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Background This phase 1b/2 PCYC-1123-CA study evaluated efficacy and safety of the combination of ibrutinib, lenalidomide, and rituximab (iR2 regimen) in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) ineligible for stem cell transplantation.Methods In phase 2, patients with relapsed/refractory non-germinal centre B-cell-like DLBCL received oral ibrutinib 560 mg once daily and oral lenalidomide 20 mg or 25 mg once daily on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity and intravenous rituximab 375 mg/m2 on Day 1 of Cycles 1-6. The primary endpoint was overall response rate (ORR) in the response-evaluable population (received any study treatment and had >= 1 post-baseline disease assessment). The study was done at 24 academic and community hospitals in Belgium, Germany, United Kingdom, and USA. This study was registered with ClinicalTrials.gov, NCT02077166. Findings Between March 13, 2014 and October 2, 2018, 89 patients were enrolled with a median time on study of 35.0 months. Best ORR in the response-evaluable population (n = 85) was 49% (95% confidence interval [CI], 38-61) across dose cohorts and 53% (95% CI, 39-67) and 44% (95% CI, 26-62) in the 20 mg and 25 mg lenalidomide cohorts, respectively, with complete responses in 24/85 (28%), 17/53 (32%), and 7/32 (22%) patients, respectively. Grade 3/4 adverse events (AEs) occurred in 81/89 patients (91%), most frequently neutropenia (36/89; 40%), maculopapular rash (16/89; 18%), anaemia (12/89; 13%), and diarrhoea (9/89; 10%). Serious adverse events occurred in 57/89 patients (64%). Fatal AEs occurred in 12/89 patients (13%); causes of death were worsening of DLBCL (n = 7), pneumonia (n = 3), sepsis (n = 1), and cardiac arrest (n = 1). Interpretation The most frequent AEs (diarrhoea, neutropenia, fatigue, cough, anaemia, peripheral oedema, and maculopapular rash) were consistent with known safety profiles of the individual drugs. The iR2 regimen demon-strated antitumour activity with durable responses in patients with relapsed/refractory DLBCL.Copyright (c) 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Post-transplant lymphoproliferative disorder (PTLD) is a rare but life-threatening complication after transplantation. In this retrospective, monocentric study we aimed to collect real life data regarding PTLD and determine the role of Epstein Barr Virus (EBV) status and year of diagnosis on prognosis. We identified 196 biopsy-proven PTLD after solid organ transplantation (SOT) diagnosed at the University Hospitals Leuven (Belgium) from 1989 to 2019. EBV status was positive in 61% of PTLD. The median overall survival (OS) was 5.7 years (95% CI: 2.99–11.1). Although EBV positivity was not significantly correlated with OS in multivariate analyses (HR: 1.44 (95% CI: 0.93–2.24); p = 0.10), subgroup analysis showed a significantly better median OS for EBV negative post-transplant diffuse large B-cell lymphoma (DLBCL) compared to EBV positive post-transplant DLBCL (8.8 versus 2.5 years respectively; p = 0.0365). There was a significant relation between year of PTLD diagnosis and OS: the more recent the PTLD diagnosis, the lower the risk for death (adjusted HR: 0.962 (95% CI: 0.931–0.933); p = 0.017). In conclusion, the prognosis of PTLD after SOT has improved in the past decades. Our analysis shows a significant relation between EBV status and OS in post-transplant DLBCL.

This phase 1b/2 PCYC-1123-CA study evaluated efficacy and safety of the combination of ibrutinib, lenalidomide, and rituximab (iRIn phase 2, patients with relapsed/refractory non-germinal centre B-cell-like DLBCL received oral ibrutinib 560 mg once daily and oral lenalidomide 20 mg or 25 mg once daily on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity and intravenous rituximab 375 mg/mBetween March 13, 2014 and October 2, 2018, 89 patients were enrolled with a median time on study of 35.0 months. Best ORR in the response-evaluable population (n = 85) was 49% (95% confidence interval [CI], 38-61) across dose cohorts and 53% (95% CI, 39-67) and 44% (95% CI, 26-62) in the 20 mg and 25 mg lenalidomide cohorts, respectively, with complete responses in 24/85 (28%), 17/53 (32%), and 7/32 (22%) patients, respectively. Grade 3/4 adverse events (AEs) occurred in 81/89 patients (91%), most frequently neutropenia (36/89; 40%), maculopapular rash (16/89; 18%), anaemia (12/89; 13%), and diarrhoea (9/89; 10%). Serious adverse events occurred in 57/89 patients (64%). Fatal AEs occurred in 12/89 patients (13%); causes of death were worsening of DLBCL (n = 7), pneumonia (n = 3), sepsis (n = 1), and cardiac arrest (n = 1).The most frequent AEs (diarrhoea, neutropenia, fatigue, cough, anaemia, peripheral oedema, and maculopapular rash) were consistent with known safety profiles of the individual drugs. The iRPharmacyclics LLC, an AbbVie Company.

Parsaclisib, a potent, highly selective, next-generation PI3Kδ inhibitor, was evaluated as monotherapy in CITADEL-202 (NCT02998476), an open-label, multicenter, phase 2 study in patients with relapsed or refractory diffuse large B-cell lymphoma. Patients enrolled into 2 groups (A, Bruton tyrosine kinase [BTK] inhibitor naïve, n = 55; B, BTK inhibitor experienced, n = 5) received oral parsaclisib 20 mg once daily for 8 weeks, then 20 mg once weekly while deriving benefit. The futility boundary was crossed at the interim analysis of Group A, resulting in a negative study. Parsaclisib monotherapy demonstrated an objective response rate (ORR) of 25.5% (8 complete metabolic responses/6 partial metabolic responses) and a median duration of response of 6.2 months. ORR in Group B was 20.0% (1 complete metabolic response). Parsaclisib monotherapy demonstrated manageable toxicities with no new safety signals reported. Further evaluation of parsaclisib in combination with standard therapies and active investigational agents is underway. ispartof: LEUKEMIA & LYMPHOMA vol:62 issue:2 pages:368-376 ispartof: location:United States status: published

PURPOSE Immunochemotherapy with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has become standard of care for patients with diffuse large B-cell lymphoma (DLBCL). This randomized trial assessed whether rituximab intensification during the first 4 cycles of R-CHOP could improve the outcome of these patients compared with standard R-CHOP. PATIENTS AND METHODS A total of 574 patients with DLBCL age 18 to 80 years were randomly assigned to induction therapy with 6 or 8 cycles of R-CHOP-14 with (RR-CHOP-14) or without (R-CHOP-14) intensification of rituximab in the first 4 cycles. The primary end point was complete remission (CR) on induction. Analyses were performed by intention to treat. RESULTS CR was achieved in 254 (89%) of 286 patients in the R-CHOP-14 arm and 249 (86%) of 288 patients in the RR-CHOP-14 arm (hazard ratio [HR], 0.82; 95% CI, 0.50 to 1.36; P = .44). After a median follow-up of 92 months (range, 1-131 months), 3-year failure-free survival was 74% (95% CI, 68% to 78%) in the R-CHOP-14 arm versus 69% (95% CI, 63% to 74%) in the RR-CHOP-14 arm (HR, 1.26; 95% CI, 0.98 to 1.61; P = .07). Progression-free survival at 3 years was 74% (95% CI, 69% to 79%) in the R-CHOP-14 arm versus 71% (95% CI, 66% to 76%) in the RR-CHOP-14 arm (HR, 1.20; 95% CI, 0.94 to 1.55; P = .15). Overall survival at 3 years was 81% (95% CI, 76% to 85%) in the R-CHOP-14 arm versus 76% (95% CI, 70% to 80%) in the RR-CHOP-14 arm (HR, 1.27; 95% CI, 0.97 to 1.67; P = .09). Patients between ages 66 and 80 years experienced significantly more toxicity during the first 4 cycles in the RR-CHOP-14 arm, especially neutropenia and infections. CONCLUSION Early rituximab intensification during R-CHOP-14 does not improve outcome in patients with untreated DLBCL.

Primary central nervous system lymphoma (PCNSL) is a rare type of non-Hodgkin lymphoma with an aggressive clinical course. To investigate the potential of immune-checkpoint therapy, we retrospectively studied the tumor microenvironment (TME) using high-plex immunohistochemistry in 22 PCNSL and compared to 7 secondary CNS lymphomas (SCNSL) and 7 "other" CNSL lymphomas with the presence of the Epstein-Barr virus and/or compromised immunity. The TME in PCNSL was predominantly composed of CD8+ cytotoxic T cells and CD163+ phagocytes. Despite molecular differences between PCNSL and SCNSL, the cellular composition and the functional spectrum of cytotoxic T cells were similar. But cytotoxic T cell activation was significantly influenced by pre-biopsy corticosteroids intake, tumor expression of PD-L1 and the presence of EBV. The presence of low numbers of CD8+ T cells and geographic-type necrosis each predicted inferior outcome in PCNSL. Both M1-like (CD68 + CD163low) and M2-like (CD68 + CD163high) phagocytes were identified, and an increased ratio of M1-like/M2-like phagocytes was associated with a better survival. PD-L1 was expressed in lymphoma cells in 28% of cases, while PD1 was expressed in only 0.4% of all CD8+ T cells. TIM-3, a marker for T cell exhaustion, was significantly more expressed in CD8posPD-1pos T cells compared to CD8posPD-1neg T cells, and a similar increased expression was observed in M2-like pro-tumoral phagocytes. In conclusion, the clinical impact of TME composition supports the use of immune-checkpoint therapies in PCNSL. Based on observed differences in immune-checkpoint expression, combinations that boost cytotoxic T cell activation (by blocking TIM-3 or TGFBR1) prior to the administration of PD-L1 inhibition could be of interest.

Background Relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is associated with a poor prognosis despite the availability of multiple treatment options. Preliminary evidence suggests that DLBCL may be responsive to programmed death ligand 1 (PD-L1)/programmed death 1 inhibitors. Objective The JAVELIN DLBCL study was conducted to assess whether a combination of agents could augment and sustain the antitumor immunity of avelumab, an anti-PD-L1 antibody, in R/R DLBCL. Methods This was a multicenter, randomized, open-label, parallel-arm study with a phase Ib and a phase III component. Reported here are the results from the phase Ib study, wherein 29 adult patients with DLBCL were randomized 1:1:1 to receive avelumab in combination with utomilumab (an immunoglobulin G2 4-1BB agonist) and rituximab (arm A), avelumab in combination with utomilumab and azacitidine (arm B), or avelumab in combination with bendamustine and rituximab (arm C). The primary endpoints were dose-limiting toxicities and objective response as assessed by the investigator per Lugano Response Classification criteria. Results Of the seven patients in arm A, one (14.3%) experienced two grade 3 dose-limiting toxicities (herpes zoster and ophthalmic herpes zoster); no dose-limiting toxicities were reported in arms B or C. No new safety concerns emerged for avelumab. One partial response was reported in arm A, three complete responses in arm C, and no responses in arm B. Given the insufficient antitumor activity in arms A and B and the infeasibility of expanding arm C, the study was discontinued before initiation of the phase III component. Conclusions The low level of clinical activity suggests that PD-L1 inhibitor activity may be limited in R/R DLBCL. ClinicalTrials.gov Identifier NCT02951156. Supplementary Information The online version contains supplementary material available at 10.1007/s11523-021-00849-8.

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas with poor prognosis. Up to 30% of PTCL lack distinctive features and are classified as PTCL, not otherwise specified (PTCL-NOS). To further improve our understanding of the genetic landscape and biology of PTCL-NOS, we perform RNA-sequencing of 18 cases and validate results in an independent cohort of 37 PTCL cases. We identify FYN-TRAF3IP2, KHDRBS1-LCK and SIN3A-FOXO1 as new in-frame fusion transcripts, with FYN-TRAF3IP2 as a recurrent fusion detected in 8 of 55 cases. Using ex vivo and in vivo experiments, we demonstrate that FYN-TRAF3IP2 and KHDRBS1-LCK activate signaling pathways downstream of the T cell receptor (TCR) complex and confer therapeutic vulnerability to clinically available drugs., Peripheral T cell lymphoma (PTCL) not otherwise specified (NOS) is a subgroup of PTCL, which has no distinctive features and is poorly characterized at the genetic level. Here, the authors identify two fusion transcripts that activate T cell receptor complex signalling and confer therapeutic vulnerability in PTCL-NOS.

Hydroxyurea (HU) resistance or intolerance occurs in 15 to 24% of patients with polycythemia vera (PV). Resistance to HU is associated with a shortened life expectancy, intolerance has no prognostic value. We assessed the occurrence of HU resistance or intolerance comparing the original (ELNo) versus the modified European Leukemia Net (ELNm) criteria as applied in recent large clinical trials including PV patients. We retrospectively analyzed 106 patients with PV treated with HU at the University Hospitals of Leuven between 1990 and 2016 for occurrence of HU resistance/intolerance when using both ELNo as ELNm. After a mean duration of treatment of 5.1 years, when applying the ELNo 20.7% of patients had shown resistance or intolerance to HU in comparison to 39.6% when using the ELNm. When using the ELNo 4.7% of patients were resistant to HU versus 23.6% when applying the ELNm. In total, 16.0% of patients were HU intolerant. This rate was identical when using both ELNo and ELNm. 20.7% of PV patients were considered as HU-resistant or intolerant when using the original ELN criteria. However, when applying the modified ELN criteria 39.6% of PV patients were resistant or intolerant to HU. In our hands, no patient received a minimum dose of 2 g HU a day, as such the ELNm seem better adapted for daily clinical use. However, the prognostic value of HU-resistance in PV, when defined by the ELNm, still needs to be confirmed. ispartof: ANNALS OF HEMATOLOGY vol:98 issue:6 pages:1421-1426 ispartof: location:Germany status: published

Summary Background In the LYM-3002 study, the efficacy and safety of frontline bortezomib plus rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) and rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) were compared in transplant-ineligible patients with untreated, newly diagnosed, mantle cell lymphoma. We report the final overall survival and safety outcomes for patients in the long-term follow-up phase after the primary progression-free-survival endpoint was met. Methods LYM-3002 was a randomised, open-label, phase 3 study done at 128 clinical centres in 28 countries in Asia, Europe, North America, and South America. Adult patients with confirmed stage II–IV previously untreated mantle cell lymphoma, Eastern Cooperative Oncology Group performance status score of 2 or less, who were ineligible for bone marrow transplantation, were randomly assigned (1:1) to receive six or eight 21-day cycles of VR-CAP (intravenous rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and bortezomib 1·3 mg/m2, plus oral prednisone 100 mg/m2) or R-CHOP (intravenous vincristine 1·4 mg/m2 [2 mg maximum], rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and doxorubicin 50 mg/m2, plus oral prednisone 100 mg/m2). Randomisation was done according to a computer-generated randomisation schedule prepared by the sponsor; permuted blocks central randomisation was used (block size of 4), and was stratified by International Prognostic Index score and disease stage at diagnosis. The primary endpoint of this final analysis was overall survival, which was analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov , number NCT00722137 , and is closed to new participants with follow-up completed. Findings Between May 22, 2008, and Dec 5, 2011, 487 patients were enrolled and randomly assigned. 268 patients (140 in the VR-CAP group and 128 in the R-CHOP group) were included in the follow-up analysis, which included patients with data available after the primary analysis clinical cutoff date of Dec 2, 2013. After median follow-up of 82·0 months (IQR 74·1–94·2), median overall survival was significantly longer in the VR-CAP group than in the R-CHOP group (90·7 months [95% CI 71·4 to not estimable] vs 55·7 months [47·2 to 68·9]; hazard ratio 0·66 [95% CI 0·51–0·85]; p=0·001). Three new adverse events were reported since the primary analysis cutoff (one each of grade 4 lung adenocarcinoma and grade 4 gastric cancer in the VR-CAP group, and one case of grade 2 pneumonia in the R-CHOP group). 103 (42%) of 243 patients in the VR-CAP group, and 138 (57%) of 244 in the R-CHOP group died; the most common cause of death was progressive disease. Interpretations Compared with R-CHOP, VR-CAP was associated with significantly longer survival, and had a manageable and expected safety profile. Our results support further assessment of VR-CAP in patients with previously untreated mantle cell lymphoma. Funding Janssen Research & Development.

Peripheral T cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas with poor prognosis. Up to 30% of PTCL lack distinctive features and are classified as PTCL, not otherwise specified (PTCL-NOS). To further improve our understanding of the genetic landscape and biology of PTCL-NOS, we performed RNA-sequencing of 18 cases and validated results in an independent cohort of 37 PTCL cases. We identified FYN-TRAF3IP2, KHDRBS1-LCK and SIN3A-FOXO1 as new in-frame fusion transcripts, with FYN-TRAF3IP2 as a recurrent fusion detected in 8 of 55 cases. Using ex vivo and in vivo experiments, we demonstrate that FYN-TRAF3IP2 and KHDRBS1-LCK activate signaling pathways downstream of the T cell receptor (TCR) complex and confer therapeutic vulnerability to clinically available drugs.

The phase 2 portion of this open-label phase 2/3 study assessed the efficacy and safety of blinatumomab as second salvage for aggressive relapsed or refractory (r/r) aggressive B-cell non-Hodgkin lymphoma (B-NHL) following platinum-based first salvage chemotherapy. Forty-one patients with aggressive disease (32% relapsed; 68% refractory) enrolled and received stepwise blinatumomab (9-28-112 μg/day) in a 70-day cycle 1 and an optional 28-day cycle 2; 19 (46%) completed cycle 1 and 3 (7%) completed cycle 2. The overall response rate after 12 weeks was 37%, including 9 (22%) complete metabolic responses. Eight (20%) patients (all responders) subsequently received stem cell transplants. Grade ≥3 adverse events were reported in 29 (71%) patients. Grade 3 cytokine release syndrome occurred in one patient. Grade 3 neurologic events occurred in 10 (24%) patients; all resolved. Blinatumomab monotherapy appears effective as second salvage therapy in patients with r/r aggressive B-NHL. Trial registration: NCT02910063. ispartof: LEUKEMIA & LYMPHOMA vol:61 issue:9 pages:2103-2112 ispartof: location:United States status: published

Patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) have adverse outcomes. We evaluated the efficacy and safety of the phosphatidylinositol 3-kinase inhibitor copanlisib in patients with relapsed/refractory DLBCL and assessed the relationship between efficacy and DLBCL cell of origin (COO; activated B-cell like [ABC] and germinal center B-cell like [GCB]) and other biomarkers. The primary endpoint was objective response rate (ORR) in DLBCL COO subgroups (ABC, GCB, and unclassifiable) and by CD79B mutational status (NCT02391116). Sixty-seven patients received copanlisib (ABC DLBCL, n = 19; GCB DLBCL, n = 30; unclassifiable, n = 3; missing, n = 15). The ORR was 19.4%; 31.6% and 13.3% in ABC and GCB DLBCL patients, respectively. ORR was 22.2%/20.0% for patients with/without CD79B mutations (wild type, n = 45; mutant, n = 9; missing, n = 13). Overall median progression-free survival and duration of response were 1.8 and 4.3 months, respectively. Adverse events included hypertension (40.3%), diarrhea (37.3%), and hyperglycemia (32.8%). Aberrations were detected in 338 genes, including BCL2 (53.7%) and MLL2 (53.7%). A 16-gene signature separating responders from nonresponders was identified. Copanlisib treatment demonstrated a manageable safety profile in patients with relapsed/refractory DLBCL and a numerically higher response rate in ABC vs. GCB DLBCL patients.

International audience; JAK2 constitutive activation/overexpression is common in classical Hodgkin lymphoma, and several cytokines stimulate Hodgkin lymphoma cells by recognizing JAK1-/JAK2-bound receptors. JAK blockade may thus be therapeutically beneficial in Hodgkin lymphoma. In this phase II study we assessed the safety and efficacy of ruxolitinib, an oral JAK1/2 inhibitor, in patients with relapsed/refractory Hodgkin lymphoma. The primary objective was overall response rate according to the International Harmonization Project 2007 criteria. Thirty-three patients with advanced disease (median number of prior lines of treatment: 5; refractory: 82%) were included; nine (27.3%) received at least six cycles of ruxolitinib and six (18.2%) received more than six cycles. The overall response rate after six cycles was 9.4% (3/32 patients). All three responders had partial responses; another 11 patients had transient stable disease. Best overall response rate was 18.8% (6/32 patients). Rapid alleviation of B-symptoms was common. The median duration of response was 7.7 months, median progression-free survival 3.5 months (95% CI: 1.9-4.6), and the median overall survival 27.1 months (95% CI: 14.4-27.1). Forty adverse events were reported in 14/33 patients (42.4%). One event led to treatment discontinuation, while 87.5% of patients recovered without sequelae. Twenty-five adverse events were grade 3 or higher. These events were mostly anemia (n=11), all considered related to ruxolitinib. Other main causes of grade 3 or higher adverse events included lymphopenia and infections. Of note, no cases of grade 4 neutropenia or thrombocytopenia were observed. Ruxolitinib shows signs of activity, albeit short-lived, beyond a simple anti-inflammatory effect. Its limited toxicity suggests that it has the potential to be combined with other therapeutic modalities. ClinicalTrials.gov: NCT01877005.

Introduction : Vodobatinib is a novel third generation TKI effective against wild-type and mutated BCR-ABL1 (except T315I) with limited off-target activity. We present updated results from the Phase 1 dose-escalation (DEs) and expansion (DEx) study in CML and Ph+ALL patients (pts) failing ≥ 3 prior TKIs (< 3 prior TKIs if approved TKI is not clinically advised or available); patients with T315I are not eligible (NCT02629692). Methods: This is an open-label, phase 1, multicentre, 3+3 study evaluating maximum tolerated dose (MTD), safety and efficacy of vodobatinib administered once daily in 28 day cycles (dose range: 12 to 240 mg). MTD was established at 204 mg. DEx study enrolled chronic phase CML (CP-CML) patients at 174 mg dose of vodobatinib. Treatment continued until unacceptable toxicity, disease progression, consent withdrawal or death. Adverse events were assessed using NCI-CTCAE v4.03. Results: As of 15 Jul 2021, 52 pts are enrolled in DEs and DEx cohorts. Forty one of these pts received doses from 12 to 240 mg in the DEs cohort;32 chronic phase (CP-CML), 3 accelerated phase CML (AP-CML), 4 blast phase CML (BP-CML), 2 Ph+ ALL. Eleven CP-CML pts were enrolled in DEx cohort at 174 mg dose. The baseline demographics and disease history are represented in Table 1. Efficacy : Of the 32 CP-CML pts enrolled in DEs: At baseline, 21 (65%) pts had no cytogenetic response, 4 (12.5%) were in PCyR, 7 (22%) were in CCyR. On vodobatinib therapy, 11(34%) pts achieved CCyR, 3 (9%) achieved PCyR and 7 (22%) maintained baseline CCyR. Baseline major molecular response (MMR) was present in 1 (3%) pt; and 14 pts (44%) achieved MMR on study. Of the remaining 11 pts, 5 (16%) had haematologically stable disease (no CyR and molecular response) and 6 (19%) had disease progression (cytogenetic or hematological) as their best response (Table 2 and 3). Seventeen CP-CML pts had prior ponatinib treatment, of which 11 (65%) had MCyR (4 achieved CCyR, 4 maintained CCyR, 3 achieved PCyR); while 8 (47%) achieved MMR. In the remaining 15 pts ponatinib naïve CP-CML: 10 (66%) had CCyR (7 achieved CCyR, 3 maintained CCyR); with 7 (47%) with MMR (6 achieved, 1 maintained). Two of the 3, AP-CML pts had baseline hematological response (CHR) with absence of cytogenetic and molecular response. The 3 pts further deepened their responses with 1 pt achieving CCyR with MMR and 2 pts in PCyR. Of the 4 BP-CML pts, 2 achieved CHR and 2 patients had disease progression as their best response; Of the 2 Ph+ ALL pts, 1 pt maintained CCyR and MMR while the other reported disease progression as the best response. Median duration of treatment overall was 23 (0.5-51) months [CP-CML 23 (0.5-51); AP-CML 36 (9-40); BP-CML 3 (0.5-18) and Ph+ ALL 4 (0.7-7.3) months]. Twenty one pts continue in study. In the DEx cohort, 1 of the 11 CP-CML pts was in PCyR at baseline. No pts had molecular response. Of the 11 patients, 6 (54 %) pts achieved CCyR, 1(10%) pt achieved PCyR. MMR was achieved by 1 pt (10%). Data is maturing for 1 pt. Median duration of treatment is 16 (0.3-19) months and 10 pts continue in study. Safety : Forty nine of 52 pts reported at least 1 TEAE. Most common any grade TEAEs included thrombocytopenia (33%), cough (19%), anaemia & diarrhoea (17% each). Thirty one pts (60%) reported Grade 3 and 4 treatment emergent AEs: most common were thrombocytopenia (15%), neutropenia and anaemia (12%), increased amylase and lipase (8% each). Ten (19%) pts reported cardiovascular TEAEs (Grade 1: angina pectoris, palpitations, ventricular extra-systoles, arteriosclerosis, hot flush, hypotension, intermittent claudication; Grade 2: hypertension, hypotension; Grade 3: cardiac failure congestive, hypertension); with a Grade 2 hypertension being vodobatinib related. Nineteen pts (37%) reported SAEs; vodobatinib related SAEs were reported in 3 pts (fatal intracranial haemorrhage (ICH), Grade 2 back pain and Grade 3 amnesia reported in 1 pt each). There were 5 deaths on study: 1 was related to use of vodobatinib (1 ICH, confounded by disease progression to blast phase that included extra- medullary sites) and the remaining unrelated (1 sudden death, 1 disease progression, 1 pneumonia fungal, 1 suspected COVID-19). Conclusion: Vodobatinib continues to be associated with favourable long term safety and efficacy in heavily pre-treated CML failing ≥ 3 prior TKIs, including ponatinib. Phase 2 study evaluating vodobatinib in pts failing at least 3 prior lines of therapy, including ponatinib, is ongoing. Figure 1 Figure 1. Disclosures Cortes: Novartis: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sun Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Kim: Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; ILYANG: Research Funding; Takeda: Research Funding. Alvarado: MEI Pharma: Research Funding; Daiichi-Sankyo: Research Funding; Sun Pharma: Consultancy, Research Funding; CytomX Therapeutics: Consultancy; Jazz Pharmaceuticals: Research Funding; BerGenBio: Research Funding; Astex Pharmaceuticals: Research Funding; FibroGen: Research Funding. Nicolini: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; Incyte Biosciences: Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; BMS: Honoraria; Sun Pharma Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Apperley: Incyte, Pfizer: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb, Novartis: Honoraria, Speakers Bureau. Deininger: Fusion Pharma, Medscape, DisperSol: Consultancy; Novartis: Consultancy, Research Funding; SPARC, DisperSol, Leukemia & Lymphoma Society: Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Blueprint Medicines Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding. de Lavallade: Bristol Myers Squibb: Research Funding; Incyte: Honoraria, Research Funding; Novartis: Speakers Bureau. Charbonnier: Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Gambacorti-Passerini: Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy. Mauro: Novartis: Consultancy, Research Funding; Takeda: Consultancy; Pfizer: Consultancy; Sun Pharma / SPARC: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding. Vandenberghe: Pfizer: Research Funding; Bristol Myers Squibb/Celgene: Consultancy; Miltenyi Biotec: Consultancy; Novartis: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy; Gilead Sciences: Consultancy, Other: Travel support. Radhakrishnan: Intas Pharmaceuticals: Research Funding; Emcure Pharmaceuticals: Research Funding; Dr Reddy's Laboratories: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen India: Honoraria; Cipla Pharmaceuticals India: Research Funding; Bristol-Myers-Squibb India: Membership on an entity's Board of Directors or advisory committees, Research Funding; Aurigene: Speakers Bureau; AstraZeneca India: Honoraria, Speakers Bureau; NATCO Pharmaceuticals: Research Funding; Novartis India: Membership on an entity's Board of Directors or advisory committees; Roche India: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Yao: Sun Pharma: Current Employment. Inamdar: Sun Pharma Advanced Research Company: Current Employment. Sreenivasan: Sun Pharma Advanced Research Company: Current Employment. Dillu: Sun Pharma Advanced Research Company: Current Employment. Chimote: Sun Pharma Advanced Research Company: Current Employment.

Introduction: In an open-label phase 2 study, blinatumomab demonstrated efficacy with a manageable safety profile as second salvage in patients with relapsed or refractory B-cell Non-Hodgkin's lymphoma (R/R B-NHL) following platinum-based salvage regimens (Coyle et al. Leukemia & Lymphoma. 2020: 1-10). Blinatumomab is a BiTE® (bispecific T-cell engager) immuno-oncology therapy that activates endogenous cytotoxic T cells to kill target B cells. Here, findings from the updated analysis are reported (NCT02910063). Methods: Patients aged >18 years with biopsy-confirmed B-NHL without prior complete response or complete metabolic response (CMR) following first-line treatment with anthracycline- based chemotherapy and anti-CD20 therapy, had progressive metabolic disease (PMD), no metabolic response (NMR), or partial metabolic response (PMR; Lugano Classification) after ≥2 cycles of platinum-based S1 therapy were eligible. Blinatumomab was given by continuous intravenous infusion for a single 70-day cycle 1 (9 µg/day for 7 days, 28 µg /day for 7 days, and 112 µg /day for 42 days, followed by a 14-day treatment free interval) and an optional 28-day second cycle (9 µg /day for 7 days, 28 µg /day for 7 days and 112 µg / day for 14 days) at the investigator's discretion. Primary endpoint was CMR by central PET. Additional endpoints included objective response rate (ORR; CMR plus PMR), overall survival (OS), progression- free survival (PFS), duration of response, post-response HSCT rate, and the incidence and severity of adverse events (AEs). Results: As of the data cut date (June 3, 2020) for this updated analysis, 41 patients were enrolled between 23 January 2017 and 15 January 2018; 28 (68%) patients were refractory and 13 (32%) relapsed to first-line therapy, 66% had progressive disease following first salvage (S1), and 9 (22%) had double or triple hit status at baseline (Figure 1). ORR was 37% (15/41; 95% CI, 22-53) after 12 weeks of treatment, including 9 (22%) patients who achieved CMR and 6 (15%) achieved PMR. Of the 41 patients enrolled, 17 (42%) were double refractory; of which, 3 (7%) achieved CMR, and 3 (7%) achieved PMR. Of the 41 patients who received blinatumomab, median OS (95% CI) was 11.2 (5.9-NE) months with median follow-up time of 27.9 months. Among the 9 patients who achieved CMR, median OS (95% CI) was NE (7.0, NE) and median PFS (95% CI) was 8.4 (4.9-11.6) months with median follow of time of 4.7 months; of which, 3 patients had disease progression and 0 died. Of the 13 patients who achieved HSCT, median OS (95% CI) was NE (13.1-NE) with 69% of patients alive at 30 months and median PFS (95% CI) was 8.4 (5.3-13.9) months with 21% of patients alive at 12 months (Figure 2 and 3). In total, 29 (71%) patients had grade ≥3 treatment-emergent AEs, including included infections (n=8; 20%), neutropenia (n=4; 10%), pulmonary embolism (n=1; 2%), and acute pancreatitis (n=1; 2%). Consistent with previous blinatumomab reports, neurologic events (NEs) were reported in 23 (56%) patients, including 10 (24%) with grade 3 NEs and 3 (7%) with NEs leading to treatment discontinuation. Grade 3 cytokine release syndrome was reported in only 1 patient. 7 (17%) patients discontinued treatment due to AEs and 7 (17%) had fatal AEs of which were related to disease progression. Conclusions: In conclusion, durable complete remissions can be achieved with a manageable safety profile using blinatumomab as second salvage in patients with aggressive R/R B-NHL following platinum based first salvage regimens Figure 1 Disclosures Coyle: Amgen: Other: Travel support. Morley:Janssen: Honoraria, Other: Fees; AbbVie: Honoraria, Other: Fees; Roche: Other: travel support; Amgen: Honoraria, Other: Fees, travel support. Rambaldi:Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Omeros: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support from Gilead.; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Advisory board and speaker fees from Pfizer.; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Research grant from Amgen Inc.; BMS/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Astellas: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of parent study and funding of editorial support. Received travel support., Research Funding; University of Milan: Current Employment. Furness:Amgen: Other: Travel Support. Desai:IQVIA: Current Employment. Mergen:Amgen: Current Employment, Current equity holder in publicly-traded company. OffLabel Disclosure: Durable complete remissions can be achieved with a manageable safety profile using blinatumomab as second salvage in patients with aggressive R/R B-NHL following platinum based first salvage regimens

The pivotal LYM-3002 study compared frontline rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) with bortezomib, rituximab, cyclophosphamide, doxorubicin and prednisone (VR-CAP) in newly diagnosed mantle cell lymphoma (MCL) patients for whom stem cell transplantation was not an option. This post hoc subanalysis of the VR-CAP data from LYM-3002 evaluated the effect of bortezomib dose intensity on OS in patients who completed ≥6 cycles of treatment. From the end of cycle 6, patients receiving ≥4.6 mg/m2/cycle of bortezomib had significantly longer OS (but not PFS) compared with those receiving

Post-transplantation lymphoproliferative disorder is an aggressive complication of transplantation, most frequently of diffuse large B-cell lymphoma morphology and associated with Epstein-Barr virus (EBV) infection/reactivation. In this study the microenvironment of EBV+ (n=23) and EBV- (n=9) post-transplant non-germinal center B-cell diffuse large B-cell lymphoma was characterized. Of EBV+ cases somatic hypermutation analysis, gene expression profiling, and extensive phenotyping were performed. Our results demonstrated variable cytotoxic T-cell infiltration and significantly increased CD163+ M2 macrophage infiltration in EBV+ compared with EBV- post-transplant diffuse large B-cell lymphoma. On the basis of IgM staining and hypermutation analysis, two EBV+ post-transplant diffuse large B-cell lymphoma subgroups were identified: IgM+ tumors lacking somatic hypermutations and IgM- tumors harboring somatic hypermutations. IgM- tumors arose late following transplantation (median interval: 16 months), mainly in kidney recipients. IgM+ tumors on the other hand arose early (median interval: 3 months, P-value=0.0032), almost exclusively following stem cell transplantation and were associated with worse outcome (median survival 1 month for IgM+ versus 41 months for IgM- tumors, log-rank/Wilcoxon P-value 0.07/0.04). Notably, IgM+ tumors were characterized by plasma cell features (monotypic kappa/lambda expression, high MUM1 expression, and partial CD138 expression) and a high proliferation index. Consistent with the plasma cell phenotype, unfolded protein response signaling was upregulated. In contrast, IgM- EBV+ post-transplant diffuse large B-cell lymphoma did not express kappa, lambda, IgD, or CD138 and expressed limited MUM1. In these tumors T-cell signaling was enhanced associated with increased T-cell infiltration compared with IgM+ cases. Overall, our results allow further molecular classification of EBV+ post-transplant diffuse large B-cell lymphoma and provide a rationale for the use of subtype-specific-targeted therapies (eg, bortezomib in IgM+ tumors). Our findings also provide a biological basis for the clinical differences between post-transplant lymphoproliferative disorder following solid organ and stem cell transplantation, which are regarded as different disorders.

Treatment options for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) are limited, with no standard of care; prognosis is poor, with 4- to 6-month median survival. Avadomide (CC-122) is a cereblon-modulating agent with immunomodulatory and direct antitumor activities. This phase 1 dose-expansion study assessed safety and clinical activity of avadomide monotherapy in patients with de novo R/R DLBCL and transformed lymphoma. Additionally, a novel gene expression classifier, which identifies tumors with a high immune cell infiltration, was shown to enrich for response to avadomide in R/R DLBCL. Ninety-seven patients with R/R DLBCL, including 12 patients with transformed lymphoma, received 3 to 5 mg avadomide administered on continuous or intermittent schedules until unacceptable toxicity, disease progression, or withdrawal. Eighty-two patients (85%) experienced ≥1 grade 3/4 treatment-emergent adverse events (AEs), most commonly neutropenia (51%), infections (24%), anemia (12%), and febrile neutropenia (10%). Discontinuations because of AEs occurred in 10% of patients. Introduction of an intermittent 5/7-day schedule improved tolerability and reduced frequency and severity of neutropenia, febrile neutropenia, and infections. Among 84 patients with de novo R/R DLBCL, overall response rate (ORR) was 29%, including 11% complete response (CR). Responses were cell-of-origin independent. Classifier-positive DLBCL patients (de novo) had an ORR of 44%, median progression-free survival (mPFS) of 6 months, and 16% CR vs an ORR of 19%, mPFS of 1.5 months, and 5% CR in classifier-negative patients (P = .0096). Avadomide is being evaluated in combination with other antilymphoma agents. This trial was registered at www.clinicaltrials.gov as #NCT01421524.

Up to 10 % of chronic lymphocytic leukemia (CLL) patients present with aggressive secondary B-cell lymphoma (most frequently diffuse large B-cell lymphoma, DLBCL) which may be clonally related to the CLL (i.e., Richter transformation, RT, 80 % of the cases) or de novo (20 % of the cases). Several genetic lesions associated with RT have already been identified, but the potential role of the Epstein-Barr virus (EBV) has been largely overlooked. In this study, we describe six CLL patients who developed a secondary EBV-positive (EBV+) B-cell lymphoma (five DLBCL, one Hodgkin lymphoma) and compare their clinicopathological characteristics to ten CLL patients with EBV-negative (EBV−) secondary B-cell lymphomas (all DLBCL). All 16 patients had a history of iatrogenic immunosuppression or chemotherapy. Eighty percent had received fludarabine as part of the CLL treatment. Most secondary lymphomas were clonally related to the previous CLL (3/4 EBV+, 7/7 EBV− cases tested). Notably EBV+ RT was associated with a trend for older age at onset (median 72 vs. 63 years, p value >0.05), longer interval between CLL and RT diagnosis (median 4.2 vs. 2.9 years, p value >0.05), and shorter overall survival (median 4 vs. 10 months, p value >0.05). These differences were not significant, probably due to small sample size. Immunohistochemical profiling suggested more frequent overexpression of TP53 and MYC in EBV− compared to EBV+ secondary lymphoma. Based on this small retrospective single center series, we hypothesize that EBV+ RT may constitute a separate subgroup of RT. Larger series are required to validate this suggestion. Electronic supplementary material The online version of this article (doi:10.1007/s12308-016-0273-8) contains supplementary material, which is available to authorized users.

Background: Fluorine-18-fluorodeoxyglucose positron emission tomography (PET) has an established and central role in diagnosis, staging and response evaluation of lymphoproliferative diseases. It has shown a high sensitivity and specificity at diagnosis in posttransplant lymphoproliferative disorders (PTLDs). However, little is known about the performance of interim and end of treatment (EOT) PET in PTLD patients with regards to response assessment, relapse prediction and outcome. Methods: We performed a single-center retrospective study in which we analyzed consecutive patients diagnosed with CD20-positive PTLD after solid organ transplantation between 2008 and 2017, who all received risk-stratified sequential treatment according to the PTLD-1 phase II trial. Interim and EOT PET studies were scored according to the Deauville criteria. Results: Forty-one patients were included with median follow-up of 41.5 months (range 1-108). Positive and negative predictive values for disease recurrence were 13% and 85% for interim and 33% and 87% for EOT PET, respectively. There was no significant difference in overall survival, progression-free survival nor time to progression between negative versus positive patients on interim and EOT scans. Conclusions: Negative interim and/or negative end of treatment PET identify PTLD patients with low risk of disease recurrence. ispartof: ACTA ONCOLOGICA vol:58 issue:7 pages:1041-1047 ispartof: location:England status: published

METHODS: This is a retrospective analysis of immunosuppression, patient baseline characteristics, and relapse risk measured as landmark time to progression (TTP) starting 1 year after start of therapy in 159 patients with B cell PTLD after solid organ transplantation treated in the prospective, international, multicenter PTLD-1 trials with either sequential treatment (rituximab followed by cyclophosphamide (CHOP-21 chemotherapy) 750 mg/m intravenously [IV] day (d) 1, doxorubicin 50 mg/m IV d1, vincristine 1.4 mg/m (maximum, 2 mg) IV d1, and prednisone 50 mg/m PO d1-5, every 21 days) or risk-stratified sequential treatment (rituximab followed by rituximab or rituximab (R-CHOP-21 immunochemotherapy) 375 mg/m IV day (d) 1, cyclophosphamide 750 mg/m IV d1, doxorubicin 50 mg/m IV d1, vincristine 1.4 mg/m (max. 2 mg) IV d1, and prednisone 50 mg/m PO d1-5, every 21 days).BACKGROUND: Current guideline recommendations for immunosuppression reduction after diagnosis of posttransplant lymphoproliferative disorder (PTLD) include stopping antimetabolites, reducing calcineurin inhibitors, and maintaining corticosteroids. However, the effect of immunosuppression on PTLD relapse risk after up-to-date therapy is unclear.RESULTS: Patient baseline characteristics at diagnosis of PTLD differed significantly depending on immunosuppression before diagnosis. Compared with immunosuppression before diagnosis, significantly fewer patients received an antimetabolite or a calcineurin inhibitor (CNI) after diagnosis of PTLD. Relapse risk measured as landmark TTP was significantly higher for patients on corticosteroids compared to all others (P = 0.010) as well as for patients on ciclosporin compared with those on tacrolimus (P = 0.002), but similar for those on antimetabolites compared with all others (P = 0.912). In a Cox regression analysis of landmark TTP, corticosteroid-containing immunosuppression after diagnosis of PTLD (P = 0.002; hazard ratio, 11.195) and age (P = 0.001; hazard ratio, 1.076/year) were identified as independent, significant risk factors for PTLD relapse.CONCLUSIONS: In the prospective PTLD-1 trials, corticosteroid use after diagnosis of PTLD is associated with an increased risk of relapse, whereas the use of antimetabolites is not. These findings require prospective validation.

PURPOSE: To evaluate the prognostic utility of apparent diffusion coefficient (ADC) changes at whole-body diffusion-weighted (WB-DW) MRI after one treatment cycle for aggressive non-Hodgkin lymphoma (NHL) compared with response assessment at interim and end-of-treatment fluorine 18 ((18)F) fluorodeoxyglucose (FDG) PET/CT. MATERIALS AND METHODS: This was a secondary analysis of a prospective study (ClinicalTrials.gov identifier: NCT01231269) in which participants with aggressive NHL were recruited between March 2011 and April 2015 and underwent WB-DW MRI before and after one cycle of immunochemotherapy. Volunteers were recruited for test-retest WB-DW MRI (ClinicalTrials.gov identifier: NCT01231282) to assess ADC measurement repeatability. Response assessment was based on ADC change after one treatment cycle at WB-DW MRI and Deauville criteria at (18)F-FDG PET/CT. To evaluate prognostic factors of disease-free survival (DFS), Kaplan-Meier survival analysis and univariable and multivariable Cox regression were performed; intraclass correlation coefficient (ICC) and mean difference with limits of agreement were calculated to determine inter- and intraobserver repeatability of ADC measurements. RESULTS: Forty-five patients (mean age, 58 years ± 17 [standard deviation]; 31 men) and nine volunteers (mean age, 22 years ± 3; seven men) were enrolled. Median DFS was 48 months (range, 2–48 months). Outcome prediction accuracy was 86.7% (39 of 45), 71.4% (30 of 42), and 73.8% (31 of 42) for WB-DW MRI and interim and end-of-treatment (18)F-FDG PET/CT, respectively. WB-DW MRI (hazard ratio [HR], 17.8; P < .001) and interim (HR, 5; P = .008) and end-of-treatment (HR, 4.3; P = .017) (18)F-FDG PET/CT were prognostic of DFS. After multivariable analysis, WB-DW MRI remained an independent predictor of outcome (HR, 26.8; P = .002). Intra- and interobserver agreement for ADC measurements were excellent (ICC = 0.85–0.99). CONCLUSION: Quantitative WB-DW MRI after only one cycle of immunochemotherapy predicts DFS in aggressive NHL and is noninferior to routinely performed interim and end-of-treatment (18)F-FDG PET/CT. Keywords: MR-Diffusion Weighted Imaging, Lymphoma, Oncology, Tumor Response, Whole-Body Imaging Supplemental material is available for this article. © RSNA, 2021

Heavy chain diseases are rare variants of B-cell lymphomas that produce one of three classes of immunoglobulin heavy chains, without corresponding light chains. We describe two patients with asymptomatic heavy chain monoclonal gammopathy. The first patient is a 51-year-old woman with alpha paraprotein on serum immunofixation. The second case is a 46-year-old woman with gamma paraprotein on urine immunofixation. Neither patient had corresponding monoclonal light chains. Workup for multiple myeloma and lymphoma was negative in both patients. These two cases illustrate that heavy chain monoclonal gammopathy can exist in the absence of clinically apparent malignancy. Only a few reports of "heavy chain MGUS" have been described before. In the absence of specialized guidelines, we suggest a similar follow-up as for MGUS, while taking into account the higher probability of progression to lymphoma than to myeloma. ispartof: Case Reports in Oncological Medicine vol:2016 pages:1-4 ispartof: location:United States status: published

Background: Mantle cell lymphoma (MCL) is a distinct subtype of lymphoma with a wide variation of clinical course. Based on randomized trials of our network, current standard of care is a cytarabine-containing immunochemotherapy induction (Hermine, Lancet 2016) followed by autologous stem cell transplantation (SCT; Zöllner, ICML 2019) and rituximab maintenance for 3 years (Le Gouill, NEJM 2018). In relapsed MCL the BTK inhibitor ibrutinib achieves high response rates and ongoing remissions (Wang, NEJM 2013; Dreyling, Lancet 2016). This approach achieved especially longer remission durations in earlier treatment lines (Rule, Hamatologica 2019). We aim to clarify whether ibrutinib added to induction and as maintenance with or without autologous stem cell transplantation might improve outcome. Study design and methods: In this international, randomized three-arm phase III trial (EudraCT-no. 2014-001363-12) young, fit patients ( up to 65 years) with histologically confirmed, untreated mantle cell lymphoma advanced stage II-IV qualify for 1:1:1 randomization after written informed consent according to ICH/EU GCP. In the control arm A, patients receive an alternating R-CHOP/R-DHAP induction followed by myeloablative consolidation (either BEAM or THAM: TBI, high dose Ara-C and melphalan). In arm A+I Ibrutinib is added to the R-CHOP cycles (560 mg day 1-19) and applied as maintenance (continuous dosing) for 2 years. In arm I the same induction and maintenance is applied but high dose consolidation and autologous SCT is skipped. A rituximab maintenance (single doses every 2 months up to 3 years) may be added in all study arms according to national clinical routine. The primary study aim is to show superiority of one of three study arms as future standard of care based on the comparison of the investigator-assessed failure-free survival (FFS), i.e. to investigate if the addition of ibrutinib improves the efficacy of standard 1st line treatment, and can even challenge the use of high-dose chemotherapy with autologous SCT. Secondary study aims include the efficacy of the three treatment arms and the safety and tolerability of ibrutinib during induction immuno-chemotherapy and maintenance. Accordingly, overall and complete response rates, progression-free and overall survival will be determined as well as adverse events during induction immuno-chemotherapy and follow-up including the cumulative incidence rates of SPMs. In addition, minimal residual disease is regularly determined based on patient-specific PCR assay according to the standardized Biomed-2 procedure. Results: As of July 30th, 511 of up to 870 patients have been randomized from 12 different European countries. In a meanwhile completed safety run-in of the initial 50 patients, feasibility of the two experimental arms was confirmed with no major differences in hematological and other toxicities and no major delays during induction. Disclosures Dreyling: Acerta: Other: Scientific advisory board; Novartis: Other: Scientific advisory board; Mundipharma: Other: Scientific advisory board, Research Funding; Janssen: Other: Scientific advisory board, Research Funding, Speakers Bureau; Gilead: Other: Scientific advisory board, Speakers Bureau; Celgene: Other: Scientific advisory board, Research Funding, Speakers Bureau; Bayer: Other: Scientific advisory board, Speakers Bureau; Sandoz: Other: Scientific advisory board; Roche: Other: Scientific advisory board, Research Funding, Speakers Bureau. Ladetto:Roche: Honoraria; AbbVie: Honoraria; J&J: Honoraria; Celgene: Honoraria; Pfizer: Honoraria, Speakers Bureau; Acerta: Honoraria, Speakers Bureau; ADC Therapeutics: Honoraria. Doorduijn:Roche: Honoraria, Research Funding. Gine:Janssen: Other: Travel expenses, Research Funding; Gilead: Other: Travel expenses, Research Funding; Roche: Other: Travel expenses, Research Funding. Jerkeman:Janssen: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Acerta: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Mey:Janssen-Cilag: Consultancy; Roche: Consultancy, Research Funding. Hutchings:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Celgene: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding. Kolstad:Merck: Research Funding; Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees, Research Funding. Trneny:Roche: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Gilead sciences: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria. Gomes da Silva:AbbVie: Consultancy, Other: Travel support; Roche: Consultancy, Other: Travel support; Janssen-Cilag: Consultancy, Other: Travel support; Celgene: Consultancy; Gilead Siences: Other: Travel support, Research Funding. Klapper:Roche, Takeda, Amgen, Regeneron: Honoraria, Research Funding. Unterhalt:F. Hoffmann-La Roche: Research Funding. Hoster:Janssen: Research Funding; Roche Pharma AG: Other: Travel Support.

Introduction: Despite availability of several BCR-ABL1 TKIs for treatment of CML, some patients (pts) fail ≥3 TKIs and/or have co-morbidities that limit use of 2nd generation TKIs (2GTKI: Nilotinib, Dasatinib and Ponatinib). K0706 is a novel third generation TKI effective against wild-type and mutated BCR-ABL1 isoforms with significantly less off-target activity compared to existing TKIs. We report Phase I results of K0706 in pts who were resistant and/or intolerant to ≥3 prior TKIs or who had co-morbidities precluding the use of 2GTKI (NCT02629692). Methods: This was a multicentre, open-label, dose-escalation and expansion study of K0706 to evaluate the safety and anti-leukemic activity of K0706, and determine the MTD. Patients with CML or Ph+ ALL resistant and/or intolerant to ≥3 prior TKIs received escalating doses of K0706 capsules (single daily dose) in 28 day cycles. Treatment continued until unacceptable toxicity, disease progression, consent withdrawal or death. Results: At data cut-off of 30 June 2019, 35pts (19 male) have been treated with K0706 at doses of 12mg (n=1), 24mg (n=1), 48mg (n=6), 66mg (n=7), 90mg (n=3), 126mg (n=5), 174mg (n=5), 204mg (n=4), and 240mg (n=3); median age 61.6 (range 23.5-85.6) years; median time from diagnosis 10.13 (range 0.7-22.9) years. Diagnoses included 27 chronic phase [CP], 3 accelerated phase [AP], 4 blast phase [BP] CML and 1 Ph+ ALL. Eleven and 19pts received ≥3 prior TKIs and ≥4 prior TKIs respectively (intolerant, n=11; resistant and intolerant, n=24). 13pts had BCR-ABL mutations detectable at study entry (F317L, n=2; E255V/K, n=2; T315I, n=2; 1pt each had: Y253H, Y253F, V299L, Q252H and G250E respectively; 1pt each had 2BCR-ABL mutations: E255V, F317L and F359V, E255V respectively). At a median follow-up of 6.9 months (range 0.5-26 months), 68.6% of pts remained on K0706 and 31.5% completed ≥12 months of therapy. 11pts (31.4%) discontinued [10 due to disease progression (with 2 deaths) and 1 with a possibly related AE of CNS bleed confounded by disease progression]. The most common K0706-related AEs included transient mild to moderate gastrointestinal disturbances (18.5%), general disorders [i.e.: myalgia, fatigue, asthenia] (15.7%), neutropenia (12%) and thrombocytopenia (10%). At 240mg, 2 of 3pts had dose-limiting toxicities (DLTs) of ≥25% of doses missed in Cycle 1 because of toxicity (dyspnoea (1x grade 2, 1x grade 3) and non-cardiac chest pain (1x grade 2) DLTs were reversible and pts resolved at 174 mg without recurrence. Of 27 CML CP pts, 7pts achieved a complete cytogenetic remission (CCyR) and 4 maintained CCyR. 1pt achieved partial CyR (PCyR), 1pt had disease progression in Cycle 1 and 5pts are yet to complete post baseline assessments. Of the 12 CML CP cytogenetic responders, 11 remain on treatment [mean duration 6.9 (range 2.9 -26) months in major cytogenetic response (MCyR) while 1pt had disease progression at 9.5 months]. Cytogenetic responses were observed in 2 of 11 CML-CP pts with mutations [CCyR in 1 of 2 pts with F317L and in 1pt with G250E]. Pts with T315I mutations had disease progression in Cycle 1. Following this, protocol was amended to enrol subjects with T315I mutations only when target plasma concentrations required preclinically to inhibit T315I clone are achieved. Five of 27 pts achieved major molecular response (MMR), 2 pts in MR 4.5. Of 8 pts with CML AP (n=3), BP (n=4) or Ph+ ALL (n=1), 4 achieved confirmed MaHR; 2 entered the study in MaHR; 3 had MCyR [2 had CCyR and 1 had PCyR] and 2 had disease progression. 1pt in CML BP had a confirmed MaHR for 12 months. 1pt in AP with chromosome 3 inversion, had CCyR at 3 months and maintaining for 13 months. Conclusion:K0706 has acceptable safety profile with activity in heavily pre-treated patients who had failed at least ≥3 prior lines of TKIs. The study provides early proof of principle for the effectiveness of K0706 in a setting with few available treatment options. Disclosures Cortes: Sun Pharma: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Biopath Holdings: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding. Kim:Novartis: Research Funding; Pfizer: Research Funding; Il-Yang co.: Research Funding; Takeda: Research Funding; BMS: Research Funding. Charbonnier:Pfizer: Consultancy; Novartis: Consultancy; Incyte: Speakers Bureau. Apperley:Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Deininger:Blueprint: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Research Funding; Ascentage Pharma: Consultancy, Honoraria; Fusion Pharma: Consultancy; TRM: Consultancy; Sangoma: Consultancy; Novartis: Honoraria; Sangamo: Consultancy; Incyte: Honoraria; Adelphi: Consultancy; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Humana: Honoraria. De Lavallade:Bristol Myers Squibb: Research Funding; Bristol Myers Squibb: Research Funding. Whiteley:Seattle Genetics: Speakers Bureau; Jazz pharmaceuticals: Speakers Bureau. Mauro:Pfizer: Consultancy; Takeda: Consultancy; Novartis Oncology: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy. Gambacorti-Passerini:Bristol-Meyers Squibb: Consultancy; Pfizer: Honoraria, Research Funding. Lucchesi:Novartis: Honoraria; Incyte: Honoraria; Pfizer: Honoraria. Yao:Sun Pharma Advance Research Company: Employment. Kothekar:Sun Pharma Advance Research Company: Employment. Chimote:Sun Pharma Advance Research Company: Employment.

Objectives: To assess interruptions/discontinuations of tyrosine kinase inhibitor (TKI) treatment in Belgian patients with chronic myeloid leukaemia (CML). Methods: This retrospective study included patients with TKI interruptions/discontinuations of ≥4 continuous weeks (no clinical trial context) between May 2013 and May 2016. Data collection took place between October 2016 and February 2017. Results: All 60 participants (69 interruptions/discontinuations) had chronic-phase CML and 75% had at least a major molecular response (≥MMR) at interruption/discontinuation. Most interruptions/discontinuations occurred while on imatinib (36/69; 49%) and dasatinib (20/69; 29%). Most interruptions/discontinuations occurred due to side effects/intolerance (46/69; 67%); other reasons included a wish to conceive (6/69; 9%) and attempts to achieve treatment-free remission (TFR) (6/69; 9%). Interruptions due to side effects occurred later for imatinib- or dasatinib-treated patients than for those on nilotinib or ponatinib. Treatment was re-initiated in 62% (43/69) of cases. Most interruptions caused by side effects/intolerance were followed by treatment changes. All 4 patients with ≥MR 4.5 at interruption/discontinuation and ≥11-month follow-up who had not restarted treatment maintained the response. Conclusion: Although TKIs are used for long-term CML treatment, physicians sometimes recommend interruptions/discontinuations. In this study, interruptions/discontinuations were mainly caused by side effects or intolerance, rather than TFR attempts.

As diagnosing therapy-related myeloid neoplasms (t-MN) is often challenging, we reviewed clinicopathological features of t-MN patients. Medical records of 138 patients, diagnosed with t-MN between 1995 and 2017, were reviewed. Of 138 patients, 80 had t-MDS, 53 t-AML, and 5 t-MDS/MPN (age, 22–88 years; median 64 years; male/female ratio, 0.8). The median latency time was 6 years and 5 months. Of 115 patients, 56 patients received cytotoxic-/radiotherapy for a solid tumor, 56 for hematological malignancy, and 3 for an auto-immune disorder, respectively. Another 21 patients had a combination of 2 disorders. Moreover, 2 patients had 3 previous malignancies. Breast cancer was the most prevalent tumor, followed by low-grade B non-Hodgkin lymphoma. Immunophenotyping and immunohistochemistry showed aberrant expression of B-, T-, or NK-cell markers in 21% and 6%, respectively. In 90% of the patients, dysplasia in ≥ 1 lineage was found. KMT2A fusion gene transcripts were seen in 5%. Cytogenetic analysis showed complex karyotypes (31%) and chromosome 5 and/or 7 abnormalities (40%). Almost 82% of the patients died and the median overall survival was about 1 year. Our study confirms that previous therapy for breast cancer is the most important cause of t-MN. KMT2A fusion genes are prevalent and complex karyotypes and/or chromosomes 5 and/or 7 abnormalities are common.

Ongoing development of new drugs, as well as novel indications in the treatment of autoimmune diseases leads to the increasing use of immunomodulatory and immunosuppressive drugs. Immunomodulatory agent-related lymphoproliferative disorders are a known and potentially life threatening complication of chronic administration of these drugs, but are less well characterized compared with post-transplant lymphoproliferative disorders. The heterogeneous drug targets, various underlying disease indications, different drug combinations used and relatively low incidence render data collection and interpretation difficult. In this retrospective paper, we describe the clinicopathological characteristics of a larger single-center series of 72 immunomodulatory agent-related lymphoproliferative disorder cases. We divided the cases according to the therapy, administered in the year preceding diagnosis of a lymphoproliferative disorder, in an immunosuppressive drug, an immunomodulatory drug and a combination of immunosuppressive and immunomodulatory drugs group. We observed differences in "time to lymphoproliferative disorder development" with a shorter time for all the immunomodulatory drug-related cases combined (immunomodulatory and immunomodulatory + immunosuppressive = immunomodulatory-all) vs immunosuppressive-only (p = 0.0031). The proportion of malignant cases in patients receiving immunomodulatory therapy was, however, also significantly lower when compared with the immunosuppressive treated cases (43 vs 88%; p = 0.0184). The immunomodulatory/suppressive agent-related lymphoproliferative disorders were less often associated with the Epstein-Barr virus (EBV) (31 vs 66%; p = 1.829e-05) and the lymphoproliferative disorders incidence in the first year after immunomodulatory/immunosuppressive therapy initiation was lower (18 vs 41%; p = 0.04151)-compared with a published series of 140 post-transplant lymphoproliferative disorder cases from the same center. However, a similar histopathological spectrum from nondestructive, to polymorphic and monomorphic lesions as in post-transplant lymphoproliferative disorders is observed. With increasing use of immunosuppressive and especially immunomodulatory therapy, a higher incidence of immunomodulatory/suppressive agent-related lymphoproliferative disorders is to be expected. Life-long awareness for development of immunomodulatory/suppressive agent-related lymphoproliferative disorders with clinical follow-up and timely biopsies of suspicious lesions is required since these lymphoproliferative disorders arise both early after therapy initiation and many years later. Histopathological confirmation and correct classification is necessary to guide therapy and EBV ISH should be a part of routine pathological diagnostics. ispartof: MODERN PATHOLOGY vol:31 issue:9 pages:1457-1469 ispartof: location:United States status: published

This phase II, single-arm, multicenter study examined the efficacy and safety of coltuximab ravtansine (an anti-CD19 antibody drug conjugate) in 61 patients with histologically documented (de novo or transformed) relapsed or refractory diffuse large B-cell lymphoma who had previously received rituximab-containing immuno-chemotherapy. Patients had received a median of 2.0 (range 0-9) prior treatment regimens for diffuse large B-cell lymphoma and almost half (45.9%) had bulky disease (≥1 lesion >5 cm) at trial entry. Patients received coltuximab ravtansine (55 mg/m2) in 4 weekly and 4 biweekly administrations until disease progression or unacceptable toxicity. Forty-one patients were eligible for inclusion in the per protocol population. Overall response rate (International Working Group criteria) in the per protocol population, the primary end point, was 18/41 [43.9%; 90% confidence interval (CI:) 30.6-57.9%]. Median duration of response, progression-free survival, and overall survival (all treated patients) were 4.7 (range 0.0-8.8) months, 4.4 (90%CI: 3.02-5.78) months, and 9.2 (90%CI: 6.57-12.09) months, respectively. Common non-hematologic adverse events included asthenia/fatigue (30%), nausea (23%), and diarrhea (20%). Grade 3-4 adverse events were reported in 23 patients (38%), the most frequent being hepatotoxicity (3%) and abdominal pain (3%). Eye disorders occurred in 15 patients (25%); all were grade 1-2 and none required a dose modification. Coltuximab ravtansine monotherapy was well tolerated and resulted in moderate clinical responses in pre-treated patients with relapsed/refractory diffuse large B-cell lymphoma. (Registered at: clinicaltrials.gov identifier: 01472887). ispartof: HAEMATOLOGICA vol:103 issue:8 pages:1351-1358 ispartof: location:Italy status: published

e19038 Background: Parsaclisib, a potent, highly selective, next-generation PI3Kδ inhibitor, showed preliminary efficacy as monotherapy for relapsed or refractory non-Hodgkin lymphoma, including DLBCL (Abstract 410, ASH 2017), in a phase 1/2 study. This phase 2 study further assessed parsaclisib in patients (pts) with relapsed or refractory DLBCL (NCT02998476). Methods: Pts enrolled into 2 groups (A, Bruton tyrosine kinase [BTK] inhibitor naïve; B, BTK inhibitor experienced) and received oral parsaclisib 20 mg QD for 8 wks, then 20 mg QW. In a planned interim futility analysis conducted in the first 40 pts treated in Group A, if ≤13 (≤32.5%) responded by IRC assessment, Group A was to be terminated. Results: At data cutoff (22 Jun 2018), 60 pts (Group A, n = 55; Group B, n = 5) were treated (median age, 71 y [range, 36—94]; men, 63.3%; ≥3 prior systemic therapies, 60%). At the planned interim analysis in Group A, ORR (by PET) was 25% (10/40 pts; 5 CMR, 5 PMR); the futility boundary was crossed. At data cutoff, ORR in Group A was 25.5% (14/55 pts; 8 CMR, 6 PMR); median PFS was 2.2 mo (95% CI: 2.0‒4.1); median DOR was 4.5 mo (95% CI: 2.1‒5.1). ORs were observed in germinal center B-cell (GCB) and non-GCB subtypes. ORR in Group B was 20% (1/5 pts; 1 CMR). The most common non-hematologic treatment-emergent adverse events (TEAEs) occurring in > 10% of all pts (all grade [Gr]; Gr 3/4) were rash events (21.7%; 1.7%), colitis/diarrhea events (16.7%; 5%), nausea (16.7%; 0%), cough (15%; 0%), and pyrexia (15%; 8.3%). Gr 3/4 AST and ALT elevations occurred in 5% and 1.7% of pts, respectively; Gr 3/4 neutropenia and anemia occurred in 5% of pts each. The most frequent ( > 5%) serious TEAEs were pyrexia (8.3%), general physical health deterioration (6.7%), and hypercalcemia (6.7%). TEAEs led to therapy discontinuation in 7 pts (2 treatment-related), dose interruption in 20 pts (10 treatment-related), and dose reduction in 3 pts (all treatment-related). Median duration of therapy was 57.5 d (range, 11–318). Conclusions: Parsaclisib monotherapy using a QD followed by QW dosing regimen was well tolerated with no new safety signals reported. Further evaluation of parsaclisib in all subtypes of DLBCL is ongoing in a combination study Clinical trial information: NCT02998476.