Introduction
Rituximab (R) administration results in significant outcome improvement in B cell precursor acute lymphoblastic leukemia (B-ALL) patients (pts), but is usually restricted to pts with ...≥20% CD20+ leukemic blasts. Yet, this arbitrary cut-off is not proven biologically sensible. Moreover, CD20 expression might differ between blood (pb) and bone marrow (bm) and varies under prednisone during early treatment. In the present GMALL08/2013 trial R is administered to all BCR-ABL1-negative B-ALL pts irrespective of the initial leukemic CD20 expression. We assessed the initial and post-prephase CD20 expression in GMALL08/2013 pts and correlated the values with MRD response after Induction I (Ind I) and Consolidation I (Cons I). A historical B-ALL GMALL07/2003 cohort without R treatment and with available CD20 expression and MRD data was used to evaluate for R-unrelated effects.
Methods
Comparative immunophenotypic quantification of CD20 expression in 207 B-ALL pts was performed at diagnosis (pb d0 and/or bm d0) and/or (a/o) after a 5-day dexamethasone- and cyclophosphamide-containing prephase (pb d6) under EuroFlow standardized procedures. CD20 median fluorescence intensities (CD20-MFI) and percentages of CD20+ B-ALL blasts/all blasts (%CD20+ BL) were assessed.
Minimal residual disease (MRD) was determined after Ind I (after 1x R) and Cons I (after 4x R) by quantitative PCR for clone-specific immune gene rearrangements to stratify pts as molecular complete response (MolCR, MRD negativity, assay sensitivity at least 1x10 -4), molecular intermediate response (MolIR, MRD positive non-quantifiable or positive <1x10 -4) and molecular failure (MolFAIL, MRD ≥1x10 -4).
Results
bm d0/pb d0. In 91 paired bm d0/pb d0 samples %CD20+ BL as well as the CD20-MFI were significantly higher in pb in common/pre-B ALL (c/pre-B ALL) (n=76: paired t-test: p<.0001 and p<.0001) and in normal mature B cells (CD20-MFI paired t-test; pro-B/ c/pre-B p=0.026/p<.0001), but not in pro-B ALL (n=15: paired t-test: p=.81 and p=.76) (Fig. 1A, 2A). Notably, in 6/76 (7.9%) c/pre-B ALL pts the %CD20+ BL in bm d0 was lower and in corresponding pb d0 higher than the arbitrary cut-off of 20%.
pb d0/pb d6. CD20 expression of circulating blasts significantly increased after a 5-day prephase in c/pre-B ALL but not in pro-B ALL in 106 paired pb d0/pb d6 samples (paired t-test of CD20-MFI and %CD20+ BL; n=20 pro-B ALL, p=.09 and p=.25; n=86 c/pre-B ALL, p<.0001 and p<.0001). Normal mature B cells presented with the opposite effect (CD20-MFI paired t-test; pro-B/ c/pre-B: p=0.005/p<.0001) (Fig. 1B, 2B). Notably, the %CD20+ BL in pb d0 was lower and in corresponding pb d6 higher than the arbitrary cut-off of 20% in 2/20 (10.0%) pro-B ALL and 12/86 (13.9%) c/pre-B ALL pts.
Molecular response under R. The values of %CD20+ BL were correlated with MRD response after Ind I and Cons I (Fig. 3). Since the CD20 expression in the present cohort was shown to be significantly modulated in a drug- and compartment-dependent manner, we used the highest measured value of %CD20+ BL out of the three available values per patient (bm d0, pb d0 a/o pb d6). In the historical cohort (n=145) one value per patient for %CD20+ BL was available.
Due to low CD20 expression pro-B ALL did not show any differences in the %CD20+ BL among the risk groups in the present (Ind I n=23, Cons I n=20) and the historical (Ind I n=11; Cons I n=11) cohort. The differences in %CD20+ BL in relation to molecular response were significant in c/pre-B ALL between MolCR and MolFAIL after Ind I (n=127) and Cons I (n=120) (Mann-Whitney test: p=.0002 and p=.0028) and of lower significance between MolIR and MolFAIL after Ind I (p=.013) and between MolCR and MolIR after Cons I (p=.029) in the present cohort. Within the historical cohort (Ind I n=145, Cons I n=143) no significant differences were observed.
Conclusions
Leukemic CD20 expression was modulated between compartments (bm d0/pb d0) and showed a significant increase in a drug-dependent manner in c/pre-B ALL (pb d0/pb d6) probably in response to dexamethasone. The results might challenge the conventional eligibility criteria for CD20 targeted treatment in c/pre-B ALL.
MRD persisters showed lower initial CD20 expression compared to MRD responders in the present cohort consistently receiving R, but not in the historical cohort without R treatment. Accordingly, R seems to improve the early MRD response predominantly in pts with higher CD20 expression.
Supported by DJCLS
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Szczepanowski: Amgen: Speakers Bureau. Trautmann: Amgen: Speakers Bureau. Ritgen: Roche: Consultancy, Other: Travel support, Research Funding; Abbvie: Consultancy, Other: Travel support, Research Funding; Chugai: Consultancy; MSD: Consultancy, Other: Travel support; Celgene: Other: Travel support. Nachtkamp: Celgene: Other: Travel Support; bsh medical: Speakers Bureau; Jazz: Speakers Bureau. Viardot: Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; University Hospital of Ulm: Current Employment. Baldus: Jazz: Honoraria; Celgene/BMS: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Schwartz: Morphosys: Research Funding; Gilead: Other: Travel grants, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau; Novartis: Speakers Bureau; Jazz Pharmaceuticals: Other: Travel grants, Speakers Bureau; BTG International Inc: Membership on an entity's Board of Directors or advisory committees; MSD Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Basilea: Other: Travel grants. Goekbuget: Pfizer: Consultancy, Other: Research funding for institution; Amgen: Consultancy, Other: Invited talks for company sponsored symposia (with honoraria); Research funding for institution; Astra Zeneca: Other: Invited talk for company sponsored symposia (with honor); Gilead/Kite: Consultancy; Novartis: Consultancy, Other: Research funding for Institution; Jazz Pharmaceuticals: Other: Research funding for institution; Incyte: Other: Research funding for Institution; Cellestia: Consultancy; Erytech: Consultancy; Morphosys: Consultancy; Servier: Consultancy, Other; Abbvie: Other. Brüggemann: Amgen: Other: Advisory Board, Travel support, Research Funding, Speakers Bureau; Incyte: Other: Advisory Board; Janssen: Speakers Bureau.
Rituximab administration to patients with CD20-negative (<20% CD20+ blasts/all blasts) BCR-ABL-negative B-ALL.
•Truncating mutations in MS4A1 with subsequent antigen loss is a major mechanism of resistance to CD3 × CD20 bispecific antibodies.•Spatial heterogeneity and branching evolution underlie progression ...in lymphoma during CD19 and CD20 targeting immunotherapy.
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CD19 chimeric antigen receptor (CAR) T cells and CD20 targeting T-cell–engaging bispecific antibodies (bispecs) have been approved in B-cell non-Hodgkin lymphoma lately, heralding a new clinical setting in which patients are treated with both approaches, sequentially. The aim of our study was to investigate the selective pressure of CD19- and CD20-directed therapy on the clonal architecture in lymphoma. Using a broad analytical pipeline on 28 longitudinally collected specimen from 7 patients, we identified truncating mutations in the gene encoding CD20 conferring antigen loss in 80% of patients relapsing from CD20 bispecs. Pronounced T-cell exhaustion was identified in cases with progressive disease and retained CD20 expression. We also confirmed CD19 loss after CAR T-cell therapy and reported the case of sequential CD19 and CD20 loss. We observed branching evolution with re-emergence of CD20+ subclones at later time points and spatial heterogeneity for CD20 expression in response to targeted therapy. Our results highlight immunotherapy as not only an evolutionary bottleneck selecting for antigen loss variants but also complex evolutionary pathways underlying disease progression from these novel therapies.
Duell et al traced aggressive and indolent B-cell lymphomas as the tumors escaped elimination by T-cell–redirecting immunotherapy in patients. The authors showed that truncating mutations in MS4A1 with subsequent CD20 antigen loss are a major mechanism of resistance to CD3×CD20 bispecific antibodies. However, there was considerable spatial and temporal heterogeneity in target antigen expression during relapses, including reemergence of CD20 expressing clones. These data indicate complex branching evolutionary trajectories under the selection pressure of serial immunotherapy.
Introduction:
Imaging by PET/CT scan with FDG is the gold standard for initial staging for malignant lymphoma. This sequence is very robust for Hodgkin lymphoma, aggressive lymphomas and follicular ...lymphoma but lacks sensitivity for marginal zone lymphoma (MZL), irrespectively of the different MZL subsets e.g. mucosa-associated lymphoid tissue (MALT), and nodal marginal lymphoma (NMZL ), splenic marginal zone lymphoma (sMZL) and extranodal marginal zone lymphoma (eNMZL). Limited disease of MZL (Stage I/II) are commonly treated by irradiation. Extensive disease (Stage III/IV) is either followed by watch and wait if clinically asymptomatic and or treated with anti-CD20 directed immune chemotherapy if clinically prudent.
Hence, better diagnostic procedure are highly warranted to improve the accuracy of the Ann Arbor staging in MZL for Stage adapted treatment of MZL patients.
Method:
Nineteen patients with newly diagnosed MZL (13 MALT, 5 NMZL, 1 sMZL) received a PET/CT scan with FDG as tracer and bone biopsy as standard staging procedures. All patients with MALT MZL were further subject to gastric endoscopy and coloscopy with tissue biopsy. All patients received in addition a CXCR4-directed radiotracer 68Ga Pentixafor PET/CT scan, which has shown to be of diagnostic value in multiple myeloma patients. If a lesion was negative by FDG PET scan but positive by CXCR4 PET, additional tissue was acquired to confirm MZL infiltration by immunohistochemistry in selected patients.
Results:
From 05/2017 to 05/2018 nineteen newly diagnosed MZL were staged by conventional PET/CT scan resulting in 2 patients with limited disease status and 12 in extensive disease status. 5 patients had no lesions with FDG PET confirmed as a false negative readout. Utilizing CXCR4 PET/CT SCAN 4 had limited disease and 15 had extensive disease. Only 1 patient with a minimal gastral infiltration and low proliferation frequency was not detected. All bone marrow infiltrations could be detected by CXCR4 (3 out of 3) but none with FDG PET scan. For intestinal involvement of the lymphoma 2 out of 3 patients were true positive (confirmed by biopsy) with CXCR4 PET scan but 0 out of 3 patients with FDG PET scan. 12 out of 13 patients with MALT Lymphoma were PET CXCR4 positive in all leasions. In contrast, only 6 out 13 patients with MALT could be detected with FDG PET scan. In the group of NMZL 5/5 patients demonstrated CXCR4 PET positivity. In contrast only 5 out 5 had a FDG uptake. For the single case of sMZL, the CXCR4 PET was positive but on FDG PET negative.
Taken together, 94.7% of the MZL patients were positive by CXCR4 PET/CT scan but only 42.1% with FDG PET CT scans. In addition, CXCR4 PET showed also uptake in the bone marrow and GI tract in most cases with corresponding involvement whereas FDG/PET missed this involvement all patients.
Conclusion:
CXCR4 PET adapted staging of newly diagnosed marginal zone lymphoma has the potential of becoming the new standard for MZL staging and allocating MZL to the respective front line therapy algorithms. Larger studies are highly warranted to confirm these findings in the future.
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Topp:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Research Funding; Regeneron Pharmaceuticals, Inc.: Honoraria, Research Funding.
Tafasitamab, an anti-CD19 immunotherapy, is used with lenalidomide for patients with autologous stem cell transplant-ineligible relapsed/refractory diffuse large B-cell lymphoma (DLBCL) based on the ...results of the phase II L-MIND study (NCT02399085). We report the final 5-year analysis. Eighty patients (≥18 years, 1–3 prior systemic therapies, ECOG PS 0–2) received co-administered tafasitamab and lenalidomide for up to 12 cycles, followed by tafasitamab monotherapy until disease progression (PD) or unacceptable toxicity. Primary endpoint was best objective response rate (ORR). Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Exploratory analyses evaluated efficacy endpoints by prior lines of therapy (pLoT). At data cut-off on November 14, 2022, ORR was 57.5%, with complete response (CR) of 41.3% (n=33), which was consistent with prior analyses. With median follow-up (mFU) of 44.0 months, median DoR was not reached. Median PFS was 11.6 months 95% CI, 5.7–45.7 (mFU 45.6), and median OS was 33.5 months 95% CI, 18.3–NR (mFU 65.6). Patients with 1 pLoT (n=40) showed higher ORR (67.5%; 52.5% CR) compared with patients with ≥2 pLoT (n=40; 47.5%; 30% CR), but median DoR was not reached in either subgroup. Other exploratory analyses revealed consistent long-term efficacy results across subgroups. Adverse events were consistent with previous reports and manageable, and their frequency decreased during tafasitamab monotherapy, with no new safety concerns. This final 5-year analysis of L-MIND demonstrates that this immunotherapy combination is well tolerated and has long-term clinical benefit with durable responses.
•The novel combination of tafasitamab ± lenalidomide + R-CHOP showed signs of efficacy in patients with untreated DLBCL, with no new safety signals.•The results, including a post hoc analysis in ...patients with high-risk disease (IPI 3-5), support the ongoing phase 3 frontMIND trial.
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Anti-CD19 immunotherapy tafasitamab is used in combination with lenalidomide in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who are ineligible for autologous stem cell transplant. Open-label, phase 1b, First-MIND study assessed safety and preliminary efficacy of tafasitamab + R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) ± lenalidomide as first-line therapy in patients with DLBCL. From December 2019 to August 2020, 83 adults with untreated DLBCL (International Prognostic Index 2-5) were screened and 66 were randomly assigned (33 per arm) to R-CHOP-tafasitamab (arm T) or R-CHOP-tafasitamab-lenalidomide (arm T/L) for 6 cycles. Primary end point was safety; secondary end points included end-of-treatment (EoT) overall response rate (ORR) and complete response (CR) rate. All patients had ≥1 treatment-emergent adverse event, mostly grade 1 or 2. Grade ≥3 neutropenia and thrombocytopenia occurred, respectively, in 57.6% and 12.1% (arm T) and 84.8% and 36.4% (arm T/L) of patients. Nonhematologic toxicities occurred at similar rates among arms. R-CHOP mean relative dose intensity was ≥89% in both arms. EoT ORR was 75.8% (CR 72.7%) in arm T and 81.8% (CR 66.7%) in arm T/L; best ORR across visits was 90.0% and 93.9%. Eighteen-month duration of response and of CR rates were 72.7% and 74.5% (arm T) and 78.7% and 86.5% (arm T/L); 24-month progression-free and overall survival rates were 72.7% and 90.3% (arm T) and 76.8% and 93.8% (arm T/L). Manageable safety and promising signals of efficacy were observed in both arms. Potential benefit of adding tafasitamab + lenalidomide to R-CHOP is being investigated in phase 3 frontMIND (NCT04824092). This study is registered at www.clinicaltrials.gov as #NCT04134936.
In a phase 1b trial of the addition of the anti-CD19 antibody tafasitamab to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), Belada et al randomly assigned patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) with a poor prognosis (International Prognostic Index score of 2-5) to also receive lenalidomide. The authors’ data from 66 patients suggest acceptable safety and encouraging efficacy with 2-year progression-free survival exceeding 74%, thereby forming the basis for a phase 3 trial in high-risk patients with DLBCL.
Because of gastral and extranodal manifestations, guideline-compatible diagnostic work-up of marginal zone lymphoma is challenging. We aimed to determine the diagnostic performance of C-X-C motif ...chemokine receptor 4 (CXCR4)-directed PET/CT compared with routine diagnostics, along with PET/CT-based retrospective changes in therapeutic management. The predictive potential of the PET signal was also investigated, and the number of patients eligible for CXCR4-directed radioligand therapy in a theranostic setting was determined.
For this study, 100 marginal zone lymphoma patients underwent CXCR4-directed PET/CT. We compared staging results and treatment decisions from molecular imaging with respective results from guideline-compatible work-up (CT, esophagogastroduodenoscopy, and bone marrow-derived biopsy). Prognostic performance of the in vivo CXCR4 PET signal for progression-free survival (PFS) was evaluated (using log-rank test and Kaplan-Meier curves).
Relative to CT, CXCR4-directed imaging led to Ann Arbor (AA) staging changes for 27 of 100 patients (27.0%). Among those, clinically relevant upstaging from AA I or AA II to AA III or AA IV was observed for 23 patients (85.2%), along with respective changes in therapeutic management (escalation, 6/23 26.1%; deescalation, 17/23 73.9%). CXCR4 PET/CT yielded diagnostic accuracy of 94.0% relative to esophagogastroduodenoscopy and 76.8% relative to bone marrow-derived biopsy. An increased CXCR4 PET signal was linked to shorter PFS (707 d vs. median PFS not reached; hazard ratio, 3.18; 95% CI, 1.37-7.35;
= 0.01). CXCR4-directed radioligand therapy would have been feasible for 18 of 100 patients (18.0%).
Relative to CT, CXCR4-directed PET/CT led to AA changes for 27 of 100 patients. Chemokine receptor PET/CT may improve current diagnostic algorithms and influence management relative to CT alone, potentially obviating some biopsies.
Background: Chimeric antigen receptor T-cells have revolutionized treatment in many B-cell neoplasias. In MCL, brexucabtagene autoleucel (brexu-cel) has been the first product approved based on ...results of the ZUMA-2 trial for patients failing prior chemoimmunotherapy and BTK-inhibitor. However, in ZUMA-2, strict criteria have been used for patient selection, e.g. no use of intensive bridging/holding treatment was allowed, excluding patients with high treatment needs. In contrast to this, in the real-world scenario patient selection is much more diverse questioning whether the results of controlled trials can be reproduced in the regular treatment landscape. In this intent, we have analyzed the results obtained with brexu-cel as standard-of-care treatment (SOC) of r/r MCL in Germany and Switzerland. Patients/methods: Eligible for this first analysis of an ongoing registry study were all German and Swiss patients with r/r MCL who have been treated with SOC brexu-cel since 09/2020 and were registered with the German Stem Cell Registry (DRST) and the Registry of the European Mantle Cell lymphoma (EMCL), respectively. Of note, some patients have received more than one CAR-T-treatment. Data were analyzed for patient and disease characteristics, prior treatment history, response to treatment, and complications as well as post treatment outcomes. Due to the character of this analysis based on real world data, with heterogeneous surveillance strategies we have used primarily time to next treatment (TTNT) instead of progression-free survival, due to the potential biases for the latter. While still adding patients to the analysis, an additional follow-up data cut is planned 10/2023. Results: 111 patients have been identified: median age at diagnosis was 64.3 years (range 42.3-79.5; 19/99 patients ≥ 70), 18% female (not known (nk) 2.7%); ethnicity 66.7% Caucasian (nk 30.6%). Disease characteristics: 80/88 had stage 3/4 (91%), histology was classical in 34/57 cases (60%) and blastoid in 19/57 (33%), respectively. MIPI score was low 14/53 (26%), intermediate 17 (32%), high 21 (40%). TP53 alteration was present in 13/58 (22%), Ki67-expression was ≤ 30% in 18/50 (36%). TTNT for last treatment preceding CAR-T-treatment was 7.7 months. Overall survival (OS) for the entire patient population from diagnosis was 12.8 years. Preceding CAR-T, median number of treatments was 3 (range 1-9), all patients had prior Rituximab and Ibrutinib, 62 patients (56%) had received autologous stem cell transplantation (SCT) and 11 patients had received an allogeneic SCT. Median age at this time point was 68.1 years (range 49-82y). 50/110 patients were >70 years. Bridging treatment had been used in 88/112 (79%) preceding CAR. Based on investigator evaluation ORR was 86%, best response to CAR-T was CR in 47/76 patients (62%) and PR in 18/76 (24%). Time to death or new treatment after CAR-T was 8 months (mo) for patients ≤ 70y and 12 mo for patients > 70y. There was no difference for the number of prior lines (≤ 3 vs. > 3). The estimated median OS was 1.9 years. 26 patients have received at least 1 additional line of treatment after progression. Safety: Post-CAR CRS was seen in 95/114 (83%), Grade 1/2 77/95 (81%), Grade 3/4 (18%), Grade 5 (1%); ICANS was noted in 57/111 (51%), Grade 1/2 43/57 (75%), all other Grade 3/4. The rate of ICU admissions was 25/106 (24%). However, within 28 days after CAR-T-cell treatment 9/98 (9%) patients have died. Overall, in the post CAR-T-period 20 patients died of reasons other than progression: 4 CAR-related, 11 infections, 5 other/unknown. Discussion: In this real-world analysis, we could demonstrate, despite a more heterogeneous pre-treated patient population, a high overall and complete response rate. Median post CAR-T-cell survival was promising with 1.9 years. While CRS and ICANS risks seem to be comparable to trial data, the high non-relapse mortality (NRM) observed after SOC brexu-cel for r/r MCL is a concern and warrants refinement of anti-infectious surveillance and prophylaxis. Further work focusses on the identification of potential risk factors, e.g. using risk scores such as CAR-HAEMATOTOX, EASIX, and Severe4.
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