Cyclophosphamide, Doxorubicin, Vincristine And Prednisolone Research Articles

Targeted agents plus CHOP compared with CHOP as the first-line treatment for newly diagnosed patients with peripheral T-cell lymphoma (GUIDANCE-03): an open-label, multicentre phase 2 clinical trial

Peripheral T-cell lymphoma (PTCL) is a heterogeneous disease with dismal outcomes. We conducted an open-label, phase 2 nonrandomised, externally controlled study to evaluate the efficacy and safety of targeted agents plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) (CHOPX) for PTCL in the front-line setting. Eligible patients were ≥18 years of age and newly diagnosed PTCL. Patients in the CHOPX group received standard CHOP at Cycle 1. Specific targeted agents were added from Cycle 2, decitabine if TP53 mut, azacytidine if TET2/KMT2D mut, tucidinostat if CREBBP/EP300 mut, and lenalidomide if without mutations above. Patients in the CHOP group received CHOP for 6 cycles. The primary endpoint was the complete response rate (CRR) at the end of treatment (EOT). Secondary endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. The study was registered with ClinicalTrials.gov, NCT04480099. Between July 29, 2020, and Sep 22, 2022, 96 patients were enrolled and included for efficacy and safety analysis with 48 in each group. The study met its primary endpoint. CRR at EOT in the CHOPX group was superior to the CHOP group (64.6% vs. 33.3%, OR 0.27, 95%CI 0.12-0.64; p=0.004). At a median follow-up of 24.3 months (IQR 12.0-26.7), improved median PFS was observed in the CHOPX group (25.5 vs. 9.0 months; HR 0.57, 95%CI 0.34-0.98; p=0.041). The median OS was similar between two groups (not reached vs. 30.9 months; HR 0.55, 95%CI 0.28-1.10; p=0.088). The most common grade 3-4 hematological and non-hematological adverse events in the CHOPX group were neutropenia (31, 65%) and infection (5, 10%). Targeted agents combined with CHOP demonstrated effective and safe as first-line treatment in PTCL. Biomarker-driven therapeutic strategy is feasible and may lead to promising efficacy specifically toward molecular features in PTCL. This study was supported by the National Key Research and Development Program (2022YFC2502600) and the General Program of the Shanghai Municipal Health Commission (202040400).

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Peripheral T-cell lymphoma (PTCL) is a heterogeneous disease with dismal outcomes. Standard CHOP (Cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy is still the most widely used regimen for front-line management. To explore new targeted drugs in PTCL, we conducted a phase 2, multi-center, non-randomized clinical trial, comparing the efficacy and safety of targeted agents combined with CHOP (CHOPX) with CHOP in newly diagnosed patients with PTCL. Methods: The primary outcome was complete response rate (CRR) at the end of treatment (EOT). Patients with newly diagnosed PTCL had enough tumor tissue for next generation sequencing (NGS) and were assigned to CHOPX and CHOP group based on investigators’ discretion. Patients in CHOPX group received intravenous cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 (up to a maximum of 2 mg) on day 1, and oral prednisone 60 mg/m2 (up to a maximum of 100 mg) on day 1–5 every 21 days at the first cycle. X (i.e., targeted agent) was added from the second to sixth cycles as following, intravenous decitabine 10 mg/m2 on day -5 to -1 if with TP53 mutation. Subcutaneous azacytidine 100 mg on day −7 to −1 if with TET2/KMT2D mutation. Oral chidamide 20 mg on day1, 4, 8, 11 if with CREBBP/EP300 mutation. Oral lenalidomide 25 mg on day 1–10 if without above mutations. Patients in control group received standard CHOP regimen for 6 cycles. Analysis of efficacy and safety was of the intent-to-treat population. The study was registered with ClinicalTrials.gov, number NCT04480099. Results: Between 20 June 2020 and 22 September 2022, 108 patients were assessed for eligibility in the study. Ten patients met exclusion criteria and 2 patients withdrew informed consent before treatment. Forty-eight patients in the CHOPX group and 48 patients in the CHOP group were included into intent-to-treatment population. Baseline patient characteristics like age, gender, Ann Arbor stage, performance status, prognostic risk group was comparable between CHOPX and CHOP groups. The most common pathological subtypes were angioimmunoblastic T-cell lymphoma (67% vs. 60%), PTCL-not otherwise specified (17% vs. 21%), anaplastic T-cell lymphoma (6% vs. 8%) in the CHOPX and CHOP groups. As of 1 February 2023, 91 patients completed response evaluation at EOT. CRR in the CHOPX group was higher than the CHOP group (58% [25/43] vs. 33% [16/48]). The most common grade 3–4 hematological adverse events in CHOPX group were neutropenia (61%) and febrile neutropenia (27%). Conclusions: Preliminary analysis showed targeted agents combined with CHOP was effective and safe compared with standard CHOP in PTCL. Therapeutic strategy specifically towards molecular features may change current PTCL management in front-line setting. Keywords: combination therapies, molecular targeted therapies No conflicts of interests pertinent to the abstract.

Signet ring cell-like diffuse large B-cell lymphoma involving the breast: a case report

BackgroundDiffuse large B-cell lymphoma (DLBCL) with signet ring cell components is extremely rare. Here, we present a case of DLBCL with signet ring cell components involving the breast, which can be easily confused with invasive lobular carcinoma of the breast or metastatic signet ring cell carcinoma of gastrointestinal origin.Case presentationA 66-year-old woman presented with a painless mass in her left breast. Enhanced magnetic resonance imaging (MRI) of the breast revealed a 42 × 29 × 28 mm mass in the left breast. Histological examination revealed a diffuse or scattered arrangement of round cells mixed with signet ring-like cells. Immunohistochemically, the neoplastic cells were positive for PAX-5, CD79a, CD20, Bcl-6, and MUM-1 but and negative for cytokeratin, ER, PR, E-cadherin, and P120. The Ki-67 proliferation index was approximately 70%. Fluorescence in situ hybridisation (FISH) demonstrated non-rearrangement of Bcl-2, Bcl-6, and c-MYC genes. Immunohistochemistry and FISH examination confirmed the diagnosis of DLBCL. Subsequently, immunofluorescence showed both IgM and IgG deposits in the signet ring-like lymphocytes. After confirming the diagnosis, the patient received four courses of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy in a specialist hospital and achieved partial remission; however, she unfortunately died of secondary pneumocystis pneumonia infection 3 months later.ConclusionMalignant lymphoma with signet ring cell morphology is quite uncommon, and this variant can be a diagnostic pitfall. We emphasise that pathologists should consider lymphoma in the differential diagnosis of malignant breast tumours.

64 HIGH-DOSE STEROIDS IN HAEMATOLOGICAL MALIGNANCY: A RED FLAG FOR BONE HEALTH

Abstract Background Bone-protective treatment should always be considered when commencing glucocorticoid therapy in individuals at high risk of fracture, as outlined in recent guidelines (National Osteoporosis Guideline Group, July 2018). Despite this, many patients receive high dose glucocorticoids (>7.5mg/kg/day or equivalent for >3 months) during treatment of haematological malignancy without formal assessment of bone health. Methods Twenty-five patients with Non-Hodgkin’s Lymphoma (NHL) on high dose steroid chemotherapy protocols were retrospectively assessed. The inclusion criterion was defined as any patient commenced on a cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) containing protocol from 1/8/2020 to 1/8/21. Data was collected from electronic and written patient records. Information regarding patient age, diagnosis, steroid preparation and dose, presence of risk factors for osteoporosis and calcium and vitamin D prescriptions were collected. Radiological imaging was reviewed to assess for the occurrence of fragility fractures. Each patient had a FRAX® score calculated to assess fracture risk. Results The mean age of patients studied was 67 years and equally distributed between males and females. All patients had NHL. 32% (n=25) of patients were identified to be at high risk for fracture (FRAX® score >20% ten-year probability of major osteoporotic fracture). 16% had already established fragility fractures prior to commencing steroid treatment. 28% of patients were females over the age of 70 years. Only 12% of patients received vitamin D and calcium supplementation. No patient commenced bone protection therapy. Conclusion Omission of bone health assessment prior to high dose glucocorticoid treatment is prevalent in haematological malignancy and places patients at risk of significant morbidity. Patients are not routinely considered for protective measures including calcium and vitamin D supplementation and bone protection therapy. A simple risk-assessment tool and education to staff and patients prior to glucocorticoid therapy could significantly improve practice in this area. It is now planned to introduce routine risk assessment for this cohort of patients, with re-audit following implementation.

Cepp in Previously Untreated Patients with Mature T Cell Lymphomas

▪IntroductionThere is currently no standard of care for the upfront management of patients with mature T cell non-Hodgkin lymphomas (T-NHL). The role of anthracyclines in the treatment of T-NHL remains unclear and is also associated with significant toxicity. CEPP (cyclophosphamide, etoposide, procarbazine, and prednisone), a non-anthracycline regimen, is an effective salvage regimen for relapsed/refractory NHL and has shown a favourable toxicity profile. Since 2005, CEPP has been used in Singapore in the upfront treatment of T-NHL patients either with a contraindication to anthracyclines or at physicians' discretion. Our study aimed to assess the efficacy of CEPP in the upfront treatment of T-NHL.MethodsA retrospective study of all patients with newly diagnosed T-NHL treated with CEPP with curative intent from 2005-2021 was undertaken across 2 national cancer centers in Singapore. Outcomes of this population was also compared with a 1:1 control group treated with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) in the same time period, and matched for age, T-NHL subtype, clinical stage and international prognostic index (IPI). Patient demographics, disease characteristics and clinical outcomes (progression free survival, PFS and overall survival, OS) were evaluated. None of the patients had upfront autologous transplantation.ResultsWe identified 34 patients treated with CEPP who met the inclusion criteria. Clinical characteristics were as follows: Median age was 71 (range 39-85), 24 (71%) were male, 26 (76%) had advanced disease (Stage III-IV) and 21 (62%) had a high intermediate or high risk IPI ( IPI 3, 14 (41%) and IPI 4-5, 21 (21%)). The most common T-NHL subtypes were peripheral T-NHL (PTCL-NOS) not otherwise specified, 11 (32%) as well as angioimmunoblastic T cell lymphoma (AITL), 16 (47%). At a median follow up of 20 months (range 2-197months), the median PFS and OS were 17.6mths and 37.2mths respectively for the CEPP group. 15/34 (44%) CEPP patients have died (8 with lymphoma, 2 from treatment toxicity and 5 from unrelated causes). In the matched control comparison, the 5yr PFS and OS were both similar for patients treated with CEPP compared to patients in the CHOP control group, PFS 30% vs 32%, p= 0.43 and OS 47% vs 52%, p = 0.32, respectively (Figure 1)ConclusionOur findings show that CEPP is a well-tolerated regimen which can cure a proportion of patients with T-NHL even without autologous transplantation consolidation. Outcome of these patients do not seem to be significantly different compared to a similar population treated with standard CHOP. This study supports CEPP as a tolerable treatment option for selected patients who cannot tolerate anthracyclines and as an alternative to CHOP regimen for older patients who are not planned for ASCT. [Display omitted] DisclosuresJeyasekharan: Turbine Ltd: Consultancy; Janssen: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Perkin Elmer: Other: travel funding ; MSD: Consultancy.

Diagnosis and Management of Diffuse Large B Cell Lymphoma in Resource Constraint Settings: Society of Medical Oncology Pakistan, Pakistan Society of Haematology and Pakistan Society of Clinical Oncology Joint Clinical Practice Guideline

Purpose: To provide evidence-based recommendations for health care professionals on diagnosis and management of diffuse large B cell lymphoma (DLBCL) in resource constraint settings with variable and often limited access to standard of care and advanced diagnostic and therapeutic facilities.Methods: Modified Delphi methodology[1] was used to generate consensus by experts of three major cancer societies of Pakistan; namely Society of Medical Oncology Pakistan (SMOP), Pakistan Society of Hematology (PSH) and Pakistan Society of Clinical Oncology (PSCO). Guidelines questions were drafted and meetings were convened by steering committee to develop initial recommendations based on local challenges and review of the literature. Consensus panel reviewed the initial draft recommendations and rated the guidelines on five-point Likert scale; recommendations achieving more than 75% consensus were accepted. Resource grouping initially suggested by Breast Health Global Initiative[2] was applied for resource stratification into basic, core and enhanced resource settings.Results: The expert panel advised use of limited immunohistochemistry (IHC) including CD20, CD3 and Ki67% for initial diagnosis in core (limited) resource settings and extended panel in enhanced resources. Cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) with or without rituximab (as per resource setting) remains the standard first line treatment while second line treatment should be offered based on resource availability and patient related factors. Both intra thecal and high dose methotrexate can be used for CNS prophylaxis. Recommendations by guideline committee are listed in Table 1.Conclusion: Diagnosis and treatment recommendations in resource constraint settings should be developed based on available diagnostic, therapeutic resources and management expertise.

Tre-P-26 - Cutaneous and systemic lymphomas of concordant or discordant B- and T-cell phenotype in the same patient: two case reports

<h3>Background:</h3> The development of two different non-Hodgkin lymphomas in the same patient is an unlikely coincidence due to the low prevalence of each malignancy. However, a significantly increased risk of developing a second lymphoma was observed in patients with cutaneous T-cell lymphoma (CTCL) in both population-based and clinic-based data [1]. Most cases reported describe the occurrence of concomitant lymphomas of discordant B- and T-cell phenotypes, mainly MF and chronic lymphocytic leukemia [2]. On the opposite, few cases of concomitant systemic and cutaneous B-cell lymphomas have been reported [3,4]. <h3>Case 1:</h3> A young woman with the diagnosis of three B-cell lymphomas. At 37 years-old, primary cutaneous marginal zone lymphoma (pcMZL) was diagnosed on a right cervical cutaneous nodule and relapsed 3 years later on the temporal region; both lesions were excised. One year later, diffuse large B-cell lymphoma (DLBCL) diagnosis was made on an isolated cervical right lymphadenopathy. She was staged as Ann Arbor stage I and treated with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) regimen for 6 cycles with complete response (CR). Two years later, the diagnosis of follicular lymphoma was made on a lymph node biopsy. The patient remained with asymptomatic cervical and inguinal lymph node enlargement for 10 years until extra-nodal involvement ensued. At that time, treatment with R-FC (rituximab-fludarabine and cyclophosphamide) followed by radiotherapy achieved partial response (PR). In the following 3 years, follicular lymphoma progressed twice and was retreated with radiotherapy with PR. After 5 years of follow-up, the patient remains asymptomatic without further treatment. <h3>Case 2:</h3> A patient with two lymphomas of discordant phenotype. The 51 years-old Caucasian man presented at our dermatology clinic with a 10-years history of cutaneous erythematous patches and plaques on the abdomen and upper limbs. The 3 cutaneous biopsies made were consistent with the diagnosis of mycosis fungoides and workup excluded systemic involvement. As such, a diagnosis of mycosis fungoides (MF) stage IB was made. The patient had been observed on another hospital facility 3 months before, when he presented bilateral inguinal lymph node enlargement. The excisional biopsy revealed follicular lymphoma but the pathology examination review of the sample at our hospital diagnosed DLBCL, non-germinal center type, that was staged as Ann Arbor II. He started chemoimmunotherapy with R-CHOP regimen for 6 cycles, leading to CR and a mild improvement on MF (downstaging to IB). The patient is currently on topical steroids for MF and DLBC lymphoma is still on remission after 1 year of follow-up. <h3>Conclusions:</h3> The occurrence of concomitant systemic and cutaneous lymphomas of discordant or concordant lineages may represent a diagnostic challenge. As the treatment of each lymphoma is often different, their correct identification is critical for optimal management of both diseases.

A Phase II Study of THP-COP (pirarubicin, cyclophosphamide, vincristine and prednisolone) in Patients with Newly Diagnosed Advanced Peripheral T-Cell Lymphoma: THP-3 Study of Japan Hematopoietic Malignancy Clinical Study Group (HMCSG)

BackgroundAlthough CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) has been established as a standard of care in patients (pts) with newly diagnosed peripheral T-cell lymphoma (PTCL), new treatment regimen or strategy has been awaited since the outcome of pts with PTCL treated with CHOP is still poor. Pirarubicin (THP) is, an anthracycline drug, which is not affected by the multidrug resistance mediating p-glycoprotein, and is less cardiotoxic than doxorubicin. THP exhibits activity against some doxorubicin-resistant cell lines.ObjectiveA multicenter phase II study was conducted to evaluate the efficacy and toxicity of THP-COP (pirarubicin, cyclophosphamide, vincristine and prednisolone) therapy in pts with newly diagnosed PTCL by Japan Hematopoietic Malignancy Clinical Study Group.Patients and MethodsEligibility criteria were as follows; newly diagnosed PTCL including PTCL-not otherwise specified (NOS), anaplastic large cell lymphoma (ALCL) and angioimmunoblastic T-cell lymphoma (AITL); clinical stage of bulky II, III or IV; aged 20 to 79 years; PS 0-2 by ECOG's scale. THP-COP consists of pirarubicin (50mg/m2 on Day1), cyclophosphamide (750mg/m2 on Day1), vincristine (1.4mg/m2 max. 2mg, on Day 1) and prednisolone (100mg on Days 1 to 5) every 3 weeks up to 8 cycles in younger pts less than 69 years, and 6 cycles in elderly pts aged 70 to 79 years, The primary endpoint was complete response rate (%CR) including unconfirmed CR (CRu). The planned sample size was 40 pts, which provided at least 80% power with the expected %CR of 55%, threshold of 35%, and a one-sided α of 5%.ResultsFrom October 2007 to December 2012, 41 pts with a median age of 63 (21-77) yrs were enrolled. The numbers of pts with PTCL-NOS, AITL and ALCL was 21 (51%), 14 (34%) and 6 (15%), respectively. The numbers of stage II bulky, III and IV was 2 (5%), 22 (54%) and 17 (41%), respectively.Fifty-four % were International Prognostic Index high/intermediate or high risk. The %CR including %CRu and overall response rate were 51.2% (90% CI; 37.4-64.9) which met the primary endpoint, and 70.7% (95% CI; 54.5-83.9), respectively. The progression-free survival and overall survival at 3 years (3-yr PFS and 3-yr OS) were 43.5% (95% CI; 27.5-58.4) and 62.9% (95% CI; 43.3-77.4), respectively. Most common Grade 4 toxicities were hematologic: %Grade 4 neutropenia and thrombocytopenia were 80.5% and 9.8%, respectively. Cardiac adverse events were observed in 2 patients with Grade 1 arrhythmia. No secondary malignancies were observed.ConclusionsIn pts with untreated advanced PTCL including PTCL-NOS, AITL and ALCL, THP-COP demonstrated high efficacy with durable PFS and OS and acceptable toxicity profiles. Further large-scaled randomized study to compare with CHOP is warranted. DisclosuresOgura:Celgene: Consultancy, Honoraria; Mundipharma: Consultancy; Takeda: Consultancy, Honoraria; Astrazeneca: Honoraria; SymBio: Consultancy, Research Funding; Celltrion, Inc: Consultancy, Honoraria; MeijiSeika Pharma: Consultancy. Ohmachi:Kyowa Hakko Kirin Co., Ltd.: Honoraria; Eisai Co., Ltd.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Pfizer Inc: Honoraria; Takeda Pharmaceutical Co., Ltd: Honoraria. Suzuki:MundiPharma: Consultancy; Chugai Pharmaceutical: Honoraria; Sawai Pharmaceutical: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Mochida Pharmaceutical: Honoraria; MSD: Honoraria; Jazz Pharmaceuticals: Consultancy; Kyowa-Hakko Kirin: Honoraria; Shionogi: Honoraria; Meiji Seika Pharma: Honoraria; Ohtsuka: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Takeda Pharmaceuticals: Honoraria; Bristol-Myers Squibb: Honoraria; Gilead Sciences: Consultancy. Atsuta:Otsuka Pharmaceutical Co., Ltd.: Honoraria. Ohyashiki:Chugai: Research Funding; Dainippon Sumitomo: Honoraria; Nippon Shinyaku: Honoraria; Celegen: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria; Novartis pharma: Honoraria; Novartis: Research Funding; Asteras: Research Funding; Taiho pharmaceutical: Honoraria; Alexion: Honoraria; MSD: Honoraria; Otsuka pharmaceutical: Honoraria; Jansen Pharma: Honoraria, Research Funding; Pfizer: Honoraria; Fujirebio: Honoraria; KyowaHakko Kirin: Honoraria, Research Funding. Hidaka:Chugai: Research Funding; Eisai: Honoraria. Ando:NIHON PHARMACEUTICAL: Other: Donation to institute; Nippon Shinyaku: Other: Donation to institute; Japan Blood Products Organization: Other: Donation to institute; Takeda: Other: Donation to institute; ALEXION: Other: Donation to institute; Kyowa Hakko Kirin: Other: Donation to institute; MSD: Other: Donation to institute; Bristol-Myers Squibb: Other: Donation to institute; Eisai: Other: Donation to institute; Sumitomo Dainippon Pharma: Other: Donation to institute; CHUGAI PHARMACEUTICAL: Other: Donation to institute; Meiji Seika Pharma: Other: Donation to institute; NOVARTIS: Other: Donation to institute; MOCHIDA PHARMACEUTICAL: Other: Donation to institute; TOYAMA CHEMICAL: Other: Donation to institute; TAIHO: Other: Donation to institute; Asahi KASEI: Other: Donation to institute. Fukuhara:Nihon Ultmarc, Astellas, AbbVie, Alexionpharma, Bayer Yakuhin, Bristol-Myers Squibb, Baxalta, Celgene, Chugai, Daiichi-Sankyo, Toehringer Ingelheim, Eisai, GlaxoSmithKline, Janssen, Japan Blood Products Organization, Kyowa Hakko Kirin, Mitsubishi Tanabe, : Research Funding; Eisai, Janssen, Takeda, Ono and Zenyaku Kogyo: Honoraria. Morishita:Celgene: Honoraria; Kyowa Hakko Kirin: Honoraria. Tsukasaki:Takeda: Honoraria, Research Funding; Kyowa-Kirin: Honoraria; DaiichiSankyo: Consultancy; Zenyaku Kogyo: Honoraria; Celgene: Honoraria, Research Funding; Mundypharma: Research Funding; HUYA: Honoraria; Chugai/Roche: Honoraria. Ozawa:Kyowa Hakko Kirin: Honoraria; Janssen Pharmaceutical: Honoraria; Nippon Shinyaku: Honoraria. Hotta:SymBio: Consultancy; SellSeed: Other: outside director; Jansen Pharma: Honoraria; Meiji Seika Pharma: Honoraria; Zenyaku Kogyo: Honoraria. Kinoshita:Chugai: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Zenyaku: Honoraria, Research Funding; Jansen Pharma: Honoraria; Kyowa Hakko Kirin: Honoraria; Eisai: Honoraria; Bristol-Meier's-Squib: Honoraria; Solaisia: Research Funding; MSD: Research Funding; Takeda: Research Funding.

Young survivor of a rare primary anaplastic large cell lymphoma of the trachea

Primary anaplastic large cell lymphoma of the trachea is a very rare tumor. Diagnosis is often missed for a long time because the presentation often resembles that of obstructive airway disease. A 24-year-old non-smoker male presented at an outpatient clinic complaining of gradual development of stridor and shortness of breath over a recent period of four weeks. Imaging workup revealed a large lobulated, soft tissue, mildly enhancing, eccentrically placed intraluminal proximal tracheal mass, which showed extension outside of the tracheal lumen in the peritracheal fat. The patient underwent surgery. A biopsy of the resected mass reported anaplastic large cell lymphoma. Post-operation, the patient underwent chemotherapy consisting of four cycles of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone). Follow-up imaging showed non-visualization of the mass. Primary lymphoma (anaplastic large cell lymphoma, which is a rare type of non-Hodgkin’s lymphoma) of the trachea is a rare tumor. Early curative resection with post-operative chemotherapy has a favorable outcome, as in our case.

Comparison of R-CHOP with CHOP in Patients of Diffuse Large B Cell Lymphoma

Objective: Diffuse large B cell lymphoma (DLBCL) is a lymphoid B cells neoplasm with a diffuse pattern and high proliferation rate. Cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) was considered effective as other complicated regimens with more toxicity profile. Rituximab is a monoclonal antibody directed against CD20 positive B cell. It has good activity therapeutically in patients of DLBCL. It increases response rates and survivals when added to CHOP chemotherapy. Although R-CHOP is more effective but due to high cost of Rituximab it is usually not incorporated with chemotherapy in most of our patients and CHOP is still used extensively. Due to heterogeneity of disease and difference in ethnicity, there may be difference in outcomes of two regimens. This study will help us in tailoring our management plan that will result in better outcome of patients. Methods: 70 patients aged between 20-65 years having DLBCL were taken in this study. We rando-mized patients by lottery method into two groups. Group I received CHOP with dose of Cyclophosphamide 750mg/m2, Doxorubicin 50mg/m2, Vincristine 1.4 mg/m2 and prednisolone 40mg/m2.Chemotherapy was given on Day-1 while prednisolone was given for 5 days from Day-1 of chemotherapy. Group II received R- CHOP which includes same chemotherapy with same dosage. Rituximab was included in Group II with dose of Rituximab 375 mg /m2. Each cycle was given at three weeks interval. Response in terms of CR (Complete Response), PR (Partial Response), SD (Stable Disease) or PD (Progressive Disease) was evaluated as per leukemia network after 4 cycles of chemotherapy. The quantitative variables were calculated by taking mean and standard deviation. The response was assessed in percentage and frequencies and compared by applying chi square test. Results: Group I had 37.1% while Group II had 68.6% complete response with p value of 0.019. Partial response was 48.6% in Group I while 20.0% in Group II. 14.3% in Group I and 8.6% in Group II either had stable disease or progressive disease. Conclusions: R-CHOP has superior response rates as compared to CHOP, therefore, whenever possible Rituximab should be added as target therapy in chemotherapy. Key Words: Diffuse large B cell lymphoma, CHOP, R- CHOP How to Cite: Lodhi F.R, Zafar A, Khokhar M.A, Goraya AW, Ashraf S, Yaqub S. Comparison of R-CHOP with CHOP in patients of diffuse large B cell lymphoma. Esculapio.2020;16(04):79-82.

Rare Primary Diffuse Large B-Cell Lymphoma of a Male Breast

Background: Breast lymphomas are typical extranodal types of lymphoma, also known as Extranodal-lymphoma (ENL), which occur extremely infrequently, aggregating into a very small proportion of malignant breast tumors. The rarity of breast lymphomas is attributed to the scant lymphoid tissue content of the chest wall. Aims of Study: This case report is aimed at providing an up-to-date review of the literature on breast lymphomas for clinicians to, therefore, consider the possibility of this disease entity while treating a breast mass. Case Presentation: A case was reported of a 52-year man with chief mammary non-Hodgkin breast ENL when fine-needle aspiration cytology (FNAC) was not leading to a firm conclusion or result. Following an incisional biopsy, he was found to have a primary breast lymphoma. Later, the patient was diagnosed with the diffuse large B-cell type of lymphoma also known as non-Hodgkin’s Lymphoma (NHL). He had a complete reduction and disappearances of all the signs and symptoms of the disease after a course of neoadjuvant chemotherapy: Cyclophosphamide, Doxorubicin, Vincristine and Prednisolone (CHOP). CONCLUSION: Based on the above case presentation, it is vital for health care professionals and oncologists to recognize the disease by assessing the breast mass accurately with more entities so that proper diagnosis via core biopsy (incisional biopsy) can eliminate the PBL before further treatment is required.

WHERE ARE THE EFFUSIONS?

SESSION TITLE: Fellows Pulmonary Manifestations of Systemic Disease Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: October 18-21, 2020 INTRODUCTION: Primary effusion lymphoma (PEL) is a rare and aggressive subset of B-cell lymphoma that is commonly associated with immune deficiencies such as HIV/AIDS and organ transplant. It commonly manifests as a serous effusion in either pleural, pericardial or peritoneal spaces, and is associated with human herpesvirus-8 (HHV-8) or Epstein-Barr virus (EBV). One study showed that about one third of patients with the diagnosis of PEL did not have effusions; but were diagnosed by pathology of solid tumors. CASE PRESENTATION: A 58-year-old man with a multi-decade history of HIV infection was referred to the Emergency Department for anemia and low CD4 T cell count with elevated HIV viral load. He had a long history of HIV infection. Other medical problems include Kaposi sarcoma, hypertension, and spinal osteoarthritis. His physical exam was notable for pre-auricular and inguinal lymphadenopathy. Initial laboratory evaluation included anemia, leukocytosis with left shift, thrombocytopenia, elevated serum protein, low bicarbonate and elevated lactate. He was given fluid resuscitation, broad-spectrum antibiotics, and vasopressor support. Cerebrospinal fluid studies showed high total protein at 72, 88% lymphocytes. Continued evaluation of his lymphadenopathy, anemia and thrombocytopenia included detection of EBV and HHV-8. Excisional biopsy of left cervical lymph node showed clusters and sheets of large atypical cells with plasmablastic morphology admixed with small mature lymphocytes and plasma cells. The suspected diagnosis was primary effusion lymphoma without lymphomatous effusions. His course was complicated by respiratory insufficiency requiring non invasive ventilation in the setting of new bilateral ground glass opacities. He was treated for pneumonia with clinical improvement. He became altered on the medical floor, and a guardian was appointed for his medical decision making. In light of HIV-associated lymphoma with unclear benefit to aggressive chemotherapy, his guardian opted for comfort care and he was discharged to home hospice. DISCUSSION: We present a case of PEL presenting in a patient with long-standing HIV infection and history of Kaposi sarcoma. Despite the name, not all cases have lymphomatous effusions on presentation. PEL is uncommon, and available information is based on case series. The treatment of PEL involves multi-drug chemotherapy, including use of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) and methotrexate. One case series of 28 patients treated for PEL with CHOP had median overall survival of 6.2 months . Another case series of 51 patients treated for PEL using CHOP-like regimen and the addition of methotrexate showed median overall survival 10.2 months . CONCLUSIONS: The prevalence of PEL is low; but should be considered in in patients with long standing HIV infection and Kaposi sarcoma. Reference #1: Guillet, S., Gérard, L., Meignin, V., Agbalika, F., Cuccini, W., Denis, B., Katlama, C., Galicier, L. and Oksenhendler, E. (2016), Classic and extracavitary primary effusion lymphoma in 51 HIV-infected patients from a single institution. Am. J. Hematol., 91: 233-237. doi:10.1002/ajh.24251 Reference #2: Kazuyuki Shimada, Fumihiko Hayakawa, Hitoshi Kiyoi; Biology and management of primary effusion lymphoma. Blood 2018; 132 (18): 1879–1888. doi: https://doi.org/10.1182/blood-2018-03-791426 Reference #3: Emmanuelle Boulanger, Laurence Gérard, Jean Gabarre, Jean-Michel Molina, Christophe Rapp, Jean-François Abino, Jacques Cadranel, Sylvie Chevret, and Eric Oksenhendler Prognostic Factors and Outcome of Human Herpesvirus 8–Associated Primary Effusion Lymphoma in Patients With AIDS (2005) Journal of Clinical Oncology 23:19, 4372-4380 DISCLOSURES: No relevant relationships by Saud Alrawaf, source=Web Response No relevant relationships by Benjamin DelPrete, source=Web Response No relevant relationships by Lisa Glass, source=Web Response No relevant relationships by Marwa Oudah, source=Web Response

Dose-adjusted EPOCH with or without rituximab for aggressive lymphoma patients: real world data.

CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) -/+ rituximab (R) is the standard chemotherapeutic regimen for aggressive lymphoma, but is insufficient for aggressive lymphoma with adverse prognostic factors. Dose-adjusted (DA)-EPOCH (etoposide, doxorubicin, cyclophosphamide, vincristine, and prednisolone) -/+ R demonstrates excellent efficacy against some aggressive lymphoma. Thus, we conducted a retrospective study to evaluate the feasibility and efficacy of this therapy in clinical practice. We enrolled 149 patients from 17 institutions diagnosed between 2007 and 2015. The median follow-up period for survivors was 27months (range 0.2-123). The complete response (CR) rate of newly diagnosed patients was 79% (95% CI 68-87%). All patients were hospitalized to receive this therapy and 94% of patients also received granulocyte-colony-stimulating factor support. There were no treatment-related deaths. Febrile neutropenia (FN) and grade 3 or 4 infection occurred in 55% and 28% of patients, respectively. There were no significant differences in FN or infection between young (≤ 65years) and elderly patients (> 65years). In newly diagnosed diffuse large B-cell lymphoma-not otherwise specified patients (n = 46), the CR rate was 80% (95% CI 64-91%) and the 2-year OS rate was 81% (95% CI 66-90%). In the present study, DA-EPOCH -/+ R exhibited excellent efficacy and feasibility for aggressive lymphoma.

Report of two rare cases of adrenal incidentalomas with different origins: revisiting pathological and radiological findings with a short review of the literature

BackgroundAdrenal tumors can be detected incidentally in 4 to 8% of patients radiologically. Adenomas, pheochromocytomas, and adrenocortical carcinomas represent the most common tumors of the adrenal glands. Rare histopathological findings are uncommon. We aimed to report two rare primary adrenal tumors diagnosed initially as incidentalomas to identify clinical characteristics, management, and clinical outcomes after treatment.Case presentationThe first case was a 52-year-old man presented with an incidentally discovered locally advanced primary adrenal angiosarcoma. The patient was managed surgically with no adjuvant therapy. The patient was followed up for 3 years without evidence of local recurrence. The second case was a 63-year-old woman, presented with an incidentally discovered primary diffuse B-cell lymphoma of the left adrenal gland. She was treated by adrenalectomy. Later on, adjuvant six cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy were given. After 6 months follow-up, the patient was alive and disease-free.ConclusionThe diagnosis of adrenal tumors increased nowadays because of the widespread use of imaging studies, though rare pathologies should be taken into consideration.

P27 A challenging case of multi-site avascular necrosis

Abstract Background A 32 year old gentleman was assessed in the rheumatology department in August 2018 having been referred for investigation into the cause of multi-site avascular necrosis (AVN). Methods He had mild Raynaud's symptoms in his hands and recurrent oral ulceration. He was previously fit and well without any history of thrombotic events or family history. He smoked 2 cigarettes a day and denied any alcohol intake. Results In February 2011 he was diagnosed with T-cell lymphoma while in the Navy. He underwent chemotherapy in a medical oncology department at a tertiary care centre. His chemotherapy regime involved 2 cycles of cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) and 4 cycles of cyclophosphamide, cytarabine, vincristine, doxorubicin, methotrexate, ifosfamide, etoposide, cytarabine (CODOX-M IVAC) which finished in September 2011. He developed severe bilateral hip pain 6 months after completing his chemotherapy. X-rays revealed bilateral avascular necrosis (AVN). He was discharged from the Navy on medical grounds and underwent bilateral total hip replacements in 2013. In March 2014 he developed pain involving both shoulders. An MRI scan revealed extensive bilateral humeral head AVN. He was seen by an orthopaedic surgeon at a tertiary centre and underwent re-surfacing surgery on both shoulders. Meanwhile he was reviewed by the pain team and a palliative care consultant in June- July 2014 for ongoing widespread pain in his elbows, wrists, knees and ankles. He also suffered from depression, poor sleep and expressed frustration regarding his general health and inability to work. Multiple analgesic agents used included amitriptyline, dothiepin, pregabalin, oxycodone, oxynorm and clonazepam. He also tried cognitive behavioural therapy (CBT). He developed a headache and saw a neurologist who investigated this and concluded the patient had an analgesia overuse headache. In December 2017 he developed more pain in his knees and ankles and X-rays revealed AVN of both knees. He underwent a right total knee replacement in June 2018. An MRI scan of his ankles revealed signs of bilateral AVN with bone infarction of the distal tibia and a small area of the talus bilaterally. When he was assessed in the rheumatology clinic in August 2018, he had a number of investigations which revealed normal blood counts, haemoglobin electrophoresis and clotting screen. An autoimmune screen was negative including ANA, ENA and antiphospholipid antibodies. An infection screen including HIV was also negative. A lipid screen revealed a triglyceride level of 10.9, cholesterol 8.1 and HDL ratio of 9.3. Conclusion This challenging case involves a young patient with AVN in 8 sites which is rare. The AVN is likely related to chemotherapy, steroids and untreated hyperlipidaemia. There have been devastating painful and psychological consequences to his daily functioning. Ongoing issues include widespread pain and further sites of AVN. Disclosures A. Haque None. A. Coote None.

Breast implant-associated anaplastic large-cell lymphoma: first case detected in a Japanese breast cancer patient

This paper details the first breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) case detected in Japan. The patient, a 67-year-old Japanese woman, was diagnosed with left unilateral breast cancer 17 years ago. Induration and redness presented in the left breast, which had undergone immediate breast reconstructive surgery using a tissue expander, later replaced by a silicone breast implant (SBI). Breast ultrasound showed fluid collection around the SBI. Surgery was performed to remove the left breast implant and the fragmented capsule surrounding the implant. Postoperative pathological findings did not indicate malignancy. Nine months later, a contralateral axillary lymphadenopathy was observed, and an excisional biopsy of the axillary lymph node was performed. The patient was diagnosed with BIA-ALCL and successfully underwent adjuvant CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy.

PF324 RITUXIMAB DOSE ASSOCIATED WITH OVERALL SURVIVAL IN DIFFUSE LARGE B CELL LYMPHOMA

Background:The outcome of diffuse large B cell lymphoma (DLBCL) improved significantly, due to the addition of rituximab (R) to CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy. However, significant range of patients showed relapse or refractory to R‐CHOP, and the role of body surface area (BSA) or body mass index (BMI) to overall survival (OS) was not known or still controversial.Aims:We evaluated effects of rituximab dose, BSA or BMI on OS using National Health Information Database.Methods:This study included patients 5,332 patients who were diagnosed with DLBDL and received R‐CHOP as a frontline therapy between 2006 and 2014. The exclusion criteria were as follows;1) age &lt;20 years 2) R‐CHOP was given less than 4 times or over 8 times 3) R‐CHOP 2 months after diagnosis 4) Interval between two consecutive R‐CHOP injection was over 60 days. We extracted age, sex, prescribed medication list, and date of death from NHID. Weight and height of patients who had national general health examination before 1st cycle of R‐CHOP was collected.Results:Median age was 58(20–92) years, and 57%(n = 3021) of them were male. Thirty‐eight % of patients (n = 2019) received R‐CHOP 4–5 times, and 62% (n = 3303), 6–8 times. Median dose of injected rituximab was total 7200(1,600–16,800) mg, and median mean dose of rituximab per each cycle was 600(400–1,000) mg. A total 2,523 patients (47.4%) were treated at medical institution in capital (Seoul) area. About 72% of patients (n = 3813) had national health examination before chemotherapy. Their median weight and height were 63(31–121) kg and 163(131–196) cm, respectively. Median BSA and BMI were 1.69m2 and 23.9 kg/m2.With median 66(24–144) months of follow up, estimated 5‐year and 10‐year overall survival was 37.1% and 25.6% respectively. Log‐rank test for 10‐year OS, age≤60 (vs age&gt;60), female (vs male), 6–8 times of R‐CHOP injection (vs 4–5 times of R‐CHOP), total R dose≥7200 mg (vs &lt;7200), mean R dose≥600 mg, and medical institution in Seoul (vs others) were associated OS, significantly (p &lt; 0.05). However, total R dose did not affect OS in multivariate analysis (p = 0.152).Among 3813 patients who had national health examination before R‐CHOP, patients whose BSA &lt;1.69m2 had worse OS than BSA≥1.69m2. But BMI did not differentiate OS.Summary/Conclusion:With 66 (24–144) months of median follow up, estimated OS at 5‐year and 10‐year of DLBCL patients were 37.1% and 26.5%, respectively. Mean rituximab dose ≥600 mg showed better OS than &lt;600 mg. High BSA showed favorable OS, but BMI did not affected OS significantly. image

Effect of Everolimus on Epstein-Barr Virus-positive T Cell PTLD After CHOP Chemotherapy and Angiofibroma in Pediatric Tuberous Sclerosis Complex

A 15-year-old Japanese female with end-stage kidney disease, kidney cysts, and angiomyolipoma due to tuberous sclerosis complex (TSC) received an ABO-matched preemptive kidney transplantation from her father. Basiliximab induction therapy was done on days 0 and 4, and tacrolimus, mycophenolate mofetil, and methylprednisolone were administered. Six months later, cervical lymphadenopathy developed, and computed tomography revealed an abdominal mass. Epstein-Barr virus-positive T cell post-transplant lymphoproliferative disorders (PTLD) was diagnosed. The pathology showed a monomorphic type lymphoma, and the Ki-67 index, a cell proliferation marker, was above 90%. The patient received four courses of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) therapy, and tacrolimus was switched to everolimus, an inhibitor of the mammalian target of rapamycin (mTOR) pathway. Everolimus acts not only as an immunosuppressant, but also has an anti-tumor effect which may inhibit lymphoma development and proliferation. Three years later, the patient has shown no sign of PTLD recurrence. Her kidney function remains good, and a pathological examination detected no sign of rejection. In addition, her facial angiofibroma has improved. Although this study is based only on a single case observed over a short period of time, we consider everolimus to be a possible option in the treatment of PTLD after CHOP chemotherapy, especially in patients with TSC.

Genomics of Limited-Stage Diffuse Large B-Cell Lymphoma Developing Late Relapse: Analysis of Gene Alterations in Paired Primary and Late Relapsed Tumors By Target Sequencing

Genomics of Limited-Stage Diffuse Large B-Cell Lymphoma Developing Late Relapse: Analysis of Gene Alterations in Paired Primary and Late Relapsed Tumors By Target Sequencing

A New Prognostic Index for Waldenström Macroglobulinemia Based on a Multicenter Retrospective Study of the Japanese Society of Myeloma

Background: We recently reported that the International Prognostic Scoring System for Waldenström macroglobulinemia (ISSWM), which is widely used to predict the prognosis of WM patients, might not be applicable to Japanese patients, and evidence of pleural effusion might be a novel adverse prognostic factor for symptomatic WM in the rituximab era. Further studies with a large number of patients are deemed to be conducted.Methods: We retrospectively analyzed the clinical data of 498 patients with WM diagnosed between January 2001 and December 2015 from 44 institutes involved with the Japanese Society of Myeloma. The overall survival (OS) was analyzed using Kaplan-Meier methods and compared using log-rank test. Several clinical characteristics at the diagnosis were assessed by Cox regression for univariate and multivariate analyses of the OS.Results: We included 420 cases diagnosed with symptomatic (n=314) and asymptomatic WM (n=106) in accordance with the classification of the Second International Workshop on WM. The median age at the diagnosis was 69 (range, 32-91) years, with 75.5% male, and 16.0% had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 2-4. Oral alkylating agents, purine analogs, cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) or CHOP-like regimens ± rituximab, rituximab monotherapy, or dexamethasone, rituximab and cyclophosphamide (DRC) were mainly administered as initial treatment. Rituximab-containing therapy was administered in 76.8% of all patients. The median follow-up was 45 months. The 5-year OS rate for all patients was 77.9%, while the rates for those with symptomatic and asymptomatic WM were 72.9% and 92.2%, respectively. Significant differences in the survival were seen between risk groups of ISSWM in symptomatic WM patients (5-year OS: high, 55.4%; intermediate, 81.2%; low, 90.2%; p<0.0001) (Figure 1). A univariate analysis showed that age >65 years, platelet count ≤10×104/µL, serum β2-microglobulin (β2-MG) >3 mg/L, ECOG PS 2-4, abnormal karyotype, pleural involvement, WBC <4000/µL, amyloidosis, fluid retention, pleural effusion, ascites, serum albumin ≤3.5 g/dL, serum creatinine >1.5 mg/dL, CRP >2.0 mg/dL and sIL-2R >4000 U/mL were significant adverse prognostic factors for the OS. A multivariate analysis revealed that a platelet count ≤10×104/µL (hazard ratio [HR] 5.942; 95% confidence interval [CI] 2.265-14.761), serum β2-MG >3 mg/L (HR 2.748; 95% CI 1.091-7.655), ECOG PS 2-4 (HR 2.899; 95% CI 1.219-6.290), and pleural involvement (HR 11.066; 95% CI 3.672-29.829) were adverse independent risk factors for symptomatic WM. We constructed a prognostic model by combining these prognostic variables as follows: patients with good risk (n=219), no adverse factors or only serum β2-MG >3 mg/L or ECOG PS 2-4; patients with poor risk (n=81), ≥1 adverse factors with a platelet count ≤10×104/µL, pleural involvement, or both serum β2-MG >3 mg/L and ECOG PS 2-4. The 5-year OS rates were 82.3% for good risk and 44.4% for poor risk, and this prognostic model significantly stratified symptomatic WM patients separately by the survival (p<0.0001) (Figure 2). The survival of patients with both poor risk in our model and high risk in ISSWM were extremely poor (5-year OS: poor and high [n=57], 24.7%; poor and intermediate [n=14], 80.0%; poor and low [n=2], not available; p=0.0031). In contrast, no significant differences were observed for the survival for the ISSWM risk groups in patients with good risk in our model (5-year OS: good and high [n=69], 76.0%; good and intermediate [n=83], 81.6%; good and low [n=42], 89.5%; p=0.2045).Conclusion: Although ISSWM may be useful for survival risk stratification in Japanese patients, we found that intermediate- and high-risk patients seemed to have a better prognosis than those in Western studies in the rituximab era (Dimopoulos MA, et al. Haematologica. 2008; 93: 1420-22). Thrombocytopenia and pleural involvement were found to be strong adverse prognostic factors in symptomatic WM, and our new prognostic index including them was easy to use in daily clinical practice and superior to ISSWM for detecting high-risk patients. Further studies are warranted to validate our prognostic index, especially in the era of novel agents. DisclosuresYamamoto:Bristol-Myers Squibb: Honoraria. Hagiwara:Celgene: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Sunami:Celgene: Honoraria, Research Funding; Sanofi: Research Funding; Janssen: Research Funding; Daiichi-Sankyo: Research Funding; Ono: Honoraria, Research Funding; Bristol-Myers Squibb K.K.: Honoraria, Research Funding; AbbVie: Research Funding; Takeda: Research Funding; MSD: Research Funding; GlaxoSmithKline: Research Funding; Novartis: Research Funding. Kurokawa:Teijin Pharma: Research Funding; Eizai: Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Chugai Pharmaceutical: Research Funding; Sumitomo Dainippon Pharma: Research Funding; Pfizer: Research Funding; Takeda Pharmaceutical: Research Funding; MSD: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Nippon Sinyaku: Honoraria, Research Funding; Astellas Pharma: Research Funding; Otsuka Pharmaceutical: Research Funding. Takamatsu:Janssen: Honoraria; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Ono: Research Funding. Ito:Bristol-Myers Squibb, Celgene: Honoraria. Tamura:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria; Takeda Pharmaceutical: Honoraria.