Hodgkin Transformation Research Articles

Hodgkin transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma

Introduction. In rare cases, chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma may transform into Hodgkin lymphoma, with about a hundred cases reported in the literature so far. We present a case of the Hodgkin variant of Richter transformation. Case report. After a one-year watch and wait period, a 60-year-old male with CLL developed B symptoms, generalized lymphadenopathy, and splenomegaly. Upon initial staging (Binet B/Rai 3), he was started on fludarabine, cyclophosphamide, and rituximab (FCR) regimen. After the third cycle of treatment, the right-sided axillary lymphadenopathy persisted and became pain-ful, while the dimensions of the remaining organs affected by the disease decreased. Upon the finalization of the final sixth FCR cycle, the painful right-sided axillary lymphadenopathy persisted (though partially decreasing in size), with the development of local redness and swelling. A biopsy of the residual axillary node was performed, which revealed disease transformation into Hodgkin lymphoma. Upon multislice computed tomography-based staging (IV E clinical stage) and prognostic assessment (unfavorable prognosis), it was decided that the treatment be continued with doxorubicin, vinblastine, dacarbazine (AVD) regimen. The presented patient died two months after the diagnosis of Hodgkin transformation (HT) was established during the initial cycle of AVD. Conclusion. Although CLL is an indolent malignancy, in rare cases of HT, the prognosis is largely dismal. The available treatment strategies demonstrate suboptimal results, although novel immunotherapies may change the landscape of HT therapy in the near future.

Updated Results from a Multicenter, Phase 2 Study of Acalabrutinib, Venetoclax, Obinutuzumab (AVO) in a Population of Previously Untreated Patients with CLL Enriched for High-Risk Disease

Background While venetoclax (V) plus obinutuzumab (O) is a highly effective frontline CLL regimen, outcomes remain suboptimal for high-risk patients (pts). The efficacy of ibrutinib plus VO in such pts is encouraging, but cardiac and infectious toxicities (tox) are common. We hypothesized that a time-limited triplet with the more selective BTKi acalabrutinib (A) would be active and well-tolerated. We previously published results on an initial cohort unrestricted by genetic risk (Davids et al., 2021), and now report on a new cohort with enrollment restricted to high-risk pts, as well as longer follow-up on the initial cohort. Methods Treatment (tx)-naïve pts with CLL with any genetic risk profile were initially enrolled in this investigator-sponsored, phase 2 study (cohort 1), followed by a multi-center expansion restricted to previously untreated pts with TP53-aberrant CLL (cohort 2). A starts at 100 mg BID for 28 days, followed by 2 cycles of AO (O at standard dosing), and V starts on C4D1 at 20 mg, then 50 mg on C4D2, with weekly ramp-up thereafter to 400 mg QD (total 4 week V ramp-up). AVO continues C5-7 (6 total cycles of O), and AV continues C8-15. If the primary endpoint of undetectable bone marrow MRD (BM-uMRD) CR is reached at C16D1, pts can discontinue therapy (tx); all others continue AV through C24, with the option to discontinue if BM-uMRD at C25D1. Assessments: efficacy by 2018 iwCLL criteria, toxicities (tox) by CTCAE v5, MRD by central 8-color flow (10-4 sensitivity) and NGS clonoSEQ (up to 10-6 sensitivity, Adaptive). BH3 profiling work is ongoing, performed as previously described (Ryan J et al., 2016) on peripheral blood (PB) samples after 1 and 3 cycles. Association of BCL-2 dependence with clinical response was compared by an unpaired t-test. Results As of 13 July 2022, 68 pts were enrolled (cohort 1 all-comers: n=37, cohort 2 TP53-aberrant: n=31) in this ongoing study (NCT03580928), with median follow-up of 35 mos (range 2-45). In all 68 pts, median age 63 yrs (range 36-80); 25% ≥70 yrs; 66% male; 60% TP53-aberrant (del(17p) or mut); 24% complex karyotype (≥3 abnormalities); 74% unmutated IGHV. Of the 56 pts evaluable to date at C16D1, 43% (24/56) achieved the primary endpoint BM-uMRD CR. The best ORR is 98% (48% CR, 50% PR). At C16D1, MRD by flow: 86% PB-uMRD, 86% BM-uMRD (Fig 1A). In a subset of 49 pts with available samples, 59% were PB-uMRD by NGS at 10-5 sensitivity (at 10-6, 59% of pts had indeterminate results due to low cell counts). In the 29 pts with TP53-aberrant disease evaluable at C16D1, the best ORR is 100% (52% CR, 48% PR), and 45% (13/29) achieved BM-uMRD CR, MRD by flow: 86% PB-uMRD, 83% BM-uMRD (Fig 1A). There were no differences in response or MRD based on IGHV status. 79% (19/24) of pts in BM-uMRD CR electively discontinued tx after 15 cycles; median time off tx for these pts is 22.9 mos (range 1-30). 2 of the 19 pts who discontinued tx have had MRD only recurrence, and 1 had CLL disease progression; all 3 restarted tx with AV and achieved PR. 3 pts developed Richter's syndrome: 1 with DLBCL after 15 mos on study, and 2 with Hodgkin transformation (one 13 mos after completing study tx and one 12 mos into study tx; both achieved CR to Hodgkin-directed tx). 93% of all pts (63/68) remain progression-free. In all 68 pts, all-grade heme tox included: neutropenia (75%; 37% Gr3/4), thrombocytopenia (73%; 28% Gr3/4), anemia (49%, 3% Gr3). Non-heme tox: headache (78%, 1% Gr3), fatigue (76%, 1% Gr3), bruising (66%, all Gr1/2), nausea (49%, all Gr1/2), diarrhea (40%, 4% Gr3), infusion-related reaction (30%, 4% Gr3), hypertension (27%; 9% Gr3), increased ALT (27%, 1% Gr3), arthralgia (25%, all Gr1), and infection (6% Gr3; 1 case of Gr5 COVID-19 pneumonia). 2.9% (2/68) pts had afib. 14 pts (21%) required dose-reduction of either only A (4%), only V (9%), or both drugs (7%). BH3 profiling is ongoing, and initial data suggest that pts who later went on to achieve CR may have a greater increase in BCL-2 dependence at C4D1 than pts who achieved PR as best response (p=0.05, Fig 1B). Conclusion AVO is a highly active, well-tolerated triplet in a frontline CLL population enriched for high-risk disease, with 83% of TP53-aberrant pts achieving BM-uMRD after 15 mos of tx. Responses are durable, with 93% PFS in all pts at a median follow-up of nearly 3 yrs. Low rates of cardiac and infectious tox were observed. Our data support continued investigation of the MRD-guided, time-limited AVO triplet. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

PB1882: RICHTER TRANSFORMATION FEATURES, SURVIVAL AND TREATMENT OUTCOME IN HEMATOLOGY CLINIC OF CRAIOVA, ROMANIA

Background: Richter transformation is a rare but potential lethal complication in patients diagnosed with chronic limphocytic leukemia. The most common histological transformation is of Hodgkin lymphoma or Diffuse Large B-cell lymphoma type. Aims: The aim is to assess the clinicopathological characteristics survival and treatment in Richter transformation patients diagnosed and treated in Hematology Clinic of Craiova in the last 10 years. Methods: Between January 2012 and January 2022, 453 patients with chronic lymphocytic leukemia (CLL) were diagnosed and treated in our clinic, 121 female and 332 male. Results: Median age of the patients was 68 years and the male:female ratio was 2,74. The majority were diagnosed in A stage (52%), 27% in B stage and 21% in C stage. 29% of patients required treatment initiation upon diagnosis. Richter transformation occurs in 1,76 % cases (8/453) of all CLL. The transformation occurred as follows: 5 diffuse large B-cell lymphoma (DLBCL)-type pacients and 3 Hodgkin lymphoma-type pacients. In all cases the mutational status was unmutated, CD38 was positive in 6 patients and 3 patients were positive for TP53 mutation. The time until transformation lasted between 6 and 42 months, measured from treatment initiation. In 6 patients, transformation involved peripheral lymphadenopathy and in 2 patients, intraabdominal lymphadenopathy. The treatment received was ABVD regimen in Hodgkin transformation and R CHOP in DLBCL-type. On average, survival was 16 months in Hodgkin transformation and 7,8 months in DLBCL transformation. Summary/Conclusion: The Richter transformation is a rare complication of CLL, an indolent lymphoproliferative disorder. Only 8 patients were diagnosed with Richter transformation in our clinic in the last 10 years. Chemotherapy response was poor and survival was short.

Fixed Duration Combination Therapy with Ibrutinib (ibr) and Venetoclax (ven) Leads to Deep Responses in Relapsed/Refractory (rel/ref) Chronic Lymphocytic Leukemia (CLL): Results of a Phase 2 Study

Fixed Duration Combination Therapy with Ibrutinib (ibr) and Venetoclax (ven) Leads to Deep Responses in Relapsed/Refractory (rel/ref) Chronic Lymphocytic Leukemia (CLL): Results of a Phase 2 Study

Combined Venetoclax and Ibrutinib for Patients with Previously Untreated High-Risk CLL, and Relapsed/Refractory CLL: A Phase II Trial

Combined Venetoclax and Ibrutinib for Patients with Previously Untreated High-Risk CLL, and Relapsed/Refractory CLL: A Phase II Trial

Hodgkin lymphoma arising in patients with chronic lymphocytic leukemia: outcomes from a large multi-center collaboration.

Chronic lymphocytic leukemia (CLL) patients who develop Hodgkin lymphoma (HL) have limited survival. No current therapeutic standard of care exists. We conducted a multi-center retrospective study of patients with Hodgkin transformation (HT) of CLL. Clinicobiologic characteristics, treatment type, and survival outcomes were analyzed and compared with historic case series. Ninety-four patients were identified. Median age at HT was 67 years (range, 38-85). Median time from CLL diagnosis to HT was 5.5 years (range, 0-20.2). Prior to HT, patients received a median of two therapies for CLL (range, 0-12). As initial therapy for HT, 61% (n=62) received ABVD-based regimens (adriamycin, bleomycin, vinblastine, and dacarbazine). Seven (7%) patients received hematopoietic cell transplantation (HCT) while in first complete remission (CR1). The median number of treatments for HT per patient was one (range, 0-5) with 59 (61%) patients only receiving one line of therapy. After HT, patients had a median follow-up of 1.6 years (range, 0-15.1). Two-year overall survival (OS) after HT diagnosis was 72% (95% Confidence Interval: 62-83). The patients who received standard ABVD-based therapy had a median OS of 13.2 years. Although limited by small sample size, the patients who underwent HCT for HT in CR1 had a similar 2-year OS (n=7; 67%) compared to patients who did not undergo HCT for HT in CR1 (n=87; 72%; P=0.46). In this multi-center study, HT patients treated with ABVD-based regimens had prolonged survival supporting the use of these regimens as standard of care for these patients.

Combined Ibrutinib and Venetoclax in Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL)

Combined Ibrutinib and Venetoclax in Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL)

Hodgkin transformation of chronic lymphocytic leukaemia/small lymphocytic lymphoma

Hodgkin transformation of chronic lymphocytic leukaemia/small lymphocytic lymphoma

A Case of Hodgkin Transformation of Chronic Lymphocytic Leukemia

Richter’s transformation is a serious complication of chronic lymphocytic leukemia. We present a patient with Hodgkin transformation of chronic lymphocytic leukemia. This patient was admitted to our clinic with the complaints of weakness and fatigue. She had palpable axillary and cervical lymphadenomegaly. Positron emission tomography/ computed tomography scans with fluorodeoxyglucose revealed multiple cervical axillary lymph nodes in the right axilla and the right side of the neck with minimally increased fluorodeoxyglucose uptake and paraaortic, pancreaticoduodenal, aortocaval lymph nodes with intense fluorodeoxyglucose uptake (SUVmax: 10.86). Excisional biopsy of the intraabdominal lymph node was performed which revealed classical Hodgkin disease. Combined chemotherapy was started. She died because of pneumonia after two cycles of the therapy.

Detection of Hodgkin Transformation in a Case of Chronic Lymphocytic Leukemia by PET/CT.

Richter’s transformation (RT) represents the development of high grade lymphoma, most commonly diffuse large B-cell lymphoma, in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL). CLL/SLL may convert also to Hodgkin’s lymphoma, the so-called Hodgkin’s variant of Richter transformation. Histopathological proof is needed to confirm a definitive diagnosis. Patients with RT generally have a poor prognosis, with prompt recognition optimise clinical management. Whole-body PET scan with 18F-FDG can be used for detection of RT of CLL/SLL. We describe the case of 64-year-old woman with CLL/SLL who developed Hodgkin lymphoma detected with PET/CT.

Hodgkin Transformation Of Chronic Lymphocytic Leukemia (CLL): Mayo Clinic Experience

▪ BackgroundAlthough its prevalence is not well defined, transformation to Hodgkin lymphoma (HL) is a rare but well recognized complication in patients with CLL. Prior studies have reported a median survival of 0.8-1.7 years in these patients. Prior therapy of CLL, especially with purine analogs, has been shown to have adverse impact on survival after development of HL. We used the Mayo Clinic CLL database to describe outcomes of CLL patients seen at our institution who developed HL. MethodsThe Mayo Clinic CLL database includes all consenting patients with a pathologic diagnosis of CLL. Patients who developed biopsy-proven HL were included in this analysis. For patients referred from an outside institution, pathology review at Mayo Clinic was mandatory to be included. Clinical characteristics, therapy and overall survival (OS) were analyzed for all HL patients. ResultsAmong 3124 CLL patients seen at Mayo Clinic from 1/1995 to 7/2011, 26 developed HL. In a nested cohort of 1644 patients who were seen within 12 months of CLL diagnosis and followed prospectively, the prevalence of HL was 0.05%/year (10 year risk=0.5%). All 26 patients had classical HL. The median duration between CLL diagnosis and development of HL was 6.2 years (range, 0-24.5 years). The median age at diagnosis of HL was 68 years (range, 45-88 years) and 21 (81%) were male. At the time of HL diagnosis, the median WBC count was 7.8 x 109/L (range, 1.3-87.3), median hemoglobin was 11 gm/dL (range, 7.2-13), median platelet count was 220x109/L (range, 53-627), median serum lactate dehydrogenase was 249 U/L (range, 133-658), and median serum albumin was 3.4 gm/dL (range, 2.6-4.2). According to the Ann Arbor staging system for HL, 10 (38%) were Stage II, 2 (8%) were Stage III, 11 (42%) were Stage IV, and undetermined in 3 (12%) patients. Sixteen patients (61%) received HL therapy with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD), seven (27%) received other chemotherapy, and treatment was unknown in 3 (12%) patients. No patient underwent stem cell transplantation as therapy for HL.After a median follow-up of 8.7 years from CLL diagnosis date, 16 (61%) patients have died. The median OS from date of HL diagnosis was 3.9 years (95% CI, 1.0 – 5.0 years). The International Prognostic score (IPS) for HL, originally proposed by Hasenclever in 1998, identified seven prognostic factors: serum albumin <4 gm/dL, hemoglobin <10.5 gm/dL, male sex, age >45 years, stage IV disease, WBC≥15 x 109/L, and lymphocytopenia in patients with newly diagnosed HL. When we applied these prognostic parameters (available in 22/26 patients, 85% in our cohort), the IPS score predicted median survival as follows: score of ≤2 (18% of the patients), median survival not reached; score of 3 (23% of the patients), 6.2 years; score of 4 (36% of the patients), 2.4 years; and score ≥5 (23% of the patients), 0.3 years (p-value=0.005, Figure 1). In contrast, the Richter syndrome prognostic score developed for CLL patients who transform to diffuse large B-cell lymphoma failed to predict survival in these patients (Tsimberidou, JCO, 2006). [Display omitted] Of the 26 patients with HL, 16 (61%) had received therapy for their CLL prior to developing HL, including 12 (46%) who had received more than one line of therapy. Purine analogs had been administered for treatment of CLL prior to development of HL in 13/26 (50%) patients. The median survival of HL patients who had previously received CLL therapy was significantly worse compared to those who were untreated for CLL (2.8 years vs. 7.6 years, p-value=0.02). There was a trend toward shorter survival for HL patients who had received previous purine analog therapy for CLL compared to those who received alternate therapies (1.8 years vs. 5 years, p-value: p-value=0.07).Of the 9 HL biopsy samples in which Epstein Barr virus (EBV) in-situ hybridization studies were performed, EBV was detected in 6 (67%) patients. No association was observed between prior purine analog therapy and EBV status (p-value=1.0). There was no difference in survival according to the EBV status of HL (p-value=0.33). ConclusionThe 10 year incidence of transformation to Hodgkin transformation among patients with newly diagnosed CLL is 0.5% (∼1/200 CLL patients). In this single-institution analysis, median survival of CLL patients who developed Hodgkin transformation of CLL was approximately 4 years after HL diagnosis. The IPS accurately predicted survival in our cohort of HL patients. Disclosures:Zent:Novartis: Research Funding; GlaxSmithKline: Research Funding; Biothera: Research Funding; Genzyme: Research Funding; Genentech : Research Funding. Shanafelt:Glaxo-Smith-Kline: Research Funding; Cephalon: Research Funding; Hospira: Research Funding; Celgene: Research Funding; Polyphenon E International: Research Funding; Genentech: Research Funding.

Poor prognosis of Hodgkin variant of Richter transformation in chronic lymphocytic leukaemia treated with cladribine ‐ Response to Jamroziak et al

We appreciate the thoughtful comments of Jamroziak and colleagues regarding our study of Hodgkin lymphoma as Richter transformation (Hodgkin-RT) in patients with chronic lymphocytic leukaemia (CLL) (Bockorny et al, 2012). Mirroring our pooled analysis that showed a decreased survival in Hodgkin-RT patients previously treated with fludarabine (0.7 ± 0.2 years), their retrospective analysis demonstrated similarly unsatisfactory outcomes in Hodgkin-RT patients treated with cladribine-based regimens for CLL. Of note, they showed a survival of only 0.34 years (95% confidence interval 0–1.08) in a small cohort of Hodgkin-RT patients whose CLL had previously been treated with cladribine (n = 6). A plausible explanation for this dismal outcome is the marked and prolonged T-lymphocyte depletion caused by the purine nucleoside analogues (PNAs), which amplifies the intrinsic immunosuppression of CLL and possibly leads to reactivation of a latent Epstein-Barr virus infection (Cheson et al, 1999; Dasanu, 2008). In addition, Jamroziak et al hypothesized that the first-line chemotherapy commonly used to treat Hodgkin transformation in CLL might be suboptimal against the PNA-exposed clones. In our cohort, the most commonly employed regimens for Hodgkin-RT therapy were ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), with no statistical difference in overall survival between the two groups. As of today, the best therapeutic approach for Hodgkin-RT remains to be clarified (Tsimberidou et al, 2006). Rituximab with or without chemotherapy remains an attractive option for Hodgkin-RT cases with CD20+ Reed-Sternberg cells or marrow/ nodal histologies composed of a mix of Hodgkin lymphoma and CLL. In conclusion, the outcome of the Hodgkin variant of Richter syndrome in CLL, especially when previously exposed to PNAs, should not be viewed as favourable when compared to the classic RT (as diffuse large B-cell lymphoma). Selection of a more intense first-line chemotherapy regimen, with or without targeted antibody therapy may improve the general outcome. Studies aiming to clarify the molecular basis of Hodgkin-RT along with the discovery of innovative therapeutic approaches for this rare variant of RT are awaited. The authors have no competing interests.

Fine needle aspiration diagnosis of Hodgkin transformation of small lymphocytic lymphoma/chronic lymphocytic leukaemia: a case report

Fine needle aspiration diagnosis of Hodgkin transformation of small lymphocytic lymphoma/chronic lymphocytic leukaemia: a case report

A composite small lymphocytic lymphoma and Hodgkin transformation presenting as acute appendicitis

Dear Editor, Richter's transformation occurs in 2–8% of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and usually involves transformation to diffuse large B-cell lymphoma (DLBCL) or rarely (0.4% of cases) Hodgkin lymphoma [1]. Both transformations may involve nodal or extranodal sites and both could locate in separate or in the same tissue (composite lymphoma). Molecular and immunophenotypic evidence indicates that the transformed cells usually, but not always, derive from the same clone as the original CLL/SLL [1, 2]. The vermiform appendix, naturally rich in gut-associated lymphatic tissue, is often involved in patients with nonHodgkin lymphoma. However, there have been only 13 cases of classical Hodgkin lymphoma and 1 of nodular lymphocyte-predominant Hodgkin lymphoma reported in the appendix [3–5]. To our knowledge, a composite CLL/ SLL with Hodgkin transformation heralded by acute appendicitis has not been reported. Here, we document this rare case below. A 64-year-old woman presented to our facility with bilateral axillary adenopathy and splenomegaly and was subsequently diagnosed with CLL/SLL. Sixteen months after this initial diagnosis, she presented with acute appendicitis. The appendectomy specimen showed acute serositis associated with two zonal atypical lymphoid infiltrates composed of: (1) a monotonous population of small, mature lymphoid cells with clumped nuclei and scant cytoplasm that expanded the lamina propria (Fig. 1a 1 and 2) and (2) multiple nodular proliferations consisting of numerous Reed-Sternberg (RS)like cells or Hodgkin cell variants in a matrix of polymorphous inflammatory cells, including predominantly histiocytes, small lymphocytes, and few granulocytes throughout the wall of the appendix (Fig. 1c 1 and 2). Immunohistochemical stains and in situ hybridization demonstrated two distinct phenotypic features: (1) PAX5+/CD5+/ CD23+/cyclin D1-neoplastic B cells, compatible with SLL (Fig. 1b 1 and 2) and (2) CD30+/CD15+/CD45-/ EBER+atypical large cells, compatible with classical Hodgkin lymphoma (Fig. 1d 1 and 2). Immunostains also confirmed that the small lymphocytes surrounding the RSlike cells were T cells. According to the literature, the infiltrate distribution is consistent with so-called type 2 transformation, where the RS-like cells are found in a polymorphous inflammatory background, characteristic of primary classical Hodgkin lymphoma, and separate from SLL cells. In contrast, in type 1 transformation, the RSlike cells are distributed among clonal B cells, that is, SLL cells [1]. The patient received a matched related peripheral blood stem-cell transplant 21 months after her initial diagnosis. Although Hodgkin lymphoma is among the most common malignancies to secondarily involve patients with CLL/SLL [6], Hodgkin transformation of CLL/SLL is a B. Quigley (*) Department of Pathology and Cell Biology, University of South Florida College of Medicine, 4105 W Coachman Ave, Tampa, FL 33611, USA e-mail: bquigley@health.usf.edu

MDR-1 gene polymorphisms G2677T and C3435T in a case of Hodgkin’s variant of Richter’s syndrome

Richter's syndrome is defined as the transformation of low-grade lymphoma to a more aggressive high-grade malignant form, usually diffuse large B-cell lymphoma. Hodgkin's lymphoma variant of Richter transformation is relatively rare, and only approximately 100 cases have been reported in the literature. This study examined a case of a 53-year-old woman who developed Hodgkin's lymphoma almost 5 years after the diagnosis of chronic lymphocytic leukemia (CLL). The major points of interest regarding CLL with Hodgkin's transformation were also considered, such as the potential role of MDR-1 gene polymorphisms. The patient was evaluated for two MDR-1 gene polymorphisms, G2677T polymorphism in exon 21 and silent C3435T polymorphism in exon 26, to ascertain whether polymorphisms affect the risk of Hodgkin's lymphoma variant of Richter transformation and whether genomic polymorphisms provide prognostic information on the clinical progression of the disease. According to the data obtained, the analysis of polymorphisms in the MDR1 gene exons 21 and 26 revealed that the T2677T and T3435T alleles are not a predisposing factor to Richter transformation, while the presence of the wild-type genotype may be associated with a more favorable response to therapy.

Hodgkin Variant of Richter's Syndrome: Report of 34 Cases. A Role of EBV in Transformation.

Abstract 1550Poster Board I-573Richter's syndrome represents the clinico-pathologic transformation of chronic lymphocytic leukemia to an aggressive lymphoma, most commonly diffuse large B cell lymphoma. Hodgkin lymphoma variant of Richter transformation are extremely rare. EBV infection has been identified in the lymphoma cells in a few patients with Richter's syndrome. However, the precise role of EBV remains to be established and a causative relation between EBV and Richter's syndrome has not been proven yet. Evidence supports EBV infection in the Hodgkin variant of Richter's transformation. Once the Richter's transformation has occurred, the prognosis is poor. The median survival time with conventional chemotherapy is less than 12 months. The purpose of this study is to assess the presenting characteristics, rates of response and outcomes of patients with a low grade lymphoma who developed Hodgkin lymphoma. In this study, we retrospectively collected a total of 34 patients from distinct haematology centres in France. Presenting features included a male preponderance (74%). The median age at diagnosis of low grade lymphoma was 61.6 years (range, 28-85), that of Hodgkin lymphoma was 66,4 years (range, 28-89). The median time from low grade lymphoma diagnosis to Hodgkin transformation was 3.25 years (range, 0-16), and included 1 patient who presented with concomitant low grade and Hodgkin lymphoma. The propensity of CLL to transform into Hodgkin lymphoma (45% in our study), is shared by other indolent B-cell lymphoproliferative disorder, namely follicular lymphoma (21%), marginal zone lymphoma (9%), and others. Most patients (79%) had been previously treated for low grade lymphoma, including oral chemotherapy (chlorambucil, fludarabine, and cyclophosphamide), intravenous chemotherapy (RCHOP, Gemox), immunotherapy (Rituximab), radiotherapy and splenectomy. 30% of patients had received > 1 prior therapy for treatment of low grade lymphoma. Most patients presented a nodular sclerosis subtype of Hodgkin lymphoma (65%). Epstein-Barr virus status was positive in 70% of patients. Patients presented with B symptoms were 56%. 87% patients had advanced Hodgkin disease, including 44% stage IV disease. First-line treatment for Hodgkin lymphoma consisted of chemotherapy, ABVD for 64% of patients, MOPP/ABV-25% and BEACOPP-10%; a small number of patients (1%) received other cytotoxic regimen, including rituximab (RCHOP). The overall response rate was 85% (complete response rate : 72%). The median overall survival duration was 23 months (range, 4-75). Concerning relapse, 52% of patients relapsed, half with Hodgkin lymphoma. None of localized Hodgkin lymphoma relapsed.In conclusion, patients with the Hodgkin variant of Richter's syndrome generally present with a more advanced stage of disease than do patients with de novo Hodgkin disease. The rates of response and survival in patients with this variant were inferior to those reported in patients with de novo Hodgkin lymphoma, but better than those with classic Richter's syndrome. In addition this study shows a strong association with EBV indicating that it may play an important role in the pathogenesis of Hodgkin transformation. DisclosuresNo relevant conflicts of interest to declare.

Syndrome de Richter de type pseudohodgkinien. À propos de deux cas et revue de la littérature

We report the clinical and immunohistological features of two cases of chronic lymphocytic leukaemia (CLL) with Hodgkin's transformation. These cases occurred in a 70-year-old man with a three-year history of CLL and in a 76-year-old man with a few months history of CLL. Microscopic examination showed the presence of large tumor cells with the morphological and immunophenotypic features of classical Hodgkin and Reed-Sternberg (R-S) cells, in a background of otherwise typical B-CLL. The transformation of CLL into large B cell lymphoma (Richter's syndrome) is a well-documented phenomenon. Only rarely does CLL transform into Hodgkin's lymphoma, but this diagnosis is often easy and offers few differential diagnoses. The major points of interest lie in the pathogenetic relationship between CLL and Hodgkin's disease, and in the potential clinical implications of this peculiar condition. Literature on the subject indicates that identical IgH gene rearrangements in micromanipulated R-S and CLL cells have been identified in 7/12 cases. In these patients, the R-S and CLL cells belong to the same clonal population, suggesting a progression from the underlying CLL cells. This group appears to have a poor prognosis, identical to classical Richter's syndrome. In other cases, the R-S cells were often Epstein-Barr virus (EBV) positive and did not share the clonal rearrangements identified in CLL cells, suggesting that Hodgkin's disease in these patients could represent a second malignancy, EBV-related and favored by immunosuppression, associated with a better prognosis.

Hodgkin transformation of small lymphocytic lymphoma: gene usage, mutational status and clonal relationship

Hodgkin transformation of small lymphocytic lymphoma: gene usage, mutational status and clonal relationship

Hodgkin transformation of chronic lymphocytic leukemia

Hodgkin transformation is a rare complication of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). In this study, the authors assessed the incidence, presenting characteristics, and outcomes of patients with CLL/SLL who developed Hodgkin lymphoma (HL). An electronic database search of patients with CLL/SLL who presented at The University of Texas M. D. Anderson Cancer Center Department of Leukemia between 1975 and 2005 was performed. Among 4121 patients with CLL/SLL, 18 patients (0.4%) developed HL. Presenting features included B-symptoms (67%), lymph node enlargement (79%), splenomegaly (43%), hepatomegaly (29%), hypercalcemia (6%), infection (6%), and mental status changes (6%). The median age was 72 years (range, 49-81 years), and there was a male preponderance (78%). The median time from CLL to HL diagnosis was 4.6 years (range, 0-12.9 years). Fourteen patients (78%) had been previously treated for CLL/SLL. Ten patients (56%) had received >1 prior therapy. The median beta2-microglobulin level was 4.5 mg/L, and the median lactate dehydrogenase level was 610 IU/L. Epstein-Barr virus (EBV) was positive by in situ hybridization for EBV-encoded RNA in 3 of 4 tested patients. Fourteen patients (78%) received chemotherapy. The overall response rate was 44% (complete response rate, 19%). The median overall survival duration was 0.8 years (range, 0.03 years-6.7+ years). The median failure-free survival (FFS) duration was 0.4 years. The rates of response, survival, and FFS in patients with Hodgkin transformation of CLL/SLL were inferior to those reported in patients with de novo HL and were similar to those in patients with Richter syndrome.

Composite prolymphocytoid and hodgkin transformation of chronic lymphocytic leukemia.

The indolent course of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is occasionally altered by transformation to a histologically distinct, rapidly progressive, and clinically unresponsive hematologic malignant neoplasm. We report a case of CLL that, after 3 years of slowly progressive disease and treatment with single-agent chemotherapy (fludarabine phosphate), underwent a composite prolymphocytoid and classic Hodgkin lymphoma transformation. The diagnosis of classic Hodgkin lymphoma was based on the presence of Reed-Sternberg cells with typical morphologic structure and immunophenotype (CD15(+), CD30(+), CD45(-), CD20(-)) associated with the characteristic polymorphous inflammatory background consisting of numerous eosinophils, plasma cells, and reactive T lymphocytes. The remainder of the lymph node and the peripheral blood showed increased numbers of prolymphocytes admixed with typical small CLL cells. Recognition of such a transformation is of the utmost importance, since histologically similar Reed-Sternberg-like cells may be seen in Richter transformation. In contrast to prolymphocytoid transformation of CLL, Richter syndrome is rapidly fatal, with a median survival of 4 to 5 months. The patient pursued a clinical course similar to pure prolymphocytoid transformation and died with disease after 30 months following treatment with combination chemotherapy.