morphologic bone marrow changes in patients with PTLPD. To define the spectrum of morphologic bone marrow changes in such patients, we evaluated the bone marrow biopsy samples of 26 transplant patients with proven extramedullary PTLPD and of 20 transplant patients without PTLPD. Morphologic changes were present in 14 of 26 patients with PTLPD (54%) and consisted of aggregates of lymphoid and plasma cells with variable histologic and cytologic features. Cells expressing Epstein-Barr virus-encoded small transcripts (EBER) were seen in 9 of 13 bone marrow biopsy samples with morphologic changes and in none of the biopsy samples without morphologic changes. Bone marrow changes were significantly more frequent in patients with PTLPD who were younger than 18 years of age (76%) compared with those who were older than 18 years of age (11%). The difference in mortality rates between the patient groups with and without bone marrow changes was statistically not significant, possibly because of the small sample size. The finding that children with PTLPD have an increased incidence of bone marrow changes supports the notion that Epstein-Barr virus-associated PTLPD involves different pathogenetic mechanisms in pediatric patients than in adults.

Adolescent↗
PubMed2006

Retransplantation after post-transplant lymphoproliferative disorders: an OPTN/UNOS database analysis.

Post-transplant lymphoproliferative disorders (PTLD) are a life-threatening complication of immunosuppressive therapy. Retransplantation of survivors remains controversial. The Organ Procurement and Transplant Network/United Network for Organ Sharing database was reviewed for individuals who developed PTLD and underwent retransplant from 1987 through 2004. Sixty-nine retransplants have been performed: 27 kidney, 22 liver, 9 lung, 6 heart, 4 intestine and 1 pancreas. At first transplant, most subjects (63.8%) were <17 years of age and was similar at retransplant with 50.7% less than 17 years. Time from transplant to PTLD was <1 year in 33.3%, 1-3 years in 21.7%, 3-5 years in 21.7%, 5-10 years in 21.7% and >10 years in 1.4%. Time from PTLD to retransplant was <1 year in 24.6%, 1-3 years in 37.7%, 3-5 years in 17.4% and 5-10 years in 20.3%. Induction agents were used in 21.7% of first and 47.8% of retransplants. Immunosuppression for first transplant was cyclosporine (CSA) in 55.1%, tacrolimus (TAC) in 27.5% versus CSA in 26.1%, TAC in 66.7% of retransplants. At last follow-up, patient and graft survival are 85.5% and 73.9%, respectively. Most subjects retransplanted after PTLD are <17 years on TAC-based immunosuppression. Patient/graft survival is excellent and retransplantation in PTLD subjects should be considered acceptable.

Databases, Factual↗
PubMed2006

Deciphering leukemic B-cell chronic lymphoproliferative disorders.

Diagnosis of leukemic B-cell chronic lymphoproliferative disorders (B-CLPD) is a frequent challenge in hematology. In this multicentric study, we prospectively studied 165 new consecutive leukemic patients with B-CLPD selected on the basis of Royal Marsden Hospital scoring system < or =3. The primary aim of the study was to try to decipher the atypical cases and identify homogenous subgroups. Overall, morphological examination contributed to diagnosis in only 20% cases, all of them CD5 negative. Thirty additional cases were CD5 negative suggestive of leukemic marginal zone lymphoma in most cases. The significantly poorer survival of the 26 cyclin D1 positive cases justifies recommending its systematic determination among atypical B-CLPD. CD20 expression segregated clearly two subgroups among CD5 positive cyclin D1 negative B-CLPD. The 17 patients with the CD20 dim profile represent a homogeneous subgroup very close to typical B-cell chronic lymphocytic leukemia (B-CLL) on morphological, phenotypical and cytogenetical criteria. In contrast, the subgroup of 51 patients with a CD20 bright profile is heterogeneous. Their significantly lower p27 expression level suggest the presence of a proliferative component, underlying a more aggressive disease. Further genomic studies are warranted to establish their precise nature. These cases should not be included in the same therapeutic trials as B-CLL.

Aged↗
PubMed2004

Posttransplant lymphoproliferative disorder following nonmyeloablative allogeneic stem cell transplantation.

Posttransplantation lymphoproliferative disorder (PTLD) is a well-recognized complication of conventional bone marrow/stem cell and solid organ transplantation. However, not much is known about PTLD following the more recently introduced nonmyeloablative allogeneic stem cell transplantation (NMST). This study reports the findings from two cases of PTLD following NMST and compares them to the one previously reported case. The donor origin of the PTLD was determined using short tandem repeat analysis, and B- and T-cell clonalities were evaluated by polymerase chain reaction. Two cases of PTLD evolved in a total of 70 patients who have undergone NMST at our institution from 1999 to 2003. Both patients received conditioning with Fludarabine/Cytoxan/Campath 1H (alemtuzumab, anti-CD52 antibody) and T-cell-depleted donor cells with Campath-1H. Both PTLDs were EBV positive (by immunohistochemistry and in situ hybridization) with diffuse large B-cell lymphoma morphology. Our findings indicate the incidence of PTLD following NMST is 3% (2 of 70 patients from our institution and 1 of 30 from the previously reported case). All three PTLDs arose 6 to 7 months after NMST and were rapidly fatal. The pathology of the PTLD in all cases was donor origin, EBV positive, diffuse large B-cell lymphoma.

Adult↗
PubMed2003

Immunosuppressive TOR kinase inhibitor everolimus (RAD) suppresses growth of cells derived from posttransplant lymphoproliferative disorder at allograft-protecting doses.

BACKGROUND: Posttransplant lymphoproliferative disorders (PTLDs) represent a life-threatening complication of standard immunosuppressive therapy. The impact of novel, rapamycin-related immunosuppressive drugs on the pathogenesis of PTLDs remains undefined. METHODS: We tested the effect of everolimus (RAD, Novartis Pharma AG, Basel, Switzerland) on human PTLD-derived cells using in vitro assays and an in vivo severe combined immunodeficiency disease mouse xenotransplant model. RESULTS: Everolimus profoundly inhibited the proliferation, cell-cycle progression, and survival of the PTLD-1 cell line established from a pulmonary PTLD. Equally profound inhibition of PTLD-1 growth was achieved in vivo at well-tolerated everolimus doses of 0.5 to 5 mg/kg per day. Five mg/kg per day of everolimus, given once per day, inhibited PTLD-1 tumor volume gain by more than 10-fold in treated mice compared with untreated mice. Because the subsequent pharmacokinetic analysis indicated rapid everolimus absorption, distribution, and clearance in mice (with a half-life of 3 to 6 hr and maximum drug blood concentration reached after 0.5 to 1 hr), treatment was changed to a twice-daily regimen. Everolimus given twice daily at 0.5 mg/kg per dose inhibited tumor-volume gain by more than 60-fold and at 0.25 mg/kg per dose by more than 10-fold. Similar everolimus doses were required to prevent graft rejection in a mouse heart allotransplantation model; the highest dose tested (1.5 mg/kg twice daily) resulted in long-term graft survival in all mice that underwent transplantation. CONCLUSIONS: Everolimus displays a potent inhibitory effect on PTLD-derived cells in vitro and in vivo in a dose range leading to prevention of allograft rejection and may prove effective in both the prevention and treatment of PTLDs in transplant patients.

Animals↗
PubMed1997

Key features distinguishing post-transplantation lymphoproliferative disorders and acute liver rejection.

Post-transplantation lymphoproliferative disorder (PTLD) and acute rejection are two serious complications of orthotopic liver transplantation that can have a similar histologic appearance. We undertook the present study to assess the best way to distinguish these two entities. We studied histologic features, immunophenotyping, and Epstein-Barr virus (EBV) status, as assessed by immunohistochemical stain and in situ hybridization (ISH), in three groups: Group I, 8 cases of PTLD post-orthotopic liver transplantation with liver involvement; Group II, 15 cases diagnosed with acute liver rejection (control group); and Group III, a subset of 6 biopsy specimens from 4 patients of Group I whose graft rejection was diagnosed within the 2 months preceding the diagnosis of PTLD. The mean proportion of plasma to plasmacytoid cells in most cases from Group I was more than 40%, whereas from Group II it was less than 25% (P = .0001). There was a higher number of B lymphocytes than T lymphocytes in Group I. The numbers of mitotic figures and immunoblasts were significantly different in the two groups (P < .0001 and P = .0005, respectively), being higher in the patients with PTLD. EBV immunostain was most specific for the diagnosis of PTLD (75% positive in Group I, negative in Group II). ISH for EBV-encoded RNA was positive in 87% of cases in Group I and only 6.6% of cases in Group II (P = .0005). In Group III, four of the six liver biopsy specimens had a low plasma cell count and were negative for EBV studies. The other two biopsy specimens in this group had 70 to 80% plasma cell infiltrate, in addition to positive EBV immunostain and ISH in one, for which tissue was available for study. We conclude that viral studies and assessment of the number of plasma cells and B lymphocytes can help to distinguish between acute rejection and early PTLD.

Adult↗
PubMed1998

Interferon-alpha treatment of posttransplant lymphoproliferative disorder in recipients of solid organ transplants.

Posttransplant lymphoproliferative disorder (PTLD) has been treated with decreased immunosuppression, antiviral medications, anti-B lymphocyte agents, radiation therapy, and/or chemotherapy. However, a standardized stepwise approach to treatment has not been previously evaluated. In the present study, 19 consecutive patients presenting to a single institution with newly diagnosed PTLD were treated according to a sequential protocol that consisted of (1) a reduction in immunosuppressive medications plus, if feasible, resection or definitive radiation therapy of localized disease, (2) interferon-alpha, and (3) systemic chemotherapy. Of the 3 patients presenting exclusively with localized disease, two were treated with resection of pulmonary parenchymal nodules and one was treated with radiation therapy to a paraspinous mass, without evidence of recurrence at a mean follow-up of 31 months (range, 8 to 46 months). Sixteen patients presented with PTLD not amenable to local therapy, and they were treated daily with 3x10(6) units/m2 subcutaneous interferon-alpha. Total regression of PTLD (defined as disappearance of the tumor mass by physical examination or computed tomography scanning) was found in 8 of 14 patients who received at least 3 weeks of interferon therapy. Interferon-alpha therapy was continued for 6 to 9 months in the eight patients judged to be responders. None of these patients have relapsed to date with the same neoplastic clone. Two patients, however, developed new neoplastic clones. Seven patients received systemic chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) (n=1), EPOCH (etoposide, vincristine, and doxorubicin administered as a continuous infusion, with an intravenous bolus of cyclophosphamide and oral prednisone) (n=4), or EPOCH followed by DHAP (dexamethasone, cytarabine, and cisplatin) (n=2) after failure of interferon-alpha; five patients had a complete response. Only 1 of the 19 patients died of uncontrolled PTLD. These results suggest that the majority of solid organ transplant recipients who develop PTLD can be safely and successfully treated using a sequential approach to therapy.

Adult↗