Introduction: Emerging data have identified distinct genetic subtypes of DLBCL based on the diverse oncogenic molecular drivers with varying clinical outcomes when treated with standard R-CHOP. ...Relapse post frontline treatment could be curbed by integrating novel agents upfront. The phosphatidylinositol 3 kinase (PI3K) signalling pathway contributes to the oncogenesesis of both germinal center derived and activated B-cell (ABC) DLBCL subtypes (Wright, et al Cancer Cell, 2020). Zandelisib, a highly selective oral PI3Kδ inhibitor has proven efficacy in B cell lymphoma with a favorable toxicity profile when administered in intermittent dosing schedule (Pagel, et al Lancet Oncol 2022). We conducted a phase I/2 trial to evaluate the safety and efficacy of zandelisib in combination with R-CHOP chemotherapy in newly diagnosed DLBCL. The study enrollment was closed in 12/2022 after the development of zandelisib was discontinued. We present the results of the phase I (P1) trial. Methods: In this investigator-initiated trial, patients (pts) with untreated DLBCL with ECOG performance status (PS) ≤ 2, adequate bone marrow (BM) and organ function were enrolled from 08/2021-12/2022 at Cleveland Clinic (NCT04517435). ECOG PS 3 was allowed if it was attributed to the lymphoma diagnosis. The study was supported by the MEI Pharma. The P1 study had 2 dose escalation cohorts in combination with standard doses of R-CHOP every 21 days for 6 cycles; zandelisib was dosed 60 mg daily on days 1-4 in cohort 1 and daily on days 1-7 in cohort 2. If the 3 subjects in dose level 1 (D1) did not experience any dose limiting toxicity (DLT) during cycle 1 (C1), pts were enrolled into D2. In phase 2 (P2), a cycle of R-CHOP prior to the study treatment was allowed, if clinically deemed. All pts received pneumocystis jirovecii (PJP) and viral prophylaxis. Disease response was assessed after C3 and C6. Primary end point for P1 was to assess safety and tolerability of the combination and to determine recommended P2 dose (RP2D) of zandelisib. Pts who received at least 1 cycle of study treatment were included in the safety analysis. Primary objective of P2 is progression free survival (PFS) at 1 year. Pt and disease characteristics were analyzed using descriptive statistics. Results: We enrolled a total of 13 pts (P1: 9 and P2: 4) in the study prior to termination. The median age was 67 (range 46-79) years, with majority being female (53.8%), with an ECOG PS of 0-2 (100%). Most pts had stage III-IV disease 10/13 (77%), IPI ≥3 in 8/15 (62%), elevated LDH 9/13 pts (69%), and extranodal involvement 7/13 (54%). 3 pts had BM involvement. DLBCL was germinal center (GC) subtype in 77% of the pts. FISH studies revealed translocations in BCL2 (46%), BCL6 (8%) and c-myc (0%). There was no DLT observed in cohort 1 and zandelisib 60 mg daily on D1-7 was the RP2D. 12 of 13 enrolled pts completed 6 cycles of the study regimen prior to study closure. Of the 12 evaluable pts, the ORR was 100% with 9 pts (75%) achieving CR and 3 PR (25%). No pt experienced disease progression prior to study closing. Median time from treatment start to response was 165 (range 48-189) days. The most common adverse events were diarrhea (38%), neutropenia and anemia (31% each), fatigue, constipation, leukopenia and thrombocytopenia (23% each). Other AEs include colitis, nausea, hypoalbuminemia and hypokalemia (15% each). Of the 2 pts who developed colitis, 1 pt had G1 colitis which resolved, while the other pt discontinued the study after 2 cycles due to G3 colitis and bowel obstruction. Another pt experienced G3 jejunal perforation after completing cycle 6. Other G≥3 AE observed were neutropenia and leukopenia each (23% each), lung infection and lymphopenia (8% each). All pts were alive at the time of study closure. Conclusion: In this phase 1/II study, encouraging efficacy was observed with zandelisib + R-CHOP, but this should be interpreted with caution as the study was incomplete. There is a potential signal for increased gastrointestinal toxicity (one G3 colitis, one G3 bowel perforation) in this small sample size and larger prospective trials are needed to further assess the toxicity profile of the combination of oral PI3K inhibitors with R-CHOP.
Introduction Patients (pts) older than 60 years of age diagnosed with classic Hodgkin lymphoma (cHL) have worse prognosis than younger pts, including complete remission rates (CR) as well as lower ...progression free (PFS) and overall survival (OS). Age over 70 years, along with comorbidities, has been identified as a factor conferring additional worse prognosis. We sought to evaluate the prescription patterns and outcomes of pts ≥70y in comparison with “younger” elderly cHL pts diagnosed 60-69y. Methods We conducted a retrospective review of newly diagnosed cHL patients treated at our academic medical center between 2012-2022. Baseline and treatment characteristics, including planned and unplanned dose reduction events were collected from electronic medical records. Outcomes included disease response to initial therapy, PFS, OS and non - relapse mortality (NRM). All analyses were done using R and its packages. Differences between age groups were evaluated using Fisher and Wilcoxon rank-sum tests. PFS and OS were calculated using the Kaplan Meier method, comparisons done using log-rank. The cumulative incidence of NRM was calculated considering relapse as a competing risk, comparisons evaluated with Gray's test. Results We identified 81 pts ≥60 years (y) diagnosed with cHL, 37 of whom were ≥70y. Among baseline characteristics, more pts ≥70y had ECOG performance status ≥2 (30 vs. 9%, p = 0.05), and all had at least one comorbidity, compared with 77% in pts 60-69y (p = 0.002); other baseline characteristics were comparable, and the numerical difference in the rates of individual comorbidities did not reach statistical significance (table 1). A statistically significant higher proportion of pts ≥70y had planned de-intensification of their treatment (46% vs. 16%, p = 0.007), most commonly this corresponded by prescription of the doxorubicin, vinblastine and dacarbazine (AVD) as initial therapy, use of brentuximab vedotin alone or in combination with non-anthracycline containing regimens. One pt in the younger cohort did not receive therapy and died within two weeks of diagnosis. Subsequent dose reductions occurred in both age groups and pts ≥70y had a higher proportion of pts with overall reduced treatment intensity (i.e., planned + unplanned) (n = 22, 59% vs. n = 14, 33%, p = 0.024). Among pts treated with systemic therapy (n = 80), overall response rates were 73% and 85% for ≥70y and younger pts, respectively (p = 0.42). Complete response (CR) rates were 70% and 81% (p = 0.23). For pts treated with an anthracycline containing regimen, CR rates were 78% for pts ≥70y and 83% for pts 60 - 69y (p = 0.77). After a median follow up of 53 months (IQR 32-71), 18 (23%) pts had progression of their disease after initial therapy and 18 (23%) pts had died. Median progression free survival had not been reached for both groups, and four-year estimates were 65% for pts ≥70y (95% CI 51-85%) and 83% for pts 60 - 69y (95% CI 73-95%), this difference did not reach statistical significance (p = 0.08). Similar results were observed for PFS when the analysis was limited to pts treated with anthracycline-containing regimens (4-year PFS: ≥70y = 68% vs. 60-69y = 85%, p = 0.06). Median OS was not reached for both groups, four-year estimates were 75% for pts ≥70y (95% CI 61-92%) and 90% for pts 60-69y (95% CI 81-100%) (p =0.007), with comparable results when pts treated with anthracycline were studied (4-year OS: ≥70y = 75% vs. 60-69y = 92%, p = 0.003). Analysis of the cumulative incidence of NRM (with relapse as competing risk) showed there were no significant differences among pts ≥70y (1-year 5.8% 95% CI 1-17%) vs. 60-69y (4.7% 95% CI 1-14%) (p = 0.2) (figure 1). Conclusions Patients diagnosed with cHL at ages ≥70 years have more comorbidities and more often have worse performance status than pts 60-69y. Older pts more often are treated with attenuated regimens and/or require dose reductions/discontinuation after starting therapy. While the dose reductions and modifications limit NRM to rates comparable to those of younger pts, PFS and OS remain lower for pts ≥70y, suggesting long - term disease control is inferior in this patient subgroup. Systematic prospective studies of attenuated but more effective regimens are needed in cHL pts diagnosed at advanced age.
Management of chronic lymphocytic leukemia has changed markedly over the last several years with the emergence of several novel oral agents targeting B-cell receptor and Bcl-2 signaling pathways. For ...patients requiring treatment, ibrutinib, idelalisib, and venetoclax offer unique clinical benefits with a different set of therapeutic considerations compared with traditional parenteral therapy. Despite the conveniences afforded by oral therapy, these agents also carry unique logistical obstacles. Drug interactions with agents that are metabolized via the cytochrome P450 3A4 pathway are possible with all three agents. Unique treatment-related adverse events including bleeding and atrial fibrillation with ibrutinib, hepatotoxicity with idelalisib, and tumor lysis syndrome with venetoclax can be severe and dose limiting. Furthermore, dose adjustments for organ dysfunction may also be warranted. Here, we review the available literature on the pharmacokinetic and pharmacodynamic properties of these novel agents to guide the reader in the appropriate use of ibrutinib, idelalisib, and venetoclax.
Background: Despite the efficacy of venetoclax (VEN) in frontline CLL, optimal combination regimens and duration of treatment remain unclear. We hypothesized that cytoreduction with ...bendamustine/rituximab (BR) induction followed by venetoclax/rituximab (VR) consolidation for a fixed 1-year duration would be associated with an increased rate of undetectable minimal residual disease (uMRD) compared to historical controls and a reduction in the risk of tumor lysis syndrome (TLS). Here we report updated data from a fully-enrolled ongoing phase 2 multicenter, US, single-arm, open-label study (NCT03609593) designed to assess the safety and efficacy of BR-VR in previously untreated CLL patients (pts). Methods: Previously untreated CLL/SLL pts ≥ 18 years requiring therapy per iwCLL criteria initially received 3 cycles of bendamustine 50-90 mg/m 2 daily for 2 days and rituximab 375 mg/m 2 every 28 days for 3 cycles. Following BR, VEN was initiated with a standard dose escalation from 20 mg to 400 mg daily over 5 weeks. This was followed by 6 cycles of VR with rituximab given monthly and 5 cycles of VEN alone (12 cycles of VEN in total). Additional eligibility included: ECOG PS ≤ 2, hemoglobin ≥8g/dL, ANC ≥1000/mm 3, and platelets ≥50,000/mm 3. Response was assessed by 2018 iwCLL criteria with uMRD testing by central flow cytometry at a level of <10 -4 in peripheral blood (PB) and bone marrow (BM). The primary endpoint was objective response rate (ORR). Secondary endpoints included uMRD rate, time to uMRD, and adverse events (AEs) assessed by CTCAE v 5.0. Results: As of data cutoff on 15 July 2023, 42 pts were accrued. Baseline demographics were as follows: male/female (29/13), median age 61.5 yrs (range 38-84). Baseline prognostic studies showed unmutated IGHV in 22 (52%) pts, TP53 aberrant (either del(17p) and/or TP53 mutation) in 2 (5%) pt, del(11q) in 3 (7%) pts, and complex karyotype in 11 (26%) pts. TLS risk among 24 evaluable pts at baseline was high (H) in 9 (21%), medium (M) in 22 (52%), and low (L) in 6 (26%). At a median follow-up of 16.6 mo. (range, 3-40), 37 pts remain on study. Of 29 pts with at least 15 mo. follow-up (completing all therapy), the ORR was 100% (79% CR/CRi, 21% PR due to small residual nodes). 3 pts died on study (2 due to COVID-19 and 1 developed newly metastatic squamous cell carcinoma and taken off study after achieving a CR post-VEN ramp-up). 1 pt was lost to follow-up while in a CR. Bendamustine was administered at doses of 50 mg/m 2 in 11%, 70 mg/m 2 in 13%, and 90mg/m 2 in 76% of pts. In 38 evaluable pts, response assessments after cytoreduction with BR demonstrated 16% of pts achieved CR/CRi and 84% achieved PR. For evaluable pts at 16 mo., uMRD (<0.01%) in the PB and BM was observed in 80% (20/25) and 78% (18/23) of pts, respectively. MRD was intermediate (0.01% - <1.0%) in 17% (4 patients) in BM (Figure 1 ORR and MRD). Median time to uMRD was 11 mo. (range 3-15) in PB and 10 mo. (range 2.6-15) in BM. The most common treatment-emergent AEs during BR induction were (any grade/grade ≥3) anemia in 15/4 (36%/10%) pts, nausea in 9/0 (21%/0%), neutropenia in 12/8 (29%/19%), rash in 12/1 (29%/2%), constipation 7/0 (17%/0%), and infusion reactions in 7/1 (17%/2%). 2 pts (5%) developed febrile neutropenia during BR. Emergent AEs during VEN treatment included neutropenia in 21/13 (50%/31%), diarrhea in 18/0 (43%/0%) pts, leukopenia in 14/4 (24%/10%), and nausea in 11/0 (26%/0%). TLS risk was substantially reduced after BR lead-in. Of 9 H-risk pts at baseline, 1 remained H-risk after BR; of 16 M-risk pts, 5 remained M-risk, with the remainder at L-risk (89% reduction in H-risk TLS). Conclusions: BR-VR is a safe and well-tolerated regimen in untreated CLL pts. BR debulking substantially reduces TLS risk, and this sequential strategy achieves high rates of PB and BM uMRD across all prognostic risk groups.
Fetal cells are widely considered a superior cell source for regenerative medicine; fetal cells show higher proliferative capacity and have undergone fewer replicative cycles that could generate ...spontaneous mutations. Fetal cells in amniotic fluid were among the first normal primary cells to be cultured ex vivo, but the undefined composition of amniotic fluid has hindered advance for regenerative applications. We first developed a highly efficient method to generate clonal populations by dilution of amniocentesis samples in media and direct plating without intervening refrigeration, centrifugation, or exposure of cells to the paracrine effects in mixed cell cultures. More than 40 clonal populations were recovered from 4 amniocentesis samples and representative clones were characterized by flow cytometry, conventional assays for differentiation potential, immunofluorescence imaging, and transcript analysis. The results revealed previously unreported diversity among stromal and epithelial cell types and identified unique cell types that could be lost or undetected in mixed cell populations. The differentiation potential of amniotic cells proved to be uncoupled from expression of definitive cell surface or cytoplasmic markers for stromal and epithelial cells. Evidence for diversity among stromal and epithelial cells in amniotic fluid bears on interpretations applied to molecular and functional tests of amniotic cell populations.
In newly diagnosed stage III/IV classic Hodgkin lymphoma (cHL), A+AVD (brentuximab vedotin, doxorubicin, vinblastine, dacarbazine) improved overall survival (OS) versus ABVD (doxorubicin, bleomycin, ...vinblastine, dacarbazine). As clinical trial and real-world populations may differ, real-world treatment characteristics and OS (rwOS) were assessed for patients with stage III/IV cHL treated with frontline ABVD. This retrospective, observational analysis of deidentified electronic health record data (1/1/2011-8/31/2020) evaluated baseline disease and clinical characteristics, treatment patterns, and rwOS in patients with stage III/IV cHL treated with frontline ABVD. Data for 167 patients were analyzed. A median of 6 ABVD cycles were received. Baseline/interim positron emission tomography (PET) scans were obtained for 60.5%/89.8% of patients. Of patients diagnosed in 2016 or later (n = 73), 89% received an interim PET scan; 15/46 patients with no documented Deauville score, 6/15 with a score of 1 to 3, and 3/4 with a score of 4 to 5 de-escalated to AVD. Following frontline ABVD, 55.1% of patients received subsequent systemic therapy and 31.7% stem cell transplantation (SCT). At a median follow-up of 31.8 months, 82.0% of patients were alive (median rwOS, 101.2 months). Patients with stage III/IV cHL treated with frontline ABVD in the real world versus in clinical trials receive more subsequent therapy, including SCTs. Interim PET scans and Deauville scores were not universally obtained after treatment cycle 2, yet treatment de-escalation was observed. Patients with stage III/IV cHL may benefit from frontline A+AVD versus ABVD, as it improves OS and reduces the burden of subsequent therapy, including SCTs.
Patients with stage III/IV cHL treated with frontline ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) in this retrospective, observational analysis of deidentified electronic health record data versus in clinical trials were older and received more subsequent therapies, including stem cell transplantation. Interim PET scans and corresponding Deauville scores were not consistently obtained, yet treatment de-escalation was observed.
Despite the efficacy of venetoclax (VEN) in frontline CLL, optimal combination regimens and duration of treatment remain unclear.
Our study assesses the efficacy and safety of bendamustine/rituximab ...induction followed by VEN/rituximab (BR-VR) consolidation for a fixed one-year duration in treatment-naive CLL patients. We hypothesized this strategy would increase undetectable minimal residual disease (uMRD) rate and reduce tumor lysis syndrome (TLS) risk.
In this phase 2, single-arm, open-label study (NCT03609593), patients ≥18 years requiring therapy received 3 cycles of BR, followed by dose-escalated VEN and 6 cycles of VR, then 5 cycles of VEN alone. The primary endpoint was objective response rate (ORR), with secondary endpoints including uMRD rate, time to uMRD, and adverse events (AEs).
As of May 2023, 42 patients were accrued; 24 with ≥15 months follow-up completed therapy. Baseline demographics: median age 61.5 yrs (range 38-84). Prognostic studies: unmutated IGHV in 16 (66%) pts, TP53 aberrant 1 (5%) pt. The ORR was 100% (79% CR/CRi, 21% PR due to small residual nodes). After initial BR induction, 18% achieved CR/CRi and 82% achieved PR. At 16 months, uMRD (<0.01%) in peripheral blood (PB) and bone marrow (BM) was 78% and 70.5%, respectively. MRD was intermediate (0.01% - <1.0%) in 23% (4 patients) in BM. Median time to uMRD was 10 mo. (range 2-15) in PB and 12 mo. (range 3.6-15) in BM. The most common treatment-emergent AEs during BR induction were (any grade/grade ≥3) anemia in 13/3 (46%/10%) pts, nausea in 7/0 (25%/0%), neutropenia in 10/6 (36%/21%), and rash in 10/1 (36%/4%). Emergent AEs during VEN treatment included neutropenia in 17/11 (60%/39%), diarrhea in 16/0 (57%/0%) pts, leukopenia in 14/9 (50%/32%), and nausea in 10/0 (36%/0%). TLS risk was substantially reduced after BR lead-in. Of 5 H-risk pts at baseline, 1 remained H-risk after BR; of 12 M-risk pts, only 3 remained M-risk, with the remainder at L-risk.
The BR-VR regimen in treatment-naive CLL patients is safe, well-tolerated, and yields high PB and BM uMRD rates across all prognostic risk groups. The strategy substantially reduces TLS risk.
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