We examined adults with untreated Burkitt lymphoma (BL) from 2009 to 2018 across 30 US cancer centers. Factors associated with progression-free survival (PFS) and overall survival (OS) were evaluated in univariate and multivariate Cox models. Among 641 BL patients, baseline features included the following: median age, 47 years; HIV+, 22%; Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2 to 4, 23%; >1 extranodal site, 43%; advanced stage, 78%; and central nervous system (CNS) involvement, 19%. Treatment-related mortality was 10%, with most common causes being sepsis, gastrointestinal bleed/perforation, and respiratory failure. With 45-month median follow-up, 3-year PFS and OS rates were 64% and 70%, respectively, without differences by HIV status. Survival was better for patients who received rituximab vs not (3-year PFS, 67% vs 38%; OS, 72% vs 44%; P < .001) and without difference based on setting of administration (ie, inpatient vs outpatient). Outcomes were also improved at an academic vs community cancer center (3-year PFS, 67% vs 46%, P = .006; OS, 72% vs 53%, P = .01). In multivariate models, age ≥ 40 years (PFS, hazard ratio [HR] = 1.70, P = .001; OS, HR = 2.09, P < .001), ECOG PS 2 to 4 (PFS, HR = 1.60, P < .001; OS, HR = 1.74, P = .003), lactate dehydrogenase > 3× normal (PFS, HR = 1.83, P < .001; OS, HR = 1.63, P = .009), and CNS involvement (PFS, HR = 1.52, P = .017; OS, HR = 1.67, P = .014) predicted inferior survival. Furthermore, survival varied based on number of factors present (0, 1, 2 to 4 factors) yielding 3-year PFS rates of 91%, 73%, and 50%, respectively; and 3-year OS rates of 95%, 77%, and 56%, respectively. Collectively, outcomes for adult BL in this real-world analysis appeared more modest compared with results of clinical trials and smaller series. In addition, clinical prognostic factors at diagnosis identified patients with divergent survival rates.
Introduction: Historically, outcomes for BL have improved in adults using dose intensive chemotherapy regimens and early CNS prophylaxis. More recent data using a less intensive regimen, DA-EPOCH, have been reported. We analyzed detailed patient (pt) & disease characteristics and treatment patterns across 26 US CCs over a recent 9 year (yr) period and also determined survival rates & prognostication. Methods: We conducted a large multicenter retrospective study of newly diagnosed (dx) adult BL pts (6/2009 - 6/2018). Dx was established by institutional expert pathology review; all cases were verified for BL based on 2016 WHO criteria (high grade B cell lymphoma, BL like, etc were excluded). Survival rates were estimated by Kaplan-Meier with differences assessed by log rank test. Univariate (UVA) associations were derived via Cox model with variables P ≤0.05 entered stepwise into a multivariate (MVA) model. Using significant factors from the MVA, a prognostic survival model was constructed. Results: Among N=557 verified BL cases, clinical features included: median age 47 yrs (17-88 yrs; 24% ≥60 yrs); male 76%; HIV+ 22%; ECOG PS 0/1 76%; B symptoms 51%; elevated LDH 78% (3, 5, & 10x elevation: 44%, 29% & 15%, respectively); hemoglobin <10.5 gm/dL 32%; albumin <3.5 30%; bone marrow (BM) involved 35%; non-BM extranodal (EN) in 80%; >1 EN 43%; and 76% stage 3-4 disease (10% stage 1). Additionally, 16% and 3% of pts had baseline leptomeningeal (CSF or cranial nerve palsy) or parenchymal CNS involvement, respectively (see Zayac A et al. ASH 2019 for details). For MYC partner, 68% had t(8;14), 4% light chain, 5% negative FISH (otherwise classic BL) and 23% + break apart probe. HIV+ pts had several clinical differences: CSF+ 23% vs 12% P=0.003; CNS 19% vs 8% P<0.001; ECOG PS 2-4 32% vs 21% P=0.002; BM 64% vs 34% P=0.03; and >1 EN 60% vs 38% P<0.001. For all pts, 87% had Tx at an academic CC (13% at community CC). Tx regimens were: CODOX-M/IVAC (Magrath) 31%, HyperCVAD/MA 29%, DA-EPOCH 28%, other 10% (mostly CHOP-based & CALGB Tx) & 1% were never treated. 90% of pts received rituximab as part of Tx (69% inpatient (inpt) & 31% outpatient) & 2% had consolidative autologous SCT. Response among all pts were CR 72%, PR 6%, SD 1%, PD 14%, 7% not evaluable. The treatment related mortality (TRM) rate across all pts was 8.9% (HIV+ vs not: 13% vs 8% P=0.09); most common: sepsis 48%, GI bleed/perforation 14% & respiratory failure 12%. TRM by Tx: hyperCVAD/MA 11.5%, EPOCH 6.4%, Magrath 6.3% & other 18.9%. With 39 month median follow-up, 3 year progression-free survival (PFS) and overall survival (OS) were 65% and 72%, respectively (Fig 1A). Among all pts who experienced disease progression, 90% occurred <12 months from dx (4% after 2 yrs). There were 20 cases (4%) of 2nd cancers seen including 7 secondary MDS/AML (median 26 months) & 6 cases of Hodgkin or other NHL (median 54 months). For prognostication, outcomes were inferior for pts ages ≥40 yrs & LDH >3x normal (Fig 1B/C). Notably, survival rates were not different based on HIV status (Fig 1D) or by the 3 most common Tx regimens (Fig 1E). However, there were important Tx differences based on presence of CNS involvement (see Zayac A et al. ASH 2019). Additionally, use of rituximab was associated with improved PFS & OS (Fig 1F), while outcomes were similar whether rituximab was given inpt vs outpatient (inpt PFS HR 1.25, P=0.19). Furthermore, Tx at an academic CC was associated with improved outcomes, which persisted on MVA (PFS HR 0.54, 95%CI 0.33-0.88 P=0.01; OS HR 0.50, 95%CI 0.29-0.87 P=0.01) & achievement of initial CR was strongly prognostic (Fig 1G). Baseline factors significant on UVA for PFS & OS were: age ≥40 yrs; PS 2-4; LDH >3x; anemia, low albumin; BM involvement; Stage 3-4; CSF+; & >1 EN. On MVA, factors associated with inferior survival were: age ≥40 yrs (PFS HR 1.57, P<0.001; OS HR 1.89, P=0.001); PS 2-4 (PFS HR 1.57, P=0.002; OS HR 2.16, P<0.001); & LDH >3x (PFS HR 2.28, P<0.0001; OS HR 1.96, P<0.0001). Collectively, these factors yielded a BL survival model (Fig 1H/I). Conclusions: Outcomes for adult BL in this contemporary, large, multicenter RW analysis appear inferior to smaller published series. Interestingly, despite increased adverse prognostic factors, survival rates appeared similar in HIV+ pts. In addition, use of rituximab, achievement of initial CR, and Tx at an academic CC were associated with improved survival. Finally, a novel BL-specific survival model identified pts with markedly divergent outcomes. Disclosures Evens: Seattle Genetics: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Tesaro: Research Funding; Verastem: Consultancy, Honoraria. Danilov:Janssen: Consultancy; Seattle Genetics: Consultancy; MEI: Research Funding; Abbvie: Consultancy; Pharmacyclics: Consultancy; Takeda Oncology: Research Funding; Janssen: Consultancy; TG Therapeutics: Consultancy; Curis: Consultancy; Pharmacyclics: Consultancy; Aptose Biosciences: Research Funding; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Bayer Oncology: Consultancy, Research Funding; Celgene: Consultancy; Bristol-Meyers Squibb: Research Funding; MEI: Research Funding; Gilead Sciences: Consultancy, Research Funding; Abbvie: Consultancy; Bristol-Meyers Squibb: Research Funding. Reddy:KITE Pharma: Consultancy; BMS: Consultancy, Research Funding; Celgene: Consultancy; Genentech: Research Funding; Abbvie: Consultancy. Farooq:Celgene: Honoraria; Kite Pharma: Research Funding. Khan:Janssen: Other: Educational Content/Symposium; Abbvie: Membership on an entity's Board of Directors or advisory committees; Bristol Myers: Other: Research Funds; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Yazdy:Genentech: Research Funding; Bayer: Honoraria; Abbvie: Consultancy; Octapharma: Consultancy. Karmali:Gilead/Kite; Juno/Celgene: Consultancy, Speakers Bureau; Astrazeneca: Speakers Bureau; Takeda, BMS: Other: Research Funding to Institution. Martin:Janssen: Consultancy; Teneobio: Consultancy; Celgene: Consultancy; Karyopharm: Consultancy; Sandoz: Consultancy; I-MAB: Consultancy. Diefenbach:LAM Therapeutics: Research Funding; Incyte: Research Funding; Genentech: Consultancy, Research Funding; Trillium: Research Funding; Millenium/Takeda: Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; MEI: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Denovo: Research Funding. Epperla:Pharmacyclics: Honoraria; Verastem Oncology: Speakers Bureau. Feldman:Eisai: Research Funding; Amgen: Research Funding; Cell Medica: Research Funding; Roche: Research Funding; Corvus: Research Funding; Kyowa Hakko Kirin: Research Funding; Pfizer: Research Funding; Trillium: Research Funding; Viracta: Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau; Portola Pharma: Research Funding; Roche: Research Funding. Lossos:Janssen Scientific: Membership on an entity's Board of Directors or advisory committees; NIH: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Naik:Celgene: Other: Advisory board. Kamdar:Celgene: Consultancy; AstraZeneca: Consultancy; Seattle Genetics: Speakers Bureau; University of Colorado: Employment; Pharmacyclics: Consultancy. Portell:AbbVie: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Genentech: Consultancy, Research Funding; Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; TG Therapeutics: Research Funding; Xencor: Research Funding; Roche/Genentech: Research Funding; Infinity: Research Funding; Amgen: Consultancy. Olszewski:Spectrum Pharmaceuticals: Research Funding; TG Therapeutics: Research Funding; Genentech: Research Funding; Adaptive Biotechnologies: Research Funding. Alderuccio:Agios: Other: Immediate family member; Puma Biotechnology: Other: Immediate family member; Foundation Medicine: Other: Immediate family member; Targeted Oncology: Honoraria; Inovio Pharmaceuticals: Other: Immediate family member; OncLive: Consultancy.
Background: BL is associated with a high risk of primary or secondary CNS involvement, warranting intrathecal (IT) and/or systemic therapy that penetrates the blood-brain barrier (BBB). The lower-intensity DA-EPOCH-R regimen has recently shown high survival rates in BL (Dunleavy, NEJM 2013), but it omits drugs traditionally used for CNS prophylaxis (like high-dose methotrexate [HDMTX]). The objective of this multi-institutional retrospective study was to examine treatments, risk factors, and CNS-related outcomes among patients (pts) with BL. Methods: We collected data from 26 US centers on adult BL pts diagnosed (dx) in 6/2009-6/2018. Using institutional expert pathology review and 2016 WHO criteria, we excluded other high-grade lymphomas (including BL-like/unclassifiable), or cases with inadequate clinicopathologic data. We studied factors associated with baseline CNS involvement (CNSinv) using logistic regression reporting odds ratios (OR). Progression-free (PFS), overall survival (OS), and cumulative incidence function of CNS recurrence (in a competing risk analysis) were examined in Cox or Fine-Gray models reporting hazard (HR) or subhazard ratios (SHR), respectively. All estimates report 95% confidence intervals (in square brackets). Results: Among 557 BL pts (median age, 47 years [yr], 24% women, 23% HIV+), 107 (19%) had CNSinv at dx, including 89 (16%) with leptomeningeal, and 15 (3%) with parenchymal CNS disease. In a multivariable model, factors significantly associated with CNSinv at dx included stage 3/4 (OR, 11.2 [1.47-85.9]), poor performance status (PS; OR, 2.12 [1.22-3.69]), ≥2 extranodal sites (OR, 3.77 [2.02-7.03]), or marrow involvement (OR, 2.44 [1.35-4.39]), whereas intestinal involvement conferred low risk of CNSinv (OR, 0.27 [0.11-0.65]). CNSinv at dx was not significantly associated with use of specific chemotherapy regimens (Fig. A,P=.75) or receipt of IT chemotherapy (91% vs 84%, P=.065). Pts with CNSinv were less likely to achieve a complete response (62% vs 76%, P=.005), had worse 3 yr PFS (47% vs 69%; P<.001, Fig. B) and OS (52% vs 75%; P<.001, Fig. C). However, these associations were not significant when adjusted for other prognostic factors (age ≥40y, poor PS, LDH>3x upper limit of normal [LDH>3x]; see Evens AM et al, ASH 2019 for further details). With median follow up of 3.6 yrs, 33 pts (6%) experienced a CNS recurrence (82% within 1 yr from dx; 79% purely in CNS, and 21% with concurrent systemic BL). The cumulative risk of CNS recurrence was 6% [4-8%] at 3y (Fig. D). Univariate significant predictors of CNS recurrence included baseline CNSinv, HIV+ status, stage 3/4, poor PS, LDH>3x, involvement of ≥2 extranodal sites, marrow, or testis. However, in a multivariate model only baseline CNSinv (SHR, 3.35 [1.53-7.31]) and poor PS (SHR, 2.24 [1.03-4.90]) retained significance. The 3 yr risk of CNS recurrence varied from 3% for pts with no risk factor, to 10% with one, and 17% with both factors (Fig. E). In addition, the risk of CNS recurrence differed according to chemotherapy regimen, and was significantly higher for pts treated with DA-EPOCH (12% at 3y [8-18%]; Fig. F) compared with CODOX-M/IVAC (4% [2-8%]) or hyperCVAD/MA (3% [1-6%]; SHR for DA-EPOCH vs. others, 3.50 [1.69-7.22]). All pts recurring after DA-EPOCH had received IT chemotherapy. Higher risk of CNS recurrence persisted with DA-EPOCH regardless of baseline CNSinv (Pinteraction=.70), poor PS (Pint=.14), or HIV status (Pint=.89). Baseline CNSinv was the strongest factor associated with CNS recurrence after DA-EPOCH (3 yr risk, 30% vs 8%, P<.001). Of 7 pts who received HDMTX with DA-EPOCH (6 with leptomeningeal CNSinv at dx), 3 (43%) experienced CNS recurrence. Median OS among all BL pts with CNS recurrence was 2.8 months [1.9-3.9] (Fig. G). After recurrence, 67% of pts received salvage systemic and 9% IT chemotherapy, 3% radiation, and 21% hospice care. Conclusions: In adult BL, baseline CNSinv and poor PS predicted subsequent CNS recurrence, an outcome that is associated with a dismal prognosis. Furthermore, treatment with DA-EPOCH was associated with a significantly increased risk of CNS recurrence in this real-world analysis. For BL pts with baseline CNSinv treated in routine clinical practice, regimens with highly BBB-penetrant drugs (e.g. CODOX-M/IVAC, hyperCVAD/MA) may be preferred. Studies should delineate ways to mitigate the risk of CNS recurrence with lower-intensity programs. Disclosures Evens: Seattle Genetics: Consultancy, Honoraria; Research to Practice: Honoraria; Verastem: Consultancy, Honoraria; Affimed: Consultancy, Honoraria; Pharmacyclics: Honoraria, Other: DMC; Bayer: Consultancy, Honoraria; Takeda: Research Funding; Merck: Research Funding. Smith:Incyte Corporation: Research Funding; Seattle Genetics: Research Funding; Portola Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Acerta Pharma BV: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Ignyta (spouse): Research Funding; Merck Sharp & Dohme Corp: Consultancy, Research Funding; Denovo Biopharma: Research Funding; Bristol-Myers Squibb (spouse): Research Funding; Ayala (spouse): Research Funding. Naik:Celgene: Other: Advisory board. Reddy:KITE Pharma: Consultancy; Abbvie: Consultancy; Genentech: Research Funding; BMS: Consultancy, Research Funding; Celgene: Consultancy. Farooq:Celgene: Honoraria; Kite Pharma: Research Funding. Epperla:Verastem Oncology: Speakers Bureau; Pharmacyclics: Honoraria. Khan:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Educational Content/Symposium; Abbvie: Membership on an entity's Board of Directors or advisory committees; Bristol Myers: Other: Research Funds. Alderuccio:Puma Biotechnology: Other: Immediate family member; Agios: Other: Immediate family member; Inovio Pharmaceuticals: Other: Immediate family member; Targeted Oncology: Honoraria; OncLive: Consultancy; Foundation Medicine: Other: Immediate family member. Yazdy:Bayer: Honoraria; Genentech: Research Funding; Octapharma: Consultancy; Abbvie: Consultancy. Diefenbach:Bristol-Myers Squibb: Consultancy, Research Funding; Denovo: Research Funding; Genentech: Consultancy, Research Funding; Incyte: Research Funding; LAM Therapeutics: Research Funding; MEI: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millenium/Takeda: Research Funding; Trillium: Research Funding. Karmali:Astrazeneca: Speakers Bureau; Takeda, BMS: Other: Research Funding to Institution; Gilead/Kite; Juno/Celgene: Consultancy, Speakers Bureau. Martin:Celgene: Consultancy; Teneobio: Consultancy; Karyopharm: Consultancy; Janssen: Consultancy; Sandoz: Consultancy; I-MAB: Consultancy. Magarelli:Tevan Oncology: Speakers Bureau. Kamdar:Seattle Genetics: Speakers Bureau; Pharmacyclics: Consultancy; AstraZeneca: Consultancy; Celgene: Consultancy; University of Colorado: Employment. Portell:Xencor: Research Funding; Roche/Genentech: Research Funding; Infinity: Research Funding; TG Therapeutics: Research Funding; AbbVie: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Genentech: Consultancy, Research Funding; Amgen: Consultancy; Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding. Lossos:Janssen Scientific: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; NIH: Research Funding. Olszewski:Genentech: Research Funding; Adaptive Biotechnologies: Research Funding; TG Therapeutics: Research Funding; Spectrum Pharmaceuticals: Research Funding.
Post transplant lymphoproliferative disorder (PTLD) represents a life threatening disorder occurring after transplantation, ranging from a polyclonal mononucleosis like illness to a monomorphic high grade neoplasm with cytologic and histopathologic evidence indicative of transformation to lymphoma. PTLD of diffuse large B-cell lymphoma (DLBCL) subtype, isolated to the esophagus is a rare diagnosis. We describe the first case of an immunocompromised adult patient diagnosed with DLBCL-PTLD limited to his esophagus without an associated mass or locoregional lymphadenopathy on imaging since the institution of the revised Cheson criteria, which includes positron emission tomography-computed tomography as the standard staging modality. Even more unique to our case was the suggestion of underlying cytomegalovirus (CMV) gastritis leading to a hypothesis about a less well understood relationship between CMV and Epstein Barr virus (EBV). In the post transplant setting, immunocompromised state, or EBV positive state, upper gastrointestinal symptoms should prompt investigation with an upper endoscopy (EGD). Additionally, specific to our case, the fact that the patients' presentation was suspicious for CMV gastritis raises the possibility that the CMV infection predated his PTLD increasing his risk of acquiring PTLD. This reemphasizes the importance and diagnostic utility of early screening with EGD in patients after transplantation.
Background. The increasing incidence of primary cutaneous B-cell lymphomas (PCBCLs) presents new challenges for clinicians. Despite advances in the clinical and pathologic characterization of PCBCL, the significance of the current staging approach as a risk profiling tool and the effect of various treatments on outcome remain unclear. Materials and Methods. We retrospectively reviewed patients who presented with a diagnosis of PCBCL seen at The Ohio State University between 1998 and 2012. We reviewed the initial presentation and treatment modality.We then assessed whether the treatment modality (conservative skin-directed vs. definitive radiation with or without systemic therapy), stage (T1 or $T2), or histologic subtype (primary cutaneous follicle center lymphoma [PCFCL] vs. primary cutaneous marginal zone B-cell lymphoma [PCMZL]) affected the riskof recurrence. Results. We identified 67 patients referred with an initial diagnosis of PCBCL. After imaging, 12 did not meet the criteria
Background: Tenalisib (RP6530), a highly selective PI3K δ/γ and SIK3 inhibitor has shown promising activity as a single agent in T Cell lymphoma (TCL) and a differentiated safety profile (Huen A et al., Cancers,2020). In vitro studies in TCL cell lines showed synergistic activity when tenalisib was combined with romidepsin. A Phase I/II study of tenalisib in combination with romidepsin was designed to assess safety, pharmacokinetics, and efficacy in patients with relapsed/refractory (R/R) TCL peripheral (PTCL) and cutaneous T cell lymphoma (CTCL) (NCT03770000). Methods: This was a multi-center, open label study. We performed a Phase I, 3+3 dose escalation study to determine the MTD/recommended Phase II dose (RP2D), and a dose expansion study in both the subtypes separately (PTCL and CTCL). Patients received tenalisib at doses ranging from 400-800 mg BID (fasting), orally in combination with romidepsin at doses ranging from 12-14 mg/m 2, intravenously, given on Days 1,8 and 15 of a 28-day cycle. Results: Thirty-three patients (16 PTCL and 17 CTCL) who received more than 1 prior therapy were enrolled in the study; 9 in dose escalation and 24 in dose expansion. Of the 33 patients, 64% were refractory to their last therapy. The median number of prior therapies was 3. Most patients (67%) had stage III/IV disease at time of enrolment. No dose limiting toxicity (DLT) was reported during dose escalation; tenalisib 800 mg BID with romidepsin 14 mg/m 2 (given on Days 1, 8, and 15) was chosen as the RP2D. The most frequent treatment emergent adverse events (TEAEs) were nausea (All: 73% and ≥G3:0%), thrombocytopenia (All:57% and ≥G3:21%), fatigue (All: 54% and ≥G3:6%), AST elevation (All:33% and ≥G3:6%) ALT elevation (All:27% and ≥G3:18%), neutropenia (All: 27% and ≥G3:15%), vomiting (All:27% and ≥G3:0%), decreased appetite (All: 27% and ≥G3:0%). There were no unexpected TEAEs. Among CTCL patients, five related TEAEs led to drug discontinuation were sepsis, ALT elevation, GGT elevation, rash, and dysgeusia. None of the PTCL patients discontinued the study drug due to related TEAEs. Incidences of TEAEs leading to drug interruption (72%) and dose reduction (45%) of any the drugs in the combination were similar in PTCL and CTCL groups. Based on C max and AUC, dose proportional exposure of tenalisib was observed from doses 400-800 mg BID. Co-administration of romidepsin with tenalisib did not significantly alter the PK of either agent. Of the 33 patients enrolled, 27 (12 PTCL and 15 CTCL) who received at least 1 dose of study drug and provided at least 1 post-baseline efficacy assessment were considered evaluable for efficacy as per protocol. The overall response rate (ORR) was of 63%; 7 (26%) patients achieved CR and 10 (37%) patients had PR (Table 1). The median duration of response (DoR) was 5.03 months (range: 2.16 months-Not Reached). In twelve evaluable PTCL patients, the ORR was 75% with 6 CR (50%) and 3 PR (25%). Among 15 evaluable CTCL patients, 8 responded with an ORR of 53.3%, 1 CR (6.7%) and 7 PR (46.7%). The median DoR was 5.03 (range: 2.16 months-Not Reached) for PTCL and 3.8 months (1.9-18.86) for CTCL. Three of the six (50%) PTCL patients with CR were bridged to transplant. Six patients who benefitted with the treatment and completed the protocol were enrolled in an open-label compassionate medication study after Cycle 7 and are being followed up. Conclusions: The combination of tenalisib and romidepsin demonstrates a favorable safety profile and promising anti-tumor activity in patients with R/R TCL. Based on these encouraging results, further development of this combination in PTCL patients in being planned. Figure 1 Figure 1. Disclosures Huen: Rhizen: Research Funding; Elorac: Research Funding; Kyowa Kirin: Research Funding; Tillium: Research Funding; Innate: Research Funding; Galderma: Research Funding; Miragen: Research Funding. Ai: Kymria, Kite, ADC Therapeutics, BeiGene: Consultancy. Feldman: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Study investigator. Alderuccio: ADC Therapeutics: Consultancy, Research Funding; Oncinfo / OncLive: Honoraria; Puma Biotechnology: Other: Family member; Inovio Pharmaceuticals: Other: Family member; Agios Pharmaceuticals: Other: Family member; Forma Therapeutics: Other: Family member. Kuzel: Cardinal Health: Membership on an entity's Board of Directors or advisory committees; Exelixis: Membership on an entity's Board of Directors or advisory committees; Genomic Health: Membership on an entity's Board of Directors or advisory committees; Sanofi-Genzyme Genomic Health Tempus laboratories Bristol Meyers Squibb: Honoraria; Abbvie: Other; Curio Science: Membership on an entity's Board of Directors or advisory committees; AmerisourceBergen Corp: Membership on an entity's Board of Directors or advisory committees; CVS: Membership on an entity's Board of Directors or advisory committees; Tempus Laboratories: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees; Merck: Other: Data Monitoring Committee Membership; Amgen: Other: Data Monitoring Committee Membership; SeaGen: Other: Data Monitoring Committee Membership; Medpace: Other: Data Monitoring Committee Membership.
Angioimmunoblastic T-cell lymphoma (AITL) is the second most common type of peripheral T-cell lymphoma (PTCL) worldwide, and in some countries the most common form. Clinically, AITL usually presents with systemic symptoms, diffuse lymphadenopathy, hepatosplenomegaly and common laboratory abnormalities such as hypergammaglobulinemia. Skin rashes are seen in 50–80% of patients. AITL derives follicular T-helper cells (TFH), that express germinal center markes and produces hyperactivation of B-cell seen in AITL. Although the histologic features of AITL in the skin could be similar to pathologic findings present in lymph node biopsies, we present herein 2 cases of AITL with histologic and immunophenotypic features that were somewhat suggestive of extranodal marginal zone lymphoma (MALT).Caution is urged to exclude the possibility of a systemic T-cell lymphoma such as AITL in cutaneous and lymph node B-cell proliferations.
Introduction: The chemotherapy regimen dose adjusted (DA)-EPOCH (etoposide, prednisone, vincristine, doxorubicin, and cyclophosphamide) is a first line option for peripheral T-cell lymphomas (PTCLs), but for most subtypes relapses are common and long-term outcomes are poor. Checkpoint blockade is an immunotherapeutic approach that has shown efficacy as a single agent in relapsed PTCLs. The combination of checkpoint blockade and cytotoxic chemotherapy can have additive or synergistic activity by increasing the expression of neoantigens and overcoming mechanisms of resistance to immunotherapy such as weak tumor immunogenicity and an immune suppressive tumor microenvironment. Methods: We conducted a single arm, open-label clinical trial evaluating the efficacy and safety of the anti-PD1 antibody nivolumab (Nivo) in combination with DA-EPOCH in newly diagnosed PTCLs with ≥Stage II disease by Ann Arbor criteria. Pts were allowed to receive one cycle of chemotherapy prior to enrollment. Pts received Nivo (360 mg) followed by DA-EPOCH every 21 days for a planned six cycles unless treatment was stopped early for progression. For any immune related adverse event (irAE), Nivo was held until resolution to grade 1 and on ≤10mg prednisone. For serious grade 3-4 irAEs, Nivo was omitted with remaining DA-EPOCH cycles. DA-EPOCH was dose adjusted according to CALGB 50303 with the exception that pts could begin treatment at dose level -1 (i.e. 600 mg/m2 cyclophosphamide), at investigator's discretion. Pts who received one cycle of chemotherapy prior to enrollment received five cycles of Nivo + DA-EPOCH. After completing six cycles of chemotherapy, pts had the option to proceed with consolidative autologous stem cell transplant (ASCT) versus surveillance, according to patient/physician preference. Responses were assessed by PET/CT after 2 cycles of Nivo + DA-EPOCH and after the last cycle, using RECIL criteria. PFS events were defined as start of new treatment, progression, or death. Targeted next generation sequencing and multiplex immunohistochemistry of diagnostic tumor tissue are being performed. Results: We enrolled 18 pts: 4 angioimmunoblastic TCLs, 2 nodal PTCLs with T-follicular helper phenotype, 7 PTCL-NOS (not otherwise specified), 2 primary cutaneous gamma delta TCLs, 2 ALK negative anaplastic large cell lymphomas, and 1 subcutaneous panniculitis-like TCL who had progressed on methotrexate. Median age was 66 (range 43-77). International Prognostic Index (IPI) was high (4-5) in 50% (N=9), intermediate (2-3) in 33% (N=6), and low in 17% (N=3) of pts. Immune related AEs of all grades occurred in 78% (N=14) of pts and 39% (N=7) of pts experienced ≥grade 3 irAEs. 44% (N=8) of pts required discontinuation of Nivo due to irAEs. In the 8 pts whose irAEs resulted in discontinuation of Nivo, the irAE occurred prior to the second or third cycle of Nivo + DA-EPOCH. None of the 6 pts who received a cycle of anthracycline based chemotherapy prior to enrolling on trial experienced an irAE resulting in dose hold or discontinuation of Nivo, whereas 8 of 12 pts who did not receive a prior cycle of anthracycline based chemotherapy experienced an irAE requiring a dose hold or discontinuation of Nivo. The most common non-hematologic non-immune related ≥grade 2 AEs were related to infectious complications. Interim and end of induction overall response rates were 100% and 83%, respectively. We observed 10 CR, 5 PR, and 3 PD at the end of induction. There were 2 pts who received consolidation with ASCT. With a median follow up of 375 days (range 207-422), median modified PFS was 333 days (range 138-666) and median OS was not reached. The three pts with PD during induction were 2 PTCL-NOS (with a cytotoxic phenotype) and 1 AITL (with PD1+ tumor cells). Further correlative studies are ongoing to identify predictors of response. Discussion: In this pilot study using Nivo + DA-EPOCH for newly diagnosed PTCLs, we observed early immune related dose limiting AEs. Pts who received a cycle of anthracycline based chemotherapy prior to enrollment did not experience any dose limiting irAEs. We postulate that T-cell lymphoma pts are immunologically primed for irAEs, which can be mitigated by pre-treatment with chemotherapy. In a study in which half of pts were high risk by IPI, Nivo + DA-EPOCH led to encouraging high initial responses and lengthy responses in 2 PCGDTCL pts, thus warranting further investigation of this chemoimmunotherapeutic strategy. Figure 1 Figure 1. Disclosures Haverkos: Viracta Therapeutics: Consultancy. Zain: Secura Bio, DaichiSankyo, Abbvie: Research Funding; Secura Bio, Ono , Legend, Kiyowa Kirin, Myeloid Therapeutics Verastem Daichi Sankyo: Consultancy; Kiyoaw Kirin, Secura Bio, Seattle Genetics: Honoraria. Kamdar: KaryoPharm: Consultancy; Kite: Consultancy; AstraZeneca: Consultancy; Celgene (BMS): Consultancy; Adaptive Biotechnologies: Consultancy; ADC Therapeutics: Consultancy; SeaGen: Speakers Bureau; Celgene: Other; AbbVie: Consultancy; TG Therapeutics: Research Funding; Genentech: Research Funding; Genetech: Other. Smith: Syros: Research Funding; Kura: Research Funding; Argenx: Research Funding. Porcu: Viracta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Daiichi: Honoraria, Research Funding; Kiowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrum: Consultancy; DrenBio: Consultancy.
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