Large T-cell Lymphoma Research Articles

Outpatient BEAM Using Daily Etoposide and Cytarabine with Autologous Hematopoietic Stem Cell Transplantation for Lymphoma Is Feasible and Decreases Inpatient Length of Stay

Introduction: High dose therapy with carmustine, etoposide, cytarabine, and melphalan (BEAM) followed by autologous hematopoietic stem cell transplantation (AHCT) is the most common consolidation therapy for chemosensitive patients with relapsed/refractory Non-Hodgkin Lymphoma (NHL) and Hodgkin Lymphoma (HL) in the US. Inpatient hospitalization is usually required due to the twice daily dosing of etoposide and cytarabine, and patients remain admitted until neutrophil recovery. Utilizing our outpatient transplant program, we aimed to evaluate the feasibility and safety of outpatient BEAM with AHCT using daily dosed etoposide and cytarabine to enhance the patient experience and improve inpatient resource utilization. Methods: We performed a retrospective evaluation of patients treated in the outpatient setting at Memorial Sloan Kettering Cancer Center. Patients were eligible for outpatient AHCT if they did not have a clinical indication for inpatient continuous monitoring. Patients received BEAM conditioning consisting of carmustine on day -6 (300mg/m2), etoposide daily from day -5 through day -2 (200mg/m2/dose), cytarabine daily from day -5 through day -2 (400mg/m2/dose), and melphalan on day -1 (140mg/m2). AHCT on day 0, pegfilgrastim on Day +1, and supportive care were performed as per standard of care and institutional guidelines. Patients were seen daily by an advanced practice provider and HCT attending. Notably, service guidelines were revised to include a delayed emesis prophylactic regimen of oral dexamethasone (2mg bid) and lorazepam (0.5mg TID) from D+1 through D+7, which was initiated after the first three patients were treated. Patients were transfused packed red blood cells (pRBC) for hemoglobin <7g/dl and platelets for <20K/mcl. Results: From October 2018 to July of 2019, 13 patients (Hodgkin's lymphoma (n=5), mantle cell lymphoma (n=4), diffuse large B-cell lymphoma (n=2), T-cell lymphoma (n=2), and grey zone lymphoma (n=1)) were treated. The median age was 40 years (range 26-71), and the majority were male (69%). Median cell dose infused was 5.89 CD34+ cells/kg (range 2.53-10.66). Two patients received cell infusions over 2 days, and three patients received washed cell infusion products. Two patients completed transplant entirely outpatient; the remainder required hospitalization during their transplant course. Reasons for admission included neutropenic fever (n=4), nausea (n=2), tachycardia (n=2), hypoxia (n=1), and other (n=2). Patients were admitted on a median of Day +6 (range Day+1 - Day+11) and remained inpatient for a median of 4 days (range 3-14). Eight patients (62%) returned to the outpatient stem cell transplant clinic for management prior to day 30. One patient was re-hospitalized prior to day 30. The median number of hospital days saved was 13 days/per patient. In total, 170 hospital days were saved with this regimen. Engraftment and toxicities were similar to inpatient administration. Neutrophil engraftment occurred at a median of Day+9 (range 8-11) with a median of 6 days of ANC<500 (IQR 8-11). Platelets comprised most of the transfusion support required, with a median of 4 platelet (range 2-8) and 2 pRBC (range 0-2) transfusions per patient. Grade 2 or higher diarrhea occurred for a median of 3.5 days (range 3-11) with 38% not having any diarrhea. A small percentage of patients required additional antiemetics outside the standard of care (23%). The median weight lost per patient was 2.5kg (range 0 - 10.3kg). Patients received intravenous fluid support with a median of 5 normal saline boluses (range 1-10). All patients maintained normal serum creatinine peri-transplant, with a median maximum serum creatinine of 0.9mg/dl (range 0.7-1.1). Six patients (46%) had engraftment syndrome. All patients were alive with a median follow-up of 91 days (range: 29-205). Conclusion: We found that BEAM followed by AHCT using daily dosed etoposide and cytarabine is feasible and safe for the outpatient setting with tolerability matching that of the traditional inpatient BEAM regimen. Moreover, this treatment method has the potential to reduce a considerable number of inpatient hospital days, while still safely maintaining a threshold for toxicity requiring inpatient admission. Disclosures Bhatt: Incyte: Consultancy. Landau:Pfizer: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria. Scordo:Angiocrine Bioscience, Inc.: Consultancy; McKinsey & Company: Consultancy. Sauter:Juno Therapeutics: Consultancy, Research Funding; Kite/Gilead: Consultancy; Precision Biosciences: Consultancy; Genmab: Consultancy; Spectrum Pharmaceuticals: Consultancy; GSK: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Sanofi-Genzyme: Consultancy, Research Funding. Giralt:Celgene: Consultancy, Research Funding; Takeda: Consultancy; Sanofi: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Shah:Amgen: Research Funding; Janssen: Research Funding.

Outcome of Autologous Hematopoietic Cell Transplantation in First Complete Remission(CR1) in Patients with Peripheral T-Cell Lymphomas(PTCLs)

Abstract Background Patients with peripheral T cell lymphomas (PTCLs) generally have a poor prognosis with conventional chemotherapy. Most studies demonstrates that, compared to the patients who did not achieve complete remission (CR) after initial therapy, the patients of PTCL who received autologous stem cell lymphoma (ASCT) as consolidation treatment show clearly advantage in survival. However, given the absence of randomized controlled studies, it is unproven that clinical value of consolidative ASCT for PTCL patients achieving CR1. There is a possibility that the survival is similar with or without up-front ASCT group. Thus, we collected the data of PTCL patients who attain CR1 following conventional chemotherapy in our center during the past 10 years. And the objective of this study is to evaluate overall survival(OS), progression-free survival(PFS), and cumulative incidence of relapse (CIR) between observation and first-line ASCT group. Patients and Methods Weconducted a retrospective study of patients with PTCL who were treated in our center from January 2009 to April 2019. The histopathologic diagnosis of all PTCL patients according to the World Health Organization classification. Exclusion criteria were the following: (1) anaplastic lymphoma kinase (ALK)-positive anaplastic large T-cell lymphoma; (2) cutaneous T cell lymphoma (CTCL); (3) concurrent B cell lymphomas; (4) natural killer/T-cell lymphoma (NK/TCL); (5) patients who underwent allogeneic stem cell transplantation. Furthermore, patients with PTCL age ≤65 years were included. Overall survival(OS )and progression-free survival(PFS) rates were estimated using the Kaplan-Meier method and Survival was compared using the log-rank test. Cumulative incidence of relapse (CIR) was compared by Gray's test competing risk test statistic. The level of statistical significance was set at p < 0.05. Results A total of 97 patients who met inclusion criteria were enrolled in our center from January 2009 to April 2019. And 59 (59/97, 60.8%)achieved CR1 after receiving induction chemotherapy. Table 1 summarizes the baseline characteristics for the patients in CR1. Of the 59 patients, 43 patients underwent observation and waiting in CR1, 16 patients underwent consolidative ASCT. PTCL NOS accounted for more than 50% at diagnosis in both groups. However, there was significant difference in median age between Non-ASCT group and ASCT group. Patients receiving ASCT were younger and in better physical condition. There were no difference in initial chemotherapy between two groups. Median follow-up time in the entire patient cohort for CR1 (59) was 31months. The median OS and PFS for patients who underwent observation in CR1 was 105 months and 20 months, the median OS and PFS for patients who underwent ASCT as consolidation treatment was 133 months and 91 months. There were no statistical significance in OS (105m vs. 133m, P=0.541) (Figure 1) and PFS (20m vs. 91m, P=0.237) (Figure 2). The estimated 2-year OS was 68.7% and 74.5% in the non-ASCT group and ASCT group, respectively. The estimated 2-year PFS was 41.9% and 62.5%, respectively. When considering incidence of disease relapse, the 2-year cumulative incidence of relapse in the non-ASCT and ASCT group was 41% and 25%, respectively. Again, however, this did not meet statistically significant(P=0.504) (Figure 3). Notably, among patients with advanced-stage disease, elevated LDH, extranodal involvement>1 sites or intermediate-to-high IPI scores, patients who received ASCT as consolidative treatment did not have long time survival compared to the non-ASCT group. Conclusion In conclusion, for PTCL patients achieving CR1 following induction therapy, consolidative ASCT does not extend overall survival and progression-free survival compared to observation. Similarly, consolidative ASCT also failed to reduce cumulative incidence of relapse. We favor proceeding to observe and wait because of high toxic of hematopoietic stem cell transplantation. However, The finding still needs to be confirmed in a larger, prospective study. Table 1 Disclosures No relevant conflicts of interest to declare.

Human Pegivirus Infection and Lymphoma Risk: A Systematic Review and Meta-analysis.

Human pegivirus (HPgV) is a single-strand RNA virus belonging to the Flaviviridae. Although no definitive association between HPgV infection and disease has been identified, previous studies have suggested an association of HPgV viremia with risk of lymphomas. We conducted a systematic review and meta-analysis, including 1 cohort study and 14 case-control studies, assessing the association of HPgV viremia with adult lymphomas. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model, overall and by geographic region and lymphoma subtype. The overall OR for lymphoma was 2.85 (95% CI, 1.98-4.11), with statistically significantly elevated ORs observed in 8 of 15 studies. There was a small amount of heterogeneity among studies (I2 = 28.9%; Q = 18.27, P = .16), and the funnel plot provided no evidence for publication bias. The strongest association with lymphoma risk was observed for studies from Southern Europe (OR, 5.68 [95% CI, 1.98-16.3]), whereas weaker ORs (with 95% CIs) were observed for studies from North America (2.24 [1.76-2.85]), Northern Europe (2.90 [.45-18.7), and the Middle East (2.51 [.87-7.27]), but all of similar magnitude. Participants with HPgV viremia had statistically significantly increased risks (OR [95% CI]) for developing diffuse large B-cell (3.29 [1.63-6.62]), follicular (3.01 [1.95-4.63]), marginal zone (1.90 [1.13-3.18]), and T-cell (2.11 [1.17-3.89]) lymphomas, while the risk for Hodgkin lymphoma (3.53 [.48-25.9]) and chronic lymphocytic leukemia (1.45 [.45-4.66]) were increased but did not achieve statistical significance. This meta-analysis supports a positive association of HPgV viremia with lymphoma risk, overall and for the major lymphoma subtypes.

Disparities in the Concentrations of Essential/Toxic Elements in the Blood and Scalp Hair of Lymphoma Patients and Healthy Subjects

Lymphoma is one of the fastest growing malignancies worldwide and imbalance in the concentrations of trace elements can play a significant role in the onset and progression of the disease. Selected essential and toxic elements (Fe, Zn, Cu, Mn, Ni, Cr, Cd and Pb) were analysed in the blood & scalp hair of lymphoma patients (n = 59 & 58, respectively) and controls (n = 61 & 60, respectively) by atomic absorption spectrometry. On the average, Ni, Cr, Cu and Cd revealed significantly higher contents in the blood and scalp hair of the patients than the controls (p < 0.05). The correlation study showed significantly diverse relationships among the elements in blood & scalp hair of the two donor groups. Variations in the elemental levels with different types of lymphoma (non-Hodgkin and Hodgkin) were also evaluated. Disparities in the elemental concentrations were also investigated for various types of non-Hodgkin (diffuse large B-cell lymphoma, follicular lymphoma and peripheral T-cell lymphoma) and Hodgkin lymphoma (mixed cellularity, nodular lymphocyte predominant and nodular sclerosing), as well as for different stages (I, II, III & IV) of the cancer. Multivariate statistical analysis showed considerably divergent associations of the elements in the patients and controls. The study indicated profound alteration of the elemental levels in the patients; it may be implicated in elemental-induced disorders including lymphoma.

Clinical Characteristics and Treatment Outcomes of Pediatric Patients with Non-Hodgkin Lymphoma in East Asia.

PurposeThe presentations and geographic incidence of pediatric non-Hodgkin lymphoma (NHL) differ from those of adults. This study delineated the characteristics and outcomes of pediatric NHL in East Asia.Materials and MethodsMedical records of 749 pediatric patients with NHL treated at participating institutions in mainland China, Japan, Korea, and Taiwan from January 2008 to December 2013 were reviewed. Demographic and clinical features, survival outcomes, and putative prognostic factors were analyzed.ResultsFive hundred thirty patients (71%) were male. The most common pathologic subtypes were Burkitt lymphoma (BL) (36%). Six hundred seven patients (81%) had advanced diseases at diagnosis. The 5-year overall survival and event-free survival (EFS) rates were 89% and 84%. The 5-year EFS rates of BL, lymphoblastic lymphoma, and diffuse large B-cell lymphoma were 88%, 88%, and 89%, and those of anaplastic large cell lymphoma (ALCL) and peripheral T-cell lymphoma (PTCL) were 71% and 56% (p < 0.001). Central nervous system involvement, high lactate dehydrogenase level (> 250 IU/mL), and advanced disease at diagnosis (≥ stage III) were associated with poor outcomes (p < 0.05). ALCL and PTCL relapsed more frequently than other pathologic subtypes (p < 0.001).ConclusionIn East Asia, PTCL was more frequent than in Western countries, and bone marrow involvement did not affect treatment outcome. This international study should motivate future collaborative study on NHL in East Asia.

Anaplastic Large T-Cell Lymphoma in the Intestine of Dogs.

Anaplastic large T-cell lymphoma (ALTCL) is a rare subtype of non-Hodgkin T-cell lymphoma that occasionally occurs in the gastrointestinal tract of humans. Enteropathy-associated T-cell lymphoma (EATL) type 1 is the most common type of intestinal lymphoma in dogs, and ALTCL has not previously been reported in the intestinal tract of dogs. Thirteen dogs with intestinal masses diagnosed as intestinal lymphoma with anaplastic morphology were reviewed. Clinical data, including treatment protocols, were available for 11 cases. Immunohistochemistry for CD3, CD20, and CD30 was performed for all cases in addition to PCR for Antigen Receptor Rearrangements (PARR) for assessment of clonality. Eight (62%) of the cases presented with intestinal perforation, and all cases had 1 or more masses arising from the small intestine. Histologically, all cases were characterized by transmural infiltrates of large, CD3-positive and frequently CD30-positive cells. Neoplastic T cells had marked anisocytosis and anisokaryosis, prominent nucleoli, and occasionally indented to reniform nuclei. There was abundant necrosis and inflammation with occasional vascular invasion within neoplastic masses. All cases had a monoclonal T-cell receptor γ gene rearrangement. The median survival time was 5 days, with 1 dog surviving 2 years after the initial diagnosis. ALTCL can occur as an aggressive transmural lymphoma in the gastrointestinal tract of dogs and commonly causes intestinal perforation. ALTCL can be differentiated from EATL type 1 and might have implications for accurate prognostication and selection of therapeutic options in the future.

Epidemiology, clinical and cytological features of lymphoma in Boxer dogs.

The aim of this study was to evaluate the epidemiology, clinical and laboratory characteristics of canine lymphomas as well as some aspects of treatment outcomes. The study was conducted on Boxer dogs with lymphoma diagnosed by cytology and immunocytochemistry (CD3 and CD79 alpha). During the study period, lymphoma was diagnosed in 63 Boxers; 86.8% were T-cell (based on the Kiel classification: small clear cell lymphoma, pleomorphic small cell lymphoma, pleomorphic mixed T-cell lymphoma, pleomorphic large T-cell lymphoma, lymphoblastic lymphoma/acute lymphoblastic leukaemia) and 13.2% were B-cell lymphomas (according to the Kiel classification: B-cell chronic lymphocytic leukaemia, centroblastic/centroblastic polymorphic lymphoma). Overall survival (OS) was significantly longer in dogs with low-grade than with high-grade lymphoma (median OS of 6.8 and 4.7 months, respectively; P = 0.024). OS was not influenced by WHO clinical stage, WHO clinical substage, presence of splenomegaly, early administration of glucocorticoids or the time from the first presentation to the beginning of chemotherapy. There are no significant differences in clinical and laboratory parameters between low-grade and high-grade lymphomas. Boxer dogs are predisposed to T-cell lymphoma, with a predominance of high-grade tumour, especially pleomorphic, mixed small and large T-cell subtype. It is possible that Boxer dogs may respond less favourably to chemotherapy than patients of other breeds.

Phase II multi-center study of ruxolitinib phosphate for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphoma (PTCL).

e19063 Background: Constitutive activation of the JAK-STAT pathway has been reported in lymphomas, suggesting that targeting this pathway could show clinical benefit. Ruxolitinib phosphate, an oral JAK inhibitor represents a potential therapeutic agent for high grade lymphomas. This study is designed to investigate benefits of ruxolitinib in patients with relapsed or refractory PTCL and DLBCL Methods: Patients with relapsed/refractory DLBCL and aggressive T cell lymphomas who were ineligible for, or relapsed after, stem cell transplantation were eligible. Patients received ruxolitinib, at a dose of 10mg or 5mg BID, with gradual escalation to 25mg BID. Weekly hematological assessments were done during the first cycle, CT scans were done after every two cycles. Descriptive statistics for response to therapy were collected. Progression free survival (PFS), Overall survival (OS) curves were plotted using Kaplan-Meier method, comparisons between groups were made using the log rank test. Primary outcome of the study was to assess the overall response rate (ORR). Secondary objectives were to determine PFS, OS, duration of response and safety. Relationship between responses to oral ruxolitnib and gene expression profiling was explored. Results: Of the 60 patients enrolled, 25 patients had PTCL, 32 DLBCL, 3 pending path review. Median age was 62 yrs., 56.6% had stage IV disease. Median number of cycles received was 2 (min 1, max 60). At the time of evaluation, 76% patients had progressed on therapy. The median follow-up of patients was 3.7 months (min 0.9; max 61.4). Data for 41 patients was available for evaluation of response. Complete response (CR) was noted in 1 patient with PTCL. Partial response (PR) was noted in 1, stable disease (SD) in 4 patients. Among the responders, a PTCL patient with SD had a sustained response for 60 months, a patient with PR had a response duration of 31 months. The median OS and PFS were 5.9 and 1.8 months. PFS was 2.2 months in patients with PTCL and 1.8 months in DLBCL. Median OS was 5 months in patients with DLBCL, 6.9 months in PTCL. The estimated 6 month PFS and OS were 17% (95%CI: 9%, 28%) , 49% (95%CI: 35%, 62%). There was no difference in PFS or OS between PTCL and DLBCL (p = 0.42, p = 0.94). Grade 3 or higher adverse events were seen in 62%. Anemia was seen in 20%, thrombocytopenia in 8%, infections in 6%. Conclusions: Ruxolitinib can produce responses in some patients with relapsed/refractory NHL, particularly in patients with PTCL. It may play a role in combination therapies in future. Clinical trial information: NCT01431209.

Clinical characteristics and prognosis of primary breast lymphoma: Cleveland Clinic experience.

e19035 Background: Primary Breast lymphoma (PBL) is a rare form of extranodal non-Hodgkin lymphoma (NHL). The majority of PBL are diffuse large B-cell lymphoma (DLBL). Current treatments can achieve an overall survival of 5 years in 80% of the patients. We evaluated prognostic factors and survival rates in PBL patients at Cleveland clinic foundation (CCF). Methods: We retrospectively identified patients diagnosed with PBL at CCF between January 2004 and January 2018. Baseline characteristics were compared between the indolent and aggressive lymphoma groups using two sample T-test for continuous variables, chi-square test and fisher’s exact test for categorical variables. Overall survival (OS) was estimated by the Kaplan-Meier method and compared by the log-rank test. Results: A total of 36 patients with PBL were identified, of whom 35 patients (97.2%) were females with a median age of 66 years (34-95). Of all patients, 23 (63.9%) were indolent lymphoma and 13 (36.1%) were aggressive lymphoma. The most common subtypes were marginal zone lymphoma (33.3%), DLBL (25%) and follicular lymphoma (19.4%). Only 2 patients (5.6%) had implant-associated anaplastic large T-cell lymphoma. There was significant difference in presentation between indolent and aggressive lymphoma patients; 78.3% of indolent lymphoma patients presented with incidental mammogram lesions compared to 30.8% of aggressive lymphoma patients (P-value = .019).Seventy five percent of the patients presented with stage IE, 16.7 % presented with stage IIE and 8.3% presented with stage IV. Treatment received included chemotherapy (55.6%), radiotherapy (47.2%), surgeries (16.7%), and rituximab (80% of patients received chemotherapy). Six patients (16.7%) didn’t receive treatment. Only one patient received central nervous system prophylaxis. Median follow-up of patients was 37.1 months. Three-year OS for patients with indolent and aggressive PBL was 94.4% (95% CI 84.4% - 100%) and 90.9% (95% CI 75.4% - 100%), respectively (p = 0.69). Conclusions: Marginal zone lymphoma was the most common subtype in our cohort. Indolent lymphoma commonly present as incidental mammogram finding. Prognosis of PBL is not affected by histologic subtype, tumor stage and bilateral breast involvement. Current treatments achieve good control of the disease.

Investigation of lymphoid lesions of the head and neck using combined fine needle aspiration cytology and flow cytometry: Accuracy and pitfalls.

We reviewed the diagnostic utility of combined fine needle aspiration cytology (FNAC) and flow cytometry (FC) in the diagnosis of lymphoid lesions of the head and neck. In total, 1402 patients with combined FNAC-FC reports were correlated with follow-up information. Rapid on-site evaluation (ROSE) of cytological specimens was performed in 52% of cases. In total, 211 lymphoid malignancies were identified, including 198 non-Hodgkin lymphoma (NHL) and 13 Hodgkin lymphoma (HL). Accuracy measures for NHL were: sensitivity 95.5%; specificity 99.9%; PPV 99.5%; NPV 99.2%; accuracy 99.3%. Only seven of 13 cases of HL were detected by FNAC-FC. False negative cases included HL (six cases), diffuse large B-cell lymphoma (four), T-cell lymphoma (two), follicular lymphoma (one), marginal zone cell lymphoma (one) and B-cell NHL, not otherwise specified (one). Two false positive results were identified: one immunoblastic hyperplasia reported as suspicious for HL and one case reported as suggestive of NHL that was found to be reactive hyperplasia. Cases collected with ROSE had a significantly lower rate (P<0.0001) of insufficient cells for FC analysis (7.0%) than cases where ROSE was not performed (16.4%). Sensitivity (P<0.0001) and NPV (P=0.0023) were significantly higher for ROSE-collected specimens. None of the false-negative NHL cases had ROSE performed. FNAC-FC is a highly sensitive and specific test for NHL. Diagnostic errors mostly involved HL, large cell lymphomas and T-cell lymphomas. ROSE results in a significantly higher adequacy rate for FC and higher sensitivity for NHL.

Issue Highlights - March 2019.

This issue features, among others, two reviews and four original manuscripts in the field of clinical cytometry, all of them in the area of leukemia/lymphoma immunophenotyping. These may be summarized as follows: Jevremovic and colleagues reviewed the position of flow cytometry in the diagnosis, prognosis and follow-up of T- and NK-cell lymphoproliferations 1. The diagnosis of these entities is generally based on the demonstration of immunophenotypic abnormalities and demonstration of clonality. The latter studies involve V-beta T-cell receptor repertoire analysis and killer immunoglobulin like receptors (KIR). In this context it is important to realize that a T-cell clone does not need to be synonymous with “malignancy” but could also reflect the transient clonal proliferation of “reactive” T cells. Among the mature T-cell lymphoproliferative disorders, T-cell large granular lymphocytic leukemia (T-LGLL), anaplastic large T-cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma (AITL), mycosis fungoides or Sezary syndrome (MF/SS), T-cell prolymphocytic leukemia (T-PLL), hepatosplenic T-cell lymphoma (HSTCL) and peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) are distinguished. Within the NK-cell disorders, chronic lymphoproliferative disorder of NK cells (CLPD-NKs), extranodal NL/T-cell lymphoma, nasal type, aggressive NL-cell leukemia/lymphoma and NK-cell enteropathy are defined. Nowadays, flow cytometry is a sensitive and specific approach to detect T and NK-cell neoplasms but requires a thorough knowledge of the normal T-cell and NK-cell immune spectrum. Jan W. Gratama, Deputy Editor [Color figure can be viewed at wileyonlinelibrary.com] CD123, the alpha chain of IL3 receptor, is expressed in variable intensities on human leukocytes; the strongest expression is seen on plasmacytoid dendritic cells and basophils, whilst the marker is absent on nucleated red blood cells; a range of intermediate expression levels are seen on T cells, mature B cells, granulocytes and eosinophils. CD123 is expressed on AML blasts and most B-cell precursor ALL blasts whilst it is negative on most T-ALL blasts. The teams of the Laboratory for Medical Immunology at Erasmus MC (Rotterdam, Netherlands) in collaboration with the Dutch Childhood Oncology Group (The Hague, Netherlands) set out to study CD123 expression levels in 846 patients with acute leukemia in comparison to normal cell populations obtained in 1,252 unique bone marrow and peripheral blood samples 6. Immunophenotyping was performed using standardized procedures as developed by the EuroFlow collaborative project 7. Whilst published information on this topic was relatively scarce and difficult to compare due to different methodologies, Bras and colleagues confirmed most observations as they extensively document in this report 6. Importantly, they observed that in paired B-cell precursor ALL, CD123 expression was considerably higher at relapse than at initial diagnosis, whilst in AML, the leukemic stem cells (CD34pos, CD38neg fraction of tumor cells) expressed similar CD123 levels as the remainder of AML blasts. These observations make CD123 an interesting target for antibody-targeted therapy 8. Early positive minimal residual disease (MRD) is a strong predictor of response to treatment in ALL and AML. In an observational study of 125 children with B-cell precursor ALL, Loosveld and colleagues 9 investigated the prognostic value of flow cytometric assessment of MRD in peripheral blood on days 8 and 15 after start of cytoreductive therapy, compared to day 35 MRD on bone marrow using molecular techniques. Children with detectable PB MRD on day 15 and negative day 35 BM results had lower disease-free survival at 4 years follow-up, indicating the prognostic potential of this less invasive, blood-based procedure early after start of therapy as compared to conventional bone marrow studies. Mora and colleagues 10 studied 120 consecutive patients with chronic B-lymphoproliferations (81 within the CLL spectrum and 39 with other monoclonal B-cell disorders) to establish whether CD200, a member of the Ig receptors membrane proteins superfamily, would have added value to the immunological scoring system already developed by Matutes et al. 11. CD200 had already been suggested to be rather specific for B-CLL in earlier studies. This study confirmed the value of CD200 as diagnostic marker and revealed that it's addition to the Matutes score increased the accuracy of that ranking algorithm. Beke Debreceni et al. 12 analyzed the regulation of expression of the adhesion receptor L-selectin (CD62L) in a cohort of untreated patients with B-CLL. Expression of surface-bound CD62L and tumor necrosis factor alpha-converting enzyme (TACE), as well as total phosphatase and protein phosphatase-2A activities, were lower on B-CLL than on normal B cells whilst the reverse was true for soluble CD62L and phosphorylated mitogen-activated protein kinase (pp38MAPK). In separate in vitro experiments confirmed that a phosphatase inhibitor (calyculin A) could reduce the effect of pp38MAPK inhibitor on CD62L shedding. The authors concluded that the reduction of phosphatase activity in B-CLL has resulted in a downstream signaling cascade with subsequent reduction of surface-bound CD62L which is mediated by enhanced phosphorylation of p38MAPK and reduced TACE expression. Jan W. Gratama, Deputy Editor Email: j.w.gratama@erasmusmc.nl

Abstract A028: Memory stem T-cells expressing an optimized CD30-specific chimeric antigen receptor (CAR) efficiently eradicate peripheral T-cell lymphoma in vivo

Abstract Peripheral T-cell lymphomas (PTCL) represent the most aggressive form among non-Hodgkin lymphomas with a very poor prognosis (5-year survival of 30%), demanding innovative novel treatment strategies. Adoptive immunotherapy with chimeric antigen receptor (CAR) T-cells has demonstrated its therapeutic potential in advanced B-cell hematologic malignancies. However, its application to PTCL remains a formidable challenge mainly due to a lack of truly tumor-specific antigens that are not expressed on normal T-cells. Anaplastic large T-cell lymphomas (ALCL) and several other subtypes of PTCL express CD30, which is also expressed by activated normal T-cells but no other healthy tissues. Indeed, brentuximab-vedotin, an anti-CD30 antibody-drug conjugate, has shown some clinical efficacy in PTCL and ALCL patients although duration of responses is short in the majority of cases. Here, we developed a refined CD30-CAR T-cell approach to target CD30+ PTCL as a potential novel therapeutic strategy. We selected a novel targeting domain that is unaffected by soluble CD30 protein (Nagata S et al., Clin Cancer Res 2002) to prevent blockade of the CD30-CAR. Moreover, we optimized the therapy by using memory stem T-cells (TSCM) to promote engraftment and persistence of CD30-CAR T-cells after transfer.TSCM were generated with CD3/CD28 costimulation in presence of IL-7, IL-15 and IL-21 (Alvarez C et al., J Transl Med 2016). On day 2 of culture, cells were transduced with a third-generation lentiviral vector encoding the CD30-41BBz-EGFRt CAR. The cell line Karpas 299 (ALCL) was used as tumor model. Cytotoxicity assay was performed at 24 hours and the tumor cell death was detected by luminiscence. Mice were injected with Karpas 299 tumor cells (2x10^6 cells/mice; iv) and were treated with CD30-CAR TSCM (1x10^7 cells/mice; iv) when the tumor was established (day 10). Mice were followed daily for survival. The presence of CD30-CAR TSCM in lymphoid organs and their expression of immune checkpoint molecules (i.e., TIM-3, LAG-3) were analyzed at the end of the in vivo study by flow cytometry. TSCM were the most prevalent T-cell subset at day 10 of culture (84±3.1% of total cells), and the CD30-CAR expression was 82.8±1.0% in CD4+ TSCM and 85.2±2.0% in CD8+ TSCM. Although CD30 protein was detected in a fraction of activated T-cells in culture, CD30-CAR TSCM could be expanded ex vivo (CD4+ CD30-CAR TSCM: 96.0±3.2 fold expansion; CD8+ CD30-CAR TSCM: 109.0±4.2 fold expansion). CD30-CAR TSCM conferred specific cytolytic activity against Karpas 299 cells in vitro (tumor cell death 5:1 (effector:target) ratio: 70.2±5.1% vs. 0% with untransduced TSCM; p&amp;lt;0.001), which was not blockade by soluble CD30 protein. CD30-CAR TSCM were able to eliminate T-cell lymphoma in vivo (60% survival vs 0% control; p=0.001). In addition, CD30-CAR T-cells (&amp;gt;80% of detected CD4+ and CD8+ T-cells) were still present in lymphoid organs (bone marrow, spleen and lymph nodes) of surviving mice at 50 days after infusion. Tumor-bearing mice also showed CD30-CAR T-cells in their lymphoid organs (80% of total CD4+ and CD8+ T-cells) and in the tumor (67.5% of detected T-cells). Interestingly, a high expression of exhaustion markers TIM-3 (74%±6.8%) and LAG-3 (34%±9.7%) were found on those tumor-infiltrating lymphocytes (TILs). Collectively, our data demonstrate that TSCM cells can be efficiently transduced and ex vivo expanded with a novel CD30-CAR and confer potent antitumor efficacy against CD30+ PTCL in vitro and in vivo, with a potential improvement of the therapy using an immune checkpoint blockade for either TIM-3 or LAG-3. Our findings suggest the potential to improve outcome of patients with CD30+ PTCL through adoptive therapy with CD30-CAR modified T-cells. Citation Format: Laura Escribà-Garcia, Carmen Alvarez-Fernández, Ana Carolina Caballero, Rydzek Julian, Einsele Hermann, Jorge Sierra, Michael Hudecek, Javier Briones. Memory stem T-cells expressing an optimized CD30-specific chimeric antigen receptor (CAR) efficiently eradicate peripheral T-cell lymphoma in vivo [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A028.

Linfoma anaplásico de células T grandes primario cutáneo CD30+. Serie de nueve casos.

CD30+ anaplastic large T cell lymphoma is a cutaneous primary lymphoma in which there is no evidence of systemic disease; histopathological study is required for its diagnosis. To present the cases diagnosed with primary cutaneous CD30+ anaplastic large T-cell lymphoma over a 24-year period in Hospital General "Dr. Manuel Gea González" Department of Dermatology. Retrospective study. Descriptive statistics was carried out. Information was collected on gender, age, clinical characteristics, complementary test results, previous and current treatments, histopathological studies reports and immunohistochemistry test results. Of 29 309 records, nine patients (0.000034%) with a diagnosis of CD30+ anaplastic T cell lymphoma were found. Histopathological and immunohistochemical diagnosis was confirmed by two certified dermatopathologists. Average age was 61.2 years, and there was a predominance of the female gender, with initial clinical presentation as a papular or nodular lesion and varied topography. The prognosis of CD30+ anaplastic large T cell lymphoma in the studied population was dependent on clinical stage. The treatment at early stages has favorable results.

Transformed mycosis fungoide: About a moroccan case

The course of Mycosis Fungoides (MF) is indolent except when the transformation to a large T-cell lymphoma occurs. The diagnosis of transformed MF relies on the presence of more than 25% of large cells on biopsy of an MF lesion. Treatment of transformed MF is a major challenge as these patients have poor outcome. Here, we report a 53-year-old man presenting in an advanced stage of disease with nodules all over the body diagnosed as cutaneous CD30(−) large cell transformed MF.

A phase II study of a modified hyper-CVAD frontline therapy for patients with adverse risk diffuse large B-cell and peripheral T-cell non-Hodgkin lymphoma

To improve complete remission (CR) rates by reducing toxicity and enhancing delivery, we created a modified hyper-CVAD/MA regimen (cyclophosphamide, vincristine, doxorubicin, dexamethasone/methotrexate, cytarabine) by reducing the cytarabine dose (3 g/m2 to 2 g/m2) and number of cycles (eight to six). We conducted a phase II trial in the pre-rituximab era in the intermediate–high international prognostic index (IPI) (≥2) de novo diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphoma (PTCL) (ACTRN12605000105640). CR rates were compared with reported IPI-stratified rates. Sixty-three patients (n = 26 PTCL; n = 37 DLBCL) were evaluated; median follow-up of 30 months. CR rates for PTCL and DLBCL patients were 46% and 49%, respectively, similar with reported CR rates with CHOP-like chemotherapy (p = .6). Of the patients, 51 (81%) experienced ≥1 unplanned hospital admission; only 41 (65%) completed six cycles. The cytarabine modifications did not prevent significant toxicity. Modified hyper-CVAD/MA resulted in similar outcomes to CHOP-like chemotherapy in aggressive lymphomas and was associated with significant toxicity.

Acute abdominal pain in emergency room: Is it always a simple diagnosis?

Acute abdominal pain is characterized by pain arising from the abdominal area, of non-traumatic origin with a maximum duration of five days and represents a true medical emergency. It is also one of the most common reasons for referral to an emergency department and the most common cause for no trauma-related hospital admissions. Hematologic disorders represent the 0.3% of all admissions for acute abdominal pain. We report a rare case of retroperitoneal bulky mass due to anaplastic large T-cell lymphoma. This entity represents a rare tumor and early diagnosis leads to a correct diagnosis of the origin of the acute abdominal pain and chemotherapy is vital to ensure good prognosis.

Clinical Characteristics and Outcomes Among Very Elderly Patients with Major Lymphoma Subtypes: A Nordic Lymphoma Group Study

Introduction: The incidence of most lymphomas increase with age. Comorbidities, frailty and old age per se largely preclude inclusion of the very elderly in clinical trials. Thus, optimal treatment strategies and patient characteristics for elderly patients are less well defined and there is a lack of knowledge of how the oldest lymphoma patients are treated and fare. Lymphomas have a heterogeneous biology and even milder treatment may sometimes result in remission, survival benefits, and good palliation. With the rise in incidence and prevalence of lymphoma in an increasingly ageing population, improved knowledge regarding disease course, treatment and prognosis of lymphoma subtypes among the very elderly lymphoma population is warranted. Therefore, we aimed to characterise the cohort of very elderly (aged ≥85) patients with lymphoma with regard to distribution of lymphoma subtypes, choice of active treatment and overall survival (OS).Methods: The study population was identified via the Swedish lymphoma register (SLR, >95% national coverage). Data regarding stage, prognostic factors, treatment and survival among all patients aged ≥85 diagnosed with malignant lymphomas (any histology) 2007-2013 was retrieved. Diffuse large B-cell lymphoma (DLBCL), T-cell lymphomas, Hodgkin lymphoma and mantle cell lymphoma were grouped as aggressive lymphomas. Follicular lymphoma, marginal zone lymphoma and Mb Waldenström were grouped as indolent lymphomas. Overall survival (OS) proportions were computed and illustrated using the Kaplan-Meier method. Multivariate cox regression analysis was used to investigate associations of active treatment, age, Ann Arbor stage, performance status (PS) and elevated lactate dehydrogenase (LDH) with survival.Results: During the time period 1191 patients aged ≥85 were identified through the SLR. Of these, 298 (25%) were aged ≥90. The most commonly occurring lymphoma subtype was DLBCL (n=458, 38%). The number and proportion of patients with other subtypes are presented in Table 1. Among all patients, 36% presented with elevated LDH, 39% with PS score >2, 49% with Ann Arbor stage III-IV, 11% with bulky disease and 25% presented with B-symptoms. All these factors were associated with inferior outcome, as expected.Data regarding administration of active treatment was available for 75% (n= 887) of patients. Among patients with aggressive lymphoma subtypes, 389 patients (72%) received active treatment, of which 44% was specified as administered with curative intent. The most common type of treatment in this group was dose reduced R-CHOP. Among patients with indolent subtypes 124 patients (49%) received active treatment (most commonly chlorambucil, bendamustine or trofosfamide). Two-year OS for patients with aggressive and indolent lymphomas was 27.5% and 58.7%, respectively. OS rates for specific subtypes are presented in table 1 and figure 1. The increase in OS associated with administration of active treatment was more prominent among patients with aggressive lymphomas. Here, patients who received active treatment had a 2-year OS rate of 36.2%, compared to 11.3% for those who did not (adjusted hazard ratio (HR): 0.47 (0.35-0.63) p=<0.0001). Among patients with indolent lymphomas 2-year OS with active treatment was 63.4% and 57.3% without, adjusted HR: 0.76 (0.5-1.1) p=0.17).Conclusion: We demonstrate relatively encouraging overall survival data for very elderly patients from a real-world setting. Our data indicate that active treatment may be feasible also for some of the very elderly patients with lymphoma, especially among patients with aggressive lymphomas such as DLBCL. This study represents the largest cohort of its kind and this type of population based data may be useful to inform and improve clinical lymphoma management in this age group. Updated data including relative survival, comorbidity and addition of patients aged ≥85 from the Danish lymphoma register will be available and presented by the time of the ASH meeting. DisclosuresSmedby:Janssen Pharmaceuticals: Other: The Department have recieved partial funding from Janssen Pharmaceuticals.

Updates on Circulating Tumor DNA Assessment in Lymphoma.

The use of circulating tumor DNA (ctDNA) for the purposes of diagnosis, prognosis, assessment of treatment response, and monitoring for relapse is a new and developing field in lymphoma. This review aims to summarize many of the most recent advances in ctDNA applications. Recent studies have demonstrated the use of ctDNA assessment across many lymphoma subtypes including diffuse large B-cell lymphoma, follicular lymphoma, Hodgkin lymphoma, and T-cell lymphoma. In addition, many novel applications of ctDNA assessment have been described such as the development of new prognostic models, investigation of clonal evolution and heterogeneity, early assessment of treatment response, and prediction of response to targeted therapy as a form of personalized medicine. The use of ctDNA has been shown to be feasible across many lymphoma subtypes and has shown significant promise for several new applications. Additional studies will be needed to validate these findings prior to routine use in clinical practice.

The phosphoinositide-3 kinase (PI3K)-δ,γ inhibitor, duvelisib shows preclinical synergy with multiple targeted therapies in hematologic malignancies.

Duvelisib is an orally active dual inhibitor of PI3K-δ and PI3K-γ in clinical development in hematologic malignancies (HM). To identify novel pairings for duvelisib in HM, it was evaluated alone and in combination with 35 compounds comprising a diverse panel of standard-of-care agents and emerging drugs in development for HM. These compounds were tested in 20 cell lines including diffuse large B-cell, follicular, T-cell, and mantle cell lymphomas, and multiple myeloma. Single agent activity was seen in fourteen cell lines, with a median GI50 of 0.59 μM. A scalar measure of the strength of synergistic drug interactions revealed a synergy hit rate of 19.3% across the matrix of drug combinations and cell lines. Synergy with duvelisib was prominent in lymphoma lines with approved and emerging drugs used to treat HM, including dexamethasone, ibrutinib, and the BCL-2 inhibitor venetoclax. Western blotting revealed that certain duvelisib-treated cell lines showed inhibition of phosphorylated (p) AKT at serine 473 only out to 12 hours, with mTORC2 dependent re-phosphorylation of pAKT evident at 24 hours. Combination with dexamethasone or ibrutinib, however, prevented this reactivation leading to durable inhibition of pAKT. The combination treatments also inhibited downstream signaling effectors pPRAS40 and pS6. The combination of duvelisib with dexamethasone also significantly reduced p-4EBP1, which controls cap dependent translation initiation, leading to decreased levels of c-MYC 6 hours after treatment. In support of the in vitro studies, in vivo xenograft studies revealed that duvelisib in combination with the mTOR inhibitor everolimus led to greater tumor growth inhibition compared to single agent administration. These data provide a rationale for exploring multiple combinations in the clinic and suggest that suppression of mTOR-driven survival signaling may be one important mechanism for combination synergy.

Time to diagnosis and associated costs of an outpatient vs inpatient setting in the diagnosis of lymphoma: a retrospective study of a large cohort of major lymphoma subtypes in Spain

BackgroundMainly because of the diversity of clinical presentations, diagnostic delays in lymphoma can be excessive. The time spent in primary care before referral to the specialist may be relatively short compared with the interval between hospital appointment and diagnosis. Although studies have examined the diagnostic intervals and referral patterns of patients with lymphoma, the time to diagnosis of outpatient compared to inpatient settings and the costs incurred are unknown.MethodsWe performed a retrospective study at two academic hospitals to evaluate the time to diagnosis and associated costs of hospital-based outpatient diagnostic clinics or conventional hospitalization in four representative lymphoma subtypes. The frequency, clinical and prognostic features of each lymphoma subtype and the activities of the two settings were analyzed. The costs incurred during the evaluation were compared by microcosting analysis.ResultsA total of 1779 patients diagnosed between 2006 and 2016 with classical Hodgkin, large B-cell, follicular, and mature nodal peripheral T-cell lymphomas were identified. Clinically aggressive subtypes including large B-cell and peripheral T-cell lymphomas were more commonly diagnosed in inpatients than in outpatients (39.1 vs 31.2% and 18.9 vs 13.5%, respectively). For each lymphoma subtype, inpatients were older and more likely than outpatients to have systemic symptoms, worse performance status, more advanced Ann Arbor stages, and high-risk prognostic scores. The admission time for diagnosis (i.e. from admission to excisional biopsy) of inpatients was significantly shorter than the time to diagnosis of outpatients (12.3 [3.3] vs 16.2 [2.7] days; P < .001). Microcosting revealed a mean cost of €4039.56 (513.02) per inpatient and of €1408.48 (197.32) per outpatient, or a difference of €2631.08 per patient.ConclusionsAlthough diagnosis of lymphoma was quicker with hospitalization, the outpatient approach seems to be cost-effective and not detrimental. Despite the considerable savings with the latter approach, there may be hospitalization-associated factors which may not be properly managed in an outpatient unit (e.g. aggressive lymphomas with severe symptoms) and the cost analysis did not account for this potentially added value. While outcomes were not analyzed in this study, the impact on patient outcome of an outpatient vs inpatient diagnostic setting may represent a challenging future research.