The comparison of safety and cost between reference drug of rituximab and its biosimilar Riximyo in lymphoproliferative disorders and other hematological diseases. Single center experience.

Rituximab, anti-CD20 monoclonal antibody, has broad clinical application. The aim of this study is to compare the safety and cost of the original reference rituximab (MabThera) and its biosimilar (Riximyo). This retrospective analysis of 262 patients receiving Riximyo in the Department of Hematology of Wroclaw Medical University in Poland from the period of 1 October 2020 to 21 June 2021 focused on infusion-related reactions (IRRs), which occurred in 4,96% of patients (N = 13). 109 patients (41,6%) had previously been treated with the reference drug and 2 IRRs were reported after switching therapy. During the study period, after biosimilar introduction, the cost of rituximab decreased by 41%. Rixmyo while maintaining similar safety profile is much more cost-effective.

Prevalence, management, and new treatment modalities of EBV-DNA-emia and EBV-PTLD after allo-HCT: survey of Infectious Diseases Working Party EBMT.

The aim of this study was to determine the current approach of EBV-driven post-transplant complications in context of monitoring, diagnosis, prevalence and treatment in EBMT transplant centers. Routine serology testing in patient and donor before HCT is performed in 95.5% centers. Pretransplant EBV-DNA is routinely tested in all patients in 32.7% centers. Monitoring for EBV infection is feasible in 98.2% centers: including 66.7% centers using standardized PCR. Post-HCT regular monitoring is performed in all patients in 80.5% centers. Anti-EBV prophylaxis with rituximab is used in 12.4% centers. Frequency of csEBV-DNA-emia was 7.4% (adults: 6.2%, children: 12.6%). The PCR threshold used to start preemptive treatment was differentiated among centers. Frequency of EBV-PTLD was 1.6% (adults: 1.3%; children: 3.5%). First-line therapy of EBV-driven complications was rituximab and reduction of immunosuppressive therapy. The rate of failure of first-line preemptive treatment was 12.0%. EBV-specific viral-specific T-lymphocytes were available in 46.0% centers. A number of new experimental therapies were given in 28 patients with resistant/refractory PTLD. In conclusion, the prevalence of EBV-DNA-emia and EBV-PTLD over the period 2020-2021 decreased in comparison to historical data. New trends (routine pretransplant screening for EBV-DNA, wider access to VST, new experimental therapies) are being observed in management of EBV infection after allo-HCT.

Combined assessment of Epstein-Barr virus viral capsid antigen and Epstein-Barr virus nuclear antigen-1 serology for post-transplant lymphoproliferative disorder risk stratification in adult solid organ transplant recipients.

BACKGROUND: Epstein-Barr virus (EBV) seronegative solid organ transplant recipients (SOTRs) are at increased risk for post-transplant lymphoproliferative disorder (PTLD). Assays for EBV serostatus assess antibody to both EBV viral capsid antigen (VCA) and Epstein-Barr nuclear antigen-1 (EBNA-1), but PTLD risk among SOT recipients with discordant VCA and EBNA-1 results is unknown. METHODS: We performed a retrospective, single-center cohort study to determine the risk of PTLD among adult (≥ 18 years) SOTRs with discordant pre-transplant VCA and EBNA-1 IgG compared to that of SOTRs with concordantly negative or concordantly positive serology using univariable and multivariable Cox-proportional hazards models. RESULTS: Of 4106 SOTRs, the number (%) who were concordantly positive, concordantly negative, and discordant was 3787 (92.2%), 149 (3.6%), and 170 (4.2%), respectively. The adjusted hazard of PTLD was significantly higher among discordant SOTRs compared to concordantly positive SOTRs (aHR 2.6, 95% CI 1.04-6.6, p =.04) and lower compared to concordantly negative SOTRs (aHR 0.27, 95% CI 0.10-0.76, p <.001). The adjusted hazard of EBV+ PTLD among those with discordant serology was also significantly higher compared to the concordantly positive cohort (aHR 3.53, 95% CI 1.04-12.0, p =.04) and significantly lower compared to the concordantly negative cohort (aHR 0.23, 95% CI 0.06-0.82, p =.02). CONCLUSIONS: Risk of PTLD among SOTRs with discordant VCA and EBNA-1 may be intermediate between those with concordantly positive and negative serology. If confirmed in future studies, revision of national EBV serology reporting to include both VCA and EBNA results may be needed to optimize PTLD risk stratification.

Retrospective database analysis of healthcare resource utilization and costs in patients who develop post-transplant lymphoproliferative disease within the first year following allogeneic hematopoietic stem cell transplants.

AIMS: Healthcare resource utilization (HRU) and costs in post-transplant lymphoproliferative disease (PTLD) patients following allogeneic hematopoietic stem cell transplant (HCT) were evaluated in the USA. METHODS: MarketScan Commercial and Medicare Supplemental database claims from 01 July 2010 to 31 December 2017 were analyzed. Patients eligible for analysis received allogeneic HCT between 01 January 2011 to 31 December 2015, had ≥6 months of continuous enrollment before HCT, and had ≥1 claim for PTLD or ≥1 inpatient or ≥2 outpatient claims for a clinically-relevant lymphoma within 1 year following HCT (PTLD index = first claim of diagnosis). Patients with clinically-relevant lymphomas within 6 months before HCT were excluded. HRU and total paid amounts were assessed from the week before the HCT through 1-day pre-PTLD index (HCT to PTLD) and monthly from PTLD index through 1-year post-PTLD index. HRU is reported as mean (SD). Results were also provided by survival status. RESULTS: Overall, 92 patients were eligible for analysis. From HCT to PTLD, 98.9% of patients were hospitalized, with 1.7 (1.2) hospitalizations/patient. The average length of stay was 25.3 (22.2) days/patient. From HCT to PTLD, 98.9% of patients had outpatient services with 233.7 (261.1) services/patient and 91.3% of patients had a prescription fill with 32.9 (26.0) prescriptions/patient. In the first month post-PTLD index, 51.2% of patients were hospitalized. Mean paid amounts were $399,470/patient (range $7542-$1.7 M) from HCT to PTLD. Cumulative mean paid amounts 1-year post-PTLD were $429,043/patient. Total cost/patient/month was ∼7 times higher in patients who died (n = 49; $232,591) than those who lived (n = 43; $33,677). Costs were mainly driven by hospitalizations. LIMITATIONS: Limitations include those inherent to retrospective analyses (i.e. miscoding, lack of clinical detail). CONCLUSIONS: HRU and costs from HCT to PTLD were high and more than doubled within 1-year post-PTLD. PTLD patients who died had ∼7 times higher costs than those who lived, driven by hospitalizations. Effective treatments are needed to reduce the burden of PTLD.

Cost of paid transplantation abroad: possible donor-origin early multiple myeloma in a renal transplant recipient treated using bortezomib.

The incidence of cancer is greater in transplant recipients compared with the general population. Posttransplantation lymphoproliferative disorder (PTLD) is the second most common cancer in these patients. Non-Hodgkin lymphoma is most commonly observed, and multiple myeloma (PTLD-MM) accounts for less than 4% of PTLDs. Most reported PTLD-MM is of recipient origin, and to date, few cases of donor-origin PTLD-MM have been reported. Bortezomib is a protease inhibitor that has been used successfully to treat multiple myeloma. Herein, we describe the case of a patient in whom multiple myeloma developed shortly after paid living-unrelated renal transplantation performed abroad (in Egypt). The patient had no apparent risk factors for PTLD-MM. Thus, it was supposed that PTLD-MM was of donor origin, considering its early development, lack of recipient risk factors, and no available donor medical status. To our knowledge, this report is the first to describe the use of bortezomib in this setting. Although bortezomib plus dexamethasone therapy resulted in hematologic remission, the patient remained dialysis-dependent.

Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients.

T-cell immunotherapy that takes advantage of Epstein-Barr virus (EBV)-stimulated immunity has the potential to fill an important niche in targeted therapy for EBV-related cancers. To address questions of long-term efficacy, safety, and practicality, we studied 114 patients who had received infusions of EBV-specific cytotoxic T lymphocytes (CTLs) at 3 different centers to prevent or treat EBV(+) lymphoproliferative disease (LPD) arising after hematopoietic stem cell transplantation. Toxicity was minimal, consisting mainly of localized swelling at sites of responsive disease. None of the 101 patients who received CTL prophylaxis developed EBV(+) LPD, whereas 11 of 13 patients treated with CTLs for biopsy-proven or probable LPD achieved sustained complete remissions. The gene-marking component of this study enabled us to demonstrate the persistence of functional CTLs for up to 9 years. A preliminary analysis indicated that a patient-specific CTL line can be manufactured, tested, and infused for $6095, a cost that compares favorably with other modalities used in the treatment of LPD. We conclude that the CTL lines described here provide safe and effective prophylaxis or treatment for lymphoproliferative disease in transplantation recipients, and the manufacturing methodology is robust and can be transferred readily from one institution to another without loss of reproducibility.

Barriers to a functional renal transplant program in developing countries.

A successful kidney transplantation offers the best possible quality of life for patients with end stage renal disease (ESRD). Despite this, renal transplantation rates in the developing world (as with other modalities of renal replacement therapy) are considerably lower than in the developed world. Identified reasons for this include poverty, low education levels of the populations of these countries, the absence of functional dialysis and transplant units with adequately trained and motivated staff, and the lack of appropriate health policies derived from renal registry data. Measures to improve the quality of care should center around improvement of the socioeconomic and political scenario in these countries. The peculiarities of renal transplantation in these countries are also discussed.

Present status and future perspectives of intestinal transplantation.

Intestinal transplantation (ITx) is the only definitive therapy for irreversible intestinal failure. Owing to the limited short- and long-term graft survival over the years, ITx has been a complementary treatment to home parenteral nutrition. However, the development of intestinal and multivisceral transplantation has been significant over the past 15-20 years owing to the progress in immunosuppressive therapy, refinement of surgical techniques, post-transplant care, intestinal immunology, and immunological as well as anti-infectious monitoring. The improvement of patient- and graft survival over the last few years together with data on the cost effectiveness of ITx, following 2 years after transplantation, may require a redefinition of the indication for ITx.

The impact of the World Health Organization classification and clonality assessment of posttransplant lymphoproliferative disorders on disease management.

CONTEXT: The World Health Organization classification of posttransplant lymphoproliferative disorders divides them into 4 main categories. OBJECTIVE: To classify cases of posttransplant lymphoproliferative disorders diagnosed in our institution according to the World Health Organization scheme and correlate the classification and clonality with clinical data. DESIGN: Cases of posttransplant lymphoproliferative disorders were reviewed. They were classified according to the World Health Organization scheme. Clonality was determined by flow cytometry and/or polymerase chain reaction. Patients' charts were reviewed. RESULTS: Thirty-one cases were identified. Median age was 33 years. There were 19 cases of kidney, 8 cases of liver, and 4 cases of bone marrow transplant. Immunosuppression consisted of cyclosporin A and prednisone (N = 24) or FK506 and prednisone (N = 7). Twenty cases (63%) were World Health Organization type 3, 7 cases (23%) type 2, 3 cases (6.4%) type 1, and 1 case type 4 posttransplant lymphoproliferative disorder. Ten patients received chemotherapy, 20 patients had reduction of immunosuppression, and 1 had no treatment. Follow-up was available on 25 patients. Seven (43.75%) of 16 with type 3 lesions with available follow-up died of their disease. Five of these patients received reduction of immunosuppression alone. Only 2 of 9 patients with type 3 disease who received chemotherapy died of disease. Two patients with type 2 disease died of unrelated causes. One patient is alive with disease; the remaining patients with types 1 and 2 disease are alive with no disease. CONCLUSIONS: The World Health Organization classification of posttransplant lymphoproliferative disorders is valuable in the identification of subtypes. It helps identify early lesions (1 and 2) requiring reduction of immunosuppression and type 3 disease, which requires chemotherapy from the outset.

Socioeconomic/occupational risk factors for lymphoproliferative diseases in Sweden.

PURPOSE: The aim of the study is to investigate associations between socioeconomic and occupational factors and lymphoproliferative (LP) diseases. METHODS: We performed a follow-up study on the economically active Swedish population, based on the Swedish Family-Cancer Database. Standardized incidence ratios and 95% confidence intervals were calculated in different social classes and occupations. RESULTS: An increased risk for LP diseases was observed for physicians, plumbers, chemical process workers, and food manufacture workers among men and shoe and leather workers, mechanics, iron and metalware workers, and launderers and dry cleaners among women. CONCLUSIONS: Results suggest that socioeconomic and occupational factors have a minor effect on risk for LP diseases. Exposure to organic solvents may increase the risk for some LP diseases, although inconsistencies of findings between subcohorts do not rule out spurious associations.

Post-transplant lymphoproliferative disorders in kidney transplantation: histological and molecular genetic assessment.

We performed histopathological and immunohistochemical studies, in situ hybridization (ISH) for Epstein-Barr virus (EBV) and molecular genetic analysis using the PCR method for the immunoglobulin heavy chain gene in six patients with post-transplant lymphoproliferative disorders (PTLD) to clarify these problems. In two patients, PTLD developed in the graft, and in the remaining four it developed in systemic lymphoid tissues or organs. In terms of morphological classification, lesions in the graft of two patients were polymorphic with features of rejection in the background. In the other four patients, three of them presented monomorphic lesions and the remaining one presented features of reactive lymphoid hyperplasia. All the patients were positive for EBV as determined by ISH. The molecular genetic study could be performed for four patients, the cells in lesions of two patients were found to be monoclonal and those of the remaining two were polyclonal in IgH as determined by PCR. We conclude that PTLD are of two types, namely, intragraft PTLD and extra-graft PTLD. In the cases of intragraft PTLD their diagnosis is relatively difficult, because lesions are mixed with features of rejection. Molecular genetic analysis and detection of EBV by ISH are useful for diagnosis. In contrast, the diagnosis of extra-graft PTLD is easier than that of intragraft PTLD, by basing of the latest classification of malignant lymphoma. Grading of severity of PTLD should be carried out according to the newest system and protocols for treatment based on the grade of the lesion should be established as soon as possible.

Heart transplantation among 233 infants during the first six months of life: the Loma Linda experience. Loma Linda Pediatric Heart TransplantGroup.

Two hundred thirty-three heart transplantations were performed in infants during their first 6 months of life at Loma Linda University between November, 1985 and June, 1999. Survival has now exceeded 13 years. Nearly 70% of infants are expected to live at least 10 years. Those transplanted during the first 30 days of life have about a 15% survival advantage at 10 years. Scarcity of donors continues to limit the transplantation effort. While acute rejection is the most common cause of late mortality, posttransplant coronary artery disease (PTCAD) is the leading cause of graft loss affecting 22 recipients (9.5%). The majority of patients are asymptomatic prior to diagnosis of PTCAD and are either retransplanted or dead within 6 months. Retransplantation (9 of 11 retransplantations for PTCAD) has been highly successful, with 10 year actuarial survival of 91%. Posttransplant lymphoproliferative disease (PTLD) has been found in only 7 patients (3%), most commonly in lymph nodes. Causes of late mortality include acute rejection (n = 16), PTCAD (n = 9), infection (n = 7), PTLD (n = 2), chronic graft dysfunction (n = 2), arrhythmia (n = 1), recurrent pulmonary vein stenosis (n = 1), and other noncardiac causes (n = 4). Infant psychomotor development is mildly delayed although cognitive development is normal. School-age children are performing at the level of their peers with average achievement and low average intelligence testing. Heart transplantation is durable therapy for newborns and infants with structurally incurable and end-stage myopathic heart disease.

Cardiac transplantation for endstage heart disease.

Orthotopic heart transplantation (OHT), first accomplished in 1967, is currently performed in over 2000 patients per year at hundreds of centers worldwide. Selection criteria include end-stage heart failure with a limited life expectancy, intractable angina due to inoperable coronary artery disease, malignant ventricular arrhythmias refractory to maximal therapy, and unresectable cardiac tumors. While early immunosuppression was based on azathioprine and steroids, the current success of OHT is based on the addition of cyclosporine A (CyA) to this regimen. At Columbia-Presbyterian Medical Center, steroids and azathioprine are given perioperatively, and cyclosporine (OKT3 in patients with renal dysfunction) begun postoperatively. Survival rates at our institution parallel those reported by other centers, with 1- and 5-year actuarial survival of 85% and 70%, respectively. The most frequent causes of early mortality are allograft rejection and infection, while graft coronary artery disease (CAD) is responsible for most deaths occurring after the first post-transplant year. Regular endomyocardial biopsy is used to monitor for rejection, which occurs in 55% of patients within the first year. Mild or asymptomatic rejection is managed with oral steroids, followed by intravenous steroids and/or OKT3 or anti-thymocyte globulin (ATG) in refractory cases. Graft CAD occurs in 45% of patients surviving 3 years, and may require retransplantation. Heart transplantation is a proven, effective form of cardiac replacement. The recent trend of increasingly critically ill transplant candidates, however, has driven the costs of OHT to unprecedented levels. This issue, as well as the continuing organ short-age and current developments in mechanical cardiac assistance and xenotransplantation will undoubtedly assure a continually evolving role for cardiac transplantation in the treatment of endstage heart disease.

Cancers after stem cell transplantation in children: a cost of cure?

There have been many advances in the field of stem cell transplantation over the past few years. Newer preparative regimens and better supportive care measures are allowing more children to survive and lead long lives after stem cell transplantation. We are only now beginning to see what the cost of this success may be in regard to the long-term effects of this treatment. Most long-term follow up studies have been reported in the adult literature and there is very little information on the pediatric population. Children who undergo stem cell transplantation will have a long period of observation in which new and different complications can occur. This article looks at the current literature on secondary malignancies and lymphoproliferative disorders after stem cell transplantation in children, with particular focus on risk factors, possible strategies for prevention, and treatment.

Pretransplantation assessment of the risk of lymphoproliferative disorder.

Posttransplantation lymphoproliferative disorder (PTLD) is an uncommon but often fatal complication of solid organ transplantation that occurs in approximately 3% of patients. To determine the relative importance and relationship of potential risk factors for PTLD before transplantation (i.e., Epstein-Barr virus [EBV] serostatus of the recipient and the cytomegalovirus [CMV] sero-status of the recipient and the potential donor) and the principal risk factor after transplantation (immunosuppression with antilymphocyte antibody), we analyzed the findings for the first 381 consecutive adult nonrenal transplant recipients seen at Mayo Clinic. In the absence of the other risk factors, the incidence rate of PTLD for EBV-seronegative recipients was 24 times higher (95% confidence interval [CI]: 6.2, 89) than that for EBV-seropositive recipients. The additional risk factors of therapy with OKT3 for rejection and CMV seromismatch (i.e., a negative recipient and a positive donor) each further amplified this risk four- to sixfold. Together, all three risk factors acted synergistically to increase the incidence rate of fatal and/or CNS PTLD by a factor of 654 (CI: 368, 1,162) compared with the low incidence rate (.458 cases per 100 person years) when none of these risk factors were present. Pretransplantation determination of recipient EBV and CMV serostatus can identify a subgroup of patients whose risk for severe PTLD may preclude transplantation.

Socio-economic class distribution of the prognostic variants of lymphoproliferative cancers in Nigerians.

One hundred and twenty Nigerians with various lymphoproliferative cancers were grouped according to socio-economic class and the prognosis of their disease. The best prognostic variant of acute lymphoblastic leukaemia occurred mainly in the highest socio-economic class and the worst variant mostly in the low socio-economic class. Chronic lymphocytic leukaemia, a low grade malignancy, and the high grade Burkitt's type of Non-Hodgkin's lymphoma occurred predominantly in the low class. The relationship between prognosis and socio-economic class was not so remarkable in patients with Hodgkin's disease and multiple myeloma. The precise mechanisms by which socio-economic strata influence development of the different prognostic variants of individual lymphoproliferative cancers are not certain.