B-Cell Phenotypes in Solid Organ Transplant Pediatric Patients with Hypogammaglobulinemia

Abstract Introduction: Immunotherapy with rituximab alone or in combination with sequential chemotherapy such as CHOP, in addition to a reduction in immunosuppression (IST), has been shown to be effective in achieving long-term, disease-free survival in patients with B-cell PTLD. We have recently observed an increased incidence of HGBL in patients receiving IST following solid-organ transplant. Intensive induction regimens (ex: DA-R-EPOCH) in non-transplant HGBL has been associated with improved complete responses. Intensive regimens have not been previously evaluated in patients with PTLD. The aim of this study is to compare the tolerability of DA-R-EPOCH to R-CHOP in post-transplant patients with HGBL. Methods: Patients treated with either DA-R-EPOCH or R-CHOP were included in this study following IRB approval. Eligible patients were ≥18 years, had biopsy-confirmed B-cell PTLD, and were treated with at least one cycle of DA-R-EPOCH or R-CHOP. The primary outcome was progression-free survival (PFS); secondary outcomes were overall survival (OS), toxicities, and hospitalizations due to treatment-related toxicities. Statistical analysis was performed using SPSS.22 software Results: Sixty-three patients had biopsy-confirmed PTLD. Of these, 26 met inclusion criteria. Among these 26 patients, 19 (73.1%) were men; median age was 57 years (18-75 years); and transplants included 3 (11.5%) lung, 4 (15.4%) heart, 9 (34.6%) kidney, 8 (30.8%) liver, 2 (7.7%) pancreas, and 1 (3.8%) stem cell. All patients were receiving IST at the time of diagnosis of PTLD. Pathology reports found that 24 (92.3%) had diffuse large B-cell lymphoma (DLBCL)-like PTLD, and 11 (57.9%) had EBV-positive disease. HGBL was observed in 10 (38.5%) patients. Seven patients received DA-R-EPOCH, and 19 received R-CHOP. Baseline characteristics were similar between treatment groups. There was a significantly higher number of patients with HGBL in the DA-R-EPOCH arm compared with the R-CHOP arm (100% [7/7] vs. 15.8% [3/19]; 95% CI, -0.01-1.00; p=0.001). The median number of cycles administered was not significantly different between the groups (4.6 cycles vs. 5 cycles; 95% CI, 4.33-6.07; p=0.645). Dose intensification occurred in 8 of 32 cycles for patients who received DA-R-EPOCH. The median follow-up time for patients treated with DA-R-EPOCH was shorter (10 months) than for patients treated with R-CHOP (29 months). PFS was not found to be significantly different between the DA-R-EPOCH and R-CHOP arms (10.4 months vs. 61.4 months; 95% CI, 1.80-18.99; p=0.31). Patients with EBV-positive disease had inferior PFS compared with EBV-negative disease (7.37 months vs. NR; 95% CI, 1.02-10.2; p=0.046). In addition, OS, neutropenia, thrombocytopenia, hospitalizations, and hospitalizations due to febrile neutropenia were not significantly different between groups, though trends toward higher rates of grade 3 or 4 neutropenia, thrombocytopenia, and hospitalizations was observed in the DA-R-EPOCH group. Conclusion: To our knowledge, this is the first study evaluating the role of intensive induction therapy in patients with HGBL with MYC and BCL2 rearrangements observed in solid organ transplant recipients. In patients with PTLD, DA-R-EPOCH is a well-tolerated regimen with concurrent taper in IST. However, this strategy may not overcome the poor prognosis of HGBL. Dose adjustments beyond level 2 were limited by cytopenias. Figure Figure. Disclosures Reddy: KITE: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; GILEAD: Membership on an entity's Board of Directors or advisory committees; INFINITY: Membership on an entity's Board of Directors or advisory committees.

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Solid organ transplant in individuals with monoclonal B-cell lymphocytosis and chronic lymphocytic leukaemia

British Journal of Haematology ◽

10.1111/bjh.13759 ◽

2015 ◽

Vol 174 (1) ◽

pp. 162-165 ◽

Cited By ~ 4

Author(s):

Paolo Strati ◽

Kamel A. Gharaibeh ◽

Nelson Leung ◽

Ferdinando G. Cosio ◽

Timothy G. Call ◽

...

Keyword(s):

Chronic Lymphocytic Leukaemia ◽

B Cell ◽

Lymphocytic Leukaemia ◽

Organ Transplant ◽

Solid Organ Transplant ◽

Solid Organ

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Outcome of Post Solid Organ Transplant Burkitt Lymphoma (PSOT-BL): A Report from the Pediatric PTLD Collaborative (PPC)

Blood ◽

10.1182/blood-2021-149033 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2498-2498

Author(s):

Zeinab Afify ◽

Manuela Orjuela ◽

Christine Moore Smith ◽

Mansi Dalal ◽

James B. Ford ◽

...

Keyword(s):

Burkitt Lymphoma ◽

Pediatric Patients ◽

Collaborative Study ◽

Organ Transplant ◽

B Cell Lymphoma ◽

Solid Organ Transplant ◽

Outcome Data ◽

The Other ◽

Cardiac Transplant ◽

Solid Organ

Abstract Background Post solid organ transplant Burkitt lymphoma (PSOT-BL) is a rare form of monomorphic post-transplant lymphoproliferative disease (M-PTLD). Outcome data in pediatric patients are limited and guidelines on optimal treatment in PSOT-BL are lacking. Methods Retrospective study and analysis of clinical characteristics, treatment, and outcome data from patients diagnosed with PSOT-BL at age ≤ 21 years (y) in 11 US pediatric transplant centers. Results We identified 28 patients transplanted between 1993-2016 who developed PSOT-BL. Median age at organ transplantation and at diagnosis of PSOT-BL was 2.9y (range, 0.1-14) and 7.5y (range, 7-17), respectively, with median interval from transplant to PSOT-BL diagnosis of 3.8y (range 2-7). Heart and liver were the most frequently transplanted organs (n=14, 11), while bowel, kidney, and lung were each transplanted in one patient. Immunosuppressive therapy at the time of PSOT-BL diagnosis was tacrolimus alone (n=9), or in combination with mycophenolate (n=7), azathioprine (n=6), cyclosporin (n=3), or prednisone (n=3). None were receiving an mTOR inhibitor at time of PSOT-BL diagnosis. Six, twelve, and ten patients corresponded to Murphy stages II, III, and IV, respectively. Lactate dehydrogenase was elevated in 23 patients (82%) and was > 2x upper limit of normal in 14 (50%). All tumors were pathologically consistent with BL; MYC FISH testing was positive in 10/10 tumors tested, while 21/23 tumors (90%) had detectable Epstein Barr Virus. Rituximab-containing regimens were given to 25/28 patients (93%). These treatment regimens were as follows: rituximab alone (n=2), low dose cyclophosphamide, prednisone, and rituximab (CPR) (n=10), Burkitt lymphoma specific therapy: (FAB/LMB chemotherapy (n=3) or FAB/LMB therapy with rituximab (n=8)), reduced dose FAB/LMB (n=2), diffuse large B-cell lymphoma (DLBCL) regimens including EPOCH-R (n=2) and R-CHOP (n=1). Treatment modifications/reductions were infrequent. Methotrexate dose modification and/or omission were required in four patients due to renal dysfunction (n=3) and ascites (n=1). Doxorubicin was electively eliminated in one cardiac transplant recipient due to concern for cardiotoxicity and dose-reduced in another due to prolonged myelosuppression. There was no treatment related mortality. There were two episodes of rejection, one was a liver rejection that was successfully treated without graft loss, the other occurred after achieving partial response (PR) to 3 cycles of CPR, required intensive immune suppression, and was followed by PTLD/DLBCL and death from PTLD progression. There were two additional cases of a second PTLD/DLBCL. One died of PTLD progression nine months after developing a second PTLD and the other is alive in complete remission (CR) 17 months after diagnosis of a second PTLD. Of the two patients treated with rituximab alone, one had no response and the other relapsed. Both were subsequently treated with BL chemotherapy and are alive in CR 15- and 7-years following BL diagnosis, respectively. For all study patients over a median of 6.8y follow-up (range, 0.5-17), 3-year event-free survival (EFS) was 73.5% and 3-year overall survival (OS) was 92.6%, see figure. Three patients died of Burkitt lymphoma (all had been treated with CPR, experienced treatment failure and required treatment escalation to intensive BL chemoimmunotherapy but died of progressive disease). Of the 11 patients who received Burkitt lymphoma intensive therapy, all are alive in CR. One had progressed on treatment but achieved CR with further treatment intensification. Another developed a second PTLD/DLBCL, with subsequent CR. Conclusion This collaborative study represents the largest pediatric series of PSOT-BL reported to date. In this study patients with PSOT-BL treated with intensive BL directed therapy appear to have comparable outcome to immunocompetent pediatric patients with BL. Figure 1 Figure 1. Disclosures Orjuela: ATARA Pharmaceuticals: Other: Scientific Advisory Board.

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High Risk Cytogenetic and Immunohistochemistry Findings in Monomorphic Post-Transplant Lymphoproliferative Disorder Following Solid Organ Transplant - a Single Center Experience

Blood ◽

10.1182/blood-2019-126228 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2915-2915

Author(s):

Timothy J Voorhees ◽

Natalie S Grover ◽

Jonathan Galeotti ◽

Nathan D Montgomery ◽

Dominic T. Moore ◽

...

Keyword(s):

In Situ Hybridization ◽

High Risk ◽

B Cell ◽

Organ Transplant ◽

Solid Organ Transplant ◽

Solid Organ ◽

Front Line ◽

Poor Outcomes ◽

Line Setting

Background: Post-transplant lymphoproliferative disorders (PTLD) represent a heterogeneous group of immune-deficiency related lymphoid malignancies occurring after solid organ transplant (SOT) or bone marrow transplant. Monomorphic PTLD (mPTLD) is typically characterized by diffuse large B-cell lymphoma (DLBCL), though other mature B and T-cell lymphomas make up a small contribution. In one of the largest prospective clinical trials in PTLD, Trappe et al described a risk stratified sequential treatment approach using rituximab (R) monotherapy induction followed by either (R) consolidation or chemoimmunotherapy (chemoR) based on interim response. The role of cytogenetic and immunohistochemistry (IHC) risk stratification have not been fully described in mPTLD. In this study, we aim to identify clinical factors which may lead to differences in clinical outcomes in mPTLD. Methods: Pts diagnosed with mPTLD following SOT at the University of North Carolina at Chapel Hill were identified by an IRB approved EMERSE query of the medical record. Histologic classification was determined by pathologist review at the time of diagnosis. DLBCL subtype was determined as either germinal center B-Cell (GCB) type, non-GCB type, or unclassifiable using Hans IHC criteria. Double-Hit lymphoma (DHL) was defined as the presence of a MYC rearrangement in combination with either a BCL2 or BCL6 rearrangement by in-situ hybridization. Double expressor lymphoma (DEL) was defined as the presence of MYC and BCL2 co-expression by IHC. Additional copies of MYC or BCL2 were determined by in-situ hybridization. Clinical responses were determined per Lugano criteria. Cox regression was used to evaluate the association of covariates of interest with overall survival (OS). Results: A total of 29 pts were diagnosed with mPTLD between 2010 and 2019. The median age at diagnosis was 55 years (range, 19-84 years). Transplanted organs included 16 kidney (56%), 5 lung (17%), 4 liver (14%), 3 heart (10%), and 1 kidney/heart (3%). The median time from transplant to diagnosis was 7.1 years (range, 0.2 to 24.5 years). Sub-classification of mPTLD revealed 11 non-GCB type (38%), 10 GCB type (35%), 7 unclassifiable DLBCL (24%), and 1 PTCL (3%). EBV encoded RNA (EBER) in-situ hybridization was positive in 10 pts (35%) and concurrent EBV reactivation was detected in 7 of the 10 pts. Both categorized EBV encoded RNA (EBER) in-situ hybridization, and GCB vs non-GCB type mPTLD did not appear to be significantly associated with OS. mPTLD that was DHL (1 pt), DEL (3 pts), or had extra copies of MYC/BCL2 (3 pts) had significantly shorter OS (p=0.006, Figure 1). The 1 year OS for those with high risk cytogenetics and IHC was 29% [95% CI: 4% to 61%] versus those without at 76% [52% to 89%]. Consistent with prior studies, pts with revised International Prognostic Index (R-IPI) high (3-5) had a significantly shorter OS (p=0.001, Figure 2). The 1 year OS for those with dichotomized R-IPI high was 38% [95% CI: 14% to 63%] versus those with R-IPI low at 87% [95% CI: 56% to 96%]. All pts had a reduction in immunosuppression at diagnosis. Fourteen pts (48%) were treated with front-line (R) monotherapy. Seven of these pts achieved a CR (50%), 3 pts achieved a PR, 3 pts developed progressive disease and 1 pt died during therapy. Eleven pts (38%) were treated with front-line chemoR. Seven of these pts achieved a CR, 3 pts achieved a PR, and 1 pt died during therapy. Pts who achieved a CR or PR with (R) monotherapy induction had a better OS compared to pts who either had no response to (R) or were treated with chemoR (p=0.01, Figure 3). The 1 year OS for (R) CR/PR was 90% [47% to 99%] versus all other pts including those treated with combination chemoR at 47% [23% to 68%]. Of note, pts who achieved a CR with either (R) induction or chemoR in the front-line setting had borderline significantly improved OS (p=0.06). Conclusion: Response to therapy within mPTLD is quite variable. In this study, we reveal a population of mPTLD with particularly poor outcomes (DHL, DEL, and extra copies of MYC/BCL2). To our knowledge, this is the first study to show the dramatic impact of poor risk cytogenetic and IHC findings on clinical outcomes in mPTLD. As seen in other cohorts, high R-IPI score was associated with poor outcomes. Objective response to (R) induction in the front-line setting was associated with improved survival. Disclosures Grover: Seattle Genetics: Consultancy. Dittus:Seattle Genetics: Consultancy.

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Post-Transplant Lymphoproliferative Disorder after Heart Transplant in the Pediatric Population: A Systematic Review

Blood ◽

10.1182/blood-2020-143435 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 37-37

Author(s):

Mobeen Zaka Haider ◽

Muhammad Taqi ◽

Hasan Mahmood Mirza ◽

Zarlakhta Zamani ◽

Hafsa Shahid ◽

...

Keyword(s):

Monoclonal Antibody ◽

B Cell ◽

Induction Therapy ◽

Graft Rejection ◽

Lymphoproliferative Disorder ◽

Organ Transplant ◽

Solid Organ Transplant ◽

Solid Organ ◽

Post Transplant ◽

Transplant Patients

Background: Post-transplant lymphoproliferative disorder (PTLD) is a B-cell proliferation disorder that results from disruption in the physiological mechanisms for proliferation in an immunocompromised host after a solid organ transplant. Our study aims to review the demographic characteristics and clinical outcomes after transplantation. We also aim to study the role of immunosuppression induction therapy, the effect of PTLD on survival, and the effective chemotherapy used for B-cell disorders leading to improved survival. Methods: Following the PRISMA guideline, we performed a comprehensive literature search on PubMed, Cochrane Library, Embase, and clinicaltrials.gov from the past decade on May 04, 2020. We used the MeSH terms of organ transplantation and lymphoproliferative disorders. 1741 articles were screened. We excluded all case reports, case series, pre-clinical trials, review articles, and meta-analysis and included three cohort studies and one prospective multicentric study. We extracted the data for baseline characteristics, the reason for transplantation, recipient & donor EBV status, immunosuppression used, type & stage of PTLD, organ system involved, duration between transplant and PTLD diagnosis, treatment, response to therapy, adverse effects of therapy and mortality. Results: We studied 9617 patients in the included four studies, out of which 499 patients developed PTLD. Data in these studies was collected over the last 20-26 years. Median follow-up of patients since transplant was 3-9 years (average 7.5y). Table 1 The age of the patients ranged from 3-18 years with a male: female gender ratio of 48:52% and around 50% of the patients were seronegative to EBV pretransplant. The following drugs were used for immunosuppression: cyclosporin, tacrolimus, azathioprine, mycophenolate, interleukin 2 receptor antagonist (basiliximab), corticosteroids, anti-thymocyte globulins(ATG). Kindel et al. narrated that the development of eosinophilic oesophagitis may be a marker for the development of PTLD.Gajarski et al. concluded that Post-transplant Immunosuppressive induction therapy with cytolytic drugs (e.g OKT3 monoclonal antibody, ATG, thymoglobulin Basiliximab and daclizumab) , lowers the rate of PTLD, graft rejections, and early infections in post-transplant patients as compared patients who did not receive induction therapy . This depends upon the type of induction e.g OKT3 monoclonal antibody was associated with increased PTLDs and graft rejection, while Thymoglobulin/IL-2R antagonists demonstrated to decrease both the outcomes. Claire et al. described that overall mortality is decreasing due to the ongoing better understanding of pathophysiology and treatment options related to solid organ transplant. The mortality of the post-transplant congenital heart disease group was higher as compared to the cardiomyopathy group due to high comorbidities and surgical complications. The study by Christopher et al. showed that EBV seronegativity before transplant is associated with an increased risk of PTLD. PTLD is associated with lower survival rates as compared to non-PTLD groups. Conclusion: Our review illustrates that pretransplant seronegativity, OKT3 monoclonal antibody, and the development of eosinophilic esophagitis during the immunosuppressive regime increase the risk of PTLD. This study demonstrates that with a better understanding of PTLD and tumor behavior, the all-cause mortality rates are falling significantly. PTLD is one of the leading causes of mortality in post-transplant patients. However, the immunosuppressive induction therapy, absence of eosinophilic esophagitis, thymoglobulin/IL-2R antagonists improve survival and outcomes in the post-transplant patient in terms of graft rejection, graft failure, and development of PTLD. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

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