HHV-8-Negative, Idiopathic Multicentric Castleman Disease (iMCD): A Description of Clinical Features and Therapeutic Options through a Systematic Literature Review

Abstract Background: Multicentric Castleman disease (MCD) describes a heterogeneous group of poorly-understood diseases involving proinflammatory hypercytokinemia that ultimately results in systemic inflammatory symptoms, generalized lymphadenopathy, multiple organ system dysfunction, and even death. HHV-8 is responsible for driving MCD in immunosuppressed patients (HHV-8-associated MCD). There is also a cohort of HHV-8-negative MCD cases, referred to as idiopathic MCD (iMCD), in which the etiology remains unknown. No formal diagnostic criteria exist for iMCD, and knowledge is limited to small case series and case reports. Objectives: We conducted a systematic literature review to describe demographic, clinical, and laboratory features of iMCD as well as the treatments currently used in practice. Methods: PubMed was queried using a comprehensive list of terms to identify all published cases of HHV-8-negative MCD. Criteria for study inclusion were as follows: (1) Pathology-confirmed Castleman disease in multiple lymph nodes; (2) Exclusion of another cause of Castleman-like histopathology, such as SLE or POEMS syndrome; (3) Negative testing for HHV-8 via PCR of blood, PCR of lymph node tissue, serum serologies, and/or IHC for LANA-1; (4) Written in English and published from January 1995 to July 2013; and (5) Availability of specified minimum data elements. HIV-positive cases were excluded. Inclusion criteria were confirmed by three independent investigators, who also extracted data into a standardized database. Case report authors were contacted to gather additional data in a standardized case report form. Results: 3,428 articles were identified on PubMed. Initial evaluation for exclusion criteria yielded 1,951 MCD cases; 629 patients were HIV-positive (32%). Of the 999 HIV-negative and 323 HIV-unknown MCD cases, 626 were HHV-8 negative (32% of total MCD), 517 were HHV-8-unknown (26%), and 179 were HHV-8-positive (9%).129 cases of HHV-8-negative MCD met all inclusion criteria and were included in the final analysis. 58% were male and median age was 50 years (range: 2-80). Frequently reported clinical features included: fever (51/64), enlarged liver and/or spleen (45/60), pleural effusion (29/38), edema (26/36), and weight loss (21/29). There were 43 plasmacytic, 26 mixed, and 23 hyaline vascular cases out of 108 cases that reported histopathological subtype. The most commonly reported laboratory abnormalities included elevated CRP (70/79), anemia (76/90), hypergammaglobulinemia (63/82), hypoalbuminemia (57/63), elevated IL-6 (57/63), and positive ANA (14/38). Of cases with abnormal platelet levels, 28 had thrombocytopenia and 14 had thrombocytosis. There were 19 reported cases with elevated soluble IL-2R levels and 15 with elevated VEGF. 27 patients were diagnosed with a malignancy before (5), concurrently with (12), or after (10) diagnosis. Most commonly employed first line therapies included corticosteroid monotherapy (36%), combinations of cytotoxic chemotherapies (36%) that included regimens with cytoxan (17%) and rituxan (12%), and anti-IL-6 therapies, such as siltuximab and tocilizumab, without a cytotoxic agent (10%). Thalidomide, bortezomib, anakinra, and IVIG were used less frequently. Patients experienced no response (21%), partial response (42%), and complete response (37%) to first-line therapies. Failure (relapse, death, additional treatment) of first line therapy occurred in 41% of patients, and median time to treatment failure was 6 months. Overall, 22% of patients died by the time of most recent follow up (median: 28 months) with median length of survival among fatal cases being 26 months (range: 1-120). The most common causes of death were septic shock, multi-organ failure, including renal and cardiac, pulmonary complications, and malignancy. Conclusion: This study identified a significant proportion of MCD patients who are HIV-negative and HHV-8-negative (iMCD). 45% of patients did not demonstrate the plasmacytic variant alone, which has been classically associated with MCD. It is striking that 22% of patients died by the time of most recent follow up, which had a median length of 26 months. Despite the many limitations of analyzing case reports, this study provides the most comprehensive data on HHV-8-negative MCD to date. A global natural history study and Castleman disease registry are urgently needed to gather more extensive data on MCD. Disclosures Fajgenbaum: Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Cyclophosphamide, rituximab, tocilizumab, thalidomide, bortezomib, anakinra, and intravenous immunoglobulin will be presented as drugs used in HHV-8-negative MCD. It is very important to inventory the treatments that a physician has available when conventional therapies do not work, which is frequent in MCD. At the time that this data set was assembled, there were no FDA approved therapies for this orphan disease. van Rhee:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Plasmablastic Lymphoma: 28 Patient Single Institution Experience

Blood ◽

10.1182/blood.v122.21.4310.4310 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4310-4310 ◽

Cited By ~ 1

Author(s):

Krina Patel ◽

Lei Feng ◽

Yasuhiro Oki ◽

Muzaffar Qazilbash ◽

Tariq Muzzafar ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Early Stage ◽

Case Reports ◽

Stage I ◽

Hiv Positive ◽

Advisory Committees ◽

First Line Therapy ◽

Cd20 Expression ◽

Hiv Negative

Abstract Introduction Plasmablastic lymphoma (PBL) is a rare, aggressive subtype of non-Hodgkin lymphoma. Published data are predominantly in the form of case reports and small retrospective case series. Initial reports of PBL were described in HIV positive patients (pts) with disease in the oral cavity, and in pts after organ transplantation on immunosuppressive therapy. The natural history may have evolved recently, with case reports of PBL in immunocompetent patients. There is no established standard of care therapy, though HIV positive pts benefit from initiation of anti-retroviral therapy, tend to respond to chemotherapy, have historically been associated with CD20 expression, and have increased overall survival rates compared with HIV negative pts with PBL. We now describe our experience in pts with PBL who received treatment at the University of Texas MD Anderson Cancer Center (UTMDACC). Methods We conducted a retrospective analysis of pts diagnosed with PBL between August 2000 and August 2012. We evaluated the baseline demographics, stage, therapy, response rate, progression-free survival (PFS) and overall survival (OS). Results 28 pts (males n=23) with PBL were identified, with a median age of 51 (range 26-81). 10 patients had a diagnosis of HIV, and 15 were EBV positive. 7 pts had stage I disease, 2 had stage II, 1 had stage III and 18 had stage IV disease. The primary site of disease in the 7 pts with stage I disease was: 2 in the maxillary sinus, 2 in the nasal cavity, and 1 each in the colon, testicle, and lower jaw. 2 pts with stage II disease had primary sites in bowel and tonsils. 7/17 (41%) of HIV negative pts and 2/10 (20%) of HIV positive pts had stage I/II disease. The median LDH was 492 IU/L (313-618), median Ki-67 proliferation index was 85%, and all pathological samples were CD20 negative. Median follow up was 16 months (1-120). 27 pts received systemic therapy (1 pt elected hospice care). PBL was an initial cancer diagnosis for 25 pts who received the following as first line therapy: Hyper-CVAD (cyclophosphamide, vincristine, Adriamycin, dexamethasone alternating with methotrexate and cytarabine) (n=10), CHOP (cyclophosphamide, Adriamycin, vincristine, prednisone) (n=7), modified CVAD, 2 with EPOCH (etoposide, vincristine, cyclophosphamide, Adriamycin, prednisone) (n=4), bortezomib/dexamethasone (n=1), and the DeAngelis protocol (methotrexate, vincristine, procarbazine, with intrathecal methotrexate) (n=1) for CNS involvement. 2 pts had prior therapy for diagnosis of diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL) prior to diagnosis of PBL. The first pt with DLBCL was treated with Rituximab-hyper-CVAD 6 years earlier, and gemcitabine/oxaliplatin for the diagnosis of PBL. The second pt had CLL which underwent Richter's transformation to PBL, and was treated with hyper-CVXD (cyclophosphamide, vincristine, liposomal daunorubicin and dexamethasone). 1 pt underwent auto-stem cell transplant, while 8 pts received localized radiation (5 for consolidation and 3 for palliative therapy); 5/7 pts with stage I disease received consolidation with involved field radiation. After first line therapy, 20/27 patients (74%) achieved complete response, 5/27 (19%) partial response, and 2/27 (7%) stable disease. Median PFS and OS were 24.1 and 28.8 months, respectively. 5 year PFS and OS were 40% and 38%, respectively. Early stage disease (stage I or II) and younger age at diagnosis (less than 40 years old) were associated with improved survival. 5 year PFS for stage I/II pts was 90%. Conclusion 41% of HIV negative pts had stage I/II disease. Early stage PBL pts who received combined chemotherapy followed by radiotherapy achieved a good PFS of 90% at 5 years. PBL consistently lacked CD20 expression irrespective of HIV status. PBL can be seen in both HIV+ and HIV– patients with overall 40% long term survival. Disclosures: Qazilbash: Otsuka Pharmaceuticals: Research Funding. Fanale:Seattle Genetics, Inc.: Advisory/scientific board membership and travel expenses Other, Consultancy, Honoraria, Research Funding. Orlowski:Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene Corporation: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millenium Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Genentech: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Array Biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Membership on an entity’s Board of Directors or advisory committees.

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EBV+ HHV-8+ Multicentric Castleman Disease With Plasmablastic Aggregates in an HIV+ Man: An Evolving Clinicopathologic Entity

International Journal of Surgical Pathology ◽

10.1177/1066896917745584 ◽

2017 ◽

Vol 26 (4) ◽

pp. 338-341 ◽

Cited By ~ 3

Author(s):

Aditya Shivane ◽

Amy Pearce ◽

Nadia Khatib ◽

Mark E. F. Smith

Keyword(s):

Human Herpesvirus ◽

Cervical Lymphadenopathy ◽

Castleman Disease ◽

Hiv Positive ◽

Herpesvirus 8 ◽

Multicentric Castleman Disease ◽

Barr Virus ◽

Positive Individual ◽

Epstein Barr

We report a case of EBV+ and HHV-8+ multicentric Castleman disease with plasmablastic aggregates in an HIV-positive individual. A 41-year-old man presented in early 2015 with fevers, sweats, weight loss, intractable itching, and on subsequent testing was found to be HIV positive. Investigations showed cervical lymphadenopathy and splenomegaly. He was treated for HIV and his symptoms resolved. His symptoms recurred in January 2016, and a provisional diagnosis of multicentric Castleman disease was entertained. The HHV-8 (human herpesvirus-8) and EBV (Epstein-Barr virus) viral load was elevated. A left supraclavicular lymph node core biopsy was performed, which showed features of multicentric Castleman disease with plasmablastic aggregates that are EBV (EBER) and HHV-8 positive. He responded well to rituximab treatment and remains well with no symptoms at recent follow-up.

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A Longitudinal Population Level Analysis of Healthcare Resource Utilization, Comorbidity, and Survival in Idiopathic Multicentric Castleman Disease Patients

Blood ◽

10.1182/blood-2020-140449 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 11-11

Author(s):

Sudipto Mukherjee ◽

Rabecka Martin ◽

Brenda Sande ◽

Chad Glen ◽

Jeremy Paige ◽

...

Keyword(s):

Emergency Room ◽

Research Funding ◽

Hematologic Malignancies ◽

Healthcare Resource Utilization ◽

Castleman Disease ◽

Emergency Room Visits ◽

Advisory Committees ◽

Multicentric Castleman Disease ◽

Average Survival

BACKGROUND: Human herpesvirus-8-negative/idiopathic multicentric Castleman disease (iMCD) is a heterogenous group of diseases characterized by proinflammatory hypercytokinemic state with a wide range of systemic manifestations ranging from generalized lymphadenopathy to death in severe cases. Limited data has shown an increased prevalence of organ dysfunction and cancers in iMCD patients either as a result of underlying disease pathophysiology or treatment received. The objective of this study was to assess the healthcare resource utilization, patterns of iMCD-related comorbidities, and survival of iMCD patients in a real-world setting. METHODS: We performed a retrospective analysis of administrative claims data for >30 million United States patients continuously enrolled over a three-year study period from January 1, 2017 and December 31, 2019. Patients were identified as iMCD if they had an ICD-10 diagnosis code for Castleman disease (D47.Z2) and ≥2 diagnostic codes corresponding to the minor criteria from the international evidence-based consensus diagnostic criteria for iMCD. Exclusion criteria included history of HIV, HHV-8, lymphoma, myeloma, lupus, or rheumatoid arthritis within one year of diagnosis of Castleman disease. Index diagnosis date (IDD) was defined as the first time a patient received a diagnosis for Castleman disease using the new ICD-10 code (D47.Z2) or the general code for lymphadenopathy (785.6) in ICD-9 that included Castleman disease, whichever was diagnosed first between 2006 and 2019. Included patients were followed for up to 5 years from IDD and evaluated for post-diagnosis hospitalizations, emergency room visits, hematologic malignancies, non-hematologic malignancies, thromboses, and organ dysfunction. Estimated average survival was calculated based on estimated incidence and prevalence rates for the iMCD patient population, assuming a stable incidence. RESULTS: We identified 191 iMCD patients including 109 women (57%) and 82 men (43%) with a mean age of 51 years (range: 6 - 90). The average post-diagnosis follow up was 3.2 years after IDD (range: 0.3 - 14.1). Within the first year of iMCD diagnosis, 58.9% of patients required inpatient hospitalization and 53.4% had at least one emergency room visit. Among the patients who remained enrolled after the first year, an average of 25.1% were hospitalized and 36.1% visited the emergency room during each subsequent year (Table 1). The annual rate of hospitalizations and emergency room visits for the entire database of >30 million patients was 9.0% and 20.6%, respectively. As shown in Table 2, the annual prevalence of iMCD-related comorbidities in this cohort was 18.2% for non-hematologic malignancies, 6.3% for hematologic malignancies (including lymphomas and myelomas from second year follow up onwards), 5.8% for thromboses, 5.7% for renal failure, and 5.2% for respiratory failure. Based on an average annual incidence of 2.45 (95% CI, 0.85 - 8.60) per million and average prevalence of 6.31 (95% CI, 3.25 - 13.05) per million, we estimated an average survival of 2.57 (95% CI, 1.59 - 4.25) years after diagnosis in this study time period. DISCUSSION: Using a large nationally representative health claims database, we identified a cohort of iMCD patients and found a high rate of hospitalizations and emergency room visits in the first five years following diagnosis. The annual prevalence of iMCD-related organ failure was approximately 5-6% primarily involving renal and respiratory systems. This study provides further evidence to support the previously reported increase in frequency of subsequent hematologic and non-hematologic malignancies in iMCD patients. In the five-year follow up period, the average estimated survival of iMCD patients was 2.57 (95% CI, 1.59 - 4.25) years after diagnosis, which is shorter than previously published average survival durations based on academic medical centers. The worse survival in this cohort may represent iMCD survival outside of academic medical centers or may reflect inaccuracies in estimated incidence and prevalence which were used to estimate average survival. Further studies are needed to compare outcomes to age-matched controls and to determine whether these adverse outcomes are broadly seen across iMCD patients or instead attributable to a smaller subset of more severe cases. Disclosures Mukherjee: Bristol Myers Squib: Honoraria; Partnership for Health Analytic Research, LLC (PHAR, LLC): Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Aplastic Anemia and MDS International Foundation: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; EUSA Pharma: Consultancy; Celgene/Acceleron: Membership on an entity's Board of Directors or advisory committees. Martin:EUSA Pharma: Current Employment. Sande:EUSA Pharma: Current Employment. Glen:HVH Precision Analytics: Current Employment. Paige:HVH Precision Analytics: Consultancy. Yarlagadda:HVH Precision Analytics: Current Employment. Fajgenbaum:EUSA Pharma: Research Funding; Janssen Pharmaceuticals: Research Funding.

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HHV-8-negative, idiopathic multicentric Castleman disease: novel insights into biology, pathogenesis, and therapy

Blood ◽

10.1182/blood-2013-12-545087 ◽

2014 ◽

Vol 123 (19) ◽

pp. 2924-2933 ◽

Cited By ~ 171

Author(s):

David C. Fajgenbaum ◽

Frits van Rhee ◽

Christopher S. Nabel

Keyword(s):

Gene Mutations ◽

Castleman Disease ◽

Unknown Etiology ◽

Hiv Positive ◽

Human Herpes Virus 8 ◽

Multicentric Castleman Disease ◽

Disease Mechanisms ◽

Systemic Inflammatory Disease ◽

Criteria For Diagnosis ◽

Hiv Negative

Abstract Multicentric Castleman's disease (MCD) describes a heterogeneous group of disorders involving proliferation of morphologically benign lymphocytes due to excessive proinflammatory hypercytokinemia, most notably of interleukin-6. Patients demonstrate intense episodes of systemic inflammatory symptoms, polyclonal lymphocyte and plasma cell proliferation, autoimmune manifestations, and organ system impairment. Human herpes virus-8 (HHV-8) drives the hypercytokinemia in all HIV-positive patients and some HIV-negative patients. There is also a group of HIV-negative and HHV-8-negative patients with unknown etiology and pathophysiology, which we propose referring to as idiopathic MCD (iMCD). Here, we synthesize what is known about iMCD pathogenesis, present a new subclassification system, and propose a model of iMCD pathogenesis. MCD should be subdivided into HHV-8-associated MCD and HHV-8-negative MCD or iMCD. The lymphocyte proliferation, histopathology, and systemic features in iMCD are secondary to hypercytokinemia, which can occur with several other diseases. We propose that 1 or more of the following 3 candidate processes may drive iMCD hypercytokinemia: systemic inflammatory disease mechanisms via autoantibodies or inflammatory gene mutations, paraneoplastic syndrome mechanisms via ectopic cytokine secretion, and/or a non-HHV-8 virus. Urgent priorities include elucidating the process driving iMCD hypercytokinemia, identifying the hypercytokine-secreting cell, developing consensus criteria for diagnosis, and building a patient registry to track cases.

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Ibrutinib for Relapsed Mantle Cell Lymphoma after Standard First Line Therapy and ASCT Is Efficacious but Does Not Overcome the Impact of POD24 - a Retrospective Study from the LWP-EBMT

Blood ◽

10.1182/blood-2019-123442 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 701-701

Author(s):

Claire Burney ◽

Stephen Robinson ◽

Ariane Boumendil ◽

Hervé Finel ◽

Irma Khvedelidze ◽

...

Keyword(s):

Board Of Directors ◽

Inclusion Criteria ◽

First Line ◽

Advisory Committees ◽

First Line Therapy ◽

Line Therapy ◽

Mantle Cell ◽

Duration Of Response ◽

The Impact

Introduction Standard first line treatment for mantle cell lymphoma (MCL) in fit patients is induction with cytarabine containing chemo-immunotherapy and a consolidative autologous stem cell transplant (ASCT). Responses are excellent but there is a continuous pattern of relapse. Progression within 24 months (POD24) of standard first line therapy including ASCT has been shown to predict poorer outcomes, which may be ameliorated by alloSCT. Ibrutinib, a Bruton's Tyrosine Kinase inhibitor, is an effective therapy for relapsed MCL. However, there is a paucity of published data of ibrutinib's efficacy in patients treated at relapse after standard first line treatment with ASCT and very little regarding the impact of POD24 on outcomes after ibrutinib and outcomes of subsequent alloSCT. Methods This was a retrospective analysis of the EBMT registry. The inclusion criteria were: patients with MCL ≥18 years old, 1st line therapy containing cytarabine and rituximab, ASCT in first CR/PR between 2009 and 2016 and received ibrutinib for 1st relapse after ASCT. POD24 was defined as progressive disease in less than 24 months after ASCT. Results 66 patients met the inclusion criteria (Table 1) relapsing at a median of 25 months (range 15-33) post ASCT. Thirty-two patients progressed in less than 24 months after ASCT. Ibrutinib was started at a median of 30 days after relapse (range 10-54). Overall response rate (ORR) was 74% [32 (48%) achieving CR and 18 (27%) PR]. The median duration of response was 10.1 months (available for 28 patients). There were no significant differences in the duration of response to ibrutinib for patients with POD24 (median: 10.4 months, IQR 4.0-15.4) compared to POD after 24 months or more (POD≥24) [(median 9.8 months, IQR 6.5-20.7) p=0.9]. Relapse after/during ibrutinib occurred in 21 patients (33%) at a median of 12 months (range 1-34). 13 of those patients were on ibrutinib at the time of relapse and the remaining 8 after ibrutinib had been stopped for a SCT or because of toxicity. Ibrutinib therapy continues at last follow-up in 23 (35%) patients. Ibrutinib was stopped for the following reasons: 16 patients subsequent SCT, 13 relapse, 5 toxicity (cytopenia, infection, tachycardia, hepatitis and poor tolerance, 1 case each), 9 other/unknown reasons. Second SCT was undertaken in 23 patients (22 alloSCT, 1 ASCT), 16 of whom were in CR/PR after only ibrutinib at the time of relapse. For alloSCT recipients, the donor was MUD in 11, MSD in 5 and mismatch related in 6. The majority (n=19) had reduced intensity conditioning. 50% of the patients developed acute GvHD and 50% chronic GvHD (3 extensive). With a median follow up of 17 months post alloSCT, 18 (63%) are in remission. There were no significant differences in PFS (p=0.173) or OS (p=0.336) post alloSCT for patients with POD24 and POD≥24. At last follow up (median follow-up of 22 months after starting ibrutinib), 35 (71%) patients were in CR and 4 (8%) in PR. 17 patients have died; the most common reason was MCL (14 patients), 2 deaths were secondary to alloSCT toxicity and in 1 case the cause of death was unknown. 2-year OS after starting ibrutinib was 72% (69% for alloSCT patients) and 2-year PFS 62%. PFS after starting ibrutinib was significantly better for patients with POD≥24 compared to those with POD24 (72% vs. 53% at 2 years post ASCT, p=0.017) and this translated to an OS benefit (80% vs. 68% at 2 years post ASCT, p=0.019) (figures 1 and 2). Conclusion Ibrutinib therapy did not overcome the poor outcome for patients with POD24 after first line therapy and although there was a high ORR to ibrutinib the median duration of response is only 10.1 months. AlloSCT should therefore be undertaken if possible, in our retrospective cohort of patients it appeared to overcome the poor prognosis of POD24 patients. Disclosures Hunter: Jazz pharamceuticals: Honoraria, Other: speaker fees, Meeting attendance support; Novartis: Honoraria, Other: speaker fees; celegene: Other: Meeting attendance support. Peggs:Autolus: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Speakers Bureau. Foà:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees. Pillai:Celgene: Honoraria. Mufti:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Cellectis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Protective Effect of Rituximab Against Lymphoma Risk In HIV-Associated Multicentric Castleman Disease

Blood ◽

10.1182/blood.v116.21.2869.2869 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2869-2869

Author(s):

Jean Marie Michot ◽

Laurence Gérard, MD ◽

Claire Fieschi ◽

Sarah Burcheri ◽

Eric Oksenhendler ◽

...

Keyword(s):

Overall Survival ◽

Castleman Disease ◽

Control Group ◽

First Line ◽

Multicentric Castleman Disease ◽

Median Period ◽

History Of ◽

Lymphoma Risk

Abstract Abstract 2869 Human Immunodeficiency Virus (HIV)-associated multicentric Castleman disease (HIV-MCD) is a rare lymphoproliferative disorder occurring in patients co-infected with HHV-8. Long-term prognosis remains severe mainly because of the high incidence of aggressive HHV-8 associated non-Hodgkin lymphoma (NHL). Chemotherapy is usually the first line therapy in active HIV-MCD. Most patients remain dependent on chemotherapy. Recent studies have demonstrated that rituximab allows to resume chemotherapy in most patients. However, effect of rituximab on long-term incidence of lymphoma is unknown. All consecutive patients with HIV-MCD from the national HIV-lymphoproliferative cohort (Clinical site, Saint-Louis Hospital, Paris, France) were enrolled in combination antiretroviral therapy (cART) era. Patients with NHL within the 2 months prior or following rituximab were excluded from analysis. Patients treated with rituximab received 4 infusions, 375 mg per m2 at weekly intervals. Primary objective of the study was to compare incidence of NHL between patients who received rituximab (rituximab group) and who did not received rituximab (control group). Secondary objectives were to compare overall survival and to describe tolerance to rituximab. Survival and NHL incidence was estimated using Kaplan-Meier method and tested with log-rank test. 115 patients with HIV-MCD were included in the HIV-lymphoproliferative cohort until november, 2009. Patients were followed for a mean period of 3 years. 7 patients received rituximab as part of LNH therapy and were excluded from analysis. 33 patients (29%) received rituximab as part of MCD therapy. In rituximab group at MCD diagnosis, mean age was 41 years, 24 patients (73%) received antiretroviral therapy, HIV viral load was undetectable (< 500 c/ml) in 10 patients (30%), median CD4 cell count was 233 × 106/L [IQR, 101–368], median nadir CD4 was 160 × 106/L [IQR, 61–194], 14 patients (42%) had an history of Kaposi sarcoma (KS) before rituximab therapy, which was in complete remission or stable at time of rituximab therapy. All 33 patients received chemotherapy as first line MCD treatment: etoposide (n=27), vinblastine (n=4), anthracyclines (n=2). The median period from MCD diagnosis to rituximab therapy was 7.7 months [IQR, 4.6–23.8]. All but 2 patients received the 4 scheduled infusions. These 2 patients discontinued rituximab after the second infusion; one died at day 15 from progressive MCD and the other one discontinued for investigation of rectal tumor. 4 patients received a second course of 4 rituximab infusions for MCD relapse, after a median period of 19.5 months (IQR, 15 to 23). The 3-years probability of developing lymphoma was 0.04% [95%CI,0.01-0.99] in rituximab group (n=33) and 23% [95%CI,14-34] in control group (n=74) (P=0.001). The only lymphoma in rituximab group occurred 22 months after rituximab therapy and patient died. In rituximab group, the median overall survival was 15.7 years compared to 5.2 years in control group (P=0.0007). During total follow-up, 5 patients (15%) died in rituximab group and 28 patients (38%) died in control group. Causes of death in rituximab group was MCD attack (n=1), lymphoma (n=1), acute myeloid leukemia (n=1), infection (n=1), cardiovascular disease (n=1). No severe adverse event was observed during rituximab infusions. Within the first year following rituximab therapy, 9 patients (27%) developed mild to moderate infections; pneumonia (n=2), herpes reactivation (n=2), enterocolitis (n=2), dacryocystitis (n=1), folliculitis (n=1), staphylococcus catheter-related infection (n=1). Transient grade 3 neutropenia occurred in 2 patients (6%). Exacerbation of KS was observed in 4 out of the 15 patients with prior history of KS (4, 4, 7, 36 months after rituximab therapy, respectively), and required specific treatment in 2 patients. Despite improvement in overall survival of HIV-MCD in cART era, risk for developing lymphoma remains high (23% at 3 years). Rituximab seems to induce long-term protection against lymphoma risk, with only one patient developing lymphoma during the 3-year follow-up period in our cohort. Disclosures: No relevant conflicts of interest to declare.

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Improved outcome with rituximab in patients with HIV-associated multicentric Castleman disease

Blood ◽

10.1182/blood-2011-02-333633 ◽

2011 ◽

Vol 118 (13) ◽

pp. 3499-3503 ◽

Cited By ~ 50

Author(s):

Christian Hoffmann ◽

Holger Schmid ◽

Markus Müller ◽

Christian Teutsch ◽

Jan van Lunzen ◽

...

Keyword(s):

Overall Survival ◽

Antiviral Agents ◽

Castleman Disease ◽

Cytostatic Agents ◽

First Line ◽

Multicentric Castleman Disease ◽

Remission Rates ◽

Potential Risk Factors ◽

The Mean

Abstract Although HIV-associated multicentric Castleman disease (HIV-MCD) is not classified as an AIDS-defining illness, mortality is high and progression to lymphoma occurs frequently. At present, there is no widely accepted recommendation for the treatment of HIV-MCD. In this retrospective (1998-2010), multicentric analysis of 52 histologically proven cases, outcome was analyzed with respect to the use of different MCD therapies and potential prognostic factors. After a mean follow-up of 2.26 years, 19 of 52 patients died. Median estimated overall survival (OS) was 6.2 years. Potential risk factors, such as older age, previous AIDS, or lower CD4 T cells had no impact on OS. Treatment was heterogeneous, consisting of cytostatic and/or antiviral agents, rituximab, or combinations of these modalities. There were marked differences in the outcome when patients were grouped according to MCD treatment. Patients receiving rituximab-based regimens had higher complete remission rates than patients receiving chemotherapy only. The mean estimated OS in patients receiving rituximab alone or in combination with cytostatic agents was not reached, compared with 5.1 years (P = .03). Clinical outcome and overall survival of HIV-MCD have markedly improved with rituximab-based therapies, considering rituximab-based therapies (with or without cytostatic agents) to be among the preferred first-line options in patients with HIV-MCD.

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Evolving Unmet Need in Patients Refractory to Lenalidomide: Overview of the Clinical Trials in Relapsed/Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2020-142642 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 22-23

Author(s):

Maria-Victoria Mateos ◽

Rohan Medhekar ◽

Istvan Majer ◽

Mehmet Turgut

Keyword(s):

Multiple Myeloma ◽

Clinical Trials ◽

Literature Review ◽

Board Of Directors ◽

Unmet Need ◽

Publicly Traded ◽

First Line ◽

Advisory Committees ◽

Line Of Therapy

Introduction: The majority of newly diagnosed multiple myeloma (NDMM) patients are currently treated with lenalidomide-based regimens as their first line of therapy. This trend is likely to continue in the coming years. Typically, lenalidomide is administered until disease progression and has significantly contributed to better outcomes in these patients. However, most patients relapse, and prognosis worsens with each relapse. The choice of optimal treatment for patients who relapse while receiving lenalidomide as first line of therapy is unclear. Moreau et al (Blood Cancer J. 9, 38 [2019]) concluded that there is limited data on approved combinations for treating these patients and are restricted by the low number of lenalidomide-refractory patients enrolled in the pivotal trials. Results from the ongoing clinical trials of the combination of carfilzomib and anti-CD38 antibodies were not available at the time of the Moreau et al publication. The aim of this targeted literature review was to include this new data and to summarize currently available evidence on progression-free survival (PFS) for the treatment of RRMM patients who progressed on lenalidomide-based regimens. Methods: A targeted literature review was conducted to identify registrational clinical trials in patients with RRMM reporting PFS outcomes. PubMed, congress proceedings, and product labels were searched between Jan 2014 to July 2020. In addition to PFS, demographic, disease characteristics and treatment history were extracted for the trial populations to contextualize potential variations in study outcomes. The regimens studied in these trials were classified as lenalidomide-based, proteasome inhibitor (PI)-based and pomalidomide-based. Number of prior lines of therapy, prior exposure and refractoriness to lenalidomide and bortezomib were reported. Results: Twelve registrational trials were identified based on the search criteria (Table 1). Most pivotal trials assessing lenalidomide-based regimens (POLLUX, ELOQUENT-II, TOURMALINE-MM1) except the ASPIRE trial excluded patients who were refractory to lenalidomide. Trials evaluating PI-based regimens (e.g., CANDOR) or pomalidomide-based regimens (e.g., OPTIMISMM) included these patients, with more recent studies enrolling a larger proportion. Percentage of lenalidomide-exposed (and lenalidomide refractory) ranged from 40% (32%) in CANDOR to 98% (90%) in ELOQUENT III. These studies also enrolled a larger proportion of patients who were bortezomib-exposed, although most of these patients were at first relapse, with the exception of ELOQUENT III and ICARIA where most patients were at third relapse. Among lenalidomide-refractory patients, the median-PFS (mPFS) observed for the pomalidomide-based regimens ranged from 9.5 to 10.1 months and that observed for PI-based regimens ranged from 4.9 to 25.7 months. PFS in the lenalidomide-refractory subgroup was considerably shorter than in the ITT population. The mPFS for patients receiving carfilzomib/daratumumab/dexamethasone (KDd; CANDOR) and isatuximab/carfilzomib/dexamethasone (IsaKd; IKEMA) was not reached at median follow-up of 16.9 and 20.7 months respectively. While the mPFS for (KDd) for lenalidomide-refractory patients in CANDOR trial was not yet reached at median follow up of 16.9 months; the mPFS of 25.7 months for KDd in the MMY-1001 trial appears to be the longest among the assessed regimens. Conclusion: Patients refractory to lenalidomide have shorter PFS and represent a population with high unmet need. This targeted literature review suggests that the PI-based KDd regimen provides longer PFS compared to other lenalidomide-sparing regimens in lenalidomide-refractory populations. Heterogeneity across trial populations may limit the comparability of these treatments. Disclosures Mateos: Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; PharmaMar-Zeltia: Consultancy; GlaxoSmithKline: Consultancy. Medhekar:Amgen Inc.: Current Employment, Current equity holder in publicly-traded company. Majer:Amgen (Europe) GmbH: Current Employment, Current equity holder in publicly-traded company.

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Clinical and Biological Characteristics and Outcomes of Richter Transformation : A French Multicenter Study from the Filo Group

Blood ◽

10.1182/blood-2019-128053 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4112-4112

Author(s):

Charline Moulin ◽

Romain Morizot ◽

Thomas Remen ◽

Hélène Augé ◽

Florian Bouclet ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Intermediate Risk ◽

Line Treatment ◽

First Line ◽

Advisory Committees ◽

Long Term Survivors ◽

First Line Treatment

Introduction: About 2 to 10% of patients (pts) diagnosed with Chronic Lymphocytic Leukemia (CLL) develop diffuse large B-cell lymphoma (DLBCL, so-called Richter transformation (RT)) over long-term follow-up. The outcomes of pts with RT are variable and poorly understood and there is no consensus on the best therapeutic approach. The aim of this study was to analyze the clinical characteristics, outcomes and factors predictive of survival in a large series of RT from the French Innovative Leukemia Organization (FILO). Methods: Biopsy-confirmed RT (limited to DLBCL and excluding Hodgkin lymphoma) diagnosed from 2001 to 2018 were identified from eight FILO centers. Clinical and biological characteristics of CLL and RT at diagnosis, including cytogenetics, clonal relation with the pre-existing CLL, Epstein-Barr virus (EBV) status, cell of origin (COO) analyzed by immunohistochemistry and RT score (Tsimberidou AM et al, J Clin Oncol, 2006) were analyzed as well as treatment and outcomes. Overall survivals (OS) were defined as time from CLL and RT diagnosis to death from any cause and analyzed using the Kaplan-Meier method. Statistical analyses were performed with SAS version 9.4. Results: A total of 70 CLL pts who developed RT were identified. The median age at CLL diagnosis was 62 years old (range 35-82), and 50 (71.4 %) were male. The median time to transformation was 5.5 years (range 0 to 22 years), with 12 simultaneous diagnosis of CLL and RT. Prior to RT, 20 (29%) pts had not been treated for CLL, 50 received one (n=21) or more (n= 29) line of treatment ; 6 pts had received a novel agent (ibrutinib, idelalisib or venetoclax). The median age at RT diagnosis was 68 years old (range 42-88). All biopsies were centrally reviewed; 38/58 pts (66%) had elevated LDH (>1.5N) ; 35/65 pts (54 %) had bulky disease (≥ 5 cm); 10/54 (18.5%) pts had del(17p) or TP53 mutation ; 9/42 pts (21%) had a complex karyotype (at least 3 abnormalities). The CLL and RT were clonally related in 27/27 (100%) tested pts. COO by Hans algorithm was non germinal center B cell-like (GCB) in 26/28 pts (93%). EBV was positive or detected in 5/40 (12.5%) pts. The median of Ki67 positivity was 70% (range 30% to 100%). The RT score (based at RT diagnosis on ECOG performance status 2-4, LDH >1.5 x normal, platelets<100 x 109/L, tumor size >5 cm and >1 prior therapy for CLL) was : low risk in 17 pts (31%), low-intermediate risk in 10 pts (19%), high-intermediate risk in 14 pts (25%) and high risk in 14 pts (25%). The most common first-line treatment of RT was immunochemotherapy (n=57, 87%) including R-CHOP-like regimen (n=48, 73%). Autologous or allogeneic transplantation was performed for 7 pts (11%). Response to first-line treatment was complete or partial response in 26 pts (40%), and stable disease or progression in 39 pts (60%). After a median follow-up of 8 years, 51/64 pts (80%) have died. The main causes of death were progressive DLBCL (n=36, 71%), infection (n=8, 16%) or progressive CLL (n=2, 4%). The median OS of the cohort from CLL and RT diagnosis (Figure 1) were 7.8 years and 9.5 months, respectively. In univariate analysis, patients with TP53 disruption at CLL stage, low platelets count, elevated LDH, elevated beta2-microglobulin, high ECOG score, high RT score, EBV positivity and absence of response to first-line RT treatment had worse OS. The ECOG score, platelets count and TP53 disruption remain significant in multivariate Cox-regression. Last, we compared the clinical and biological parameters of two Richter groups defined as: (i) short-term survivors (<12 months, n = 34) and (ii) long-term survivors (>48 months, n = 18). Long survival was significantly associated with elevated platelets count, low LDH, low ECOG, low RT score and response to RT first-line treatment. Discussion: The clinical outcomes of RT patients is poor and novel treatment options are needed. However, a group of long-term survivors was identified, characterized by elevated platelets count, low LDH, low ECOG, low RT score and response to immunochemotherapy. Disclosures Leblond: Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Cymbalista:Janssen: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria; Sunesis: Research Funding; Roche: Research Funding; Abbvie: Honoraria. Guièze:Abbvie: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Roche: Honoraria. Broseus:Janssen: Honoraria; Gilead: Honoraria; Novartis: Research Funding. Feugier:gilead: Honoraria, Research Funding, Speakers Bureau; janssen: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau.

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Radioimmunotherapy for Mantle Cell Lymphoma: 5-Year Follow-up of 90 Patients from the International RIT-Registry

Blood ◽

10.1182/blood-2019-124192 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5263-5263

Author(s):

Karin Hohloch ◽

Christine Windemuth-Kieselbach ◽

Pier Luigi Zinzani ◽

Roberto E. Cacchione ◽

Wojciech Jurczak ◽

...

Keyword(s):

Follicular Lymphoma ◽

Mantle Cell Lymphoma ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Primary Therapy ◽

First Line ◽

Advisory Committees ◽

Mantle Cell

To assess the efficacy of radioimmunotherapy (RIT) with 90yttrium-ibrutinib-tiuxetan (90Y-IT) in mantle cell lymphoma, data from 90 patients registered in the RIT Network with a median follow-up (FU) of 5.5 years after RIT were evaluated. 90Y-IT was given as first-line therapy in 45 (50%) (consolidation 44 pts., primary therapy 1 pt.) and at relapse in 45 (50%) patients (consolidation 24 pts., recurrence 12 pts., therapy refractory 3 pts., conditioning 2 pts., other 4 pts.). As a first-line treatment, 30 patients (pts.) (67%) achieved CR, 10 pts. (22%) PR%., 1 pt. (2%) PD, and for 4 pts. (9%) no response data was available. At relapse, CR was achieved in 17 pts. (38%), PR in 6 pts. (13%), SD in 2 pts. (4%), and 6 pts. (13%) had PD, while the response was not documented for 14 pts. (31%). After a median FU of 5.5 years, median PFS for all patients was 2.11 (95%CI: 1.03-2.32) years, and median OS was 4.05 (95%CI 2.79-7.21) years. Eleven pts. (12.2%) developed second malignancy. In conclusion, this is the largest report of MCL pts. treated with 90Y-IT to date. 90Y-IT was most often used as consolidation after first- and second-line chemotherapy and may improve the results achieved using chemoimmunotherapy alone. However, the results are less encouraging compared to treatment with small molecules such as ibrutinib. Disclosures Zinzani: TG Therapeutics: Honoraria, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy. Jurczak:Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Roche: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bayer: Research Funding; Gilead: Research Funding; MorphoSys: Research Funding; Incyte: Research Funding; Novo Nordisk: Research Funding; Servier: Research Funding; TG Therapeutics: Research Funding; Celtrion: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Truemper:Seattle Genetics, Inc.: Research Funding; Takeda: Consultancy, Research Funding; Roche: Research Funding; Nordic Nanovector: Consultancy; Mundipharma: Research Funding; Janssen Oncology: Consultancy. Scholz:Janssen-Cilag: Consultancy; Hexal: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Pfizer: Speakers Bureau; Roche: Consultancy; GILEAD: Consultancy, Speakers Bureau; Daiichi Sankio: Consultancy. OffLabel Disclosure: Yttrium 90 (90Y) Ibritumomab Tiuxetan (Zevalin) is approved for treatment of patients with relapsed follicular lymphoma and as consolidation therapy after chemo(immuno)therapy of patients with follicular lymphoma.

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